Synthesis and Structural Investigation of Some Electron-Rich Nitroaromatics

Article abstract of DOI:10.1071/CH18523

2,4-Difluoro-, 2,4,6-Trifluoro-, and 2,3,4,6,tetrafluoronitrobenzenes undergo nucleophilic aromatic substitution, once, twice, and three times with a variety of amine substituents with a high degree of regiochemical control to provide a range of electron-

Full text of DOI:10.1071/CH18523

CSIRO PUBLISHING
Aust. J. Chem. 2019, 72, 311–327
Full Paper
https://doi.org/10.1071/CH18523
Synthesis and Structural Investigation of Some
Electron-Rich Nitroaromatics
A D
,
A
B
B
Jonathan M. White,
Colin E. Skene, John Deadman, Ruwan Epa,
A
A
A
A
Sarah Foenander, Kyle Hamer, Thomas Fellowes, Shea Fern Lim,
Sebastian M. Marcuccio, and Roger F. Martin
B
C
A
School of Chemistry and BIO-21 Institute, The University of Melbourne, Parkville,
Vic. 3010, Australia.
B
Advanced Molecular Technologies Pty Ltd, Unit 1, 7-11 Rocco Drive, Scoresby,
Vic. 3179, Australia.
C
Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, Victorian
Comprehensive Cancer Centre, 305 Grattan Street, Vic. 3000, Australia.
D
Corresponding author. Email: whitejm@unimelb.edu.au
2,4-Difluoro-, 2,4,6-trifluoro-, and 2,3,4,6,tetrafluoronitrobenzenes undergo nucleophilic aromatic substitution, once,
twice, and three times with a variety of amine substituents with a high degree of regiochemical control to provide a range of
electron-rich nitrobenzene derivatives. In these structures the nitro group proves a useful structural probe to reveal the
varying extents of electron donation from the varying number of amino substituents onto the nitro group as revealed by
accurate low temperature X-ray crystal structure analysis, thus increasing electron donation manifests in a decrease in the
Ar–NO2 distance consistent with increased double bond character, while the N–O bond distance increases as the oxygens
accept the electron density. The effect of delocalization of the aniline nitrogen lone pair onto the nitro group impacts on the
geometry and hybridization of the nitrogen substituent and also impacts on the ability of the nitrogen lone pair electrons to
participate in other competing electronic interactions, such as the nN–s*C–S anomeric effect as demonstrated by the
thiazolidine substituted derivatives 3c, 4c, and 6c.
Manuscript received: 23 October 2018.
Manuscript accepted: 16 December 2018.
Published online: 30 January 2019.
Introduction
substituent. The synthesis and structural analysis of these
interesting molecules is also described below.
Amino-substituted nitrobenzenes of the general structure shown
in Fig. 1 are key intermediates for the synthesis of a range of
bibenzimidazoles which we have been preparing for use as
DNA-binding radioprotectors.[1] The preparation of these
intermediates by the sequential displacement of the activated
fluorine substituents in either 2,4-difluoronitrobenzene, 2,4,6-
trifluoronitrobenzene, or 2,4,5,6-tetrafluoronitrobenzene, with a
variety of amine substituents is described in this paper.
Throughout this investigation the various intermediates, where
possible, were characterized by X-ray crystallography, which
gave rise to a wide range of nitrobenzenes with varying numbers
of electron-rich amino substituents conjugated to the nitro
Results and Discussion
Synthesis
The three activated fluorine atoms of 2,4,6-trifluororoni-
trobenzene can be replaced by amine nucleophiles by an
addition elimination mechanism, and since each substitution
reaction gives a product which is less reactive towards further
substitution, careful control of the reaction conditions allows
the sequential incorporation of three different amine sub-
stituents. 2,4,6-Trifluoronitrobenzene reacts with ammonia
and methylamine at the sterically more hindered ortho position
in preference to the para position, a result which has been
rationalised by stabilization of the zwitterionic intermediate
by hydrogen bonding between the polarized N–H hydrogens
with the negatively charged nitro oxygen in the Meisenheimer
intermediate.[2] The selectivity towards ortho attack is high in
THF, but decreases in strong H-bond acceptor solvents such as
DMSO. Reaction with NH3 in liquid ammonia gives
predominantly ortho substitution, while substitution with
sodamide in liquid ammonia gives predominantly para sub-
stitution, this supports Sitzmann’s explanation as the NH2
O
N
X
Y
NO2
NR1R2
X ꢀ H or F , Y ꢀ H or NH2
Fig. 1. General structure of amino-substituted nitrobenzene derivatives.
Journal compilation Ó CSIRO 2019
www.publish.csiro.au/journals/ajc

312
J. M. White et al.
O
F
F
F
F
R1R2N
F
N
NR1R2
NO2
NO2
NO2
NO2
F
NR1R2
F
F
2a, b, c, d,
e, g, j
1
3a, b, c, e, g
5a, h, i
a R1 ꢀ R2 ꢀ H
b R1 , R2 ꢀ morpholine
c R1 , R2 ꢀ thiazolidine
O
O
F
NH2
NO2
N
NH2
NO2
N
NR1R2
NO2
d R1 ꢀ cyclopropyl, R1 ꢀ H
e R1 ꢀ cyclopropyl, R2 ꢀ Me
f R1 ꢀ –CH2CH2SCPh3, R2 ꢀ H
g R1 ꢀ R2 ꢀ –CH2CH2SCPh3
h R1 ꢀ Me, R2 ꢀ H
NR1R2
NR1R2
NR1R2
i R1 ꢀ R2 ꢀ Me
j R1 ꢀ R2 ꢀ 1,2,5-dithiazepine
4a, c, d, f, i, j
6c, d, h, i
7h
Scheme 1.
X
substituent is a significantly weaker H-bond donor than an
NH3þ substituent.[3]
O
F
N
In this work the sequential displacement of fluorine in 2,4,6-
trifluoronitrobenzene 1 was carried out as outlined in Scheme 1.
While the nitroaniline 2a could be envisaged as a common
intermediate for most targets, better yields and isomer ratios
were often achieved by displacing the more reactive initial
fluorine with the more elaborated amines. The reactions were
carried out at room temperature in either DMF or DMSO except
in the case of 2a where THF and a sealed tube were used.
Varying regioisomeric mixtures of 2 and 3 were generally
obtained, again except in the case of 2a where the product was
almost exclusively the desired ortho product. Purification was
often assisted by trituration of the crude product with petroleum
spirit/dichloromethane mixtures (,10 : 1), resulting in super-
natants greatly enriched in the ortho product 2 and leaving
friable solids similarly enriched in the para product 3. Final
purification was achieved by either chromatography (silica gel)
or recrystallization.
Displacement of the second fluorine in 2a to give examples
4f and 4i was done in DMSO at room temperature, affording
mainly the desired ortho substitution regioisomer in good yield.
Treatment of N-substituted difluoronitroanilines 2 and 3b with
excess ammonia in THF required heating at 70–808C (sealed
tube) and provided the desired regioisomers 4 and 5a in very
good yield, with no indication of displacement of the remaining
fluorine due to the presence of excess ammonia. However
treatment of 3b with excess methylamine solution led to the
formation of the bis-methylamino 7h as well as the desired 5h.
More vigorous conditions were required for the displacement
of the final para fluorine in 4 to give the fully substituted targets
6. The reactions were done in dimethylamine or DMSO and
heated to 1008C or higher with 4–7 equivalents of amine. In
contrast, 6h was prepared from 5a in good yield using excess
methylamine solution and THF in a sealed tube at lower
temperature.
NO2
ꢁ
NO2
N
NO2
F
F
a X ꢀ F
b X ꢀ NMe2
O
8
9a, 9b
10a
Scheme 2.
were similar to those for the preparation of 2b/3b. Treatment
of 9a with excess dimethylamine solution in refluxing ethanol
then afforded 9b in quantitative yield.
A more highly substituted series of nitrobenzenes were made
by the sequential displacement of the ortho and para fluorine
substituents in 2,3,4,6-tetrafluoronitrobenzene 11, as outlined in
Scheme 3. While the reaction of 11 with dimethylamine gave the
para substituted 12 as the major product. However the required
and more sterically hindered ortho product 14 was subsequently
prepared by treatment of 11 with ammonia to give 13, followed
by alkylation with methyl iodide. Treatment of 14 with ammo-
nia gave a mixture of ortho and para anilines 15a and 16a in a
3 : 5 ratio respectively. Reaction of 14 with 2-methoxyethyla-
mine at 1008C again gave the para substituted product 16b as the
predominant isomer (1 : 2 ratio of 15b to 16b). The displacement
of the para fluorine in 15b was performed with ammonia
solution at the elevated temperature of 1458C to give the desired
nitroaniline 17.
X-Ray Structural Studies
Cambridge Crystallographic Database Studies
The nitro substituent is a strong electron withdrawing sub-
stituent with a significant resonance component, as evidenced
by the Hammett s and s –– constants, which are 0.78 and 1.24
respectively.[5] The resonance component, which is a reflection
of the extent of delocalization of electron density from the
aromatic ring onto the nitro group can be represented by
Of interest was a second series of less highly substituted
intermediates derived from 2,4-difluoronitrobenzene 8 (see
Scheme 2).[4] The preparation of 9a and 10a required an
elevated reaction temperature (808C), otherwise conditions

Electron-Rich Nitroaromatics
313
F
F
F
F
F
F
F
Me2N
F
HNMe2
NH3
NO2
NO2
NO2
NH2
F
F
13
11
12
NaH
Mel
F
F
NR1R2
NO2
R1R2N
F
F
F
F
F
NO2
NO2
NMe2
NMe2
NMe2
14
15a, b
16a, b
a R1 ꢀ R2 ꢀ H
NH3
b R1 ꢀ CH2CH2OMe, R2 ꢀ H
H
N
H2N
F
OMe
NO2
NMe2
17
Scheme 3.
Oꢂ
in contributions of the resonance forms A and B to the ground
state structure (Fig. 4).
O
N
N
ꢁ
To assess the extent of these delocalizing interactions in the
structures reported here, a survey of the CSD was also conducted
for aromatic compounds (Ar) containing NH2, NHMe, NMe2,
morpholino, thiazolidine, and dithiazepane substituents, the
results of these searches is summarized in Fig. 5.
ꢁ
Oꢂ
Oꢂ
ꢁ
R
R
Fig. 2. Resonance interaction between a nitro group and an aromatic ring.
For those substituents (NH2, NHMe, and NMe2) for which
there are multiple hits, the range of C–N bond distances is
˚
relatively broad (0.15 A for NH2, 0.10 A for NHMe, and
˚
0.23 A for NMe2 substituents), reflecting the sampling of struc-
˚
contributions of the right hand resonance structure to the ground
state structure (Fig. 2). The C–N and N–O bond distances are
expected to provide an indication of the contribution that this
resonance form makes to the ground state structure of any given
nitroaromatic compound.
In order to obtain the structure parameters for an aryl nitro
group for comparison with the electron rich nitrobenzene
derivatives reported here, a search of the Cambridge Crystallo-
graphic Database (CSD)[6] was carried out using a generalised
Ar-NO2 search fragment (where Ar is any substituted aromatic
ring) with those structures having R factors . 5 % and those
containing metals being filtered out. This search resulted in 6772
hits with 11212 observations, and of these structures 8472 had
the nitro group within 208 to being co-planar with the aromatic
ring, and 280 nitro groups were within 208 to orthogonal to the
aromatic ring. Structural parameters for these two extreme
conformations are summarized in Fig. 3.
tures where the amine substituent has varying degrees of conju-
gation with the aromatic ring. This variation arises for two
reasons: 1) the presence of substituents with widely varying
electronic properties on the aromatic ring, and 2) rotation of the
amine substituent out of plane with the aromatic ring which
breaks the conjugation with the ring. The effect of rotation of the
amine substituent out of plane with the aromatic ring is demon-
strated by plotting the C–N bond distance versus the C(ortho)–C
(ipso)–N–CH3 dihedral angle for the dimethylamino derivatives
(Fig. 6), or by simply plotting the C–N bond distance versus the
angle between the plane defined by the NMe2 group and the
plane defined by the aromatic ring (Fig. 7). Lengthening of
the C–N bond distance as the NMe2 rotates out of plane with the
aromatic ring is consistent with decreasing conjugation of the
nitrogen lone pair with the aromatic ring. Also associated with
rotation of the plane of the NMe2 away from conjugation with the
aromatic ring is a change of apparent hybridization of the NMe2
nitrogen from sp2 towards sp3, which can be obtained by plotting
the sum of the bond angles at the nitrogen versus the interplanar
angle (Fig. S161, Supplementary Material). The relatively nar-
row range for the C–N bond distances for the NHMe derivatives
is very likely due to the fact that of the 80 observations, 75 are
within 208 of co-planarity with the aromatic ring.
The slightly shorter C–NO2 combined with the slightly
longer N–O bond distances for the coplanar structures compared
to the orthogonal structures is suggestive of greater contribu-
tions of the right hand resonance form (Fig. 2), while this
interaction is essentially absent when the nitro group is orthog-
onal to the aromatic ring.
Delocalization of the non-bonded electron pair from an
amine substituent onto a para or ortho nitro substituent results

314
J. M. White et al.
O
N
ꢁ
Oꢂ
C
R
Dihedral angle ꢁ/ꢂ 20ꢃ C–N
1.465(10) Å Dihedral angle 70–110ꢃ C–N
1.465(5) Å
N–O
O–N–C
O–N–O
1.222(10) Å
118.3ꢃ
123.3ꢃ
N–O
O–N–C 117.7ꢃ
O–N–O 124.5ꢃ
1.205(16) Å
Fig. 3. Structural parameters obtained from the CSD for the search fragment Ar-NO2 for coplanar and
orthogonal structures.
Oꢂ
ꢁN
ꢁ
Oꢂ
O
O
R2N
R2N
N
N
N
Oꢂ
ꢁ
Oꢂ
ꢁ
Oꢂ
ꢁ
Oꢂ
ꢁ
R2N
R2N
A
B
Fig. 4. Conjugative interactions between amine substituents with para and ortho nitro group.
NHMe
NH2
1354 hits, 1806 observations
C–N distance 1.38 Å
Range 1.309–1.450 Å
70 hits, 80 observations
C–N distance 1.37 Å
Range 1.325–1.421 Å
R
R
O
NMe2
790 hits, 1080 observations
C–N distance 1.39 Å
28 hits, 35 observations
N
C–N distance 1.41 Å
Range 1.369–1.479 Å
Range 1.297–1.526 Å
R
R
R
S
S
S
1 hit
0 hits
N
N
C–N distance 1.381(2) Å
Refcode: VITTEZ
Fig. 5. Selected structural parameters for selected aryl-substituted amines obtained from the CSD.
Structural Studies, This Work
triamine 22, which was supplied by Australian Molecular
technologies, have been included in the following analysis
(Chart 1).
Crystals of suitable quality for X-ray analysis were obtained
for 2a–d, 3a–c, 3e, 3g, 4c, 4d, 4f, 4j, 5a, 5i, 6c, 6d, 6h, 6i, 9b,
10a, 12, 15b, 16a, 16b, and 17. Interestingly there were
examples where crystallization of mixtures of compounds in
an attempt at purification gave rise to co-crystals of different
derivatives, the individual components of these co-crystals
were also subsequently crystallized as single components after
careful chromatographic purification. Thus co-crystals of 2b
and 3b and co-crystals of 3b and 5i were obtained. In addition
to those compounds prepared here, the low temperature
redetermination of 4-morpholino-nitrobenzene (18)[7] and
2-amino-4-morpholino-nitrobenzene (19),[14] which had been
previously determined in our group, o-nitroaniline (20),[8]
p-nitroaniline (21)[9] 5-fluoro-2-nitrobenzene-1,3-diamine
(4a) (a minor by-product in the synthesis of 2a), and
To allow for convenient comparisons to be made between the
structures the numbering system shown in Fig. 8 has been
employed for structural studies, treating the structures as substi-
tuted nitrobenzene derivatives.† In addition the structures have
been categorized based on the number of amino substituents on
the aromatic ring in conjugation with the nitro group.
Selected geometrical parameters for the monoamino-nitro-
benzenes, diamino-nitrobenzenes, and triamino-nitrobenzenes
are presented in Tables 1–3 respectively. In addition to these
structures the low temperature structural data for 18–21 which
have been previously determined by us and others have been
included.[10–12] In the three classes of compound the mean C–
˚
NO2 bond distances, which are 1.443, 1.426, and 1.405 A
†While we note that this does not represent systematic nomenclature it is the most convenient way to deal with this broad range of compounds, which can all be
considered to be nitrobenzene derivatives.

