Conformational studies of tertiary oligo-m-benzanilides and oligo-p-benzanilides in solution

Tetrahedron 66 (2010) 6936e6957

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Tetrahedron

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Conformational studies of tertiary oligo-m-benzanilides and oligo-p-benzanilides

in solution

*

Laurent Chabaud, Jonathan Clayden , Madeleine Helliwell, Abigail Page, James Raftery, Lluís Vallverdú

School of Chemistry, University of Manchester, Oxford Rd., Manchester M13 9PL, UK

a r t i c l e i n f o

a b s t r a c t

Article history:

A series of oligo-m- and p-benzanilides were made and their conformations in solution were studied by

NMR. In most cases, conformational mixtures were observed as soon as three or more monomers were

incorporated into the oligomer. Some crystal structures were obtained, which indicated that helical

conformations were adopted in the solid state.

Received 22 March 2010

Received in revised form 28 May 2010

Accepted 14 June 2010

Available online 18 June 2010

1. Introduction

or urea linkage to provide stability and rigidity.^3e6For example,

secondary benzanilides A generally adopt a rings-trans (formally Z)

Amide bond structure has been studied extensively, because the

amide moiety is one of the most important functions in biological

systems.¹Numerous synthetic foldamers,²or oligomers with a well-

deﬁned conformation, have been described which use the amide

conformation (Fig. 1) and their oligomers have proven to adopt

a well-deﬁned helical structure, a consequence of both the pre-

ferred geometry of the amide bonds and their hydrogen bonding

ability.⁴

(A)

(B)

(C)

(D)

Figure 1. Conformational control in amides.

* Corresponding author. E-mail address: clayden@man.ac.uk (J. Clayden).

doi:10.1016/j.tet.2010.06.037

L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

6937

The conformation of N-alkylated anilides has also been in-

vestigated in detail, and it has been shown that N-alkylated benza-

nilides favour the conformation B, which places the aryl rings cis

(formally E) in the crystal and in solution.⁷The conformational ratio

of tertiary benzamides can be altered by the size of substituents at the

aromatic ortho position and on the nitrogen atom.^8,9For instance, we

showed that benzanilide C bearing two iodo substituents at the ortho

position of each ring and a benzyl group on the nitrogen exhibit high

conformational control (10:1).⁹The ability of N-alkylated and para-

linked oligobenzanilides to adopt a secondary helical structure in

solution and in the solid state has been studied by Tanatani et al.¹⁰

Crystal data suggested that the helical structures are enforced

mainly by the inherent structural propensities of aromatic amide

bonds, such as regularity of amide torsion angles, as well as the cis

conformation of the amide bonds and the syn arrangement of the

benzene rings. Wilson has shown that this helical preference can be

used to favour a macrocyclisation reaction.¹¹A terminal planar chiral

residue can control the resulting screw sense of the helical oligomer

as judged by circular dichroism.¹²meta-Linked benzanilides carrying

terminal carboxylic acid functions,¹³and N-methyl aromatic amide

bearing 2,6-disubstitued pyridines, also adopt a well-deﬁned con-

formation in solution.¹⁴An NMR study of related oligo ortho-linked

oligobenzanilides concluded that conformational communication

breaks down once the chain is extended to greater than three

monomers, and mixtures of conformers are evident by NMR.⁹

Our interest in the solution structure of oligomeric amides stems

for attempts to use them as a scaffold through which stereochemical

information might be relayed in the form of conformational

changes.^15e20Thus, we showed that dipole interactions within

trisxanthenehexacarboxamide D were able to mediate remote

asymmetric induction over a total of 23 bond lengths.¹⁵We recently

reported the use of NMR to examine the extent to which oligomeric

ureas⁶and peptide-like oligo-Aib amides²¹adopt a helical structure,

and in this paper we now report on the conformational behaviour of

unsubstituted and substituted oligo(m-benzanilides) 1aec (Fig. 2).

