Conformational communication between the Ar-CO and Ar-N axes in 2,2′-disubstituted benzanilides and their derivatives

Article abstract of DOI:10.1039/b602912d

Benzanilides containing two or more potentially stereogenic amide axes exist in solution as mixtures of conformers which are detectable by NMR. For simple tertiary benzanilides carrying an ortho substituent on each ring, conformational control can be high

Full text of DOI:10.1039/b602912d

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Conformational communication between the Ar–CO and Ar–N axes in
2,2ꢀ-disubstituted benzanilides and their derivatives
Jonathan Clayden,* Llu´ıs Vallverdu´ and Madeleine Helliwell
Received 27th February 2006, Accepted 3rd April 2006
First published as an Advance Article on the web 25th April 2006
DOI: 10.1039/b602912d
Benzanilides containing two or more potentially stereogenic amide axes exist in solution as mixtures of
conformers which are detectable by NMR. For simple tertiary benzanilides carrying an ortho
substituent on each ring, conformational control can be high (up to about 10 : 1) providing the
substituents are large, indicating that the two axes are in conformational communication with one
another. For more complex diamides, conformational communication breaks down, and mixtures of
conformers are evident by NMR.
that mono-ortho-substituted anilides may also exhibit chirality
Introduction
provided that the ortho substituent is iodo.9
Over the last few years there has been a growing interest in
the preparation of non-biaryl atropisomers.1,2 Because of the
rigidity of the amide group, the most studied of these non-biaryl
atropisomers have been either benzamide derivatives 1 or anilides
We now report the preparation and conformational studies of
compounds combining the amide structural motifs of both 1 and
2—2,2ꢁ-disubstituted benzanilides 3 (Fig. 1). Using NMR, we
demonstrate a degree of conformational interaction between the
Ar–CO and N–CO axes, suggesting their potential application in
stereochemical relay systems.10
2 (Fig. 1). Our own work has concentrated primarily on ortho-
substituted tertiary benzamides 1,3 in which the amide group lies
more or less perpendicular to the plane of the aromatic ring.3c
Provided rotation about the Ar–CO bond is slow enough, which is
Results and discussion
usually the case with 2,6-disubstituted benzamides (1: X, Y
ꢀ=
H), atropisomeric chirality results from this perpendicular ar-
rangement. Even for less hindered compounds (mono-ortho-
substituted benzamides for example, 1: X or Y = H), transient
chirality (on the NMR timescale) manifests itself spectroscopically
in the diastereotopicity of groups attached to the ring or the amide
nitrogen atom.
Conformational ratios in benzanilides
Compounds 3a–o were prepared by the standard method shown in
Scheme 1: available anilines and benzoyl chlorides were condensed
to yield secondary anilides 4 (R = H). Alkylation of these
compounds gave tertiary benzanilides 3a–o, whose 1H-NMR
spectra at 25 ◦C in CDCl3 show that they exist as a mixture of
conformers about two or more of the Ar–CO, Ar–N and N–CO
bonds in solution. All of these bonds are expected to rotate slowly
on the NMR timescale at 25 ◦C, though fast on the laboratory
timescale: typical barriers to rotation of such bonds in similar
compounds lie in the region of 60–80 kJ mol−1.3h,9 Table 1 shows
the ratios of the two or more conformers quantified by integration
of the paired signals.
Fig. 1 Benzamides, anilides and benzanilides.
Axial chirality in ortho-substituted anilides 2 was recognized
more than fifty years ago.4,5 While differentially N,N-disubstituted
amides generally prefer to exist as Z-rotamers (i.e. largest group
cis to the oxygen) for steric reasons, it has been known for
some time that N-alkyl acetanilides 2 (R2 = Me)6 and many
N-alkyl benzanilides 2 (R2 = Ar)7 prefer to exist as the E-
rotamer, which places the aryl group and the amide oxygen in the
trans conformation, as shown for 2. In general, atropisomerism
is observed when an anilide carries two different non-hydrogen
ortho-substituents X and Y. A large number of anilides with axial
chirality have been described,8 and we have recently reported
Scheme 1 Synthesis of 2,2ꢁ-disubstituted benzanilides.
The degree of conformational control is governed by the size
of the substituents at the ortho positions (X and Y) and also the
substituent at the nitrogen (R): the bulkier they are, the higher the
conformational ratio. In 3a (X = Y = I, R = Bn) and 3j (X =
NO2, Y = I, R = Bn) the ratios reach a remarkable 10 : 1 and 12 :
1 respectively. Addition of a third bulky ortho-substituent, i.e. an
School of Chemistry, University of Manchester, Oxford Road, Manchester,
UK M13 9PL. E-mail: clayden@man.ac.uk; Fax: +44 (0) 161 275 4612
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Table 1 Conformational ratios of benzanilides 3a–o
Compound
X
Y
R
Conformer ratioa
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
I
I
I
I
I
I
I
I
Bn
o-I–Bn
Et
i-Pr
Bn
Bn
Bn
Bn
Bn
Bn
Et
Me
Bn
Et
Me
10 : 1
16 : 1.2 : 1
4.3 : 1
2.5 : 1
7 : 1
Benzob
Benzob
Benzob
I
I
CO2Et
CO2H
CO2Et
CO2H
I
I
I
I
I
I
5 : 1
Fig. 3 X-Ray structure of 3b.
3.25 : 1
5.3 : 1
3.5 : 1
12 : 1
6.4 : 1
3.6 : 1
Broad
Broad
Broad
I
Scheme 2 shows the four possible conformations of 3 that result
from rotation about the Ar–N, Ar–CO and N–CO bonds, starting
from the E-anti conformer. Molecular mechanics calculations
(MMFF force field implemented by Spartan) for 3a (X = Y =
I; R = Bn) are in agreement with assignment of the E-anti
conformation to the lowest energy conformer. The calculations
also indicate that both E rotamers (syn and anti) have lower energy
levels than the two Z rotamers. From this analysis we assume
NO2
NO2
NO2
NH2
NH2
NH2
a Ratio in CDCl3 at 25 ◦C. b 1-naphthamide.
1
that the minor conformers observed by H-NMR are the E-syn
extra iodo group at the ortho position of the N-benzyl group, adds
a third conformer to the mixture: 3b displays a conformational
ratio of 16 : 1.2 : 1. The ratio between the two major conformers
is nonetheless similar to the one observed for 3j.
As the size of any of the substituents (X, Y or R) decreases,
the conformational ratio also drops. For example, taking 3a as a
reference with X = Y = I and R = Bn, a reduction in size of any
of the three groups shows lower ratios, as can be observed in 3c
and 3d with a smaller R (Et, i-Pr), 3e with a smaller X, and 3f and
3g with smaller Y groups.
conformers, and that the ratios in Table 1 represent the ratio of
E-anti-3 to E-syn-3, with the exception of 3b, in which another
conformer is evident, probably a Z rotamer about the amide N–
CO bond.
The broad signals in the NMR spectra of 3m–o indicate fast
interconversion of the possible conformations, making determi-
nation of the conformational ratio impossible. In contrast, spectra
of the analogous compounds with a NO2 group, 3j–l, have sharp
signals characteristic of slow exchange. Fast Ar–CO rotation in
3m–o is most likely due to stabilisation of the planar transition
state for Ar–CO rotation by the electron-donating amino group.3h
Scheme 2 Rotational interconversions in 3. (a) Energy calculated
(MMFF, Spartan) in kJ mol−1 relative to E-anti-3 for X = Y = I; R = Bn.
Identification of the conformers
The X-ray crystal structures of 3a and 3b showed the expected
E-rotamer6,7 about the N–CO bond in the solid state, with the
two iodo substituents on opposite faces of the plane of the
amide, presumably in order to avoid steric interactions (Fig. 2
and 3). We confirmed that this E-anti conformer observed in
the crystal structure is also the major conformer in solution by
dissolving a crystal of 3a in cold CDCl3. The 1H-NMR spectrum
of this solution at low temperature showed a single conformer
corresponding to the major conformer in the spectrum at room
temperature. Allowing the solution to warm restored the 10 : 1
ratio. By contrast, a sample prepared at room temperature and
cooled to −50 ◦C showed a mixture of conformers throughout.
Variable temperature NMR studies of 3a, 3b and 3c were carried
out. 3a and 3b showed no change in their spectra over the range
−50 to +50 ◦C in CDCl3 or at +90 ◦C in d6-DMSO, indicating that
all three pertinent bond rotations have barriers of >75.1 kJ mol−1.
In contrast, VT NMR studies of 3c in toluene (−70 to +100 ◦C)
showed coalescence of the signals due to the two conformers of 3c,
allowing us to estimate a barrier to rotation for either the Ar–CO
or Ar–N bond (whichever is the lower) of only 63.5 kJ mol−1.
Conformational ratios in diamides
The high levels of conformational control in certain benzanilides
3 indicate that there is some degree of conformational com-
munication between the Ar–CO and the N–CO axes, provided
that the rings bear sufficiently large substituents. We recently
reported a case in which conformational communication through
a series of six Ar–CO axes facilitated the remote transmission of
stereochemical information,11 and with the aim of developing a
similar system based on benzanilides we set about the synthesis
of the diamides 5. We were encouraged in this aim by reports that
Fig. 2 X-Ray structure of 3a.
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N-alkylated oligo(p-benzamides)12 and oligo(m-benzamides)13
adopt a well-defined, helical secondary structure.
becomes impossible in some cases—for example 5c has a 1H-
NMR spectrum too complex for resolution of the signals of the
individual conformers. Inother cases, e.g. 5l and 5m, it is possible to
identify the ratio of only the two major conformers (by integration
of the signal corresponding to the methyl group). Other partly
overlapping signals suggest that other conformers are populated,
but in ratios that cannot be determined. In the absence of any ortho
substituents, i.e. 5o, faster interconversion between the conformers
leads to broad signals.
Our initial attempts to prepare diamides 5 from carboxylic acid
derivatives of 3 (3g for example) via the acyl chloride led instead to
the oxazinones 6 by cyclisation (Scheme 3). However, compounds
5a–o were eventually successfully prepared by acylation of the
amino derivatives 3m–o, themselves produced by reduction of the
nitro compounds 3j–l (Scheme 3).
Molecular mechanic calculations (Spartan MMFF) suggest that
in benzanilides with a bulky ortho substituent (here NR2COAr)
on the benzamide ring the Z rotamer becomes preferred to the E
rotamer,7 thus placing one amide group of 5 in the E conformation
and the other in the Z (Fig. 4). Even with N–CO bonds orientated
in this way, four or eight conformers can exist, and the differences
in energy between them are minimal.
Scheme 3 Synthesis of the diamides 5.
Fig. 4 Conformation of the diamide 5.
Table 2 shows the conformational ratios observed by 1H-NMR
at rt in CDCl3 for compounds 5a–o. Compounds 5a, 5d, 5f, 5h,
5k and 5n, with R2 = H, are comparable conformationally to
compounds 3 (Table 1) because a secondary amide cannot generate
a stereogenic Ar–CO axis and will exist as the Z amide rotamer (Ar
Conformational communication between benzamide and
anilide-type amide axes
=
and C O cis). These compounds display ratios from 22 : 1 to 5.5 :
With our conformational analysis of compounds 3 and 5 we have
probed the ability of a pair of amide axes connected either as shown
in Fig. 5A or Fig. 5B to communicate with one another: the results
suggest that communication can be successful (subject to the size
of the substituents) for A but is not successful for B. Compounds
of type C, which contain two adjacent benzamide-type amide axes,
are known in many cases to display high levels of conformational
control,3f ,3t,14 and a detailed publication presenting out findings
in this area is in preparation.15 A final pairing—bis-anilides of
type D—was investigated by Cheng et al.16 but with tertiary amide
groups 7d exists as a mixture of conformers in solution.17 In the
solid state the typical7 E-rotamer about the N–CO bond (Ar and
1, depending on X, Y and R1, suggesting that the benzoylamino
groups allow good levels of stereocommunication between the two
remaining axes in the molecule.11
Alkylation of the second amide group (i.e. introduction of R2
H) introduces a third (and if X
ꢀ=
ꢀ= H, a fourth) potentially
stereogenic axis to the molecule. Unfortunately, in all such cases,
complex mixtures of conformers were observed: the two amide
Ar–CO axes fail to interact with each other either directly or
via the Ar–N axis. In the majority of the compounds the ratio
between the conformers can be established by the integration
of the signals corresponding to each conformer. However this
=
C O trans) is observed, with the two anilide groups disposed
Table 2 Conformational ratios of 5a–o
anti. In the crystal structure of 7e, however, in which the ortho
positions carry a fluorine atom, while the anilides are still anti,
the unexpected opposite Z N–CO rotamer is populated,7,18 an
effect possibly related to the calculated switch from the E to the Z
conformation in one of the amide bonds of 5.