Electron-Rich Nitroaromatics
315
CN
NO2
1.48
NH2
NO2
NO2
20
1.46
1.44
1.42
1.40
1.38
1.36
1.34
1.32
1.30
NO2
NH2
H2N
NH2
NO2
22
18
19
N
O
N
O
HN
21
OCH3
NH2
Chart 1.
O2
O1
N1
C1
C6
C5
C2
C3
1.28
ꢂ200.0ꢂ160.0ꢂ120.0ꢂ80.0 ꢂ40.0
0
40.0 80.0 120.0 160.0 200.0
CCNC
C4
Fig. 8. Numbering system used for crystal structures of derivatives 2a-d,
3a-c, 3e, 3g, 4a, 4c, 4d, 4f, 4j, 5a, 5i, 6c, 6d, 6h, 6i, 9b, 10a, 12, 15b, 16a,
16b, 17, and 18–21.
˚
Fig. 6. Plot of (Ar)C–N bond distance (A) versus C–N–Ci–Co dihedral
angle (8) for Ar-NMe2 substituents.
CN
Table 1. Nitro group geometries for monoamino-nitrobenzene
derivatives
1.53
1.50
1.47
1.44
1.41
1.38
1.35
1.32
1.29
˚
˚
Compound C1–N1 [A] N1–O1 [A] N1–O2 [A] C2–C1–C6 [deg.]
˚
2a
2bA
1.4357(17) 1.2357(17) 1.2301(19)
1.4613(14) 1.2179(14) 1.2246(13)
1.4643(12) 1.2075(13) 1.2089(12)
1.4594(19) 1.2251(18) 1.2290(18)
1.4649(19) 1.2188(19) 1.2220(19)
1.4374(11) 1.2267(10) 1.2414(10)
119.15(11)
121.07(9)
121.35(8)
120.62(14)
121.26(14)
119.67(7)
122.06(8)
115.92(9)
115.60(9)
115.48(10)
116.21(14)
116.0(1)
2b
2c (M1)
2c (M2)
2d
3a
3bA
1.4308(12) 1.2321(6)
1.2321(6)
1.4465(13) 1.2258(14) 1.2276(14)
1.4290(14) 1.2298(14) 1.2313(14)
1.4382(14) 1.2259(14) 1.2297(14)
3b(M1)
3b(M2)
3bB
1.440(2)
1.227(2)
1.235(2)
3c
1.4344(15) 1.2291(14) 1.2291(15)
1.4363(17) 1.2297(18) 1.2347(19)
3e
115.48(12)
115.2(2)
3g
1.436(3)
1.4416(15) 1.2331(15) 1.2358(15)
1.439(1) 1.2304(10) 1.226(1)
1.4442(13) 1.2336(13) 1.2355(12)
1.231(3)
1.231(3)
10a
12[13]
117.99(11)
115.31(6)
122.73(9)
120.98
18
20(M1)
20(M2)
21[12]
Average
1.436
1.431
1.433
1.443
1.243
1.243
1.244
1.227
1.239
1.238
1.235
1.231
0
10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0
CNC_AR
120.95
121.30
˚
Fig. 7. Plot of (Ar)C–N bond distance (A) versus dihedral angle (8)
between the plane of the aromatic ring and the plane defined by the nitro
group.
AComponent of co-crystal of 2b and 3b.
BComponent of co-crystal with 5i.
distance (Fig. 9). These structural effects clearly increase in
magnitude as the number of amino substituents conjugated to
the nitro group increase from one amino group to three.
respectively, are significantly shorter than the mean C–NO2
distance obtained from the CSD (above), while the mean N–O
˚
distances, which are 1.229, 1.242, and 1.251 A respectively, are
Varying conjugation between the different amino substitu-
ents and the nitro group is also reflected in the C(Ar)–N(amine)
distance in these structures, and in all cases the C–N bond
distance is shorter than the mean value obtained from the CSD
for each substituent (where the data is available). In the
significantly longer. These structural effects are consistent with
delocalization of electron density from the electron rich aro-
matic rings onto O1 and O2, with increasing contributions of the
right hand resonance form (Fig. 2) which are clearly evident
from a plot of C(Ar)–NO2 bond distance versus mean N–O bond

316
J. M. White et al.
Table 2. Nitro group geometries for diamino-nitrobenzene derivatives
Table 4. Selected geometries for the aminonitrobenzene derivatives
˚
˚
˚
Compound C1–N1 [A] N1–O1 [A] N1–O2 [A] C2–C1–C6 [deg.]
˚
Ar–NH2 [A]
˚
Ar–NO2 [A]
Compound
C2–C1–NO [deg.]
4a
1.4133(9)
1.2487(8)
1.2468(8)
119.56(6)
117.11(12)
120.10(11)
120.16(12)
122.83(9)
117.02(12)
123.05(17)
119.09(12)
119.53(9)
119.97(9)
119.72(9)
120.78(12)
Ortho-aminonitrobenzenes
4c
1.4268(17) 1.2420(15) 1.2459(15)
1.4090(17) 1.2460(15) 1.2560(16)
1.4007(18) 1.2458(12) 1.2553(15)
1.4403(14) 1.2294(13) 1.2385(13)
1.4036(18) 1.2473(16) 1.2429(16)
2a
1.3465(16)
ꢀ12.0(2)
30.59(18)
ꢀ1.05(19)
41.52(15)
ꢀ7.00(19)
ꢀ16.1(2)
ꢀ27.85(19)
1.94(13)
4.62(17)
0.69(19)
19.14(2)
ꢀ6.07(18)
ꢀ6.6
1.4357(16)
1.4268(17)
1.4090(17)
1.4191(13)
1.4007(18)
1.4036(18)
1.4294(16)
1.4004(10)
1.3953(14)
1.3811(16)
1.4229(10)
1.4130(16)
1.436
4d
4c
1.3506(19)
1.3512(18)
1.3611(14)
1.353(2)
4f
4d
4j
4j
5a
5iA
4f
1.440(2)
1.223(2)
1.240(2)
5a
1.3447(19)
1.3674(17)
1.3534(10)
1.3559(16)
1.3517(17)
1.3602(11)
1.3504(17)
1.350
5i (M1)B
9b(M1)
9b(M2)
16a
1.4416(17) 1.2311(15) 1.2416(16)
1.4272(13) 1.2366(12) 1.2515(13)
1.4343(13) 1.2418(12) 1.2440(12)
1.4477(13) 1.2298(14) 1.2312(13)
1.4130(16) 1.2496(17) 1.2461(18)
6c
6d
6h(M1)
6h(M2)
6i
19[14]
Average
1.424
1.240
1.245
19
20(M1)
20(M2)
AComponent of co-crystal with 3b.
BTwo molecules in the asymmetric unit, the second molecule had some
1.344
2.5
1.431
Para-aminonitrobenzenes
disorder of the nitro group and is not usable.
3a
1.3442(11)
ꢀ11.70(5)
ꢀ46.52(14)
ꢀ33.52(14)
ꢀ1.36
1.4308(12)
1.4477(13)
1.4111(13)
1.433
16a
17
1.3623(13)
1.3507(14)
1.355
Table 3. Nitro group geometries for triamino-nitrobenzene
derivatives
21
˚ ˚ ˚
C1–N1 [A] N1–O1 [A] N1–O2 [A] C2–C1–C6 [deg.]
Compound
ꢂ
O
ꢂ
O
ꢂ
6a.Ph3COH[15] 1.396(2)
1.254(2)
1.246(2)
118.57(17)
122.83(9)
118.79(7)
118.80(10)
118.75(11)
119.66(7)
118.84(9)
121.43(9)
119.21(9)
O
H
O
H
N
N
ꢁ
ꢁ
6c
1.4403(15) 1.2294(13) 1.2385(13)
1.4004(10) 1.2532(11) 1.2538(10)
1.3953(14) 1.2506(14) 1.2632(14)
1.3811(16) 1.2617(14) 1.2646(16)
1.4229(10) 1.2376(10) 1.2523(10)
1.3953(13) 1.2557(12) 1.2588(12)
1.4111(13) 1.2473(13) 1.2507(12)
1.4093(13) 1.2538(13) 1.2497(13)
6d
N
H
N
ꢁ
H
6h(M1)
6h(M2)
6i
7h
Fig. 10. Resonance-assisted hydrogen bonding in o-nitroaniline
17
derivatives.
22
Average
1.405
1.249
1.252
Amino-Substituted Nitrobenzenes
The Ar–NH2 bond distances for 2a, 3a, 4c, 4d, 4f, 4j, 6c, 6d, 6h,
6i, 16a, and 17–20 (Table 4) are all shorter than the mean
Ar–NH2 distance obtained from the CSD (above), consistent
with strong delocalization of the NH2 non-bonded electrons into
the aromatic ring due to conjugation with the nitro group.
Comparison between 2a and 3a and between the two indepen-
dent molecules of 20 (M1 and M2) with 18, for which the nitro
substituent is essentially coplanar with the aromatic ring, sug-
gests very similar degrees of conjugation between a p-amino
group with the nitro group and an o-amino group with the nitro
group. This suggests that any structural effects associated with
resonance assisted hydrogen bonding,[16] which can conceiv-
ably occur in the o-nitroaniline derivatives, are not significant in
these derivatives (Fig. 10).
1.270
1.265
1.260
1.255
1.250
1.245
1.240
1.235
1.230
1.225
1.220
1.215
1.36
1.38
1.4
1.42
1.44
1.46
1.48
Morpholino-Substituted Nitrobenzenes
Selected structural parameters for the morpholino-substituted
nitrobenzene derivatives are summarized in Table 5. These are
separated into o-morpholino and p-morpholino substituted
derivatives. The parameter defined as Q in this table is an esti-
mation of the lp–N–Co–Cm dihedral angle, and provides an
indication of the overlap between the lone pair on the nitrogen
and the aromatic p-system.‡ The geometry of the p-morpholino
substituted nitrobenzene derivatives all allow for effective
˚
Fig. 9. Plot of C–NO2 bond distance (A) versus mean N–O bond distance
˚
(A) in mono-, di-, and tri-amino-nitroaromatics. As a result of large torsional
motion of the nitro group in pure crystals of 2b the N–O bond distances were
not used in this plot.
following discussion we have focussed on the amino, morpho-
lino, and thiazolyl substituents.
‡The lp–N–Co–Cm dihedral angle was estimated by attaching a methyne-type hydrogen onto the morpholine nitrogen using the SHELX AFIX 13 command.[19]

Electron-Rich Nitroaromatics
317
Table 5. Selected geometries for the morpholino-nitrobenzene derivatives
O1
O
O
Ca
N
O
N1
C1
N
Co
C1
C2
Cb
C2
Ci
Θ ꢀ lp–N–C1–C2
dihedral angle
˚
Ar–N [A]
Compound
CO–Ci–N–Ca [deg.]
CO–Ci–N–Cb [deg.]
C2–C1–N1–O [deg.]
C–N–C (av)
Q
Ortho-morpholino-nitrobenzenes
2bA
1.3935(13)
1.3994(11)
1.3976(13)
1.4024(13)
ꢀ61.94(13)
ꢀ66.14(12)
ꢀ62.60(11)
ꢀ60.42(11)
163.91(10)
163.92(8)
164.17(9)
166.78(9)
ꢀ52.89(12)
ꢀ70.82(11)
2.70(16)
114.74
113.60
114.62
114.47
51
49
50
53
2b
9b(M1)
9b(M2)
ꢀ12.19(15)
Para-morpholino-nitrobenzenes
Monoamino derivatives
3bA
1.3767(13)
1.3748(10)
1.3600(13)
1.3669(14)
1.3785(15)
1.3723(13)
ꢀ12.44(17)
ꢀ12.42(11)
9.99(17)
ꢀ160.69(11)
ꢀ158.83(8)
163.60(10)
175.01(10)
ꢀ150.51(11)
ꢀ166.50(9)
ꢀ52.89(12)
34.57(12)
25.43(17)
33.98(16)
ꢀ9.12(18)
0.41(14)
117.60
117.25
118.38
117.77
116.61
118.09
94
94
3bB
3b(M1)
84
3b(M2)
23.93(17)
ꢀ7.54(16)
ꢀ14.62(13)
97
10a
101
89
18
Diamino derivatives
5a
1.3668(18)
1.3846(16)
1.3831(9)
1.3833(15)
ꢀ1.5(2)
ꢀ158.23(14)
142.26(13)
ꢀ168.91(8)
163.21(11)
ꢀ16.1(2)
119.07
117.18
117.58
117.12
100
68
5i(M1)
5iC
ꢀ3.74(19)
ꢀ20.85(12)
17.24(17)
39.97(19)
ꢀ41.76(12)
ꢀ6.07(18)
94
19
89
Triamino derivatives
6a[15]
1.385(3)
ꢀ9.5(3)
ꢀ155.68(19)
161.79(13)
178.27(7)
ꢀ0.4(3)
ꢀ27.85(19)
1.94(13)
4.62(17)
0.69(19)
19.14(12)
117.17
116.61
115.89
116.47
117.07
115.91
97
87
6c
1.3878(16)
1.3868(10)
1.3830(14)
1.3821(15)
1.3917(10)
19.25(19)
39.59(11)
17.25(15)
24.15(17)
9.27(11)
6d
108
89
6h(M1)
6h(M2)
6i
160.24(10)
169.83(10)
149.17(8)
95
82
ACo-crystal with 2a.
BCo-crystal with 5i.
1.395
1.390
1.385
1.380
1.375
1.370
1.365
1.360
shorter than the o-substituted derivatives. For the p-substituted
derivatives the extent of delocalization of the morpholino
nitrogen lone pair is sensitive to the number of amine sub-
stituents in conjugation with the nitro group. Hence the Ar–N
(morpholino) distances are shortest for the monoamino deriva-
tives indicating significant delocalization, while the Ar–N
(morpholino) distances in the diamino- and triamino-nitro-
benzenes are longer, consistent with the effects of competing
conjugation to the nitro group from the other amine substituents
on the aromatic ring. The varying strength of conjugation of the
p-morpholino substituent with the nitro group also leads to
systematic effects on the C–N–C bond angles at the morpholino
nitrogen, consistent with changes in the hybridization of this
nitrogen. For an sp2 hybridized nitrogen the mean C–N–C angle
is expected to be 1208 while that for an sp3 hybridized nitrogen
should be close to 109.58. The result of plotting the Ar–N bond
distance versus the mean C–N–C bond angle (Fig. 11) reveals
that for those substituents where the Ar–N(morpholino) bond
distance is short, consistent with strong conjugation, the mean
C–N–C bond angle is close to 1208 consistent with an sp2
hybridized nitrogen, while when the Ar–N(morpholino) bond
distance is long, consistent with weak conjugation, the mean C–
N–C bond angle is around 1158, consistent with more apparent
sp3 character.
1.355
115
116
117
118
119
120
˚
Fig. 11. Plot of the Ar–N(morpholino) bond distance (A) versus the
average bond angle (8) at the morpholine nitrogen.
conjugation of the nitrogen lone pair electrons with the aromatic
ring, with Q being close to orthogonal for the majority of deri-
vatives. However steric interactions between the morpholino
substituent and nitro group for the o-substituted derivatives
twists the morpholino substituent substantially away from
conjugation with the aromatic ring with Q values ranging from
51–538 for these derivatives. Consistent with this the Ar–N
distances for the p-morpholino derivatives are substantially