We also report preliminary studies on some analogous oligomers,

principally those of p-aminobenzoic acid. Much of the work made

use of low temperature NMR analysis, and it became a signiﬁcant

challenge to establish whether a single set of peaks was due to

a single conformer or to sets of rapidly interconverting oligomers in

fast exchange. In most cases more extended oligomers frequently

showed mixtures of conformers. Our pragmatic aim of identifying

well-controlled oligomeric structures meant that the question of

whether this is due to a slowing of rotation with greater steric

hindrance, or due to a loss of control in more complex systems was

in these cases left unanswered.

reduced with tin(II)chloride; reaction with a further equivalent of

the freshly prepared acid chloride derivative of 2aec gave the

secondary amides 5.⁵Alkylation was achieved by treating amides 5

with sodium hydride and then quenching with MeI or BnBr to

Figure 2. Oligo(m-benzanilides) 1aec (n¼0e2).

2. Results and discussion

The general approach to the oligomers 1 derived from m-ami-

nobenzoic acid is depicted in Scheme 1. The synthesis began with

commercially available 3-nitrobenzoic acid or its methylated ana-

logues 2aec. These were converted into the corresponding acid

chlorides using thionyl chloride or oxalyl chloride and condensed

with N-methylaniline or N-benzylaniline under basic conditions

(Et₃N or pyridine) to yield monomers 4. The nitro group was

Scheme 1. Synthesis of oligo(m-benzamides).

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L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

generate the set of six diamides 6. The sequence of nitro group

reduction, acylation (to give the seven triamides 7) and alkylation

was then repeated to increase the length of oligomers, ﬁnally

supplying the set of fully alkylated triamides 8.

2.1. Conformational analysis of oligo-m-benzanilides 1a

We ﬁrst examined the conformational behaviour of simple,

unsubstituted oligo(m-benzamides) 1a (R¹¼Bn, R²¼Me), exempli-

ﬁed by diamide 6a and triamide 8a. A characteristic shift of aro-

matic protons upﬁeld was evident on alkylation of the secondary

amides 5a and 7a to yield the tertiary amides 6a and 8a, suggesting

adoption of a cis amide geometry as expected.^7,8A simple, well

resolved spectrum at 25 ^ꢀC suggested that 8a was conformationally

uniform about the CeN bond of the amides.⁹However lack of ev-

ident diastereotopicity in the geminal CH₂Ph protons of the benzyl

group of 6a or 8a indicated that if a helical structure was present in

solution, the enantiomeric helices were interconverting rapidly on

the NMR timescale and therefore not amenable to study by NMR.⁶

Modiﬁcation was therefore made to the structure of 8a by li-

gating 6a with 2-iodobenzoyl chloride to yield 7a⁰and hence 8a⁰

Because of expected slow rotation about the AreCO axis of the

iodobenzamide unit,²²we hoped that coupling of the rate of helical

inversion with this bond rotation would allow us to detect helicity

from evidence of local chirality in the form of the CH₂signal arising

from the terminal N-benzyl group of 8a⁰. However, at 25 ^ꢀC and at

ꢁ60 ^ꢀC in CDCl₃these signals appeared as a simple 2H singlet. This

suggests that 8a⁰is either not helical, or that the o-iodophenyl

substituent is unable to induce a preferred helicity in 8a⁰.

Figure 3. Conformational stereochemical features of 6e8.

2.2. Conformational analysis of oligo-4-methyl-m-

benzanilides 1b

Commercially available 4-methyl-3-nitrobenzoic acid was chosen as

the starting material for oligomers 1b (R¹¼Bn, exempliﬁed by 6b,

6b⁰, 8b and 8b⁰) with the intention that the additional aromatic

Lack of informative data from NMR of 8a,a⁰led us to adopt a more

stepwise approach to identiﬁcation of conformational preferences.

Table 1

Conformational isomerism

Amide linkages

Possible observable amide

Possible observable AreN

and AreCO diastereoisomeric

conformers^b

Ratio of conformers evident in NMR^c

NeCO cis/trans conformers^a

6b

6b⁰

7b

7b⁰

8b

8b⁰

6c

2

3

2

4

8

4

1

>95:5

90:10

>95:5

1^d

1

1^d

2

4

60:30:10

e

80:20

6c⁰

88:12 (ꢁ60 ^ꢀC)

82:18 (C₆D₆)

87:13 (THF)

87:13 (DMSO)

85:15

84:16

>95:5

77:23

75:25

6c⁰⁰

6d

6e

2

3

4

8

4

2 (or 4)

2

4

7c

7c⁰

7c⁰⁰

7d

7e

4

83:17

95:5

2 (or 4)

2

16

4 (or 16)

4

90:10

e

8c

e

8c⁰

8c⁰⁰

8d

8e

a

Excluding secondary amides, which always lie trans.