Compound
X
Y
R1
R2
Ratio
5a
5b
5c
I
I
I
I
I
I
Bn
Bn
Bn
H
CH3
Bn
12 : 1
6.8 : 2 : 1
Complex
mixture
22 : 1
4.5 : 1 : 1
6.5 : 1
3.2 : 2.5 : 1.5 : 1
5.5 : 1
4.5 : 2 : 1
4.2 : 4 : 1
4.5 : 1
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
NO2
NO2
NO2
NO2
NO2
NO2
NO2
H
H
H
H
H
I
I
I
I
I
I
I
I
I
I
H
H
Bn
Bn
CH3
CH3
Et
H
CH3
H
Et
H
CH3
CH3
H
Bn
Et
H
Bn
Et
CH3
CH3
CH3
CH3
Bn
1.33 : 1 : ?
2 : 1 : ?
8 : 1
Fig. 5 Conformational communication between pairs of amide axes (axes
are represented by bold bonds).
Bn
Broad
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We prepared 7b and 7c (Scheme 4) with ortho-iodo substituents
in order to slow the rotation about the bonds associated with
the amide groups with the aim of establishing the conformational
Experimental
1H and 13C-NMR spectra were recorded on a Varian XL 300 MHz
or Bruker Ultrashield 500 MHz instrument. VT NMR studies
were recorded on an Inova 300 MHz instrument. NMR data
are presented as follows: chemical shift d (in ppm relative to
dTMS = 0), multiplicity, coupling constant J (quoted in hertz,
Hz), integration, and assignment. IR spectra were recorded on
an ATi Matson Genesis Series Fourier Transform spectrometer.
Wavelengths of maximum absorbance are quoted in wavenumbers
(cm−1). Low resolution mass spectra (EI and CI) were recorded
on a Fisons VG Trio 2000 quadrupole mass spectrometer. High
resolution mass spectra were recorded on a Kratos Concept-IS
mass spectrometer. Analytical TLC was carried out on Machery-
Nagel pre-coated 0.2 mm silica plates with fluorescent indicator on
aluminium. Flash column chromatography was carried out using
Fluorochem Davisil 40–63 lm 60 A silica under a positive pressure
of air. Conformational ratios were calculated by integration of the
NMR signals corresponding to the same proton(s) relating to
each conformer. When only two conformers are observed they
are referred to as major and minor conformers, when more than
two are observed they are referred to as conformers A, B, C· · ·
listed in decreasing ratio. The purity of compounds 5b, 5c, 5e,
5g, 5l, 5m, 5o and 7b was confirmed by HPLC (Supelcosil LC
18 DB 4.6 mm × 250 mm, 90 : 10 hexane–isopropanol, flow
0.5 mL min−1).
1
ratios in such compounds in solution. The H-NMR spectrum
showed a simple 5 : 1 ratio between only two conformers of 7b at rt
in CDCl3. In the solid state, 7b adopted a conformation with both
N–CO bonds Z and the anilides anti, comparable to that reported
for 7e18—the X-ray crystal structure of 7b is shown in Fig. 6. We
assume that this is the major conformer in solution, but we have
no evidence to allow assignment of the conformation of the minor
conformer. It is notable that each crystal of 7b contains only one
enantiomeric conformer—the crystals have a chiral space group:
monoclinic P2(1).19 An analogue, 7c, carrying N benzyl groups,
showed only broad signals in its 1H-NMR spectrum.
Scheme 4 Synthesis of the diamides 7.
2-Iodo-N-(2-iodophenyl)benzamide 4a
To a solution of 2-iodoaniline (1 g, 4.56 mmol) and triethylamine
(3.2 ml, 22.9 mmol) in ethyl acetate (25 mL) was added a solution
of 2-iodobenzoyl chloride (1.22 g, 4.58 mmol) in ethyl acetate
(25 mL). The mixture was stirred at rt under nitrogen overnight.
The resulting suspension was filtered and the solid was washed
with ether and NaHCO3 aqueous saturated solution to yield the
1
title compound as a white solid (1.1 g, 53%). H-NMR (CDCl3,
300 MHz) d 6.91 (td, J = 7.8 and 1.5 Hz, 1H), 7.18 (td, J = 7.8
and 1.5 Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.47 (t, J = 7.5 Hz,
1H), 7.58 (d, J = 7.5 Hz, 1H), 7.75 (bs, 1H), 7.83 (dd, J = 8.1 and
1.5 Hz, 1H), 7.97 (dd, J = 8.1 and 1 Hz, 1H), 7.97 (d, J = 8.1 Hz,
1H). 13C-NMR (CDCl3, 75.5 MHz) d 90.3 (Cq), 92.5 (Cq), 122.3
(CH), 126.6 (CH), 128.1 (CH), 128.4 (CH), 129.4 (CH), 131.7
(CH), 137.9 (Cq), 138.9 (CH), 140.4 (CH), 141.6 (Cq), 167.2 (Cq).
IR (film) 3245, 1650 cm−1. HRMS calcd for C13H9ONI2: 448.8768.
Found: 448.8776. Anal. calcd for C13H9NOI2 (449.0)·1/4 H2O: C,
34.43; H, 2.11; N, 3.09. Found: C, 34.18; H, 1.87; N, 2.99%. Mp
184–185 ◦C.
Fig. 6 X-Ray crystal structure of 7b.
Conclusion
Conformational analysis of representative members of three
classes of aromatic amides and diamides—compounds 3a–o for
those represented as Fig. 5A, 5a–n, for those represented as
Fig. 5B, and 7b for those represented as Fig. 5D—shows that
for compounds of types A and D moderate to high levels of
conformational control can be achieved when the amides carry
bulky substituents. Type B compounds 5 with two tertiary amide
groups exist as complex conformational mixtures whereas the
analogous compounds with meta13 and para12 substituted amides
exist largely as single conformers. Poor control in this situation
may be due to population of the usually disfavoured (for anilides)
Z N–CO conformer, a feature also seen in 7. Type C compounds, as
previously reported,3f ,3h,3t show excellent conformational control in
solution, and a detailed report concerning this class of compounds
is in preparation.15
N-(2-Iodophenyl)-1-naphthamide 4b
To a solution of 2-iodoaniline (1 g, 4.56 mmol) and triethylamine
(3.2 ml, 22.9 mmol) in ethyl acetate (50 mL) was slowly added
1-naphthoyl chloride (0.7 mL, 4.64 mmol). The mixture was
stirred overnight at rt under nitrogen. The resulting suspension
was filtered and the solid was washed with ether and NaHCO3
aqueous saturated solution to yield the title compound as a yellow
1
solid (909 mg, 53%). H-NMR (CDCl3, 300 MHz) d 6.92 (ddd,
J = 7.8, 7.5 and 1.5 Hz, 1H), 7.45 (td, J = 8.4 and 1.2 Hz, 1H),
7.53–7.64 (m, 3H), 7.84 (dd, J = 7.8 and 1.5 Hz, 1H), 7.87 (dd,
J = 8.4 and 1.2 Hz, 1H), 7.92 (dd, J = 7.5 and 1.8 Hz, 1H), 8.01
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(d, J = 8.4 Hz, 1H), 8.08 (bs, 1H), 8.48–8.54 (m, 2H). 13C-NMR
(CDCl3, 75.5 MHz) d 90.7 (Cq), 122.1 (CH), 124.8 (CH), 125.3
(CH), 125.4 (CH), 126.3 (CH), 126.7 (CH), 127.5 (CH), 128.4
(CH), 129.4 (CH), 130.2 (Cq), 131.5 (CH), 133.8 (Cq), 133.9 (Cq),
138.5 (Cq), 138.9 (CH), 167.4 (Cq). IR (film) 3248 and 1648 cm−1.
HRMS calcd for C17H13NOI: 374.0036. Found: 374.0044. Anal.
calcd for C17H12NOI (373.2): C, 54.71; H, 3.24; N, 3.75. Found: C,
54.71; H, 3.14; N, 3.68%. Mp 160–161 ◦C.
N-(2-Iodophenyl)-2-nitrobenzamide 4e
To a solution of 2-iodoaniline (2.13 g, 9.72 mmol) and pyridine
(2.6 mL, 32.2 mmol) in DCM (30 mL) was slowly added 2-
nitrobenzoyl chloride (2 g, 9.70 mmol). The mixture was stirred
overnight at rt under nitrogen. Petroleum ether was added and the
resulting suspension was filtered and the solid was washed with
NaHCO3 aqueous saturated solution to yield the title compound
1
(3.54 g, 99%). H-NMR (CDCl3, 300 MHz) d 6.98 (td, J = 7.5
and 1.5 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.66–7.82 (m, 3H), 7.87
(dd, J = 7.8 and 1.5 Hz, 1H), 8.19 (d, J = 8.1 Hz, 1H), 8.33 (d,
J = 6.9 Hz, 1H). 13C-NMR (CDCl3, 75.5 MHz) d 90.8 (Cq), 123.0
(CH), 124.9 (CH), 127.0 (CH), 128.3 (CH), 129.5 (CH), 131.1
(CH), 132.5 (Cq), 134.0 (CH), 137.6 (Cq), 138.9 (CH), 146.6 (Cq),
164.2 (Cq). IR (film) 1635 cm−1. HRMS calcd for C13H10O3N2I:
368.9731. Found: 368.9727. Mp 182 ◦C.
Ethyl 2-(1-naphthamido)benzoate 4c
To a solution of 2-ethoxycarbonilaniline (1 g, 6.05 mmol) and
triethylamine (4.5 mL, 32.3 mmol) in ethyl acetate (50 mL)
was slowly added 1-naphthoyl chloride (0.91 mL, 6.04 mmol).
The mixture was stirred overnight at rt under nitrogen. The
mixture was diluted with ethyl acetate and washed with water. The
aqueous layer was extracted with ethyl acetate and the combined
organic layers were dried, filtered and the solvent was removed
under reduced pressure. The crude product was purified by flash
chromatography (DCM) to yield 4c (1.14 g, 58%). 1H-NMR
(CDCl3, 300 MHz) d 1.37 (t, J = 7.2 Hz, 3H), 4.33 (q, J = 7.2 Hz,
2H), 7.17 (ddd, J = 8.1, 7.2 and 1.2 Hz, 1H), 7.53–7.61 (m, 3H),
7.66 (td, J = 7.2 and 1.5 Hz, 1H), 7.88 (dd, J = 7.2 and 1.2 Hz,
1H), 7.90 (dd, J = 7.8 and 1.2 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H),
8.12 (dd, J = 8.1 and 1.8 Hz, 1H), 8.54 (dd, J = 8.1 and 1.5 Hz,
1H), 9.03 (dd, J = 8.4 and 0.9 Hz, 1H), 11.74 (bs, 1H). 13C-NMR
(CDCl3, 75.5 MHz) d 14.1 (CH3), 61.4 (CH2), 115.6 (Cq), 120.5
(CH), 122.8 (CH), 124.9 (CH), 125.4 (CH), 125.6 (CH), 126.4
(CH), 127.2 (CH), 128.3 (CH), 130.4 (Cq), 130.9 (CH), 131.3 (CH),
133.9 (Cq), 134.5 (Cq), 134.6 (CH), 141.7 (Cq), 167.9 (Cq), 168.2
(Cq). IR (film) 3261, 1675 cm−1. HRMS calcd for C20H18NO3:
320.1281. Found: 320.1281. Anal. calcd for C20H17NO3 (319): C,
75.22; H, 5.37; N, 4.39. Found: C, 74.79; H, 5.39; N, 4.35%. Mp
83–84 ◦C.