318
J. M. White et al.
O
F
NH2
NO2
N
NH2
NO2
S
N
F
N
NO2
N
F
S
S
3c
1.3531(13) Å
4c
1.3707(17) Å
6c
C(Ar)–N
1.3970(17) Å
O2
N3
C6
O2
N1
F2
C6
O1
N1
C1
C5
C1
C2
C5
O1
C9
C4
C2
C9
C4
N2
F1
C8
N2
F1
C3
C3
C8
C7
S1
C7
S1
3c
4c
O2
N4
C6
O1
C5
C13
N1
C4
C1
N2
C12
N3
C2
C9
O3
C3
C7
C10
C11
C8
S1
6c
Fig. 12. Thermal ellipsoid plots and selected bond distances for the thiazole derivatives 3c, 4c, and 6c.
˚
are 1.8013(12) and 1.8079(13) A for 3c and 1.8164(15) and
Thiazolidino Substituted Nitrobenzenes
˚
1.8063(14) A for 4c respectively. The absence of an nN–s*C–S
The C–N bond distances for the thiazolidine substituted
derivatives 3c, 4c, and 6c increase with increasing amino
substitution on the aromatic ring reflecting the decreasing
electron demand of the nitro group, resulting in less delocal-
ization from the thiazolidine nitrogen onto this group. Inter-
estingly in the triamino substituted derivative 6c the
thiazolidine ring adopts a different conformation to that
adopted by 3c and 4c (Fig. 12). This conformation appears to
be strongly influenced by an nN–s*C–S anomeric effect;[17] the
C2–N2–C7–S1 and C9–N2–C7–S1 dihedral angles which are
ꢀ97.1(1)8 and 43.4(1)8 respectively result in an antiperiplanar
relationship between the lone pair on N2 and the C7–S1 bond,
and the aromatic ring adopts a pseudo-axial position on this
ring. Consistent with this is the N2–C7 bond distance of
anomeric effect in 3c and 4c is no doubt due to the greater
extent of delocalization of the lone pair on N2 in 3c and 4c
into the more electron deficient aromatic ring, which effec-
tively competes with this interaction.
Conclusion
A wide range of useful variously substituted fluorinated
nitroanilines have been synthesized with a reasonable degree of
regioselective control, from 2,4-difluoro-, 2,4,6-trifluoro-, and
2,3,4,6,tetrafluoronitrobenzenes. In these structures the nitro
group proves a useful structural probe to reveal the varying
extents of electron donation from the varying number of amino
substituents onto the nitro group as revealed by accurate low
temperature X-ray crystal structure analysis, thus increasing
electron donation manifests in a decrease in the Ar–NO2 dis-
tance consistent with increased double bond character, while the
N–O bond distance increases as the oxygens accept the electron
density. The effect of delocalization of the aniline nitrogen lone
pair onto the nitro group impacts on the geometry and hybrid-
ization of the nitrogen substituent and also impacts on the ability
of the nitrogen lone pair electrons to participate in other com-
peting electronic interactions, such as the nO–s*C–S anomeric
effect as demonstrated by the thiazolidine substituted deriva-
tives 3c, 4c, and 6c.
˚
1.4412(16) A which is significantly shorter than the N2–C9
˚
bond distance which is 1.4632(17) A. In addition the C7–S1
˚
bond distance of 1.8588(15) A is significantly lengthened
˚
compared to the C8–S1 bond distance which is 1.8223(14) A.
In contrast the thiazolidine ring in compounds 3c and 4c does
not exhibit an nN–s*C–S anomeric effect and the aromatic ring
takes up a pseudo-equatorial position. In addition there is the
closer agreement between the N2–C7 and N2–C9 bond dis-
tances for both structures which are 1.4614(14) and 1.4640
˚
˚
(15) A for 3c and 1.4673(16) and 1.4737(16) A in 4c
respectively, and the C8–S1 and C7–S1 bond distances which

Electron-Rich Nitroaromatics
319
Experimental
Crystal data for 3b. C10H10F2N2O3, M 244.20, T 130.0(2) K,
˚
l 0.71073 A, monoclinic, space group P21c, a 7.2732(2), b
X-Ray Crystallography
3
˚
˚
12.6245(3), c 21.9200(6) A, b 91.659(3)8, V 2011.86(9) A , Z
8, Z0 2 Dc 1.612 Mg Mꢀ3, m(Mo-Ka) 0.144 mmꢀ1, F(000) 1008,
crystal size 0.44 ꢁ 0.21 ꢁ 0.16 mm3. ymax 36.598, 26779 reflec-
tions measured, 9393 independent reflections (Rint 0.0311), the
final R 0.0492 [I . 2s(I), 7109 data], and wR(F2) 0.1390 (all
data), GOOF 1.062.
Intensity data for 2a–d, 3a–c, 3e, 3g, 4a, 4c, 4d, 4f, 4j, 5a, 5i, 6c,
6d, 6h, 6i, 9b, 10a, 12, 16a, and 17 were collected with an
Oxford Diffraction SuperNova CCD diffractometer using either
Mo-Ka or Cu-Ka radiation, the temperature during all data
collections was maintained at 130.0(1) K using an Oxford
Cryosystems cooling device. The data for 18 and 22 were col-
lected on the MX1 beamline at the Australian Synchrotron.[18]
The structures were solved by direct methods and difference
Fourier synthesis.[19] Thermal ellipsoid plots were generated
using the program ORTEP-3[20] integrated within the
WINGX[21] suite of programs.
Crystal data for co-crystal 3b/5i. (C10H10N2O3F2)/
˚
(C12H16N3O3F), M 513.48, T 100.0(2) K, l 0.71073 A, triclinic,
˚
space group P-1, a 9.9668(4), b 10.0885(3), c 13.0159(4) A, a
3
˚
79.561(3)8, b 83.266(3)8, g 62.661(3)8, V 1142.46(7) A , Z 2, Dc
1.493 Mg Mꢀ3, m(Mo-Ka) 0.125 mmꢀ1, F(000) 536, crystal size
0.6 ꢁ 0.4 ꢁ 0.07 mm3. ymax 41.028, 34133 reflections measured,
14402 independent reflections (Rint 0.0307), the final R 0.0497
[I . 2s(I), 9252 data], and wR(F2) 0.1498 (all data), GOOF
1.043.
Crystal data for 2a. C6H4F2N2O2, M 174.11, T 100.0(2) K, l
˚
0.71073 A, orthorhombic, space group Pna21, a 28.8031(9) b
3
˚
˚
3.7072(1),
c
6.1858(2) A,
V
660.51(3) A ,
Z
4, Dc
1.751 Mg Mꢀ3, m(Mo-Ka) 0.169 mmꢀ1, F(000) 352, crystal
size 0.37 ꢁ 0.18 ꢁ 0.08 mm3. ymax 41.048, 18133 reflections
measured, 3889 independent reflections (Rint 0.048), the final
R 0.0502 [I . 2s(I), 3264 data], and wR(F2) 0.1341 (all data),
GOOF 1.009.
Crystal data for 3c. C9H8F2N2O2S, M 246.23, T 130.0(2) K, l
˚
0.71073 A, monoclinic, space group P21/n, a 7.5755(4), b
3
˚
˚
9.6912(5), c 13.4039(12) A, b 100.039(6)8, V 968.99(11) A ,
Z 4, Dc 1.688 Mg Mꢀ3, m(Mo-Ka) 0.350 mmꢀ1, F(000) 504,
crystal size 0.57 ꢁ 0.17 ꢁ 0.06 mm3. ymax 36.488, 7574 reflec-
tions measured, 4447 independent reflections (Rint 0.018), the
final R 0.0407 [I . 2s(I), 3486 data], and wR(F2) 0.1051 (all
data), GOOF 1.023.
Crystal data for 2b. C10H10F2N2O3, M 244.20, T 130.0(2) K,
˚
l 0.71073 A, monoclinic, space group P21/n, a 8.0668(2), b
3
˚
˚
8.2091(2), c 16.0863(3) A, b 99.499(2)8, V 1050.65(4) A , Z 4,
Dc 1.544 Mg Mꢀ3, m(Mo-Ka) 0.137 mmꢀ1, F(000) 504, crystal
size 0.61 ꢁ 0.43 ꢁ 0.21 mm3. ymax 36.528, 13918 reflections
measured, 4918 independent reflections (Rint 0.0212), the final
R 0.0469 [I . 2s(I), 4029 data], and wR(F2) 0.1338 (all data),
GOOF 1.029.
Crystal data for 3e. C10H10F2N2O2, M 278.31, T 130.0(2) K,
˚
l 1.54184 A, monoclinic, space group P21/n, a 7.0357(2), b
3
˚
˚
19.8316(5), c 7.0755(2) A, b 94.354(2)8, V 984.39(5) A , Z 4, Dc
1.540 Mg Mꢀ3, m(Cu-Ka) 1.160 mmꢀ1, F(000) 472, crystal size
0.52 ꢁ 0.14 ꢁ 0.06 mm3. ymax 76.928, 5610 reflections mea-
sured, 2032 independent reflections (Rint 0.0398), the final R
0.0434 [I . 2s(I), 1759 data], and wR(F2) 0.1224 (all data),
GOOF 1.046.
Crystal data for co-crystal 2b/3b. (C10H10F2N2O3)/
˚
(C10H10F2N2O3), M 488.40, T 130.0(2) K, l 0.71073 A, triclinic,
˚
space group P-1, a 7.7145(3), b 11.2137(5), c 13.0497(5) A, a
85.660(3)8, b 82.089(3)8, g 70.070(4)8, V 1050.69(8) A , Z 2, Dc
3
˚
Crystal data for 3g. C48H40F2N2O2S2, M 778.94, T 130.0(2)
˚
1.544 Mg Mꢀ3, m(Mo-Ka) 0.137 mmꢀ1, F(000) 504, crystal size
0.50 ꢁ 0.39 ꢁ 0.26 mm3. ymax 36.388, 14166 reflections mea-
sured, 9540 independent reflections (Rint 0.0139), the final R
0.0489 [I . 2s(I), 7190 data], and wR(F2) 0.1409 (all data),
GOOF 1.029.
K, l 1.54184 A, triclinic, space group P-1, a 9.1130(6), b 14.567
˚
(1), c 17.6856(12) A, a 102.900(6)8, b 92.339(5)8, g 95.609(6)8,
3
V 2272.8(3) A , Z 2, Dc 1.138 Mg Mꢀ3, m(Cu-Ka) 1.428 mmꢀ1
,
˚
F(000) 816, crystal size 0.18 ꢁ 0.12 ꢁ 0.04 mm3. ymax 76.958,
13929 reflections measured, 4844 independent reflections (Rint
0.0175), the final R 0.0458 [I . 2s(I), 4296 data], and wR(F2)
0.1229 (all data), GOOF 1.005.
Crystal data for 2c. C9H8F2N2O2S, M 246.23, T 130.0(2) K, l
˚
1.54184 A, triclinic, space group P-1, a 10.0977(4), b 10.2176
˚
(4), c 11.3161(4) A, a 84.325(3)8, b 87.027(3)8, g 60.552(4)8 V
Crystal data for 4a. C6H6FN3O2, M 171.14, T 130.0(2) K, l
3
1011.69(8) A , Z 4, Dc 1.62 Mg Mꢀ3, m(Cu-Ka) 3.058 mmꢀ1, F
˚
˚
0.71073 A, monoclinic, space group P21/n, a 6.9979(3), b
(000) 504, crystal size 0.44 ꢁ 0.34 ꢁ 0.04 mm3. ymax 76.418,
11707 reflections measured, 4137 independent reflections (Rint
0.0279), the final R 0.0339 [I . 2s(I), 3818 data], and wR(F2)
0.0976 (all data), GOOF 1.060.
3
˚
˚
13.5878(4), c 7.1725(2) A, b 101.365(4)8, V 668.63(4) A , Z
4, Dc 1.700 Mg Mꢀ3, m(Mo-Ka) 0.148 mmꢀ1, F(000) 352,
crystal size 0.48 ꢁ 0.31 ꢁ 0.10 mm3. ymax 40.9798, 15960 reflec-
tions measured, 4252 independent reflections (Rint 0.0237), the
final R 0.0410 [I . 2s(I), 3462 data], and wR(F2) 0.1339 (all
data), GOOF 1.103.
Crystal data for 2d. C9H8F2N2O, M 214.17, T 130.0(2) K, l
˚
0.71073 A, triclinic, space group P-1, a 7.0704(4), b 7.7318(3), c
˚
8.3933(5) A, a 77.766(4)8, b 81.173(5)8, g 87.741(4)8, V 443.09
Crystal data for 4c. C9H10FN3O2S, M 243.26, T 130.0(2) K, l
3
(4) A , Z 2, Dc 1.605 Mg Mꢀ3, m(Mo-Ka) 0.142 mmꢀ1, F(000)
˚
˚
1.54184 A, monoclinic, space group P21/n, a 8.8095(1), b
220, crystal size 0.64 ꢁ 0.64 ꢁ 0.23 mm3. ymax 40.938, 9858
reflections measured, 5652 independent reflections (Rint
0.0207), the final R 0.0479 [I . 2s(I), 3929 data], and wR(F2)
0.1496 (all data), GOOF 1.061.
3
˚
˚
11.3396(1), c 9.9484(1) A, b 91.814(1)8, V 993.309(17) A , Z
4, Dc 1.627 Mg Mꢀ3, m(Cu-Ka) 2.984 mmꢀ1, F(000) 568,
crystal size 0.58 ꢁ 0.39 ꢁ 0.09 mm3. ymax 76.898, 8230 reflec-
tions measured, 2079 independent reflections (Rint 0.038), the
final R 0.0379 [I . 2s(I), 2029 data], and wR(F2) 0.1055 (all
data), GOOF 1.032.
Crystal data for 3a. C6H4F2N2O2, M 174.11, T 130(2) K, l
˚
0.71073 A, monoclinic, space group I2/a, a 8.3135(4), b 9.0651
3
˚
˚
(4), c 8.2622(4) A, b 94.703(4)8, V 620.57(5) A , Z 4, Dc
1.864 Mg Mꢀ3, m(Mo-Ka) 0.180 mmꢀ1, F(000) 352, crystal
size 0.38 ꢁ 0.25 ꢁ 0.18 mm3. ymax 36.308, 3780 reflections
measured, 1446 independent reflections (Rint 0.0122), the final
R 0.0325 [I . 2s(I), 1289 data], and wR(F2) 0.1115 (all data),
GOOF 1.130.
Crystal data for 4d. C9H10FN3O2, M 211.20, T 130.0(2) K, l
˚
0.71073 A, orthorhombic, space group P212121, a 4.3022(2) b
3
˚
˚
12.3849(4), c 16.8247(6) A, V 896.46(6) A , Z 4, Dc
1.565 Mg Mꢀ3, m(Mo-Ka) 0.127 mmꢀ1, F(000) 440, crystal
size 0.56 ꢁ 0.31 ꢁ 0.17 mm3. ymax 34.608, 8438 reflections
measured, 3464 independent reflections (Rint 0.0209), the final

320
J. M. White et al.
R 0.0371 [I . 2s(I), 3138 data], and wR(F2) 0.0975 (all data),
GOOF 1.039.
Crystal data for 4f. C27H24FN3O2S, M 473.55, T 130.0(2) K,
reflections measured, 5813 independent reflections (Rint
0.044), the final R 0.0485 [I . 2s(I), 4851 data], and wR(F2)
0.1479 (all data), GOOF 1.080.
˚
l 1.54184 A, monoclinic, space group P21/c, a 17.0432(2), b
Crystal data for 9b. C12H17N3O3, M 251.28, T 130.0(2) K, l
3
˚
˚
˚
1.54184 A, triclinic, space group P-1, a 10.3091(5), b 11.4342
8.6942(1), c 15.1837(2) A, b 94.295(1)8, V 2243.56(5) A , Z 4,
Dc 1.402 Mg Mꢀ3, m(Cu-Ka) 1.611 mmꢀ1, F(000) 992, crystal
size 0.23 ꢁ 0.12 ꢁ 0.02 mm3. ymax 77.028, 13716 reflections
measured, 4651 independent reflections (Rint 0.0298), the final
R 0.0365 [I . 2s(I), 4259 data], and wR(F2) 0.0997 (all data),
GOOF 1.033.
˚
(4), c 12.3234(5) A, a 82.117(3)8, b 68.905(4)8, g 65.364(4)8, V
3
1231.78(10) A , Z 4, Z 2, Dc 1.355 Mg Mꢀ3, m(Cu-Ka)
0.819 mmꢀ1, F(000) 536, crystal size 0.59 ꢁ 0.24 ꢁ 0.15 mm3.
ymax 76.88, 14411 reflections measured, 5183 independent
reflections (Rint 0.0259), the final R 0.0375 [I . 2s(I), 4770
data], and wR(F2) 0.1047 (all data), GOOF 1.027.
0
˚
Crystal data for 4j. C10H12FN3O2S2, M 289.35, T 130.0(2) K,
˚
l 0.7107 A, monoclinic, space group P21/c, a 7.7523(1), b
Crystal data for 10a. C10H11FN2O3, M 226.21, T 130.0(2) K,
˚
3
˚
˚
16.9372(3), c 9.3474(2) A, b 101.712(2)8, V 1201.78(4) A , Z
4, Dc 1.599 Mg Mꢀ3, m(Mo-Ka) 0.453 mmꢀ1, F(000) 600,
crystal size 0.50 ꢁ 0.25 ꢁ 0.2 mm3. ymax 33.968, 11056 reflec-
tions measured, 4631 independent reflections (Rint 0.021), the
final R 0.0317 [I . 2s(I), 3862 data], and wR(F2) 0.0848 (all
data), GOOF 1.055.
l 1.54184 A, monoclinic, space group P21/c, a 7.1997(2), b
3
˚
˚
9.6622(2), c 14.0696(3) A, b 92.652(2)8, V 977.70(4) A , Z 4, Dc
1.537 Mg Mꢀ3, m(Cu-Ka) 1.089 mmꢀ1, F(000) 472, crystal size
0.49 ꢁ 0.18 ꢁ 0.03 mm3. ymax 76.438, 6532 reflections mea-
sured, 2026 independent reflections (Rint 0.022), the final R
0.0373 [I . 2s(I), 1809 data], and wR(F2) 0.1078 (all data),
GOOF 1.072.
Crystal data for 5a. C10 H12FN3O3, M 241.23, T 100.0(2) K,
˚
l 0.82653 A, orthorhombic, space group Pbca, a 7.1670(14)
Crystal data for 12. C8H7F3N2O2, M 220.16, T 100.0(2) K, l
3
˚
˚
˚
0.71073 A, monoclinic, space group P21/n, a 8.0099(2), b
b 13.530(3), c 21.029(4) A, V 2039.2(7) A , Z 8, Dc
1.571 Mg Mꢀ3, m 0.185 mmꢀ1, F(000) 1008, crystal size
0.10 ꢁ 0.06 ꢁ 0.01 mm3. ymax 30.038, 23699 reflections mea-
sured, 1919 independent reflections (Rint 0.0602), the final R
0.0424 [I . 2s(I), 1835 data], and wR(F2) 0.1064 (all data),
GOOF 1.075.
3
˚
˚
9.0833(2), c 11.6768(4) A, b 94.631(3)8, V 846.79(4) A , Z 4,
Dc 1.727 Mg Mꢀ3, m(Mo-Ka) 0.168 mmꢀ1, F(000) 448, crystal
size 0.38 ꢁ 0.10 ꢁ 0.08 mm3. ymax 40.888, 27805 reflections
measured, 5417 independent reflections (Rint 0.042), the final
R 0.0472 [I . 2s(I), 3756 data], and wR(F2) 0.1300 (all data),
GOOF 1.035.
Crystal data for 5i. C12H16FN3O3, M 269.28, T 130.0(2) K, l
˚
1.54184 A, monoclinic, space group P21/c, a 10.94190(10), b
Crystal data for 15b. C11H15F2N3O3, M 275.26, T 100.0(2) K,
˚
3
˚
˚
16.1098(2), c 15.2111(2) A, b 106.6840(10)8, V 2568.41(5) A ,
Z 8, Z0 2, Dc 1.393 Mg Mꢀ3, m(Cu-Ka) 0.940 mmꢀ1, F(000)
1136, crystal size 0.63 ꢁ 0.50 ꢁ 0.23 mm3. ymax 76.818, 25962
reflections measured, 5382 independent reflections (Rint 0.027),
the final R 0.0436 [I . 2s(I), 4951 data], and wR(F2) 0.1219 (all
data), GOOF 1.038.
l 1.54184 A, monoclinic, space group P21/n, a 7.2235(1), b
3
˚
˚
13.8955(2), c 12.6991(2) A, b 102.280(1)8, V 1245.50(3) A , Z
4, Dc 1.468 Mg Mꢀ3, m(Cu-Ka) 1.100 mmꢀ1, F(000) 448,
crystal size 0.34 ꢁ 0.16 ꢁ 0.12 mm3. ymax 77.928, 5963 reflec-
tions measured, 1879 independent reflections (Rint 0.0155), the
final R 0.0325 [I . 2s(I), 1749 data], and wR(F2) 0.0949 (all
data), GOOF 1.074.
Crystal data for 6c. C13H18N4O3S, M 310.37, T 130.0(2) K, l
˚
1.54184 A, monoclinic, space group P21/c, a 8.8349(2), b
Crystal data for 16a. C8H9F2N3O2, M 217.18, T 130.0(2) K, l
3
˚
˚
˚
1.54184 A, monoclinic, space group P21/c, a 13.8283(3), b
9.2999(3), c 16.8972(3) A, b 98.233(2)8, V 1374.03(6) A , Z
4, Dc 1.500 Mg Mꢀ3, m(Cu-Ka) 2.257 mmꢀ1, F(000) 656,
crystal size 0.38 ꢁ 0.15 ꢁ 0.06 mm3. ymax 76.898, 9484 reflec-
tions measured, 2861 independent reflections (Rint 0.028), the
final R 0.0359 [I . 2s(I), 2697 data], and wR(F2) 0.1039 (all
data), GOOF 1.074.
3
˚
˚
9.2460(2), c 7.3043(2) A, b 103.701(2)8, V 907.33(4) A , Z 4,
Dc 1.590 Mg Mꢀ3, m(Cu-Ka) 1.256 mmꢀ1, F(000) 448, crystal
size 0.40 ꢁ 0.40 ꢁ 0.30 mm3. ymax 77.058, 16835 reflections
measured, 2639 independent reflections (Rint 0.063), the final
R 0.0433 [I . 2s(I), 1749 data], and wR(F2) 0.1144 (all data),
GOOF 1.060.
Crystal data for 6d. C13H18N4O3, M 278.31, T 130.0(2) K, l
˚
0.71073 A, monoclinic, space group P21/n, a 11.1586(3), b
Crystal data for 16b. C11H15F2N3O3, M 275.26, T 100.0(2) K,
˚
3
˚
˚
9.6818(2), c 12.2033(3) A, b 92.066(2)8, V 1317.53(6) A , Z
4, Dc 1.3403 Mg Mꢀ3, m(Mo-Ka) 0.102 mmꢀ1, F(000) 592,
crystal size 0.70 ꢁ 0.32 ꢁ 0.26 mm3. ymax 40.998, 24661 reflec-
tions measured, 8456 independent reflections (Rint 0.0281), the
final R 0.0522 [I . 2s(I), 6150 data], and wR(F2) 0.1633 (all
data), GOOF 1.041.
l 0.71073 A, monoclinic, space group P21/c, a 4.70380(10), b
3
˚
˚
22.0393(4), c 12.2912(2) A, b 96.707(2)8, V 1265.49(4) A , Z 4,
Dc 1.445 Mg Mꢀ3, m(Mo-Ka) 0.125 mmꢀ1, F(000) 576, crystal
size 0.44 ꢁ 0.26 ꢁ 0.17 mm3. ymax 36.968, 36069 reflections
measured, 5988 independent reflections (Rint 0.0358), the final
R 0.0412 [I . 2s(I), 4612 data], and wR(F2) 0.1246 (all data),
GOOF 1.093.
Crystal data for 6h. C11H16N4O3, M 252.28, T 130.0(2) K, l
˚
1.54184 A, triclinic, space group P-1, a 7.6166(5), b 11.1505(6),
Crystal data for 17. C11H17FN4O3, M 272.28, T 130.0(2) K, l
˚
˚
1.54184 A, monoclinic, space group P21/c, a 6.1908(1), b
c 15.0183(7) A, a 100.887(4)8, b 91.804(4)8, g 108.333(6)8, V
1183.29(12) A , Z 4, Z 2 Dc 1.46 Mg Mꢀ3, m(Cu-Ka)
0.880 mmꢀ1, F(000) 536, crystal size 0.29 ꢁ 0.07 ꢁ 0.05 mm3.
ymax 76.948, 8463 reflections measured, 9080 independent
reflections (Rint 0.0360), the final R 0.0407 [I . 2s(I), 6766
data], and wR(F2) 0.1146 (all data), GOOF 1.034.
14.4297(2), c 14.9558(2) A, b 96.374(1)8, V 1327.76(3) A , Z
4, Dc 1.362 Mg Mꢀ3, m(Cu-Ka) 0.935 mmꢀ1, F(000) 576,
crystal size 0.26 ꢁ 0.18 ꢁ 0.12 mm3. ymax 76.948, 8863 reflec-
tions measured, 2757 independent reflections (Rint 0.0195), the
final R 0.0321 [I . 2s(I), 2534 data], and wR(F2) 0.0856 (all
data), GOOF 1.061.
3
3
0
˚
˚
˚
Crystal data for 6i. C12H18N4O3, M 266.30, T 130.0(2) K, l
˚
0.7107 A, monoclinic, space group P21/c, a 6.4735(2), b
Crystal data for 18. C10H12N2O3, M 208.22, T 100.0(2) K, l
3
˚
˚
˚
0.71073 A, orthorhombic, space group Pbca, a 14.193(3) b
17.5705(7), c 11.2697(3) A, b 105.281(3)8, V 1236.53(7) A ,
Z 4, Dc 1.430 Mg Mꢀ3, m(Mo-Ka) 0.105 mmꢀ1, F(000) 568,
crystal size 0.54 ꢁ 0.38 ꢁ 0.26 mm3. ymax 36.598, 23455
3
˚
˚
8.3590(17), c 16.099(3) A, V 1910.0(7) A , Z 8, Dc
1.448 Mg Mꢀ3, m 0.109 mmꢀ1, F(000) 880, crystal size