N-Benzyl-2-nitro-N-phenylbenzamide 4f
To a solution of 2-nitrobenzoyl chloride (90%, 658 mg, 3.20 mmol)
in DCM (12 mL), were added pyridine (1 mL, 12.38 mmol) and
aniline (0.3 mL, 3.29 mmol), and the mixture was stirred overnight
at rt under nitrogen. The mixture was basified with NaHCO3 aque-
ous saturated solution and extracted with DCM. The organic layer
was washed with HCl 2 M, dried and filtered and the solvent was
removed under reduced pressure. The residue was dissolved in dry
THF (40 mL), and NaH (60%, 406 mg, 10.15 mmol) and benzyl
bromide (1.6 mL, 13.4 mmol) were added and the mixture was
stirred overnight at rt under nitrogen. The solvent was removed
under reduced pressure, the residue was partitioned between ethyl
acetate and water, and the aqueous phase was extracted with ethyl
acetate. The organic extracts were dried and filtered and the solvent
was removed under reduced pressure. The crude product was
purified by flash chromatography (petroleum ether to petroleum
1
ether–AcOEt 50%) to yield 4f (1.06 g, quantitative). H-NMR
(CDCl3, 500 MHz) d 4.96 (s, 2H), 6.73–6.76 (m, 2H), 6.86–6.89
(m, 3H), 7.06–7.17 (m, 7H), 7.23–7.27 (m, 1H), 7.73 (d, J = 8 Hz,
1H). 13C-NMR (CDCl3, 75.5 MHz) d 52.9 (CH2), 124.3 (CH),
127.6 (CH), 127.8 (CH), 128.2 (CH), 128.5 (CH), 128.9 (CH),
129.1 (CH), 129.29 (CH), 129.34 (CH), 133.26 (Cq), 133.34 (CH),
136.6 (Cq), 141.1 (Cq), 155.7 (Cq), 167.1 (Cq). IR (film) 1651 cm−1.
HRMS calcd for C20H16N2O3Na: 355.1053. Found: 355.1051. Mp
97–99 ◦C.
Ethyl 2-(2-iodobenzamido)benzoate 4d
To a solution of 2-iodobenzoylchloride (1.63 g, 6.12 mmol) and
triethylamine (4.2 mL, 30.1 mmol) in ethyl acetate (50 mL)
was added ethyl 2-aminobenzoate (0.9 mL, 6.09 mmol), and the
mixture was stirred overnight at rt under nitrogen. The mixture was
basified with NaHCO3 aqueous saturated solution and extracted
with DCM. The organic layer was dried and filtered and the
solvent was removed under reduced pressure. The crude product
was purified by flash chromatography (DCM) to yield 4d (1.94 g,
80%). 1H-NMR (CDCl3, 300 MHz) d 1.43 (t, J = 7.2 Hz, 3H), 4.39
(q, J = 7.2 Hz, 2H), 7.18 (td, J = 7.5 and 1.8 Hz, 1H), 7.19 (td, J =
7.5 and 1.2 Hz, 1H), 7.48 (td, J = 7.5 and 1.2 Hz, 1H), 7.60 (dd,
J = 7.8 and 1.8 Hz, 1H), 7.67 (dd, J = 7.5 and 1.5 Hz, 1H), 7.98
(dd, J = 8.1 and 1.2 Hz, 1H), 8.13 (dd, J = 8.1 and 1.8 Hz, 1H),
8.93 (d, J = 7.8 Hz, 1H), 11.48 (bs, 1H). 13C-NMR (CDCl3, 75.5
MHz) d 14.1 (CH3), 61.5 (CH2), 92.7 (Cq), 115.7 (Cq), 120.5 (CH),
123.0 (CH), 128.0 (CH), 128.3 (CH), 130.9 (CH), 131.4 (CH),
134.6 (CH), 140.4 (CH), 141.2 (Cq), 142.0 (Cq), 167.6 (Cq), 168.1
(Cq). IR (film) 3257, 1680 cm−1. HRMS calcd for C16H15NO3I:
396.0091. Found: 396.0091. Anal. calcd for C16H14NO3I (395.2):
C, 48.63; H, 3.57; N, 3.54. Found: C, 48.61; H, 3.64; N, 3.54%.
Mp 53–54 ◦C.
2-Amino-N-benzyl-N-phenylbenzamide 4g
To a solution of 4f (1 g, 3.00 mmol) in DMF (30 mL) was
added SnCl2·H2O (7.7 g, 34.1 mmol). The mixture was stirred
at rt for 24 h and was basified with NaHCO3 aqueous saturated
solution and extracted with DCM. The organic extracts were
washed with brine, dried and filtered and the solvent was removed
under reduced pressure. The crude product was purified by flash
chromatography (petroleum ethereum ether to AcOEt) to yield
4g (783 mg, 86%). 1H-NMR (CDCl3, 500 MHz) d 4.52 (bs,
2H), 5.02 (s, 2H), 6.21 (td, J = 7.5 and 1 Hz, 1H), 6.53 (dd,
J = 8.1 and 1 Hz, 1H), 6.66 (dd, J = 7.8 and 1.5 Hz, 1H),
6.83–6.87 (m, 3H), 6.93–6.97 (m, 1H), 6.98–7.03 (m, 2H), 7.10–
7.22 (m, 6H). 13C-NMR (CDCl3, 125 MHz) d 53.3 (CH2), 116.6
(CH), 116.9 (CH), 119.9 (Cq), 126.5 (CH), 126.9 (2CH), 127.3
(CH), 128.1 (2CH), 128.5 (2CH), 128.9 (2CH), 129.6 (CH), 130.5
(CH), 137.5 (Cq), 143.6 (Cq), 146.4 (Cq), 170.9 (Cq). IR (film)
2110 | Org. Biomol. Chem., 2006, 4, 2106–2118
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3359 and 1619 cm−1. HRMS calcd for C20H19N2O: 303.1492.
Found: 303.1501.
0.40 mmol) and iodoethane (100 lL, 1.24 mmol). The mixture was
stirred at rt under nitrogen overnight. The mixture was diluted
with ethyl acetate and washed with water. The organic layer was
dried and filtered and the solvent was removed under reduced
pressure. The crude product was purified by flash chromatography
2-Iodo-N-benzyl-N-(2-iodophenyl)benzamide 3a
To a suspension of NaH (60%, 37 mg, 0.92 mmol) in THF (5 mL)
were added 2-iodo-N-(2-iodophenyl)benzamide 4a (110 mg,
0.24 mmol) and benzyl bromide (110 lL, 0.92 mmol). The
mixture was stirred overnight at rt under nitrogen. The mixture
was diluted with ethyl acetate and washed with water. The
organic layer was dried and filtered and the solvent was removed
under reduced pressure. The crude product was purified by flash
chromatography (petroleum ether to petroleum ether–AcOEt
1
(petroleum ether–AcOEt 10%) to yield 3c (196 mg, 92%). H-
NMR (CDCl3, 300 MHz) major conformer d 1.29 (dd, J = 7.2
and 6.9 Hz, 3H), 3.22 (dq, J = 14 and 6.9 Hz, 1H), 4.63 (dq, J =
14 and 7.2 Hz, 1H), 6.81 (dd, J = 7.5 and 1.5 Hz, 1H), 6.89 (dd,
J = 7.5 and 1.5 Hz, 1H), 7.07 (td, J = 7.5 and 1.2 Hz, 1H), 7.16
(td, J = 7.5 and 1.5 Hz, 1H), 7.29 (dd, J = 7.5 and 1.5 Hz, 1H),
7.41 (dd, J = 7.8 and 1.5 Hz, 1H), 7.69 (dd, J = 7.8 and 1.2 Hz,
1H), 7.81 (dd, J = 7.8 and 1.5 Hz, 1H). Minor conformer d 1.10
(dd, J = 6.9 and 7.2 Hz, 3H), 3.53 (m, 2H), 6.80–7.50 (m, 6H
masked by the major conformer), 7.89 (dd, J = 7.8 and 1.2 Hz,
1H), 7.96 (d, J = 7.8 Hz, 1H). Ratio 4.3 : 1. 13C-NMR (CDCl3, 75.5
MHz) d 12.2 (CH3), 43.3 (CH2), 94.1 (Cq), 99.7 (Cq), 126.2 (CH),
127.4 (CH), 128.6 (CH), 129.4 (CH), 129.9 (CH), 130.9 (CH),
139.0 (CH), 139.9 (CH), 141.6 (Cq), 143.1 (Cq), 169.2 (Cq). IR
(film) 1651 cm−1. HRMS calcd for C15H14NOI2: 477.9159. Found:
477.9163. Mp 139–140 ◦C.
1
20%) to yield 3a (110 mg, 91%). H-NMR (CDCl3, 300 MHz)
major conformer d 4.22 (d, J = 14.1 Hz, 1H), 6.00 (d, J =
14.1 Hz, 1H), 6.83–6.76 (m, 1H), 6.86 (dd, J = 5.7 and 1.8 Hz,
1H), 6.91 (dd, J = 6.9 and 1.5 Hz, 1H), 6.93 (dd, J = 6.9 and
1.5 Hz, 1H), 7.08 (ddd, J = 7.8, 7.5 and 1.2 Hz, 1H), 7.26–7.29
(m, 3H), 7.37–7.40 (m, 3H), 7.66 (dd, J = 8.1 and 1.2 Hz, 1H),
7.79 (dd, J = 7.8 and 1.2 Hz, 1H). Minor conformer d 4.60 (d,
J = 14.1 Hz, 1H), 4.73 (d, J = 14.1 Hz, 1H), 6.76–8.01 (m, 13H
masked by the major conformer). Ratio 10 : 1. 13C-NMR (CDCl3,
75.5 MHz) d 51.3 (CH2), 94.0 (Cq), 99.3 (Cq), 126.4 (CH), 127.3
(CH), 127.7 (CH), 128.1 (CH), 128.6 (CH), 129.5 (CH), 130.0
(CH), 131.8 (CH), 136.0 (Cq), 139.2 (CH), 139.8 (CH), 141.4
(Cq), 142.8 (Cq), 169.5 (Cq). IR (film) 1655 cm−1. HRMS calcd
for C20H16NOI2: 539.9316. Found: 539.9321. Mp 118–119 ◦C.
2-Iodo-N-(2-iodophenyl)-N-isopropylbenzamide 3d
To a solution of 2-iodo-N-isopropylaniline20 (174 mg, 0.67 mmol)
and pyridine (0.27 mL, 3.68 mmol) in dry DCM (6 mL) was added
2-iodobenzoyl chloride (268 mg, 1.00 mmol). The mixture was
stirred overnight at rt under nitrogen. The mixture was diluted with
DCM and washed with saturated aqueous NaHCO3. The organic
layer was dried and filtered and the solvent was removed under
reduced pressure. The crude product was purified by flash chro-
matography (petroleum ether to petroleum ether–AcOEt 10%)
2-Iodo-N-(2-iodobenzyl)-N-(2-iodophenyl)benzamide 3b
To a suspension of NaH (60%, 40 mg, 1 mmol) in THF (5 mL)
were added 2-iodo-N-(2-iodophenyl)benzamide 4a (104 mg,
0.23 mmol) and 2-iodobenzyl bromide (276 mg, 0.93 mmol). The
mixture was stirred overnight at rt under nitrogen. The mixture was
diluted with ethyl acetate and washed with water. The organic layer
was dried and filtered and the solvent was removed under reduced
pressure. The crude product was purified by flash chromatography
(petroleum ether to petroleum ether–AcOEt 25%) to yield 3b
(140 mg, 88%). 1H-NMR (CDCl3, 300 MHz) conformer A d 4.62
(d, J = 14.5 Hz, 1H), 6.00 (d, J = 14.5 Hz, 1H), 6.80 (dd, J = 7.5
and 1.5 Hz, 1H), 6.82 (dd, J = 7.5 and 1.5 Hz, 1H), 6.85 (dd, J = 7.5
and 1.5 Hz, 1H), 6.92 (dd, J = 7.5 and 1.5 Hz, 1H), 6.95 (dd, J = 7.5
and 1.5 Hz, 1H), 7.09 (ddd, J = 7.8, 7.5 and 1.2 Hz, 1H), 7.37 (ddd,
J = 7.8, 7.5 and 1.5 Hz, 1H), 7.42 (dd, J = 7.8 and 1.5 Hz, 1H), 7.66
(dd, J = 7.8 and 1.5 Hz, 1H), 7.67 (dd, J = 7.8 and 1.5 Hz, 1H),
7.77 (dd, J = 7.8 and 1.5 Hz, 1H), 8.07 (dd, J = 7.8 and 1.5 Hz, 1H).
Conformer B d 4.81 (d, J = 14.5 Hz, 1H), 5.97 (d, J = 14.5 Hz, 1H),
6.78–8.09 (m, 12H masked by the major conformer). Conformer
C d 4.89 (d, J = 14.5 Hz, 1H), 4.99 (d, J = 14.5 Hz, 1H), 6.78–
8.09 (m, 12H masked by the major conformer). 13C-NMR (CDCl3,
75.5 MHz) d 54.4 (CH2), 93.9 (Cq), 100.5 (Cq), 100.8 (Cq), 126.7
(CH), 127.4 (CH), 128.5 (CH), 128.8 (CH), 129.5 (CH), 129.7
(CH), 130.1 (CH), 131.6 (CH), 131.7 (CH), 139.1 (CH), 139.26
(CH), 139.27 (Cq), 140.0 (CH), 141.0 (Cq), 142.2 (Cq), 170.0
(Cq). Ratio 16 : 1.2 : 1. IR (film) 1650 cm−1. HRMS calcd for
C20H14NOI3Na: 687.8102. Found: 687.8089. Mp 182–184 ◦C.