Electron-Rich Nitroaromatics
321
0.10 ꢁ 0.10 ꢁ 0.05 mm3. ymax 27.8848, 27030 reflections mea-
sured, 2208 independent reflections (Rint 0.0302), the final R
0.0419 [I . 2s(I), 2162 data], and wR(F2) 0.1124 (all data),
GOOF 1.082.
removed under reduced pressure and the residue treated with
brine (50 mL) and extracted with ethyl acetate (3 ꢁ 50 mL). The
extract was washed with water (100 mL), dried (MgSO4), and
evaporated to give a viscous orange oil that crystallized on
standing (6.21 g). The solid was treated with petroleum spirit
(30 mL) and dichloromethane (5 mL) was slowly added until the
gum became a friable solid in a coloured supernatant. The iso-
lated solid (3.32 g) was dissolved in dichloromethane (10–
15 mL), applied to an 80 g silica gel cartridge, and eluted with a
petroleum spirit/dichloromethane profile to give, in order of
Crystal data for 22. C9H13FN4O3, M 244.23, T 100.0(2) K, l
˚
0.71073 A, monoclinic, space group P21/c, a 4.5860(9), b
3
˚
˚
10.935(2), c 21.198(4) A, b 91.09(3)8, V 1062.8(43) A , Z 4,
Dc 1.562 Mg Mꢀ3, m(Mo-Ka) 0.128 mmꢀ1, F(000) 512, crystal
size 0.10 ꢁ 0.06 ꢁ 0.05 mm3. ymax 31.588, 17509 reflections
measured, 2903 independent reflections (Rint 0.0422), the final
R 0.0415 [I . 2s(I), 2595 data], and wR(F2) 0.1155 (all data),
GOOF 1.089.
elution;
4-(30,50-difluoro-20-nitrophenyl)morpholine
(2b)
(0.65 g, 11 %) as a viscous yellow oil which slowly crystallized,
and 4-(30,50-difluoro-40-nitrophenyl)morpholine (3b) (2.23 g,
37 %) as a yellow solid.
Synthesis
4-(30,50-Difluoro-20-nitrophenyl)morpholine (2b): Mp 55–
General Experimental
[24]
578C. dH
(600 MHz, CDCl3) 3.04 (m, 4H, H3/5), 3.79 (m,
Melting points are uncorrected and were performed on a
Stanford Research Systems EZ-Melt automated melting point
apparatus. Proton and carbon NMR spectra were obtained on
either a Varian Inova 600 MHz, Varian Inova 500 MHz, Bruker
UltraShield Plus 400 MHz, or Agilent 400 MR 400 MHz spec-
trometer at the indicated frequency. Samples were run in the
specified deuterated solvent(s) and referenced to residual
undeuterated solvent. High and low resolution mass spectra
were obtained on a Thermo Finnigan LTQ FT instrument or an
Agilent TOF instrument.
4H, H2/6), 6.60 (m, 2H, H40 and H60).
4-(30,50-Difluoro-40-nitrophenyl)morpholine (3b): Mp. 127–
1288C. dH[25] (600 MHz, CDCl3) 3.31 (m, 4H, H3/5), 3.84 (m,
4H, H2/6), 6.39 (m, 2H, H20/60). dC (100 MHz, CDCl3) 46.7 (C3/
5), 66.0 (C2/6), 96.6 (d, 2JCF27, C20/60), 153.6 (t, 3JCF 13, C10),
157.4 (dd, 1JCF 257, 3JCF 4, C30/50). C40 not observed.
Evaporation of the petroleum spirit/dichloromethane super-
natant from the above preparation gave a viscous golden oil
1
(2.79 g), H NMR analysis of which showed it to be a 17 : 1
mixture of 2b/3b. In another preparation the coloured superna-
tant was concentrated and allowed to stand, resulting in the
formation of a pale yellow crystalline precipitate. The solid was
isolated and shown by X-ray crystallography to be co-crystals of
4-(30,50-difluoro-40-nitrophenyl)morpholine (3b) and 4-(30,50-
difluoro-20-nitrophenyl)morpholine (2b), mp 107–1178C.
Unless otherwise stated, chromatography was performed on
a Biotage Isolera One automated flash system, using either 12 g,
40 g, or 80 g Reveleris silica gel cartridges from Grace Discov-
ery Sciences, as indicated. Petroleum spirit refers to the fraction
with bp 60–808C unless stated otherwise.
Preparation of 3,5-Difluoro-2-nitroaniline (2a) and
3,5-Difluoro-4-nitroaniline (3a)
Preparation of 3-(30,50-Difluoro-20-nitrophenyl)thiazolidine
(2c) and 3-(30,50-difluoro-40-nitrophenyl)thiazolidine (3c)
To a solution of 2,4,6-trifluoronitrobenzene (1) (2.00 g,
11.3 mmol) in dry tetrahydrofuran (50 mL) stirring in a sealed
tube and chilled in an ice-water bath, was added aqueous
ammonia solution (25 %, 1.7 mL, 22.7 mmol, 2 equiv.). The tube
was then sealed and allowed to stir at room temperature for 20 h
before the solvent was removed by rotary evaporator and the
residue taken up in ethyl acetate (100 mL). The ethyl acetate
solution was washed with brine (100 mL), dried (MgSO4), and
evaporated to give an orange solid (1.65 g), which was recrys-
tallized from 5 : 1 petroleum spirit/ethyl acetate to give 3,5-
difluoro-2-nitroaniline (2a) as an orange crystalline solid
(1.32 g, 67 %), mp 107.5–108.58C (lit.[22] 107–1088C). dH
(600 MHz, CDCl3) 5.90, (br, 2H, H2, NH2), 6.24–6.30 (m, 2H,
H4, H6).
Isolation of the minor isomer 3a and the minor by-product 4a
was achieved by chromatographic separation of the supernatant
from the crystallization of 2a. Recrystallization from dichlor-
omethane gave 3a as pale yellow blocks, mp 183–1858 (Lit.[23]
179–181), while 4a (20 mg) was obtained as a red crystalline
solid from dichloromethane, mp 137–1398. dH (400 MHz,
CDCl3) 6.28 (br, 4H, H2, NH2), 5.71 (d, J 8, 2H, H4, H6).
To a solution of 2,4,6-trifluoronitrobenzene (1) (7.084 g,
40.0 mmol) in dry dimethylformamide (40 mL) was added
potassium carbonate (6.63 g, 48.0 mmol, 1.2 equiv.) and the
mixture cooled in an ice/water bath and stirred under argon. A
solution of thiazolidine (3.575 g, 40.0 mmol) in dry DMF
(10 mL) was then added slowly by pipette over 5 min. After
10 min the ice/water bath was removed and the mixture stirred at
room temperature under argon for 94 h. The solvent was then
removed by rotary evaporator and the residue partitioned
between ethyl acetate (80 mL) and water (80 mL). The aqueous
layer was extracted with additional ethyl acetate (2 ꢁ 80 mL)
and the combined organic extract washed with brine (150 mL),
dried (MgSO4), and evaporated to give a yellow-orange crys-
talline mass (9.39 g). The solid was triturated with 10 %
dichloromethane in petroleum spirit (2 ꢁ 56 mL) and the com-
bined yellow supernatants evaporated to give 4.4 g of material
enriched in the desired ortho isomer. The material was dissolved
in 2 : 1 petroleum spirit/dichloromethane, applied to a 80 g silica
gel cartridge over multiple runs, and eluted with a dichlor-
omethane/petroleum spirit profile to give 3-(30,50-difluoro-
20-nitrophenyl)thiazolidine (2c) as a viscous yellow oil that
solidified on standing (3.07 g, 31 %), mp 47–498C. dH
(500 MHz, CDCl3) 3.06 (t, J 6.5, 2H, H5), 3.56 (t, J 6.5, 2H, H4),
4.36 (s, 2H, H2), 6.52 (ddd, J 9.5, 8.0, 2.5, 1H, H40), 6.66 (app dt,
J 11.0, 2.0, 1H, H60). dC (125 MHz, CDCl3) 30.4 (C5), 54.5, 54.6
Preparation of 4-(30,50-Difluoro-20-nitrophenyl)morpholine
(2b) and 4-(30,50-Difluoro-40-nitrophenyl)morpholine (3b)
To a solution of 2,4,6-trifluoronitrobenzene (1) (4.43 g,
25 mmol) in dry dimethylformamide (35 mL) was added
potassium carbonate (4.15 g, 30 mmol, 1.2 equiv.) followed by
morpholine (2.3 mL, 26 mmol) and the mixture stirred under
argon at room temperature for 92 h. The solvent was then
2
2
2
(C2, C4), 96.7 (dd, JCF 24, JCF 25, C40), 101.0 (dd, JCF 25,
4JCF 3, C60), 143.7 (dd, 3JCF 12, 3JCF 3, C10), 156.1 (dd, 1JCF 265,
3JCF 16, C30 or C50), 163.3 (dd, 1JCF 251, 3JCF 15, C50 or C30).

322
J. M. White et al.
2
4
C20 was not observed. m/z (ESI þve) 247 ([M þ H]þ, 100 %).
HRMS (ESI þve) m/z 247.03474; C9H9F2N2O2S requires
247.03473 (D ¼ 0.0 ppm).
2JCF 24, C4), 100.5 (dd, JCF 26, JCF 3, C6), 146.8 (m, C1),
156.7 (dd, 1JCF 256, 16), 163.2 (dd, 1JCF 250, 3JCF 16, C3, C5).
C2 was not observed. HMRS (ESI þve) m/z 229.07812;
C10H11F2N2O2 requires 229.07831 (D ¼ 0.8 ppm).
The insoluble orange solid from the trituration (4.8 g) was
shown by 1H NMR analysis to be a 9 : 1 mixture of 3c/2c. In a
separate preparation the slower eluting 3-(30,50-difluoro-40-
nitrophenyl)thiazolidine (3c) was collected during chromatog-
raphy and had the following data: mp 101–1048. dH (500 MHz,
CDCl3) 3.21 (t, J 6.5, 2H, H5), 3.67 (t, J 6.5, 2H, H4), 4.42
(s, 2H, H2), 6.19 (m, 2H, H20/60).
N-Cyclopropyl-3,5-difluoro-N-methyl-4-nitroaniline (3e):
H (600 MHz, CDCl3) 0.71 (m, 2H, H20/30), 0.97 (m, 2H, H20/
d
30), 2.61 (m, 1H, H10), 3.04 (s, 3H, NMe), 6.45 (d, J 12.6, 2H, H2/
6). dC (150 MHz, CDCl3) 9.5 (C20/30), 33.3, 38.5 (C10, NMe),
96.3 (d, 2JCF 26, C2/6), 154.1 (t, 3JCF 14, C1), 157.2 (dd, 1JCF
256, 3JCF 5, C3/5). C2 was not observed. HMRS (ESI þve) m/z
229.07823; C10H11F2N2O2 requires 229.07831 (D ¼ 0.3 ppm).
PreparationofN-Cyclopropyl-3,5-difluoro-2-nitroaniline(2d)
Preparation of 3,5-Difluoro-2-nitro-N,N-bis(20-(tritylthio)
ethyl)benzenamine (2g) and 3,5-Difluoro-4-nitro-N,N-bis
(20-(tritylthio)ethyl)benzenamine (3g)
To a solution of 2,4,6-trifluoronitrobenzene (1) (5.03 g,
28.4 mmol) in dimethylformamide (35 mL) cooled in an ice-
bath and stirred under argon, was added potassium carbonate
(4.69 g, 33.9 mmol, 1.2 equiv.) and cyclopropylamine (1.63 g,
28.6 mmol). The ice-bath was removed after 20 min and the
reaction stirred at room temperature for 121 h. The solvent was
then evaporated and the residue partitioned between ethyl ace-
tate (56 mL) and water (56 mL). The organic extract was washed
with water (2 ꢁ 56 mL) and brine (106 mL), dried (MgSO4), and
evaporated to give a bright orange crystalline solid. Recrystal-
lization from petroleum spirit (65 mL) afforded N-cyclopropyl-
3,5-difluoro-2-nitroaniline (2d) as orange crystals (4.23 g,
74 %), mp 83.4–84.88C. dH (600 MHz, CDCl3) 0.65 (m, 2H, H20/
30), 0.93 (m, 2H, H20/30), 2.52 (ttd, J 6.8, 3.7, 1.8, 1H, H10), 6.25
(ddd, J 11.4, 8.4, 2.8, 1H, H4), 6.74 (ddd, J 11.4, 2.7, 1.9, 1H,
H6), 7.62 (br, 1H, NH). dC (150 MHz, CDCl3) 7.7 (C20/30), 24.8
(C10), 93.6 (t, 2JCF 27, C4), 96.4 (dd, 2JCF 27, 3, C6), 121.6 (C1),
148.1 (d, 2JCF 15, C2), 159.3 (dd, 1JCF 262, 17, C5), 165.4 (dd,
1JCF 253, 16, C3). HRMS (ESI þve) m/z 215.06268,
C9H9F2N2O2 requires 215.06266 (D ¼ 0.1 ppm).
To a suspension of 2,4,6-trifluoronitrobenzene (1) (285 mg,
1.6 mmol) and potassium carbonate (333 mg, 2.41 mmol, 1.5
equiv.) in dimethyl sulfoxide (2 mL) in a sealed tube, was added
a suspension of bis(2-(tritylthio)ethyl)amine (1.00 g, 1.6 mmol,
1.0 equiv.) in dimethyl sulfoxide (8 mL) and the mixture stirred
at room temperature for 6 days. The reaction mixture was then
tipped into water (100 mL), extracted with ethyl acetate
(3 ꢁ 80 mL), the extract washed with water (100 mL) and brine
(100 mL), dried (MgSO4), and evaporated to give a yellow foam
(1.24 g). The material was dissolved in 3 : 1 petroleum spirits/
dichloromethane (12 mL) and applied to an 80 g silica gel
cartridge over 2 runs, eluting with a petroleum spirits/dichlor-
omethane profile to give in order of elution; 3,5-difluoro-
2-nitro-N,N-bis(20-(tritylthio)ethyl)benzenamine (2g) (157 mg,
13 %) as a pale yellow glassy solid, followed by 3,5-difluoro-4-
nitro-N,N-bis(20-(tritylthio)ethyl)benzenamine (3g) (349 mg,
28 %) as a pale yellow crystalline solid, mp 117–1198C (dec).
3,5-Difluoro-2-nitro-N,N-bis(20-(tritylthio)ethyl)benzenamine
(2g): dH (600 MHz, CDCl3) 2.18 (m, 4H, 2 ꢁ CH2S), 2.61 (m,
4H, 2 ꢁ CH2N), 6.05 (d, J 10.8, 1H, H6), 6.43 (m, 1H, H4), 7.19
(m, 6H, 2 ꢁ p-Ph3C), 7.24 (m, 12H, 2 ꢁ m-Ph3C), 7.34 (m, 12H,
2 ꢁ o-Ph3C).
Preparation of N-Cyclopropyl-3,5-difluoro-N-methyl-2-
nitroaniline (2e) and N-cyclopropyl-3,5-difluoro-N-methyl-
4-nitroaniline (3e)
To a solution of 2,4,6-trifluoronitrobenzene (1) (5.023 g,
28.37 mmol) in dimethylformamide (28 mL) stirred in an ice-
bath under argon was added potassium carbonate (4.853 g,
35.12 mmol, 1.2 equiv) and a solution of N-methylcyclopropy-
lamine (2.022 g, 28.44 mmol) in dimethylformamide (7 mL).
After 10 min the ice-bath was removed and the reaction mixture
stirred at room temperature for 22.5 h. The solvent was then
evaporated and the residue partitioned between ethyl acetate
(56 mL) and water (56 mL). The organic extract was washed
with water (2 ꢁ 56 mL) and brine (106 mL), dried (MgSO4), and
evaporated to give a yellow oil. The oil was triturated with
petroleum spirit/dichloromethane 15 : 1 (32 mL) and the insol-
uble material isolated by filtration to give N-cyclopropyl-
3,5-difluoro-N-methyl-4-nitroaniline (3e) (1.67 g, 26 %) as a
crystalline solid, mp 84.5–85.08C. The supernatant was evapo-
rated and the oil (3.65 g) dissolved in dichloromethane (10 mL)
and applied to an 80 g silica gel cartridge over two runs. Elution
with an ethyl acetate/petroleum spirit profile afforded
N-cyclopropyl-3,5-difluoro-N-methyl-2-nitroaniline (2e) as a
dark yellow oil (3.04 g, 47 %). Further elution yielded additional
3e (0.38 g) to give a total yield of 32 %.
3,5-Difluoro-4-nitro-N,N-bis(20-(tritylthio)ethyl)benzenamine
(3g): dH (600 MHz, CDCl3) 2.31 (m, 4H, 2 ꢁ CH2S), 2.76 (m,
4H, 2 ꢁ CH2N), 5.55 (m, 2H, H2/6), 7.24 (m, 6H, 2 ꢁ p-Ph3C),
7.29 (m, 12H, 2 ꢁ m-Ph3C), 7.37 (m, 12H, 2 ꢁ o-Ph3C).
Preparation of 5-(30,50-Difluoro-20-nitrophenyl)-1,2,5-
dithiazepane (2j)
To the 1,2,5-dithiazepane hydrochloride (250 mg, 1.46 mmol) in
a sealed tube was added a solution of 2,4,6-trifluoronitrobenzene
(1) (258 mg, 1.46 mmol) in dry dimethylformamide (5 mL),
followed by potassium carbonate (503 mg, 3.64 mmol, 2.5
equiv.) and the mixture stirred at room temperature for 20 h. The
reaction mixture was then tipped into water (50 mL), extracted
with ethyl acetate (3 ꢁ 30 mL), the combined extract washed
with water (70 mL) and brine (70 mL), dried (MgSO4), and
evaporatedtogiveaviscousyellowoil(0.44 g).Thematerialwas
dissolved in 2 : 1 petroleum spirit/dichloromethane (6 mL) and
applied to a 40 g silica gel cartridge eluting with a dichlor-
omethane/petroleum spirit profile to give 5-(30,50-difluoro-20-
nitrophenyl)-1,2,5-dithiazepane (2j) as a viscous yellow oil that
solidified on standing (115 mg, 27 %). dH (600 MHz, CDCl3)
2.98 (t, J 5.7, 4H, H3/7), 3.86(t, J 5.7, 4H, H4/6), 6.41(ddd, J 9.5,
8.1, 2.4, 1H, H40), 6.46 (br d, J 12, 1H, H60). m/z (ESI þve) 293
([M þ H]þ, 100 %). HRMS (ESI þve) m/z 293.02173,
C10H11F2N2O2S2 requires 293.02245 (D ¼ 2.5 ppm).
N-Cyclopropyl-3,5-difluoro-N-methyl-2-nitroaniline (2e):
d
H (600 MHz, CDCl3) 0.60 (m, 2H, H20/30), 0.77 (m, 2H, H20/
30), 2.67 (m, 1H, H10), 2.96 (s, 3H, NMe), 6.33 (ddd, J 10.2, 7.8,
2.4, 1H, H4), 6.53 (ddd, J 12, 2.4, 1H, H6). dC (150 MHz,
CDCl3) 9.4 (C20/30), 35.1, 40.1 (C10, NMe), 93.8 (dd, 2JCF 28,

Electron-Rich Nitroaromatics
323
Further elution afforded impure material enriched in the para
substitution isomer (3j), from which the following data was
obtained: dH (600 MHz, CDCl3) 3.02 (t, J 5.4, 4H, H3/7), 3.98
(t, J 5.4, 4H, H4/6), 6.19 (m, 2H, H40/60).
mp 174–1758C. dH (600 MHz, CDCl3) 2.53 (t, J 6.6, 2H, H20),
3.01 (app q, J 6.4, 2H, H10), 5.35 (dd, J 12.0, 2.4, 1H, H4 or H6),
5.63 (dd, J 10.2, 2.4, 1H, H6 or H4), 6.40 (br, 2H, 1-NH2), 7.22
(m, 3H, p-CPh3), 7.29 (m, 6H, m-CPh3), 7.44 (m, 6H, o-CPh3),
8.66 (m, 1H, 3-NH). dC (125 MHz, d6-DMSO) 30.3 (C20), 41.3
(C10, CPh3), 84.7 (d, 2JCF 29, C4 or C6), 89.1 (d, 2JCF 27, C6 or
C4), 118.2 (C2), 126.8 (p-CPh3), 128.0, 129.0 (o-CPh3, m-
CPh3), 144.3 (CPh3), 148.4 (d, 3JCF 16, C1 or C3), 151.2 (d, 3JCF
Preparation of 5-Fluoro-2-nitro-3-(thiazolidin-30-yl)aniline
(4c)
To a solution of 3-(30,50-difluoro-20-nitrophenyl)thiazolidine
(2c) (1.49 g, 6.05 mmol) in tetrahydrofuran (20 mL) in a sealed
tube, was added aqueous ammonia solution (25 %, 4.6 mL,
61 mmol, 10 equiv.), and the mixture heated in a 708C oil-bath
for 91 h. The solvent was then removed by rotary evaporator, the
residue dissolved in ethyl acetate (100 mL), washed with water
(2 ꢁ 80 mL) and brine (80 mL), dried (MgSO4), and evaporated
to give a viscous red oil (1.55 g). The material was dissolved in
the minimum amount of dichloromethane (10–15 mL) and
applied to an 80 g silica gel cartridge, eluting with a dichlor-
omethane/petroleum spirit profile to give 5-fluoro-2-nitro-3-
(thiazolidin-30-yl)aniline (4c) as a viscous red oil that solidified
on standing (1.24 g, 84 %), mp 115–1168C. dH (600 MHz,
CDCl3) 3.04 (t, J 6.0, 2H, H50), 3.52 (t, J 6.0, 2H, H40), 4.30 (s,
2H, H20), 5.24 (br, 2H, 1-NH2), 6.01 (dd, J 2.4, 10.2, 1H, H4 or
H6), 6.13 (dd, J 2.4, 10.8, 1H, H6 or H4). dC (125 MHz, CDCl3)
30.4 (C50) 54.7, 54.9 (C20, C40) 93.6 (d, 2JCF 27, C4 or C6), 94.9
(d, 2JCF 27, C6 or C4), 125.4 (C2), 145.5 (d, 3JCF 15, C1 or C3),
146.7 (d, 3JCF 13, C3 or C1), 165.2 (d, 1JCF 249, C50). m/z (ESI
þve) 244 ([M þ H]þ, 100 %). HRMS (ESI þve) m/z 244.05503,
C9H11FN3O2S requires 244.05505 (D ¼ 0.1 ppm).
1
17, C3 or C1), 166.7 (d, JCF 245, C5). m/z (ESI þve) 969
([M2 þ Na]þ, 30 %), 496 ([M þ Na]þ, 100).
Preparation of 3-Dimethylamino-5-fluoro-2-nitroaniline (4i)
To a solution of 3,5-difluoro-2-nitroaniline (2a) (2.834 g,
16.3 mmol) in dimethyl sulfoxide (20 mL) was added potassium
carbonate (7.2 g, 52.1 mmol, 3.2 equiv.) followed by a solution
of dimethylamine hydrochloride (1.46 g, 17.9 mmol, 1.1 equiv.)
in dimethyl sulfoxide (5 mL) and the mixture stirred at room
temperature under argon for 19 h. The red reaction mixture was
then diluted with water (270 mL), extracted with ethyl acetate
(3 ꢁ 100 mL), the extract washed with water (80 mL) and brine
(80 mL), dried (MgSO4), and evaporated to give a dark viscous
oil (3.22 g) that crystallized on standing. Attempted recrystal-
lization from petroleum spirit (bp 60–808C) and ethyl acetate
produced a small amount of orange crystalline solid (275 mg),
with evaporation of the filtrate affording pure 3-(dimethyla-
mino)-5-fluoro-2-nitroaniline (4i) (2.96 g, 91 %) as a deep red
viscous oil. dH (600 MHz, CDCl3) 2.87 (s, 6H, NMe2), 5.36 (br,
2H, NH2), 5.84 (dd, J 10.0, 2.5, 1H, H4 or H6), 5.92 (dd, J 11.8,
2.5, 1H, H6 or H4).
Preparation of N-Cyclopropyl-5-fluoro-2-nitrobenzene-1,3-
diamine (4d)
Preparation of 3-(10,20,50-Dithiazepan-50-yl)-5-fluoro-2-
nitroaniline (4j)
In a sealed tube N-cyclopropyl-3,5-difluoro-2-nitroaniline (2d)
(2.65 g, 12.4 mmol) was combined with tetrahydrofuran
(40 mL) and aqueous ammonia (30 %, 7.7 mL, 123 mmol) and
stirred in a 708C oil-bath for 69 h. The solvent was evaporated
and the residue was taken up in ethyl acetate (130 mL), washed
with water (2 ꢁ 80 mL) and brine (80 mL), dried (MgSO4), and
evaporated to give a crimson powder (2.58 g). The material was
recrystallized from petroleum spirit/ethyl acetate to give N-
cyclopropyl-5-fluoro-2-nitrobenzene-1,3-diamine (4d) as red
crystals (2.12 g, 81 %), mp 125.9–127.78C. dH (600 MHz,
CDCl3) 0.64 (m, 2H, H20/30), 0.88 (m, 2H, H20/30), 2.48 (m, 1H,
H10), 5.70 (dd, J 10.3, 2.7, 1H, H4 or H6), 6.16 (dd, J 11.8, 2.8,
1H, H6 or H4), 6.38 (br, 2H, NH2), 8.62 (br, 1H, NH). dC
To a solution of 5-(30,50-difluoro-20-nitrophenyl)-1,2,5-dithia-
zepane (2j) (110 mg, 0.376 mmol) in tetrahydrofuran (2 mL) in a
sealed tube, was added aqueous ammonia solution (25 %,
0.30 mL, 4.0 mmol, 10 equiv.) and the mixture heated in a 70–
808C oil-bath for 19 h. Additional concentrated ammonia solu-
tion (0.30 mL) was added and heating continued for a further
60 h. Further concentrated ammonia solution (0.30 mL) was
then added and heating continued for another 24 h. The solvent
was then removed by rotary evaporator, the residue dissolved in
ethyl acetate (40 mL), washed with water (2 ꢁ 40 mL) and brine
(40 mL), dried (MgSO4), and evaporated to give an orange-red
glassy solid (102 mg). The material was dissolved in dichloro-
methane (3 mL) and applied to a 12 g silica gel cartridge, eluting
with a dichloromethane/petroleum spirit profile to give 3-
2
(150 MHz, CDCl3) 7.7 (C20/30), 24.9 (C10), 88.4 (d, JCF 29),
90.5 (d, 2JCF 27, C4, C6), 150.0 (d, 3JCF 17), 150.8 (d, 3JCF 16,
C1, C3), 167.3 (d, 1JCF 250, C5).
(10,20,50-dithiazepan-50-yl)-5-fluoro-2-nitroaniline (4j) as
a
bright red powder (78 mg, 72 %), mp 159–1618C. dH (600 MHz,
CDCl3) 2.95 (t, J 5.4, 4H, H30/70), 3.82 (t, J 5.4, 4H, H40/60), 5.02
(br, 2H, 1-NH2), 5.96 (dd, J 2.4, 9.6, 1H, H4 or H6), 6.06 (dd, J
2.4, 11.4, 1H, H6 or H4). dC (125 MHz, d6-DMSO) 36.8 (C30/70),
53.2 (C40/60), 92.6 (d, 2JCF 27, C4 or C6), 93.0 (d, 2JCF 28, C6 or
C4), 124.7 (C2), 145.5 (d, 3JCF 13, C1 or C3), 145.7 (d, 3JCF 16,
Preparation of 5-Fluoro-2-nitro-3-(20-(tritylthio)ethylamino)
aniline (4f)
A
solution of 3,5-difluoro-2-nitroaniline (2a) (0.50 g,
2.87 mmol), 2-(tritylthio)ethylamine (0.92 g, 2.88 mmol, 1.0
equiv.), and potassium carbonate (0.60 g, 4.34 mmol, 1.5 equiv.)
in dimethyl sulfoxide (10 mL) was stirred in a stoppered flask at
room temperature for 48 h. The reaction mixture was then tipped
into water (200 mL), extracted with ethyl acetate (3 ꢁ 100 mL),
the extract washed with water (300 mL) and brine (300 mL),
dried (MgSO4), and evaporated to give 1.36 g of solid. The
material was applied to an 80 g silica gel cartridge over 3 runs,
eluting with petroleum spirits/ethyl acetate, followed by ethyl
acetate/methanol mixtures to give 5-fluoro-2-nitro-3-(20-(tri-
tylthio)ethylamino)aniline (4f) (0.72 g, 53 %) as orange needles,
1
C3 or C1), 164.6 (d, JCF 243, C50). m/z (ESI þve) 290
([M þ H]þ, 100 %). HRMS (ESI þve) m/z 290.0427;
C10H13FN3O2S2 requires 290.0433 (D ¼ 2 ppm).
Preparation of 3-Fluoro-5-morpholino-2-nitroaniline (5a)
To a solution of 4-(30,50-difluoro-40-nitrophenyl)morpholine
(3b) (0.81 g, 3.32 mmol) in tetrahydrofuran (5 mL) in a sealed
tube, was added aqueous ammonia solution (28–30 %, 0.54 mL,
8.3 mmol, 2.5 equiv.), and the mixture heated in a 758C oil-bath