1
to yield 3d (246 mg, 75%). H-NMR (CDCl3, 300 MHz) major
conformer d 1.29 (d, J = 6.6 Hz, 3H), 1.66 (d, J = 6.6 Hz, 3H), 4.61
(h, J = 6.6 Hz, 1H), 6.81 (dd, J = 7.5 and 1.5 Hz, 1H), 6.90 (dd, J =
7.5 and 1.5 Hz, 1H), 7.11 (td, J = 7.5 and 1.2 Hz, 1H), 7.21 (td, J =
7.5 and 1.5 Hz, 1H), 7.60 (dd, J = 7.8 and 1.5 Hz, 1H), 7.62 (dd,
J = 7.8 and 1.5 Hz, 1H), 7.65 (dd, J = 7.8 and 1.5 Hz, 1H), 7.79 (dd,
J = 7.8 and 1.5 Hz, 1H). Minor conformer d 1.16 (d, J = 6.7 Hz,
3H), 1.34 (d, J = 6.7 Hz, 3H), 4.13 (h, J = 6.7 Hz, 1H), 6.81–7.72
(m, 6H masked by the major conformer), 7.91 (d, J = 7.8 Hz, 1H),
8.00 (d, J = 7.8 Hz, 1H). Ratio 2.5 : 1. 13C-NMR (CDCl3, 75.5
MHz) major conformer d 19.4 (CH3), 21.6 (CH3), 51.5 (CH), 93.9
(Cq), 102.8 (Cq), 126.6 (CH), 127.1 (CH), 128.6 (CH), 129.4 (CH),
129.7 (CH), 130.9 (CH), 139.0 (CH), 140.0 (CH), 142.1 (Cq), 142.8
(Cq), 169.7 (Cq). Minor conformer d 20.8 (CH3), 23.7 (CH3), 52.8
(CH), 92.9 (Cq), 102.3 (Cq), 126.7 (CH), 128.0 (CH), 128.9 (CH),
129.4 (CH), 130.1 (CH), 130.8 (CH), 139.4 (CH), 140.1 (CH),
169.4 (Cq). IR (film) 1649 cm−1. HRMS calcd for C16H16NOI2:
491.9316. Found: 491.9322. Mp 161–162 ◦C.
N-Benzyl-N-(2-iodophenyl)-1-naphthamide 3e
To a suspension of NaH (60%, 94 mg, 2.35 mmol) in THF
(10 mL) was added N-(2-iodophenyl)-1-naphthamide 4b (257 mg,
0.69 mmol) and benzyl bromide (350 lL, 2.93 mmol). The mixture
was stirred overnight at rt under nitrogen. The mixture was diluted
with ethyl acetate and washed with water. The organic layer was
dried and filtered and the solvent was removed under reduced
2-Iodo-N-ethyl-N-(2-iodophenyl)benzamide 3c
To a suspension of NaH (60%, 70 mg, 1.75 mmol) in THF
(5 mL) was added 2-iodo-N-(2-iodophenyl)benzamide 4a (199 mg,
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pressure. The crude product was purified by flash chromatography
1H), 7.91 (d, J = 7.5 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H). Minor
conformer d 4.60–5.00 (m, 4H), 6.87–6.89 (m, 1H), 6.99–7.76 (m,
13H masked by the major conformer), 7.98 (d, J = 7.5 Hz, 1H),
8.23 (d, J = 7.2 Hz, 1H). Ratio 3.25 : 1. 13C-NMR (CDCl3, 75.5
MHz) d 53.4 (CH2), 124.4 (CH), 125.3 (CH), 126.0 (CH), 126.7
(CH), 126.9 (CH), 127.6 (CH), 127.8 (CH), 128.2 (CH), 128.3 (Cq),
128.5 (2CH), 129.2 (CH), 129.5 (2CH), 130.2 (Cq), 131.2 (CH),
132.3 (CH), 133.0 (CH), 133.2 (Cq), 133.7 (Cq), 137.2 (Cq), 142.4
(Cq), 169.7 (Cq), 170.1 (Cq). IR (film) 3060, 1718 and 1594 cm−1.
HRMS calcd for C25H19NO3Na: 404.1257. Found: 404.1260.
(petroleum ether to petroleum ether–AcOEt 20%) to yield 3e
1
(296 mg, 93%). H-NMR (CDCl3, 300 MHz) major conformer
d 4.32 (d, J = 14.1 Hz, 1H), 6.12 (d, J = 14.1 Hz, 1H), 6.37
(m, 1H), 6.66 (m, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.19 (d, J =
7.2 Hz, 1H), 7.27–7.53 (m, 7H), 7.63 (d, J = 8.4 Hz, 1H), 7.70–
7.73 (m, 1H), 7.74 (d, J = 7.2, 1H), 8.09 (d, J = 8.4 Hz, 1H).
Minor conformer d 4.54 (bd, J = 14.1 Hz, 1H), 4.82 (m, 1H),
4.40–7.99 (m, 16H masked by the major conformer). Ratio 7 :
1. 13C-NMR (CDCl3, 75.5 MHz) d 51.6 (CH2), 99.4 (Cq), 123.7
(CH), 124.2 (CH), 125.2 (CH), 125.9 (CH), 126.6 (CH), 127.7
(CH), 128.1 (2CH), 128.4 (2CH), 129.0 (CH), 129.1 (CH), 129.6
(2CH), 130.2 (Cq), 131.3 (CH), 133.1 (Cq), 133.6 (Cq), 136.8 (Cq),
139.8 (CH), 143.4 (Cq), 170.0 (Cq). IR (film) 1649 cm−1. HRMS
calcd for C24H19NOI: 464.0506. Found: 464.0507. Anal. calcd for
C24H18NOI (463.3)·1/4 H2O: C, 61.62; H, 3.99; N, 2.99. Found: C,
61.55; H, 3.98; N, 2.94%. Mp 182–184 ◦C.
Ethyl 2-(N-benzyl-2-iodobenzamido)benzoate 3h
To a solution of 4d (1 g, 2.53 mmol), in dry THF (40 mL), were
added NaH (60%, 320 mg, 8 mmol) and benzyl bromide (1.25 mL,
10.4 mmol) and the mixture was stirred overnight at rt under
nitrogen. The mixture was diluted with ethyl acetate and washed
with water. The organic layer was dried and filtered and the solvent
was removed under reduced pressure. The crude product was
purified by flash chromatography (petroleum ether to petroleum
ether–AcOEt 40%) to yield 3h (834 mg, 68%). 1H-NMR (CDCl3,
300 MHz) major conformer d 1.53 (t, J = 7.1 Hz, 3H), 4.09 (d, J =
14.3 Hz, 1H), 4.52 (q, J = 7.1 Hz, 2H), 6.03 (d, J = 14.3 Hz, 1H),
6.83 (ddd, J = 8, 7.5 and 1.8 Hz, 1H), 6.96 (dd, J = 7.5 and 1.8 Hz,
1H), 7.06 (td, J = 7.5 and 1 Hz, 1H), 7.13–7.22 (m, 3H), 7.28–7.32
(m, 3H), 7.39–7.42 (m, 2H), 7.68 (dd, J = 8 and 1 Hz, 1H), 7.87
(dd, J = 7.5 and 1.8 Hz, 1H). Minor conformer d 1.41 (t, J =
7.1 Hz, 3H), 4.30–4.80 (m, 4H masked by the major conformer),
6.80–7.44 (m, 8H masked by the major conformer), 7.50 (dd, J =
7.8 and 1.8 Hz, 1H), 7.55 (dd, J = 7.5 and 1 Hz, 1H), 7.78 (dd,
J = 7.6 and 1 Hz, 1H), 7.94 (dd, J = 8 and 1 Hz, 1H), 8.02 (dd,
J = 7.8 and 1.5 Hz, 1H). Ratio 5.3 : 1. 13C-NMR (CDCl3, 75.5
MHz) d 14.3 (CH3), 52.9 (CH2), 61.7 (CH2), 94.0 (Cq), 127.1 (CH),
127.3 (CH), 127.5 (CH), 128.0 (CH), 128.2 (2CH), 129.6 (2CH),
129.7 (CH), 131.5 (2CH), 132.4 (CH), 136.5 (Cq), 139.1 (CH),
140.9 (Cq), 142.0 (Cq), 165.7 (Cq), 169.1 (Cq). IR (film) 1716
and 1652 cm−1. HRMS calcd for C23H21NO3I: 486.0561. Found:
486.0570. Anal. calcd for C23H20NO3I (485.3): C, 56.92; H, 4.15;
N, 2.89. Found: C, 57.36; H, 4.28; N, 2.79%. Mp 102–104 ◦C.
Ethyl 2-(N-benzyl-1-naphthamido)benzoate 3f
To a suspension of NaH (60%, 111 mg, 2.77 mmol) in THF
(10 mL) were added ethyl 2-(1-naphthamido)benzoate 4c (251 mg,
0.79 mmol) and benzyl bromide (400 lL, 3.34 mmol). The mixture
was stirred overnight at rt under nitrogen. The mixture was diluted
with ethyl acetate and washed with water. The organic layer was
dried and filtered and the solvent was removed under reduced
pressure. The crude product was purified by flash chromatography
(petroleum ether to petroleum ether–AcOEt 30%) to yield 3f
1
(193 mg, 60%). H-NMR (CDCl3, 300 MHz) major conformer
d 1.45 (t, J = 6.9 Hz, 3H), 4.28 (d, J = 14.4 Hz, 1H), 4.36–4.49
(m, 2H), 6.21 (d, J = 14.4 Hz, 1H), 6.59 (d, J = 7.8 Hz, 1H),
6.94 (td, J = 7.5 and 1.5 Hz, 1H), 7.06 (td, J = 7.5 and 1.2 Hz,
1H), 7.15 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 7.30–7.48
(m, 5H), 7.53 (dd, J = 8.4 and 1.5 Hz, 1H), 7.55 (dd, J = 8.4
and 1.5 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 8.4 Hz,
1H), 7.76 (dd, J = 7.5 and 1.5 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H).
Minor conformer d 1.48 (t, J = 6.9 Hz, 3H), 4.35–4.49 (m, 4H
masked by the major conformer), 6.88–7.98 (m, 15H masked by
the major conformer), 8.11 (dd, J = 7.5 and 1.5 Hz, 1H). Ratio 5 :
1. 13C-NMR (CDCl3, 75.5 MHz) d 14.1 (CH3), 53.1 (CH2), 61.4
(CH2), 124.1 (CH), 124.6 (CH), 125.3 (CH), 125.8 (CH), 126.4
(CH), 127.46 (CH), 127.50 (CH), 128.0 (CH), 128.2 (Cq), 128.4
(2CH), 128.9 (CH), 129.3 (2CH), 130.2 (Cq), 130.9 (CH), 131.3
(CH), 131.9 (CH), 133.1 (Cq), 133.8 (Cq), 137.4 (Cq), 141.7 (Cq),
164.5 (Cq), 169.5 (Cq). IR (film) 1718 and 1648 cm−1. HRMS
calcd for C27H24NO3: 410.1751. Found: 410.1750. Anal. calcd for
C27H23NO3 (409.5)·1/4 H2O: C, 78.34; H, 5.72; N, 3.38. Found: C,
78.20; H, 5.81; N, 3.28%.
2-(N-Benzyl-2-iodobenzamido)benzoic acid 3i
To a solution of 3h (405 mg, 0.83 mmol) in EtOH (10 mL) was
added NaOH 40% aqueous solution (30 mL) and the mixture was
stirred at reflux temperature for 3 h. The mixture was acidified
with HCl 6 N and extracted with DCM. The organic extracts were
dried and filtered and the solvent was removed under reduced
pressure to yield 3i (382 mg, quantitative). 1H-NMR (CDCl3, 300
MHz) major conformer d 4.90 (d, J = 14.4 Hz, 1H), 6.10 (d,
J = 14.4 Hz, 1H), 6.84 (ddd, J = 7.8, 7.5 and 1.5 Hz, 1H), 7.00–
7.12 (m, 2H), 7.17–7.35 (m, 6H), 7.42–7.45 (m, 2H), 7.70 (d, J =
7.8 Hz, 1H), 8.01 (dd, J = 7.5 and 1.8 Hz, 1H), 10.37 (br s, 1H).
Minor conformer d 4.67–4.73 (m, 1H), 4.86–4.91 (m, 1H), 7.00–
7.75 (m, 11H masked by the major conformer), 7.97 (d, J = 7.8 Hz,
1H), 8.19 (dd, J = 7.8 and 1.2 Hz, 1H). Ratio 3.5 : 1. 13C-NMR
(CDCl3, 75.5 MHz) d 53.2 (CH2), 93.9 (Cq), 127.1 (Cq), 127.3
(CH), 127.5 (CH), 127.6 (CH), 128.26 (2CH), 128.30 (CH), 129.7
(2CH), 129.9 (CH), 131.6 (CH), 132.4 (CH), 133.3 (CH), 136.3
(Cq), 139.1 (CH), 141.4 (Cq), 141.6 (Cq), 169.6 (Cq), 169.7 (Cq).
2-(N-Benzyl-1-naphthamido)benzoic acid 3g
To a solution of 3f (516 mg, 0.99 mmol) in EtOH (10 mL) was
added NaOH 40% aqueous solution (40 mL) and the mixture was
stirred at reflux temperature for 3 h. The mixture was acidified with
HCl 6 N and extracted with ethyl acetate. The organic extracts were
dried and filtered and the solvent was removed under reduced pres-
sure to yield 3g (468 mg, 97%). 1H-NMR (CDCl3, 300 MHz) major
conformer d 4.33 (d, J = 14.4 Hz, 1H), 6.19 (d, J = 14.4 Hz, 1H),
6.61 (bd, J = 6.9 Hz, 1H), 6.98–7.04 (m, 1H), 7.10–7.21 (m, 3H),
7.30–7.59 (m, 7H), 7.67 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 7.8 Hz,
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IR (film) 3031, 1720 and 1596 cm−1. HRMS calcd for C21H15NO3I:
456.0102. Found: 456.0096.
N-Methyl-N-(2-iodophenyl)-2-nitrobenzamide 3l
To a solution of 4e (501 mg, 1.36 mmol), in dry THF (10 mL),
were added NaH (60%, 235 mg, 5.9 mmol) and methyl iodide
(0.9 mL, 14.5 mmol) and the mixture was stirred overnight at
rt under nitrogen. The solvent was evaporated under reduced
pressure. The residue was partitioned between ethyl acetate and
water, and the aqueous phase was extracted with ethyl acetate.
The organic extracts were dried and filtered and the solvent was
removed under reduced pressure. The crude product was purified
by flash chromatography (petroleum ether to AcOEt) to yield 3l
N-Benzyl-N-(2-iodophenyl)-2-nitrobenzamide 3j
To a solution of 4e (1.2 g, 3.26 mmol), in dry THF (40 mL),
were added NaH (60%, 460 mg, 11.5 mmol) and benzyl bromide
(1.6 mL, 13.4 mmol) and the mixture was stirred overnight at
rt under nitrogen. The solvent was evaporated under reduced
pressure. The residue was partitioned between ethyl acetate and
water, and the aqueous phase was extracted with ethyl acetate.
The organic extracts were dried and filtered and the solvent was
removed under reduced pressure. The crude product was purified
by flash chromatography (petroleum ether to petroleum ether–
AcOEt 50%) to yield 3j (1.43 g, 96%). 1H-NMR (CDCl3, 300 MHz)
major conformer d 4.31 (d, J = 14.1 Hz, 1H), 6.01 (d, J = 14.1 Hz,
1H), 6.72 (dd, J = 7.8 and 1.8 Hz, 1H), 6.83 (td, J = 7.5 and 1.8 Hz,
1H), 6.93 (td, J = 7.5 and 1.5 Hz, 1H), 7.30–7.42 (m, 6H), 7.51
(td, J = 7.5 and 1.5 Hz, 1H), 7.75 (dd, J = 7.8 and 1.5 Hz, 1H),
7.80 (dd, J = 7.8 and 1.5 Hz, 1H), 7.97 (dd, J = 8.1 and 1.5 Hz,
1H). Minor conformer d 4.71 (s, 2H), 6.70–7.81 (m, 10H masked
by the major conformer), 7.90 (dd, J = 7.8 and 1.5 Hz, 1H), 7.91
(dd, J = 7.8 and 1.5 Hz, 1H), 8.35 (dd, J = 8.1 and 1.5 Hz, 1H).
Ratio 12 : 1. 13C-NMR (CDCl3, 75.5 MHz) d 51.4 (CH2), 99.5
(Cq), 124.2 (CH), 127.8 (CH), 127.9 (CH), 128.4 (2CH), 128.9
(CH), 129.7 (CH), 129.89 (CH), 129.92 (2CH), 131.2 (CH), 132.7
(Cq), 133.6 (CH), 135.5 (Cq), 140.0 (CH), 142.3 (Cq), 145.4 (Cq),
166.5 (Cq). IR (film) 1653, 1527 and 1346 cm−1. HRMS calcd for
C20H15N2O3INa: 481.0020. Found: 481.0016. Mp 158–160 ◦C.
1
(407 mg, 78%). H-NMR (CDCl3, 300 MHz) major conformer
d 3.43 (s, 3H), 6.87 (td, J = 7.5 and 1.5 Hz, 1H), 7.14 (td, J =
7.5 and 1.5 Hz, 1H), 7.32 (dd, J = 7.5 and 1.5 Hz, 1H), 7.34
(ddd, J = 8.1, 7.5 and 1.5 Hz, 1H), 7.46 (td, J = 7.5 and 1.2 Hz,
1H), 7.62 (dd, J = 7.5 and 1.5 Hz, 1H), 7.76 (dd, J = 7.5 and
1.5 Hz, 1H), 7.95 (dd, J = 8.1 and 1.2 Hz, 1H). Minor conformer
d 3.09 (s, 3H), 7.10 (ddd, J = 8.1, 7.5 and 1.5 Hz, 1H), 7.50 (td,
J = 7.5 and 1.5 Hz, 1H), 7.59–7.84 (m, 4H masked by the major
conformer), 7.94 (dd, J = 8.1 and 1.2 Hz, 1H), 8.27 (dd, J =
8.1 and 1.2 Hz, 1H). Ratio 3.6 : 1. 13C-NMR (CDCl3, 75.5 MHz)
major conformer d 36.7 (CH3), 99.1 (Cq), 124.2 (CH), 127.9 (CH),
128.9 (CH), 129.71 (CH), 129.75 (CH), 129.96 (CH), 132.7 (Cq),
133.6 (CH), 140.1 (CH), 145.1 (Cq), 167.1 (Cq). Minor conformer
representative signals only, d 39.1 (CH3), 124.7 (CH), 128.2 (CH),
128.7 (CH), 129.8 (CH), 130.00 (CH), 130.1 (CH), 132.7 (CH),
134.8 (CH), 145.6 (Cq). IR (film) 1654 cm−1. HRMS calcd for
C14H12N2O3I: 382.9887. Found: 382.9883.
2-Amino-N-benzyl-N-(2-iodophenyl)benzamide 3m
To a solution of 3j (400 mg, 0.87 mmol) in DMF (9 mL) was
added SnCl2·H2O (2.02g, 8.94 mmol). The mixture was stirred at
rt for 24 h and it was basified with NaHCO3 aqueous saturated
solution and extracted with DCM. The organic extracts were
washed with brine, dried and filtered and the solvent was removed
under reduced pressure to yield the title compound 3m (374 mg,
N-Ethyl-N-(2-iodophenyl)-2-nitrobenzamide 3k
To a solution of 4e (503 mg, 1.37 mmol), in dry THF (10 mL),
were added NaH (60%, 257 mg, 6.4 mmol) and ethyl iodide
(1 mL, 12.4 mmol) and the mixture was stirred overnight at
rt under nitrogen. The solvent was evaporated under reduced
pressure. The residue was partitioned between ethyl acetate and
water, and the aqueous phase was extracted with ethyl acetate.
The organic extracts were dried and filtered and the solvent
was removed under reduced pressure. The crude product was
purified by flash chromatography (petroleum ether to petroleum
ether–AcOEt 50%) to yield 3k (458 mg, 85%). 1H-NMR (CDCl3,
300 MHz) major conformer d 1.34 (t, J = 7.2 Hz, 3H), 3.28 (dq,
J = 14 and 7.2 Hz, 1H), 4.60 (dq, J = 14 and 7.2 Hz, 1H), 6.91 (td,
J = 7.5 and 1.5 Hz, 1H), 7.16 (td, J = 7.5 and 1.5 Hz, 1H), 7.30 (dd,
J = 8.1 and 1.5 Hz, 1H), 7.37 (ddd, J = 8.1, 7.5 and 1.5 Hz, 1H),
7.47 (td, J = 7.5 and 1.5 Hz, 1H), 7.61 (dd, J = 7.5 and 1.5 Hz,
1H), 7.82 (dd, J = 7.8 and 1.5 Hz, 1H), 7.98 (dd, J = 7.5 and
1.5 Hz, 1H). Minor conformer d 1.06 (t, J = 7.2 Hz, 3H), 3.55 (q,
J = 7.2 Hz, 2H), 6.8–8.0 (m, 7H masked by the major conformer),
8.29 (dd, J = 8.1 and 1.5 Hz, 1H). Ratio 6.4 : 1. 13C-NMR (CDCl3,
75.5 MHz) major conformer d 11.6 (CH3), 43.6 (CH2), 100.1 (Cq),
124.2 (CH), 127.4 (CH), 129.2 (CH), 129.6 (CH), 129.8 (CH),
130.2 (CH), 132.9 (Cq), 133.6 (CH), 140.1 (CH), 143.2 (Cq), 166.1
(Cq). Minor conformer representative signals only, d 13.3 (CH3),
46.4 (CH2), 124.8 (CH), 128.1 (CH), 129.7 (CH), 130.1 (CH), 134.5
(CH), 139.7 (CH), 145.9 (Cq). IR (film) 1655 cm−1. HRMS calcd
for C15H14N2O3I: 397.0044. Found: 397.0043.
1
quantitative). H-NMR (CDCl3, 300 MHz) d 3.96 (bs, 2H), 4.39
(d, J = 14.4 Hz, 1H), 5.77 (d, J = 14.4 Hz, 1H), 6.34 (bs, 1H), 6.62
(d, J = 7.8 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 6.82–7.03 (m, 4H),
7.20–7.37 (m, 5H), 7.82 (d, J = 7.8 Hz, 1H). 13C-NMR (CDCl3,
125 MHz) d 51.8 (CH2), 99.2 (Cq), 116.0 (CH), 116.2 (CH), 118.8
(Cq), 127.3 (CH), 128.1 (CH), 128.2 (2CH), 128.5 (2CH), 128.6
(CH), 129.0 (CH), 130.5 (CH), 131.1 (CH), 136.4 (Cq), 139.7 (CH),
144.4 (Cq), 146.7 (Cq), 170.5 (Cq). IR (film) 3364 and 1634 cm−1.
HRMS calcd for C20H18N2OI: 429.0458. Found: 429.0462.
2-Amino-N-ethyl-N-(2-iodophenyl)benzamide 3n
To a solution of 3k (458 mg, 1.16 mmol) in DMF (10 mL) was
added SnCl2·H2O (2.77 g, 12.3 mmol). The mixture was stirred at
rt for 24 h and it was basified with NaHCO3 aqueous saturated
solution and extracted with DCM. The organic extracts were
washed with brine, dried and filtered and the solvent was removed
under reduced pressure. The crude product was purified by flash
chromatography (petroleum ether to AcOEt) to yield 3n (417 mg,
1
98%). H-NMR (CDCl3, 300 MHz) d 1.21 (t, J = 7.2 Hz, 3H),
3.44–3.55 (m, 1H), 4.29 (bs, 1H), 4.65 (bs, 2H), 6.31 (bs, 1H),
6.58 (d, J = 7.5 Hz, 1H), 6.80–7.20 (m, 5H), 7.84 (d, J = 7.2 Hz,
1H). 13C-NMR (CDCl3, 75.5 MHz) d 12.2 (CH3), 44.5 (CH2), 99.9
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(Cq), 116.7 (CH), 116.8 (CH), 119.9 (Cq), 128.6 (CH), 129.0 (CH),
129.2 (CH), 130.9 (CH), 131.1 (CH), 140.3 (CH), 147.0 (Cq), 170.9
(Cq). IR (film) 3360 and 1620 cm−1. HRMS calcd for C15H16N2OI:
367.0302. Found: 367.0302.
other signals masked by the major conformer. Ratio 6.8 : 2 : 1.