324
J. M. White et al.
for 18 h. Additional concentrated ammonia (0.20 mL, 3.1 mmol)
was then added and heating continued for a further 3 h before
stirring overnight at room temperature. The reaction mixture
was then tipped into water (40 mL), extracted with ethyl acetate
(50 mL), the extract washed with water (2 ꢁ 40 mL) and brine
(40 mL), dried (MgSO4), and evaporated to give a light orange
waxy solid (0.763 g). The material was triturated with dichlor-
omethane (4 ꢁ 8 mL) to give 3-fluoro-5-morpholino-2-nitroa-
niline (5a) (320 mg, 40 %) as a light orange powder. The
dichloromethane supernatants were applied to an 80 g silica gel
cartridge and eluted with a dichloromethane/methanol profile to
give additional 5a (298 mg, total yield 77 %), mp 198–2008C. dH
(600 MHz, d6-DMSO) 3.24 (m, 4H, H30/50), 3.67 (m, 4H, H20/
60), 6.05 (d, J 2.4, 1H, H6), 6.28 (dd, J 16.8, 2.4, 1H, H4), 7.15 (br
s, 2H, NH2). m/z (ESI þve) 242 ([M þ H]þ, 100 %). HRMS
(ESI þve) m/z 242.09357; C10H13FN3O3 requires 242.09355
(D ¼ 0.1 ppm).
The filtrate was concentrated resulting in the formation of a
bright orange crystalline solid (0.57 g). A sample was recrys-
tallized from ethanol and identified as a co-crystal of 3b and 5i
by 1H NMR and X-ray analysis, mp 133.8–133.98C.
The material (0.505 g) was re-treated with dimethylamine
(2 %, 2.5 mL, 0.98 mmol) in ethanol and potassium carbonate
(0.25 g) and refluxed for 90 min. The solution was cooled,
filtered, and the filtrate evaporated to give 3-fluoro-N,N-
dimethyl-5-morpholino-2-nitroaniline (5i) as an orange solid
(0.459 g, 80 %), mp 89.5–90.78C. dH (400 MHz, CDCl3) 2.86 (s,
6H, NMe2), 3.23 (m, 4H, H30/50), 3.83 (m, 4H, H20/60), 5.99 (s,
1H, H6), 6.09 (dd, , J 13.7, 2.4, 1H, H4). m/z (ESI þve) 270
([M þ H]þ, 100 %).
Preparation of 5-Morpholino-2-nitro-3-(thiazolidin-30-yl)
aniline (6c)
To a solution of 5-fluoro-2-nitro-3-(thiazolidin-30-yl)aniline
(4c) (0.707 g, 2.9 mmol) in dry dimethylacetamide (20 mL) in a
sealed tube, was added potassium carbonate (0.802 g, 5.8 mmol,
2 equiv.) followed by morpholine (1.53 mL, 17.5 mmol, 6
equiv.). The mixture was heated in an 85–908C oil-bath for 16 h
at which time TLC (silica gel, 1 % methanol in dichloro-
methane) indicated some starting material still remained.
Heating was therefore continued at 100–1058C for a further 24 h
at which point almost all starting material had been consumed.
The reaction mixture was then cooled, tipped into water
(200 mL), and extracted with ethyl acetate (3 ꢁ 100 mL). The
combined extract was washed with water (200 mL) and brine
(200 mL), dried (MgSO4), and evaporated to give a viscous red
oil (1.014 g). The material was dissolved in dichloromethane
(4 mL) and applied to an 80 g silica gel cartridge, eluting with a
dichloromethane/methanol profile to give 5-morpholino-2-
nitro-3-(thiazolidin-30-yl)aniline (6c) as an orange foam
(0.799 g, 89 %). Subsequent treatment with ether afforded the
product as a red powder, mp 141–1428C. dH (600 MHz, CDCl3)
2.98 (t, J 6.0, 2H, H50), 3.24 (m, 4H, H30/50), 3.53 (t, J 6.0, 2H,
H40), 3.81 (m, 4H, H20/60), 4.40 (s, 2H, H20), 5.52 (br, 2H, 1-
NH2), 5.71 (d, J 2.4, 1H, H4 or H6), 6.00 (d, J 2.4, 1H, H6 or H4).
dC (125 MHz, CDCl3) 30.4 (C50), 47.1 (C30/50), 55.7, 55.9 (C20,
C40), 66.4 (C20/60), 93.5, 94.0 (C4, C6), 122.1 (C2), 146.8, 147.0,
154.2 (C1, C3, C5). m/z (ESI þve) 311 ([M þ H]þ, 100 %).
HRMS (ESI þve) m/z 311.11720; C13H19N4O3S requires
311.11724 (D ¼ 0.1 ppm).
Preparation of 3-Fluoro-N-methyl-5-morpholino-2-
nitroaniline (5h) and N1,N3-Dimethyl-5-morpholino-2-
nitrobenzene-1,3-diamine (7h)
To a solution of 4-(30,50-difluoro-40-nitrophenyl)morpholine
(3b) (1.60 g, 6.55 mmol) in tetrahydrofuran (10 mL) in a sealed
tube, was added aqueous methylamine solution (30 %, 1.9 mL,
16.4 mmol, 2.5 equiv.), and the mixture heated in a 708C oil-bath
for 17 h. The reaction mixture was diluted with water (100 mL),
extracted with ethyl acetate (2 ꢁ 100 mL), the extract washed
with brine (150 mL), dried (MgSO4), and evaporated to give
a dark red solid (1.69 g). The material was dissolved in
dichloromethane (14 mL) and applied over two 80 g silica gel
cartridges, eluting with 0.5 % methanol in dichloromethane to
give 3-fluoro-N-methyl-5-morpholino-2-nitroaniline (5h)
(0.98 g, 59 %) as a yellow solid, mp 172–1748C. Further elution
then afforded the by-product N1,N3-dimethyl-5-morpholino-2-
nitrobenzene-1,3-diamine (7h) (0.62 g, 37 %) as a maroon solid,
mp 194–1978C.
3-Fluoro-N-methyl-5-morpholino-2-nitroaniline (5h): dH
(600 MHz, CDCl3) 2.95 (d, J 4.8, 3H, NMe), 3.33 (m, 4H,
H30/50), 3.83 (m, 4H, H20/60), 5.65 (d, , J 1.8, 1H, H6), 5.98 (dd, J
15.6, 2.4, 1H, H4), 8.15 (br, 1H, NH). dC (125 MHz, CDCl3)
4
30.0 (NMe), 46.7 (C30/50), 66.2 (C20/60), 88.8 (d, JCF 2, C6),
91.3 (d, 2JCF 28, C4), 116.6 (d, 2JCF 8, C2), 148.8 (d, 3JCF 2, C1),
154.5 (d, 3JCF 14, C5), 160.1 (d, 1JCF 258, C3). m/z (ESI þve)
256 ([M þ H]þ, 30 %), 169 ([M – morpholine]þ, 100). HRMS
(ESI þve) m/z 256.10902; C11H15FN3O3 requires 256.10920
(D ¼ 0.7 ppm).
Preparation of N-Cyclopropyl-5-morpholino-2-
nitrobenzene-1,3-diamine (6d)
N1,N3-Dimethyl-5-morpholino-2-nitrobenzene-1,3-diamine
(7h): dH (600 MHz, CDCl3) 2.92 (d, J 4.8, 6H, NHMe ꢁ 2), 3.39
(m, 4H, H30/50), 3.83 (m, 4H, H20/60), 5.24 (s, 2H, H4/6), 9.15
(br, 2H, NHMe ꢁ 2). dC (125 MHz, CDCl3) 29.9 (NHMe ꢁ 2),
46.7 (C30/50), 66.5 (C20/60), 82.7 (C4/6), 116.3 (C2), 150.5 (C1/
3), 155.8 (C5). m/z (ESI þve) 555 ([M2 þ Na]þ, 28 %), 267
([M þ H]þ, 100). HRMS (ESI þve) m/z 267.14496;
C12H19N4O3 requires 267.14517 (D ¼ 0.1 ppm).
N-Cyclopropyl-5-fluoro-2-nitrobenzene-1,3-diamine
(4d)
(0.50 g, 2.37 mmol) was combined with dry dimethylacetamide
(17 mL), potassium carbonate (0.67 g, 4.85 mmol, 2 equiv.), and
morpholine (1.4 mL, 16.2 mmol, 6.8 equiv.) in a sealed tube and
the mixture heated at 1008C for 68 h. The solution was diluted
with water (200 mL), extracted with ethyl acetate (3 ꢁ 100 mL),
the extract washed with water (200 mL) and brine (200 mL),
dried (MgSO4), and the solvent evaporated. The material was
recrystallized with petroleum spirit/ethyl acetate to give
N-cyclopropyl-5-(morpholin-4-yl)-2-nitrobenzene-1,3-diamine
(6d) as small red crystals (0.40 g, 61 %), mp 183.1–184.48C. dH
(600 MHz, CDCl3) 0.61 (m, 2H, H20/30), 0.82 (m, 2H, H20/30),
2.45 (m, 1H, H10), 3.32 (m, 4H, H30/50), 3.81 (m, 4H, H20/60),
5.43 (d, J 3.0, 1H, H4 or H6), 5.84 (d, J 2.4, 1H, H6 or H4), 6.32
(br, 2H, NH2), 8.77 (br, 1H, NH). dC (150 MHz, CDCl3) 7.5
(C20/30), 24.6 (C10), 46.7 (C30/50), 66.5 (C20/60), 86.1, 88.6 (C4,
C6), 149.3, 149.7, 155.2 (C1, C3, C5). C2 was not observed.
Preparation of 3-Fluoro-N,N-dimethyl-5-morpholino-2-
nitroaniline (5i)
A solution of dimethylamine in ethanol (2 %, 5.3 mL,
2.12 mmol, 1 equiv.) was added dropwise to a cooled suspension
of potassium carbonate (0.783 g, 5.6 mmol, 2.5 equiv.) and
4-(30,50-difluoro-40-nitrophenyl)morpholine (3b) (517 mg,
2.12 mmol) in ethanol (5 mL). The mixture was heated to reflux
for 30 min, and then cooled to room temperature and filtered.

Electron-Rich Nitroaromatics
325
HMRS (ESI þve) m/z 279.14468; C13H19N4O3 requires
279.14517 (D ¼ 1.7 ppm).
acetate/petroleum spirits (bp 40–608C), yielding 4-(30-fluoro-40-
nitrophenyl)morpholine (10a) as bright yellow crystals (2.06 g,
20 %), mp 148.3–149.18C. Evaporation of the supernatant
afforded 4-(50-fluoro-20-nitrophenyl)morpholine (9a) as an
orange oil (2.36 g, 23 %). dH[26] (400 MHz, CDCl3) 3.06 (m, 4H,
H3/5), 3.85 (m, 4H, H2/6), 6.75 (m, 2H, H40, Hþ60), 7.90 (dd, J
9.2, 6.1, 1H, H30). m/z (ESI þve) 227 ([M þ H] , 100 %).
Preparation of 3-(Methylamino)-5-morpholino-2-
nitroaniline (6h)
To a solution of 3-fluoro-5-morpholino-2-nitroaniline (5b)
(0.494 g, 2.05 mmol) in dry tetrahydrofuran (20 mL) in a sealed
tube, was added 30 % aqueous methylamine solution (1.4 mL,
12.0 mmol, 6.0 equiv.) and the mixture heated in an 808C oil-
bath for 21 h. The reaction mixture was cooled, tipped into water
(150 mL), extracted with ethyl acetate (2 ꢁ 100 mL), the extract
washed with water (100 mL) and brine (100 mL), dried
(MgSO4), and evaporated to give 3-(methylamino)-5-morpho-
lino-2-nitroaniline (6h) as a maroon solid (0.49 g, 94 %), mp
170–1728C (ethanol). dH (600 MHz, d6-DMSO) 2.82 (d, , J 4.8,
3H, NMe), 3.27 (m, 4H, H30/50), 3.68 (m, 4H, H20/60), 5.28 (d, J
2.4, 1H, H4 or H6), 5.63 (d, J 2.4, 1H, H6 or H4), 7.31 (br, 2H,
NH2) 8.57 (br q, J 4.8, 1H, NH). dC (125 MHz, CDCl3) 30.0
(NHMe), 46.7 (C30/50), 66.5 (C20/60), 83.9, 88.1 (C4, C6), 116.9
(C2), 149.5, 149.8 (C1, C3), 155.4 (C5). m/z (ESI þve) 253
([M þ H]þ, 100 %). HRMS (ESI þve) m/z 253.12955;
C11H17N4O3 requires 253.12952 (D ¼ 0.1 ppm).
Preparation of N,N-Dimethyl-3-morpholino-4-nitroaniline
(9b)
Aqueous dimethylamine solution (40 % w/w, 3.5 mL, 31 mmol,
3 equiv.) was added dropwise to a solution of 4-(5-fluoro-2-
nitrophenyl)morpholine (9a) (2.084 g, 9.20 mmol) in ethanol
(10 mL) at 08C, then the mixture was heated to reflux for 90 min.
The solution was diluted with water (100 mL) and the precipitate
filtered and dried to give N,N-dimethyl-3-morpholino-4-
nitroaniline (9b) (2.315 g, 100 %) as a bright yellow solid, mp
127.2–127.68C. dH (400 MHz, CDCl3) 3.05–3.11 (m, 10H, H30/
50, NMe2), 3.90 (m, 4H, H20/60), 6.07 (d, J 2.4, 1H, H2), 6.29 (dd,
J 9.6, 2.5, 1H, H6), 8.09 (d, J 9.4, 1H, H3). m/z (ESI þve) 252
([M þ H]þ, 100 %).
Preparation of N,N-Dimethyl-2,3,5-trifluoro-6-nitroaniline
(14)
Preparation of 3-Dimethylamino-5-morpholino-2-
nitroaniline (6i)
To a solution of 2,3,4,6-tetrafluoronitrobenzene (11) (10.0 g,
0.0513 mol) in tetrahydrofuran (100 mL) was added aqueous
ammonia solution (28 %, 6.5 mL, 0.108 mol, 2.1 equiv.). The
solution rapidly darkened and was stirred at room temperature
overnight until TLC monitoring (1 : 4 ethyl acetate/hexane)
indicated no starting material. The reaction mixture was con-
centrated before being diluted by ethyl acetate (200 mL) and
washed with brine (2 ꢁ 200 mL). The aqueous layers were re-
extracted with ethyl acetate (200 mL), the combined organic
extract dried (MgSO4), and concentrated to give crude 3,5,6-
trifluoro-2-nitroaniline (13) (9.0 g, (92 %) as a thick oil that
solidified to a brown semi-solid, and was used without further
purification (purity . 90 %) in the next step. dH (400 MHz,
CDCl3) 6.6 (ddd, J 11.0, 10.9, 6.5, 1H, H4), 6.6 (m, 2H, NH2).
To a suspension of sodium hydride (24 %, 4.27g, 0.107 mol,
3.0equiv.)indrytetrahydrofuran(200mL)inanoven-driedround
bottom flask purged with nitrogen, was added iodomethane
(6.64 mL, 0.107 mol, 3.0 equiv.) followed by a solution of 3,5,6-
trifluoro-2-nitroaniline (13) (6.83 g, 0.036 mol) in dry tetrahydro-
furan(50 mL),addedslowlyover20min.Awaterbathwasusedto
cool the reaction mixture during the addition before allowing it to
stir overnight. The reaction was quenched by slowly pouring onto
a stirred mixture of saturated ammonium chloride/ice (,1 L)
followed by extraction with ethyl acetate (3ꢁ 300 mL). The
organic extract was dried (MgSO4) and evaporated to give a red
oil (10.5 g). Column chromatography (silica gel, 55 ꢁ 110 mm)
eluting with 100% hexane afforded N,N-dimethyl-2,3,5-tri-
fluoro-6-nitroaniline (14) (4.02 g, 51%). dH (400MHz, CDCl3)
2.83 (s, 6H, NMe2), 6.6 (ddd, J 9.4, 9.4, 6.0, 1H, H4).
To a solution of 3,5-difluoro-2-nitroaniline (2a) (2.01 g,
11.5 mmol) in DMSO (20 mL) was added potassium carbonate
(5.09 g, 36.8 mmol, 3.2 equiv.) followed by dimethylamine
hydrochloride (0.94 g, 11.5 mmol, 1.0 equiv.) and the mixture
stirred under nitrogen at room temperature for 20 h. The reaction
mixture was then treated with morpholine (4.01 g, 46.0 mmol)
and heated under nitrogen in a 1108C oil-bath for 24 h. The
reaction mixture was then cooled and the solvent removed under
vacuum. The orange-red residue was partitioned between ethyl
acetate (100 mL) and water (150 mL), with the aqueous phase
re-extracted with additional ethyl acetate (2 ꢁ 80 mL). The
combined organic extract was washed with water (2 ꢁ 100 mL)
and brine (100 mL), dried (MgSO4), and evaporated to give a
dark red solid (2.43 g). The material was dissolved in ethyl
acetate (6 mL) and applied to a 80 g silica gel cartridge, eluting
over 3 runs with 1 : 1 ethyl acetate/petroleum spirit to give 1.81 g
of material, 90 % pure by 1H NMR analysis. Recrystallisation of
1.25 g from diethyl ether/acetonitrile afforded pure 3-dimethy-
lamino-5-morpholino-2-nitroaniline (6i) as a red powder
(0.766 g, 36 %), mp 136–1388C. dH (600 MHz, CDCl3) 2.85 (s,
6H, NMe2), 3.25 (m, 4H, H30/50), 3.81 (m, 4H, H20/60), 5.57 (d, J
2.4, 1H, H4 or H6), 5.61 (m, 3H, H6 or H4, NH2). dC (150 MHz,
CDCl3) 42.3 (NMe2), 47.3 (C30/50), 66.5 (C20/60), 90.7, 92.0 (C4,
C6), 147.1, 150.7, 154.6 (C1, C3, C5). C2 not observed. m/z (ESI
þve) 267 ([M þ H]þ, 100 %). HRMS (ESI þve) m/z 267.14515;
C12H19N4O3 requires 267.14517 (D ¼ 0.1 ppm).
Preparation of 4-(50-Fluoro-20-nitrophenyl)morpholine (9a)
and 4-(30-Fluoro-40-nitrophenyl)morpholine (10a)
Preparation of 4,5-Difluoro-3-dimethylamino-2-
nitroaniline (15a) and 2,5-difluoro-3-dimethylamino-4-
nitroaniline (16a)
To a suspension of potassium carbonate (8.54 g, 61.8 mmol, 1.5
equiv.) in DMSO (50 mL) was added morpholine (4.0 mL, 4.0 g,
45 mmol) and 2,4-difluoronitrobenzene (8) (5.0 mL, 7.3 g,
45 mmol). The mixture was stirred under nitrogen at room
temperature for 90 min, and then at 808C for 20 h. The mixture
was diluted with water (300 mL), extracted into ethyl acetate
(2 ꢁ 400 mL), the extract washed with brine, dried (MgSO4),
and evaporated. The residue was triturated with 1 : 1 ethyl
To a solution of N,N-dimethyl-2,3,5-trifluoro-6-nitroaniline
(14) (7.2 g, 0.009 mol) in dimethyl sulfoxide (100 mL) was
added aqueous ammonia solution (28 %, 8 mL, 4 equiv.) and the
mixture heated at 908C for 24 h. The reaction mixture was
cooled, poured onto brine (250 mL), and extracted with ethyl

326
J. M. White et al.
acetate (2 ꢁ 250 mL). The organic extract was washed with
brine (100 mL), dried (MgSO4), and concentrated to give an oil
(8.0 g). The material was pre-adsorbed onto silica gel (24 g),
followed by column chromatography (silica gel, 60 ꢁ 150 mm)
with gradient elution using 0–2 % ethyl acetate in hexane to
remove initial yellow bands, then 5 % ethyl acetate in hexane to
give 4,5-difluoro-3-dimethylamino-2-nitroaniline (15a) (2.2 g,
31 %) as a red oil. Further elution with 10 % ethyl acetate in
hexane afforded 2,5-difluoro-3-dimethylamino-4-nitroaniline
(16a) (3.5 g, 50 %).
Supplementary Material
Copies of 1H and 13C NMR data and HRMS are available on the
Journal’s website.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgements
The authors gratefully acknowledge Sirtex Medical for funding and the
Australian Synchrotron for beamtime via the Collaborative Access Program
(proposal number 13618b).
4,5-Difluoro-3-dimethylamino-2-nitroaniline (15a): dH
(400 MHz, CDCl3) 2.875 (s, 3H, Me), 2.880 (s, 3H, Me), 6.13
(dd, J 6.3, 5.1, 1H, H6).
2,5-Difluoro-3-dimethylamino-4-nitroaniline (16a): dH
(400 MHz, CDCl3) 2.875 (s, 3H, Me), 2.880 (s, 3H, Me), 6.2
(dd, J 6.9, 4.1, 1H, H6).
References
[1] R. F. Martin, S. Broadhurst, M. E. Reum, C. J. Squire, G. R. Clark, P.
N. Lobachevsky, J. M. White, C. Clark, D. Sy, M. Spotheim-Maurizot,
D. P. Kelly, Cancer Res. 2004, 64, 1067. doi:10.1158/0008-5472.
CAN-03-2423
[2] M. E. Sitzmann, J. Org. Chem. 1978, 43, 1241. doi:10.1021/
JO00400A047
Preparation of 4,5-Difluoro-N1-(2-methoxyethyl)-3-
dimethylamino-2-nitroaniline (15b) and 2,5-Difluoro-N1-
(2-methoxyethyl)-3-dimethylamino-4-nitroaniline (16b)
[3] G. Selivanova, Zh. Org. Khim. 1988, 24, 2513.
In a single necked, 100 mL round bottom flask fitted with an air
condenser and nitrogen inlet, a mixture of N,N-dimethylaceta-
mide (7 mL), N,N-dimethyl-2,3,5-trifluoro-6-nitroaniline (14)
(1.02 g, 4.6 mmol), and 2-methoxyethylamine (350 mg,
4.6 mmol, 1 equiv.) was heated at 1008C for 24 h. The reaction
was cooled, poured onto brine (100 mL), and then extracted with
ethyl acetate (2 ꢁ 300 mL). The organic extract was washed
with brine (100 mL), dried (MgSO4), and concentrated to give
the crude product (,1 g) which was pre-adsorbed onto silica gel.
Column chromatography (silica gel, 210 ꢁ 30 mm) eluting with
a step-wise gradient of ethyl acetate in hexane afforded in order
of elution; 4,5-difluoro-N1-(2-methoxyethyl)-3-dimethyla-
mino-2-nitroaniline (15b) (230 mg, 18 %), followed by 2,5-
difluoro-N1-(2-methoxyethyl)-3-dimethylamino-4-nitroaniline
(16b) (496 mg, 39 %).
4,5-Difluoro-N1-(2-methoxyethyl)-3-dimethylamino-2-
nitroaniline (15b): mp 62–638C. dH (400 MHz, CDCl3) 2.86
(s, 6H, NMe2), 3.27 (m, 2H, NCH2), 3.40 (s, OMe), 3.60 (m, 2H,
OCH2), 6.08 (dd, J 12.6, 6.3, 1H, H6).
2,5-Difluoro-N1-(2-methoxyethyl)-3-dimethylamino-4-
nitroaniline (16b): mp 64–688C. dH (400 MHz, CDCl3) 2.84
(s, 6H, NMe2), 3.30 (m, 2H, NCH2), 3.40 (s, OMe), 3.61 (m, 2H,
OCH2), 6.13 (dd, J 12.0, 6.7, 1H, H6).
[4] S. K. Sythana, S. R. Naramreddy, S. Kavitake, V. Kumar, P. R. Bhagat,
Org. Process Res. Dev. 2014, 18, 912. doi:10.1021/OP500120Z
[5] E. V. Anslyn, D. A. Dougherty, Modern Physical Organic Chemistry
2006 (University Science Books: Herndon, VA).
[6] Cambridge Crystallographic Database Version 1.21: C. R. Groom, I. J.
Bruno, M. P. Lightfoot, S. C. Ward, Acta Crystallogr. Sect. B 2016,
B72, 171. doi:10.1107/S2052520616003954
[7] L.-J. Wang, W.-W. Li, S.-Y. Yang, Acta Crystallogr. Sect. E 2012, 68,
o1235. doi:10.1107/S1600536812012172
[8] S. W. Ng, Chem. Phys. 2009, 355, 194. doi:10.1016/J.CHEMPHYS.
2008.12.010
[9] (a) M. Tonogaki, T. Kawata, S. Ohba, Y. Iwata, I. Shibuya, Acta
Crystallogr. Sect. B 1993, 49, 1031. doi:10.1107/S0108768193005130
(b) I. V. Anayev, K. A. Lyssenko, Izv. Akad. Nauk. SSSR, Ser Khim.
(Russ) (Russ. Chem. Bull.) 2014, 1270.
[10] J. M. White, T. Fellowes, CSD Communication (Private communica-
tion) 2016, Refcode: YAYCIM01.
[11] S. W. Ng, Chem. Phys. 2009, 355, 194. doi:10.1016/J.CHEMPHYS.
2008.12.010
[12] M. Tonogaki, T. Kawata, S. Ohba, Y. Iwata, I. Shibuya, Acta
Crystallogr. Sect.
B
1993, B49, 1031. doi:10.1107/
S0108768193005130
[13] M. R. Cargill, G. Sandford, A. J. Tadeusiak, D. S. Yufit, J. A. K.
Howard, P. Kilickiran, G. Nelles, J. Org. Chem. 2010, 75, 5860.
doi:10.1021/JO100877J
[14] J. M. White, K. Morgan, C. E. Skene, CSD Communication (Private
communication) 2016, Refcode: EWILAZ.
Preparation of 2-Fluoro-N5-(2-methoxyethyl)-3-
dimethylamino-4-nitroaniline (17)
[15] J. M. White, K. Hamer, C. E. Skene, CSD Communication (Private
communication) 2014, Refcode: KOXTAU.
To a solution of 4,5-difluoro-N1-(2-methoxyethyl)-3-dimethyla-
mino-2-nitroaniline (15b) (230mg, 0.83 mmol) in dimethyl
sulfoxide (10 mL) in a sealed tube was added aqueous ammonia
solution(28 %, 1.0mL, 17 mmol, 20equiv.)and the tubeheated in
a bath at 1458C for 3 h. The reaction was cooled and poured onto
brine (100mL) and extracted with ethyl acetate (2ꢁ 300mL).
The organic extract was washed with brine (100 mL), dried
(MgSO4), and concentrated to give 2-fluoro-N5-(2-methoxy-
ethyl)-3-dimethylamino-4-nitroaniline (17) (200 mg, 88 %). dH
(400 MHz, CDCl3) 2.9 (s, 6H, NMe2), 3.23 (m, 2H, NCH2), 3.40
(s, OMe), 3.59 (m, 2H, OCH2), 5.67 (d, J 7.9, 1H, H6).
[16] (a) G. Gilli, F. Belluchi, V. Ferretti, V. Bertolasi, J. Am. Chem. Soc.
1989, 111, 1023. doi:10.1021/JA00185A035
(b) T. Zych, T. Misiaszek, M. M. Szostak, Chem. Phys. 2007, 340, 260.
doi:10.1016/J.CHEMPHYS.2007.09.028
(c) I. V. Omelchenko, O. V. Shishkin, L. Gorb, F. C. Hill, J.
Leszczynski, Struct. Chem. 2012, 23, 1585. doi:10.1007/S11224-
012-9971-8
(d) D.-C. Zhang, Y.-Q. Zhang, J. Energ. Mater. 1997, 15, 205. doi:10.
1080/07370659708216084
[17] A. J. Kirby, The Anomeric Effect and Related Stereoelectronic Effects
at Oxygen 1983 (Springer Verlag: New York, NY).
[18] N. P. Cowieson, D. Aragao, M. Clift, D. J. Ericsson, C. Gee, S. J.
Harrop, N. Mudie, S. Panjikar, J. R. Price, A. Riboldi-Tunnicliffe, R.
Williamson, T. Caradoc-Davies, J. Synchrotron Radiat. 2015, 22, 187.
doi:10.1107/S1600577514021717
Crystallographic Data
Crystallographic information files (CIFs) have been deposited at
the CSD[6] and assigned CCDC codes 1852967–1852995 and
1857000–1857002.
[19] G. Sheldrick, Acta Crystallogr. Sect. C 2015, 71, 3. doi:10.1107/
S2053229614024218

Electron-Rich Nitroaromatics
327
[20] L. J. Farrugia, J. Appl. Cryst. 1997, 30, 565. doi:10.1107/
S0021889897003117
[21] L. J. Farrugia, J. Appl. Cryst. 1999, 32, 837. doi:10.1107/
S0021889899006020
[22] G. C. Finger, F. H. Reed, J. L. Finnerty, J. Am. Chem. Soc. 1951, 73,
153. doi:10.1021/JA01145A055
[23] G. A. Selivanova, T. V. Chuikova, A. A. Shtark, V. D. Shteingarts, Zh.
Org. Khim 1988, 24, 2513.
[24] C. W. Tornøe, M. Rottlaender, D. R. Greve, N. Khanzhin, A. Ritzen,
W. P. Watson, WO 2006/029623 A1, Substituted aniline derivatives.
[25] C. W. Tornøe, M. Rottlaender, N. Khanzhin, A. Ritzen, W. P. Watson,
WO 2005/087754 A1, Substituted morpholine and thiomorpholine
derivatives.
[26] A. G. O0Brien, Z. Horvath, F. Levesque, J. W. Lee, A. Seidel-
Morgenstern, P. H. Seeberger, Angew. Chem. Int. Ed. 2012, 51,
7028. doi:10.1002/ANIE.201202795