13C-NMR (CDCl3, 75.5 MHz) d 41.5 (CH3), 53.1 (CH2), 92.0 (Cq),
98.2 (Cq), 126.9 (CH), 127.3 (2CH), 128.32 (2CH), 128.41 (CH),
128.44 (CH), 128.5 (CH), 129.0 (CH), 129.1 (CH), 129.5 (CH),
130.1 (CH), 130.9 (CH), 133.6 (Cq), 133.9 (CH), 136.8 (Cq), 138.8
(CH), 139.8 (CH), 141.8 (Cq), 142.3 (Cq), 144.5 (Cq), 167.4 (Cq),
170.7 (Cq). IR (film) 1652 cm−1. HRMS calcd for C28H22N2O2I2Na:
694.9663. Found: 694.9672. Mp 156–158 ◦C. HPLC 5.49 min.
2-Amino-N-(2-iodophenyl)-N-methylbenzamide 3o
To a solution of 3l (595 mg, 1.56 mmol) in DMF (10 mL) was
added SnCl2·H2O (3.7 g, 16.40 mmol). The mixture was stirred at
rt for 24 h and it was basified with NaHCO3 aqueous saturated
solution and extracted with DCM. The organic extracts were
washed with brine, dried and filtered and the solvent was removed
N-Benzyl-N-(2-iodophenyl)-2-(N-benzyl-2-
iodobenzamido)benzamide 5c
1
under reduced pressure to yield 3o (548 mg, quantitative). H-
To a solution of 5a (200 mg, 0.30 mmol), in dry THF (5 mL),
was added NaH (60%, 54 mg, 1.35 mmol) and benzyl bromide
(0.2 mL, 1.67 mmol) and the mixture was stirred overnight at rt
under nitrogen. The mixture was partitioned between ethyl acetate
and water, and the aqueous phase was extracted with ethyl acetate.
The organic extracts were dried and filtered and the solvent was
removed under reduced pressure. The crude product was purified
by flash chromatography (petroleum ether to petroleum ether–
AcOEt 30%) to yield 5c (227 mg, quantitative). 1H-NMR (CDCl3,
300 MHz) d 3.78–6.22 (m, 4H), 6.65–8.09 (m, 22H). IR (film)
1649 cm−1. HRMS calcd for C34H26N2O2I2Na: 770.9976. Found:
770.9987. HPLC 5.48 min.
NMR (CDCl3, 300 MHz) d 3.36 (s, 3H), 4.73 (bs, 2H), 6.39 (bs,
1H), 6.69 (d, J = 8.4 Hz, 1H), 6.83–7.21 (m, 5H), 7.83 (d, J =
7.8 Hz, 1H). 13C-NMR (CDCl3, 75.5 MHz) d 37.8, (CH3), 98.8
(Cq), 116.8 (CH), 119.1 (Cq), 129.1 (CH), 129.7 (CH), 131.1 (CH),
140.3 (CH), 147.2 (Cq), 171.4 (Cq). IR (film) 3358 and 1620 cm−1.
N-Benzyl-N-(2-iodophenyl)-2-(2-iodobenzamido)benzamide 5a
To a solution of 3m (389 mg, 0.91 mmol) and pyridine (0.5 mL,
6.18 mmol) in DCM (5 mL) was added 2-iodobenzoyl chloride
(97%, 250 mg, 0.91 mmol). The mixture was stirred at rt for 24 h
and it was basified with NaHCO3 aqueous saturated solution
and extracted with DCM. The organic extracts were dried and
filtered and the solvent was removed under reduced pressure. The
crude product was purified by flash chromatography (DCM to
DCM–MeOH 0.5%) to yield 5a (436 mg, 73%). 1H-NMR (CDCl3,
300 MHz) major conformer d 4.35 (d, J = 14.4 Hz, 1H), 5.72 (d,
J = 14.4 Hz, 1H), 6.75–6.72 (m, 2H), 6.91 (ddd, J = 7.8, 7.5 and
1.5 Hz, 1H), 7.03 (dd, J = 7.8 and 1.5 Hz, 1H), 7.13 (ddd, J = 7.8,
7.5 and 1.5 Hz, 1H), 7.19–7.40 (m, 6H), 7.49–7.51 (m, 2H), 7.82
(dd, J = 8.1 and 1.5 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 8.38 (d, J =
8.1 Hz, 1H), 9.73 (s, 1H). Minor conformer d 4.57–4.64 (m, 1H),
5.21–5.27 (m, 1H), other signals masked by the major conformer.
Ratio 12 : 1. 13C-NMR (CDCl3, 75.5 MHz) d 53.7 (CH2), 92.8
(Cq), 99.8 (Cq), 122.5 (CH), 122.8 (CH), 124.4 (Cq), 127.76 (CH),
127.79 (CH), 128.2 (CH), 128.3 (CH), 128.4 (2CH), 128.9 (CH),
129.3 (2CH), 130.8 (CH), 131.3 (CH), 131.4 (CH), 136.1 (Cq),
137.1 (Cq), 140.1 (CH), 140.3 (CH), 141.7 (Cq), 144.1 (Cq), 167.1
(Cq), 169.5 (Cq). IR (film) 3338, 1683 and 1632 cm−1. HRMS calcd
for C27H20N2O2I2Na: 680.9506. Found: 680.9507. Mp 112–114 ◦C.
N-Benzyl-N-(2-iodophenyl)-2-(2-nitrobenzamido)benzamide 5d
To a solution of 3m (1 g, 2.34 mmol) and pyridine (1 mL,
12.4 mmol) in DCM (15 mL) was added 2-nitrobenzoyl chloride
(90%, 486 mg, 2.35 mmol). The mixture was stirred at rt for 24 h
and it was basified with NaHCO3 aqueous saturated solution and
extracted with DCM. The organic extracts were dried and filtered
and the solvent was removed under reduced pressure. The crude
product was purified by flash chromatography (DCM) to yield
5d (1.14 g, 85%). 1H-NMR (CDCl3, 500 MHz) major conformer
d 4.34 (d, J = 14.3 Hz, 1H), 4.65 (d, J = 14.3 Hz, 1H), 6.75–
6.79 (m, 2H), 6.89 (ddd, J = 8, 7.5 and 1.5 Hz, 1H), 7.00 (dd,
J = 7.5 and 1.5 Hz, 1H), 7.11 (ddd, J = 8, 7.5 and 1.5 Hz, 1H),
7.15–7.30 (m, 5H), 7.58 (dd, J = 7.5 and 1 Hz, 1H), 7.66 (td,
J = 8 and 1.5 Hz, 1H), 7.75 (td, J = 7.5 and 1 Hz, 1H), 7.81
(dd, J = 8 and 1.5 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.27 (d,
J = 8.5 Hz, 1H), 9.79 (s, 1H). Minor conformer d 4.61 (d, J =
15 Hz, 1H), 5.25 (d, J = 15 Hz, 1H), other signals masked by the
major conformer. Ratio 22 : 1. 13C-NMR (CDCl3, 125 MHz) d
52.9 (CH2), 99.2 (Cq), 122.6 (CH), 123.1 (CH), 124.4 (Cq), 124.7
(CH), 127.7 (CH), 128.0 (CH), 128.24 (CH), 128.28 (2CH), 129.18
(CH), 129.28 (2CH), 129.34 (CH), 130.7 (CH), 130.9 (CH), 131.5
(CH), 133.0 (Cq), 133.8 (CH), 135.9 (Cq), 136.8 (Cq), 140.2 (CH),
144.2 (Cq), 146.6 (Cq), 164.1 (Cq), 169.6 (Cq). IR (film) 3329,
1688 and 1633 cm−1. HRMS calcd for C27H20N3O4INa: 600.0391.
Found: 600.0393.
N-Benzyl-N-(2-iodophenyl)-2-(2-iodo-N-
methylbenzamido)benzamide 5b
To a solution of 5a (95 mg, 0.14 mmol), in dry THF (5 mL), were
added NaH (60%, 30 mg, 0.75 mmol) and methyl iodide (0.1 mL,
1.60 mmol) and the mixture was stirred overnight at rt under
nitrogen. The residue was partitioned between DCM and water,
and the aqueous phase was extracted with DCM. The organic
extracts were dried and filtered and the solvent was removed under
reduced pressure. The crude product was purified by flash chro-
matography (petroleum ether to petroleum ether–AcOEt 30%) to
yield 5b (90 mg, 93%). 1H-NMR (CDCl3, 300 MHz) conformer A d
3.24 (br s, 3H), 4.55 (d, J = 14.5 Hz, 1H), 6.72 (d, J = 14.5 Hz, 1H),
6.81–7.94 (m, 17H). Conformer B d 4.90 (d, J = 15 Hz, 1H), 5.20
(d, J = 15 Hz, 1H), other signals masked by the major conformer.
Conformer C d 4.32 (d, J = 14 Hz, 1H), 6.98 (d, J = 14 Hz, 1H),
N-Benzyl-N-(2-iodophenyl)-2-(N-methyl-2-
nitrobenzamido)benzamide 5e
To a solution of 5d (103 mg, 0.18 mmol), in dry THF (5 mL),
were added NaH (60%, 35 mg, 0.87 mmol) and methyl iodide
(0.1 mL, 1.60 mmol) and the mixture was stirred overnight at
rt under nitrogen. The residue was partitioned between DCM
and water, and the aqueous phase was extracted with DCM. The
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organic extracts were dried and filtered and the solvent was
removed under reduced pressure. The crude product was purified
by flash chromatography (petroleum ether to petroleum ether–
AcOEt 50%) to yield 5e (105 mg, quantitative). 1H-NMR (CDCl3,
300 MHz) conformer A d 3.23 (br s, 3H), 4.53 (d, J = 14.5 Hz, 1H),
5.72 (d, J = 14.5 Hz, 1H), 6.86–7.66 (m, 13H), 6.90 (dd, J = 7.7 and
1.5 Hz, 1H), 7.50 (dd, J = 7.9 and 1 Hz, 1H), 7.94 (dd, J = 7.9 and
1.4 Hz, 1H), 8.25 (dd, J = 7.6 and 1.8 Hz, 1H). Conformer B d 4.88
(d, J = 15 Hz, 1H), 5.14 (d, J = 15 Hz, 1H), other signals masked
by the major conformer. Conformer C d 4.32 (d, J = 13.8 Hz,
1H), 5.98 (d, J = 13.8 Hz, 1H), other signals masked by the major
conformer. Ratio 4.5 : 1 : 1. 13C-NMR (CDCl3, 75.5 MHz) d 41.2
(CH3), 53.2 (CH2), 98.3 (Cq), 124.5 (CH), 127.0 (CH), 127.3 (CH),
128.2 (3CH), 128.3 (CH), 129.1 (CH), 129.2 (2CH), 129.4 (CH),
129.6 (CH), 131.1 (CH), 133.0 (Cq), 133.5 (Cq), 133.6 (CH), 134.6
(CH), 137.1 (Cq), 139.8 (CH), 141.3 (Cq), 144.5 (Cq), 144.8 (Cq),
167.8 (Cq), 168.3 (Cq). IR (film) 1652 and 1529 cm−1. HRMS calcd
for C28H23N3O4I: 592.0728. Found: 592.0734. HPLC 5.59 min.
masked by major conformer. Ratio 3.2 : 2.5 : 1.5 : 1. IR (film) 1649
and 1528 cm−1. HRMS calcd for C23H21N3O4I: 530.0571. Found:
530.0560. HPLC 4.49 min.
N-Ethyl-N-(2-iodophenyl)-2-(2-nitrobenzamido)benzamide 5h
To a solution of 3n (417 mg, 1.14 mmol) and pyridine (0.5 mL,
6.19 mmol) in DCM (5 mL) was added 2-nitrobenzoyl chloride
(0.9%, 260 mg, 1.26 mmol). The mixture was stirred at rt overnight
and it was basified with NaHCO3 aqueous saturated solution and
extracted with DCM. The organic extracts were dried and filtered
and the solvent was removed under reduced pressure. The crude
product was purified by flash chromatography (petroleum ether to
petroleum ether–AcOEt 50%) to yield 5h (524 mg, 89%). 1H-NMR
(CDCl3, 300 MHz) major conformer d 1.18 (t, J = 7.2 Hz, 3H),
3.53 (dq, J = 7.2 and 6.9 Hz, 1H), 4.25 (dq, J = 7.2 and 6.9 Hz,
1H), 6.77 (ddd, J = 7.8, 7.5 and 1.2 Hz, 1H), 6.92 (dd, J = 7.5 and
1.2 Hz, 1H), 6.97 (dd, J = 7.5 and 1.2 Hz, 1H), 7.14 (dd, J = 7.8
and 1.5 Hz, 1H), 7.21–7.31 (m, 2H), 7.61–7.79 (m, 3H), 7.84 (dd,
J = 7.8 and 1.2 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 8.26 (d, J =
8.1 Hz, 1H), 9.91 (br s, 1H). Minor conformer d 1.15–1.21 (m, 1H,
masked by the major conformer), 3.63–3.77 (m, 1H), 3.81–3.95
(m, 1H), 6.77–8.30 (m, 12H, masked by the major conformer),
9.22 (br s, 1H). Ratio 5.5 : 1. 13C-NMR (CDCl3, 75.5 MHz) d
12.1 (CH3), 44.8 (CH2), 99.4 (Cq), 122.8 (CH), 123.2 (CH), 124.6
(Cq), 124.8 (CH), 128.3 (CH), 128.7 (CH), 129.2 (CH), 129.5 (CH),
130.8 (CH), 130.9 (CH), 131.2 (CH), 133.1 (Cq), 134.1 (CH), 136.9
(Cq), 140.3 (CH), 144.4 (Cq), 146.4 (Cq), 165.0 (Cq), 170.6 (Cq).
IR (film) 3307, 1682 and 1632 cm−1. HRMS calcd for C22H19N3O4I:
516.0415. Found: 516.0406.
N-(2-Iodophenyl)-N-methyl-2-(2-nitrobenzamido)benzamide 5f
To a solution of 3o (371 mg, 1.05 mmol) and pyridine (0.5 mL,
6.19 mmol) in DCM (5 mL) was added 2-nitrobenzoyl chloride
(0.9%, 222 mg, 1.07 mmol). The mixture was stirred overnight at
rt and it was basified with NaHCO3 aqueous saturated solution
and extracted with DCM. The organic extracts were dried, filtered
and the solvent was removed under reduced pressure. The crude
product was purified by flash chromatography (petroleum ether to
petroleum ether–AcOEt 50%) to yield 5f (460 mg, 87%). 1H-NMR
(CDCl3, 300 MHz) major conformer d 3.36 (s, 3H), 6.77 (t, J =
7.5 Hz, 1H), 6.91 (d, J = 8 Hz, 1H), 6.97 (dd, J = 8 and 1.5 Hz, 1H),
7.20–7.29 (m, 3H), 7.63–7.76 (m, 3H), 7.81 (d, J = 8 Hz, 1H), 8.10
(d, J = 8 Hz, 1H), 8.27 (d, J = 8.3 Hz, 1H), 9.97 (br s, 1H). Minor
conformer d 7.14–7.07 (m, 2H), 7.46–7.52 (m, 2H), 7.81–7.96 (m,
1H), 8.39–8.43 (m, 1H), 9.45 (s, 1H), other signals masked by the
major conformer. Ratio 6.5 : 1. 13C-NMR (CDCl3, 75.5 MHz) d
37.8 (CH3), 98.4 (Cq), 122.8 (CH), 123.2 (CH), 124.0 (CH), 124.8
(Cq), 128.6 (CH), 128.7 (CH), 129.2 (CH), 129.8 (CH), 129.9 (CH),
130.8 (CH), 131.0 (CH), 133.0 (Cq), 133.9 (CH), 137.0 (Cq), 140.1
(CH), 146.5 (Cq), 146.7 (Cq), 164.2 (Cq), 170.1 (Cq). IR (film)
3306, 1686, 1631 and 1529 cm−1. HRMS calcd for C21H17N3O4I:
502.0258. Found: 502.0264.
N-Ethyl-N-(2-iodophenyl)-2-(N-methyl-2-
nitrobenzamido)benzamide 5i
To a solution of 5h (99 mg, 0.19 mmol), in dry THF (5 mL),
were added NaH (60%, 43 mg, 1.07 mmol) and methyl iodide
(0.15 mL, 2.40 mmol) and the mixture was stirred overnight at rt
under nitrogen. The residue was partitioned between ethyl acetate
and water, and the aqueous phase was extracted with ethyl acetate.
The organic extracts were dried and filtered and the solvent was
removed under reduced pressure. The crude product was purified
by flash chromatography (petroleum ether to petroleum ether–
AcOEt 50%) to yield 5i (102 mg, quantitative). 1H-NMR (CDCl3,
300 MHz) conformer A d 1.16 (t, J = 6.9 Hz, 3H), 3.28 (s, 3H),
3.66 (dq, J = 7.2 and 6.9 Hz, 1H), 4.58 (dq, J = 7.2 and 6.9 Hz,
1H), 6.76–7.68 (m, 8H), 7.79–8.01 (m, 3H), 8.22–8.27 (m, 1H).
Conformer B d 1.12 (t, J = 7.2 Hz, 3H), 3.20 (s, 3H), 3.53–3.60 (m,
1H), 3.95 (dq, J = 7.5 and 7.2 Hz, 1H), 6.76–8.27 (m, 12H, masked
by the major conformer). Conformer C d 3.52 (s, 3H), other signals
masked by major conformer. Ratio 4.5 : 2 : 1. IR (film) 1650
and 1529 cm−1. HRMS calcd for C23H21N3O4I: 530.0571. Found:
530.0577.
N-(2-Iodophenyl)-N-methyl-2-(N-ethyl-2-
nitrobenzamido)benzamide 5g
To a solution of 5f (98 mg, 0.2 mmol), in dry THF (5 mL), were
added NaH (60%, 39 mg, 0.97 mmol) and ethyl iodide (0.2 mL,
2.48 mmol) and the mixture was stirred at rt under nitrogen
overnight. The residue was partitioned between ethyl acetate and
water, and the aqueous phase was extracted with ethyl acetate.
The organic extracts were dried and filtered and the solvent was
removed under reduced pressure. The crude product was purified
by flash chromatography (petroleum ether to petroleum ether–
N-(2-Iodophenyl)-N-methyl-2-(N-methyl-2-
nitrobenzamido)benzamide 5j
1
AcOEt 50%) to yield 5g (93 mg, 90%). H-NMR (CDCl3, 300
MHz) conformer A d 0.86–1.51 (m, 3H), 3.17–3.85 (m, 1H), 3.27
(s, 3H), 4.78–4.93 (m, 1H), 6.80–8.12 (m, 11H), 8.28–8.32 (m,
1H). Conformer B d 3.42 (s, 3H), other signals masked by major
conformer. Conformer C d 3.23 (s, 3H), other signals masked
by major conformer. Conformer D d 3.46 (s, 3H), other signals
To a solution of 5f (94 mg, 0.19 mmol), in dry THF (5 mL),
were added NaH (60%, 38 mg, 0.95 mmol) and methyl iodide
(0.15 mL, 2.41 mmol) and the mixture was stirred overnight
at rt under nitrogen. The residue was partitioned between ethyl
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acetate and water, and the aqueous phase was extracted with ethyl
acetate. The organic extracts were dried and filtered and the solvent
was removed under reduced pressure. The crude product was
purified by flash chromatography (petroleum ether to petroleum
under reduced pressure. The crude product was purified by flash
chromatography (petroleum ether to petroleum ether–AcOEt
50%) to yield 5m (67 mg, 70%). H-NMR (CDCl3, 300 MHz)
conformer A d 1.25 (t, J = 6.9 Hz, 3H), 3.23 (s, 3H), 3.60–3.90 (m,
2H), 6.54–7.98 (m, 12H). Conformer B d 3.36 (s, 3H), 4.34–4.51
(m, 1H), 4.60–4.74 (m, 1H) other signals masked by the major
conformer. Other conformers masked. Ratio 2 : 1 : ?. IR (film)
1647 cm−1. HRMS calcd for C23H21N2O2INa: 507.0540. Found:
507.0542. HPLC 5.48 min.
1
1
ether–AcOEt 50%) to yield 5j (54 mg, 56%). H-NMR (CDCl3,
300 MHz) conformer A d 3.28 (s, 3H), 3.43 (s, 3H), 6.83–8.27
(m, 12H). Conformer B d 3.22 (s, 3H), 3.31 (s, 3H), 6.83–8.27 (m,
12H). Conformer C d 3.46 (s, 3H), 3.58 (s, 3H), 6.83–8.27 (m,
12H). Ratio 4.2 : 4 : 1. IR (film) 1657, 1650 and 1529 cm−1. HRMS
calcd for C22H19N3O4I: 516.0415. Found: 516.0411.
2-Benzamido-N-benzyl-N-phenylbenzamide 5n
2-Benzamido-N-(2-iodophenyl)-N-methylbenzamide 5k
To a solution of 4g (780 mg, 2.58 mmol) and pyridine (1 mL,
12.4 mmol) in DCM (10 mL) was added benzoyl chloride (0.4 mL,
3.44 mmol). The mixture was stirred overnight at rt and it was
basified with NaHCO3 aqueous saturated solution and extracted
with DCM. The organic extracts were dried and filtered and
the solvent was removed under reduced pressure. The crude
product was purified by flash chromatography (petroleum ether
To a solution of 3o (399 mg, 1.13 mmol) and pyridine (0.5 mL,
6.19 mmol) in DCM (5 mL) was added benzoyl chloride (0.2 mL,
1.72 mmol). The mixture was stirred at rt overnight and it
was basified with NaHCO3 aqueous saturated solution and
extracted with DCM. The organic extracts were dried, filtered
and the solvent was removed under reduced pressure. The crude
product was purified by flash chromatography (petroleum ether
1
to petroleum ether–AcOEt 50%) to yield 5n (1.03 g, 98%). H-
1
to petroleum ether–AcOEt 50%) to yield 5k (335 mg, 65%). H-
NMR (CDCl3, 500 MHz) major conformer d 5.16 (s, 2H), 6.71
(ddd, J = 8, 7.5 and 1 Hz, 1H), 6.87–6.90 (m, 2H), 6.93 (dd,
J = 7.5 and 1 Hz, 1H), 7.09–7.17 (m, 3H), 7.21–7.23 (m, 3H),
7.25–7.30 (m, 3H), 7.52 (dd, J = 7.5 and 7 Hz, 2H), 7.58 (ddd,
J = 7.5, 7 and 1.5 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 8.40 (dd,
J = 8.5 and 1 Hz, 1H), 10.51 (s, 1H). Minor conformer d 7.46
(dd, J = 8 and 7.5 Hz, 1H), 8.10 (dd, J = 8.5 and 1 Hz, 1H),
other signals masked by the major conformer. Ratio 8 : 1. 13C-
NMR (CDCl3, 125 MHz) d 54.0 (CH2), 121.9 (CH), 122.4 (CH),
123.8 (Cq), 127.06 (CH), 127.16 (2CH), 127.23 (2CH), 127.5 (CH),
128.0 (2CH), 128.5 (2CH), 128.8 (2CH), 129.2 (2CH), 129.3 (CH),
130.8 (CH), 131.9 (CH), 134.4 (Cq), 136.9 (Cq), 138.0 (Cq), 143.1
(Cq), 165.1 (Cq), 170.2 (Cq). IR (film) 3332, 1677 and 1632 cm−1.
HRMS calcd for C27H23N2O2: 407.1754. Found: 407.1752.
NMR (CDCl3, 500 MHz) major conformer d 3.41 (s, 3H), 6.71 (t,
J = 7.5 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 7.5 Hz,
1H), 7.10 (d, J = 7.3 Hz, 1H), 7.23–7.29 (m, 2H), 7.52–7.57 (m,
3H), 7.78 (d, J = 7.7 Hz, 1H), 8.04 (d, J = 7 Hz, 2H), 8.48 (d,
J = 8.3 Hz, 1H), 10.70 (s, 1H). Minor conformer d 3.34 (s, 3H),
7.65–7.70 (m, 1H), 7.94–8.00 (m, 2H), 8.50–8.57 (m, 1H), 10.05
(s, 1H), other signals masked by the major conformer. Ratio 4.5 :
1. 13C-NMR (CDCl3, 125 MHz) d 38.0 (CH3), 98.5 (Cq), 121.9
(CH), 122.1 (CH), 122.9 (Cq), 127.3 (2CH), 128.8 (2CH), 129.0
(CH), 129.1 (CH), 129.57 (CH), 129.60 (CH), 131.1 (CH), 131.9
(CH), 134.6 (Cq), 138.3 (Cq), 140.3 (CH), 146.7 (Cq), 165.0 (Cq),
170.6 (Cq). IR (film) 3337, 1676 and 1634 cm−1. HRMS calcd for
C21H18N2O2I: 457.0407. Found: 457.0406.
2-(N-Benzylbenzamido)-N-(2-iodophenyl)-N-methylbenzamide 5l
N-Benzyl-2-(N-benzylbenzamido)-N-phenylbenzamide 5o
To a solution of 5k (93 mg, 0.20 mmol), in dry THF (5 mL),
were added NaH (60%, 30 mg, 0.75 mmol) and benzyl bromide
(0.1 mL, 0.84 mmol) and the mixture was stirred overnight at rt
under nitrogen. The mixture was partitioned between ethyl acetate
and water, and the aqueous phase was extracted with ethyl acetate.
The organic extracts were dried and filtered and the solvent was
removed under reduced pressure. The crude product was purified
by flash chromatography (petroleum ether to petroleum ether–
AcOEt 50%) to yield 5l (81 mg, 73%). 1H-NMR (CDCl3, 300 MHz)
conformer A d 3.25 (s, 3H), 4.24 (d, J = 15 Hz, 1H), 6.05 (d,
J = 15 Hz, 1H), 6.55–7.97 (m, 18H). Conformer B d 3.42 (s,
3H) other signals masked by major conformer. Other conformers
masked. Ratio 1.33 : 1 : ?. IR (film) 1651 cm−1. HRMS calcd for
C28H23N2O2INa: 569.0696. Found: 569.0697. HPLC 5.45 min.
To a solution of 5n (205 mg, 0.50 mmol), in dry THF (5 mL),
were added NaH (60%, 80 mg, 2 mmol) and benzyl bromide
(0.3 mL, 2.51 mmol) and it was stirred overnight at rt under
nitrogen. The mixture was partitioned between ethyl acetate and
brine, and the aqueous phase was extracted with ethyl acetate.
The organic extracts were dried and filtered and the solvent was
removed under reduced pressure. The crude product was purified
by flash chromatography (petroleum ether to AcOEt) to yield
1
5o (188 mg, 75%). H-NMR (CDCl3, 300 MHz) d 4.10 (d, J =
15 Hz, 1H), 5.10–5.30 (m, 2H), 5.97 (d, J = 15 Hz, 1H), 6.54–7.70
(m, 24H). IR (film) 1644 cm−1. HRMS calcd for C34H28N2O2Na:
519.2043. Found: 519.2044. HPLC 5.42 min.
Attempted synthesis of ethyl 2-(2-[N-benzyl-2-
iodobenzamido]benzamido)benzoate
2-(N-Ethylbenzamido)-N-(2-iodophenyl)-N-methylbenzamide 5m
A solution of 3i (200 mg, 0.44 mmol) in thionyl chloride (5 mL) was
refluxed for 3 h. The excess of thionyl chloride was removed under
reduced pressure and the residue was dissolved in AcOEt (10 mL).
To a solution of 5k (90 mg, 0.197 mmol), in dry THF (5 mL), were
added NaH (60%, 45 mg, 1.125 mmol) and ethyl iodide (0.2 mL,
2.49 mmol) and it was stirred at rt under nitrogen overnight.
The mixture was partitioned between ethyl acetate and water, and
the aqueous phase was extracted with ethyl acetate. The organic
extracts were dried and filtered and the solvent was removed
◦
The solution was cooled to 0 C and Et3N (0.5 mL, 3.59 mmol)
and ethyl 2-aminobenzoate (65 lL, 0.44 mmol) were added.
The mixture was allowed to warm to rt and stirred overnight.
The mixture was partitioned between ethyl acetate and aqueous
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NaHCO3 saturated solution, and the aqueous phase was extracted
with ethyl acetate. The organic extracts were dried and filtered
and the solvent was removed under reduced pressure. The crude
product was purified by flash chromatography (DCM) to yield 2-
(2-iodophenyl)-4H-benzo[d][1,3]oxazin-4-one 6a (114 mg, 75%).
1H-NMR (CDCl3, 300 MHz) d 7.24 (ddd, J = 7.8, 7.5 and 1.8 Hz,
1H), 7.53 (td, J = 7.5 and 1.2 Hz, 1H), 7.63 (td, J = 7.5 and
1.2 Hz, 1H), 7.79 (dd, J = 8.1 and 1.2 Hz, 1H), 7.89 (td, J =
7.8 and 1.8 Hz, 1H), 7.91 (td, J = 8.1 and 1.5 Hz, 1H), 8.08 (dd,
J = 7.8 and 1.2 Hz, 1H), 8.33 (dd, J = 7.8 and 1.5 Hz, 1H). 13C-
NMR (CDCl3, 75.5 MHz) d 94.6 (Cq), 116.9 (Cq), 127.3 (CH),
128.2 (CH), 128.6 (CH), 129.0 (CH), 130.9 (CH), 132.3 (CH),
135.5 (Cq), 136.7 (CH), 141.1 (CH), 146.2 (Cq), 157.8 (Cq), 159.2
(Cq). IR (film) 1764 cm−1. HRMS calcd for C14H9NO2I: 349.9672.
Found: 349.9672. Anal. calcd for C14H8NO2I (349.1) C, 48.16; H,
2.31; N, 4.01. Found: C, 48.59; H, 2.30; N, 3.96%. Mp 120–122 ◦C.
aqueous phase was extracted with DCM. The organic extracts
were dried and filtered and the solvent was removed under reduced
pressure. The crude product was purified by flash chromatography
(petroleum ether to petroleum ether–AcOEt 50%) to yield 7b
1
(91 mg, 85%). H-NMR (CDCl3, 300 MHz) major conformer
d 3.26 (s, 3H), 7.14 (ddd, J = 7.8, 7.5 and 1.8 Hz, 2H), 7.33–7.37
(m, 2H), 7.44 (dd, J = 7.2 and 0.9 Hz, 2H), 7.46–7.52 (m, 2H),
7.57–7.60 (m, 2H), 7.91 (d, J = 7.8 Hz, 2H). Minor conformer
d 3.57 (s, 3H), 6.88 (td, J = 7.8 and 1.5 Hz, 2H), 7.04–7.92 (m,
8H, masked by the major conformer), 7.79 (d, J = 7.8 Hz, 2H).
Ratio 5 : 1. 13C-NMR (CDCl3, 75.5 MHz) d 39.9 (CH3), 92.4 (Cq),
126.9 (CH), 128.4 (CH), 129.3 (CH), 130.5 (CH), 130.6 (Cq), 139.5
(CH), 142.1 (Cq), 170.5 (Cq). IR (film) 1649 cm−1. HRMS calcd
for C22H19N2O2I2: 596.9530. Found: 596.9530. HPLC 5.50 min.
N,Nꢀ-Dibenzyl-N,Nꢀ-di(2-iodobenzoyl)benzene-1,2-diamine 7c
To a suspension of 7a (126 mg, 0.22 mmol) in THF (25 mL),
were added NaH (60%, 96 mg, 2.4 mmol), and benzyl bromide
(0.25 mL, 2.09 mmol). The mixture was stirred at rt under nitrogen
for 24 h. The residue was partitioned between DCM and water, and
the aqueous phase was extracted with DCM. The organic extracts
were dried and filtered and the solvent was removed under reduced
pressure. The crude product was purified by flash chromatography
(petroleum ether to petroleum ether–AcOEt 50%) to yield 7c
(132 mg, 79%). 1H-NMR (CDCl3, 300 MHz) d 4.33–4.97 (m,
4H), 5.95–6.05 (m, 1H), 6.56–7.93 (m, 21H). Complex mixture of
conformers. IR (film) 1649 cm−1. HRMS calcd for C34H27N2O2I2:
749.0156. Found: 749.0154.
Attempted synthesis of ethyl 2-(2-[N-benzyl-1-
naphthamido]benzamido)benzoate
A solution of 3g (468 mg, 1.23 mmol) in thionyl chloride (10 mL)
was refluxed for 3 h. The excess of thionyl chloride was removed
under reduced pressure and the residue was dissolved in AcOEt
(12 mL). The solution was cooled to 0 ◦C and Et3N (2.6 mL,
18.6 mmol) and ethyl 2-aminobenzoate (0.18 mL, 1.22 mmol)
were added. The mixture was allowed to warm to rt and stirred
overnight. The mixture was partitioned between ethyl acetate and
aqueous NaHCO3 saturated solution, and the aqueous phase
was extracted with ethyl acetate. The organic extracts were
dried and filtered and the solvent was removed under reduced
pressure. The crude product was purified by flash chromatography
(DCM) to yield 2-(naphthalen-4-yl)-4H-benzo[d][1,3]oxazin-4-
one 6b (289 mg, 86%). 1H-NMR (CDCl3, 300 MHz) d 7.53–7.61
(m, 3H), 7.66 (ddd, J = 8.4, 6.9 and 1.5 Hz, 1H), 7.79 (dd, J =
8.1 and 1.2 Hz, 1H), 7.85 (dd, J = 6.9 and 1.5 Hz, 1H), 7.92 (dd,
J = 8.1 and 1.5 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 8.29 (dd,
J = 7.8 and 1.2 Hz, 1H), 8.31 (dd, J = 7.5 and 1.2 Hz, 1H), 9.15
(d, J = 8.4 Hz, 1H). 13C-NMR (CDCl3, 75.5 MHz) d 116.8 (Cq),
124.7 (CH), 125.7 (CH), 126.3 (CH), 126.8 (Cq), 127.3 (CH), 127.8
(CH), 128.46 (CH), 128.54 (CH), 128.8 (CH), 130.0 (CH), 130.7
(Cq), 133.1 (CH), 134.0 (Cq), 136.5 (CH), 146.7 (Cq), 157.6 (Cq),
159.7 (Cq). IR (film) 1762 cm−1. HRMS calcd for C18H12NO2:
274.0863. Found: 274.0863. Mp 108–130 ◦C.
X-Ray crystallography
Data for the X-ray crystal structures described in this paper have
been deposited with the Cambridge Crystallographic database.†
3a. Crystal data C20H15I2NO; M = 539.13; triclinic P-1; a =
˚
˚
˚
9.0770(8) A; b = 10.3330(9) A; c = 10.9250(9) A; a = 95.4550(10);
3
˚
b = 101.4960(10); c = 106.2000(10); V = 951.82(14) A ; T =
100(2) K; Z = 2; l = 3.310 mm−1; 8260 reflections; Rint = 0.0128;
R(F) 0.0188; CCDC reference number 299474.
3b. Crystal data C20H14I3NO; M = 665.02; orthorhombic
˚
˚
˚
Pbcn; a = 17.2130(10) A; b = 14.9120(8) A; c = 15.6580(9) A;
3
−1
˚
V = 4019.1(4) A ; T = 100(2) K; Z = 8; l = 4.674 mm ; 33041
reflections; Rint = 0.0250; R(F) 0.0255; CCDC reference number
299475.
N,Nꢀ-Di(2-iodobenzoyl)benzene-1,2-diamine 7a
7b. Crystal data C22H18I2N2O2·CH2Cl2; M = 681.11; mono-
To a solution of 1,2-diaminobenzene (255 mg, 2.36 mmol) and
pyridine (1 mL, 12.4 mmol) in DCM (10 mL), was added 2-
iodobenzoyl chloride (1.24 g, 4.65 mmol). The mixture was stirred
at rt under nitrogen for 24 h. To the resulting suspension petroleum
ether was added and the mixture was filtrated to obtain 7a as
an unsoluble solid (1 g, 75%) which was used without further
purification. m/z (ES−) 567 (100%, M–H+).
˚
˚
˚
clinic P2(1); a = 7.984(5) A; b = 24.878(5) A; c = 12.520(5) A;
3
−1
˚
V = 2459.5(19) A ; T = 100(2) K; Z = 4; l = 2.797 mm ; 14331
reflections; Rint = 0.0267; R(F) 0.0411; CCDC reference number
299476.
Acknowledgements
We are grateful to the EU Marie Curie programme, MEC (Spain,
EX2004-0501), the Leverhulme Trust and the EPSRC for funds.
N,Nꢀ-Di(2-iodobenzoyl)-N,Nꢀ-dimethylbenzene-1,2-diamine 7b
To a suspension of 7a (102 mg, 0.18 mmol) in THF (25 mL), was
added NaH (60%, 60 mg, 1.5 mmol), and methyl iodide (0.50 mL,
8.04 mmol). The mixture was stirred at rt under nitrogen for 24 h.
The residue was partitioned between DCM and water, and the
† CCDC reference numbers 299474 (3a); 299475 (3b); 299476 (7b).
For crystallographic data in CIF or other electronic format see DOI:
10.1039/b602912d
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