On the basis that one 2-substituent is required for the observation of conformers in tertiary benzamides and anilides [Refs. 22e25].

In CDCl₃at 23 ^ꢀC unless otherwise indicated.

A pair of slowly interconverting enantiomeric conformers indicated by diastereotopicity in the CH₂Ph group.

Complex mixture of conformers.

b

c

d

e

L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

6939

methyl group ortho to the nitrogen atom would slow the rotation

about each AreN bond to the point that diastereoisomeric confor-

mations would be distinguishable by NMR.^22e24Figure 3 shows

conformational possibilities available to these and related structures,

and Table 1 includes an analysis of the likely number of conformers

available to each oligomer studied, along with the conformational

ratio actually observed by ¹H NMR at ambient temperature or below.

In 1b however the AreCO bonds in such structures remain un-

encumbered by ortho substituents and so are unable to give rise to

distinguishable AreCO conformers.²⁵The ¹H NMR spectrum in

CDCl₃at rt suggested that compound 5b exists as a single conformer

with regard to the NeCO bonds (presumably the secondary amide

being trans and the tertiary being cis).^7,8N-Alkylation using methyl

iodide or benzyl bromide gave the diamides 6b and 6b⁰, respectively

again as single (presumably cis,cis) NeCO conformers by NMR. In-

terestingly, these compounds displayed diastereotopic benzylic

protons as a result of the slow rotation (on the NMR timescale) about

the AreN bond. In contrast, the benzylic protons of amide 5b are not

diastereotopic, because rotation about the AreN bond of a secondary

anilide is fast on the NMR timescale.²⁶

selectivities obtained in C₆D₆(82:18), THF-d₈(87:13) and DMSO-d₆

(87:13).

2.4. Detailed analysis of 6c⁰

Although disappointingly not conformationally uniform, the fact

that only two conformers appear to predominate in compound 6c⁰

with the potential to exhibit (on the NMR timescale) four geo-

metrical (cis/trans) amide conformers multiplied by four axial (syn/

syn, syn/anti etc.) conformers (Fig. 4) was remarkable. We were un-

able to determine directly which of the conformers is this principal

component in solution, although X-ray crystallography²⁷allowed us

to determine the solid state structure of 6c⁰(Fig. 5).

Addition of the third residue created the triamides 7b and 7b⁰

(entries 6 and 7). Although 7b⁰appeared as one conformer in so-

lution, a small amount of a second conformer (in which a clearly

deshielded aromatic proton was observable) was evident in 7b,

presumably arising from population of the trans conformer of the

tertiary amide, now that the cis amide bond has become signiﬁ-

cantly more hindered.^8,9

Figure 4. Conformer possibilities in 6c⁰.

After alkylation, trimers 8b and 8b⁰clearly existed as a mixture

of conformers in CDCl₃at 25 ^ꢀC. Although it was not possible to

determine the ratio of conformers of the N-benzylated trimer 8b⁰,

we quantiﬁed the ratio of the three conformers of 8b evident in the

¹H NMR spectrum at 25 ^ꢀC as 60:30:10. The signiﬁcant new feature

possessed by 8b is the possibility of syn/anti diastereoisomeric

conformers arising from two slowly rotating AreN bonds: we as-

sumed that population of both of these alternatives gives rise to the

2:1 ratio, while the further minor conformer represents population

of the trans NeCO isomer of the amide.

2.3. Conformational analysis of oligo-2-methyl-m-

benzanilide 1c

Oligomers 1c(represented by 6cec⁰⁰and 8cec⁰⁰) inwhich a methyl

group intervenes between the AreN and AreCO bond were in-

vestigated. Slowingofrotation about both bonds potentiallygives rise

to a syn/anti pair of conformers for each aromatic residue in the oli-

goamide, and thus provides a stringent test of whether conformation

is being controlled in the solution state. The overall yield and con-

formational ratios of the monomers and dimers are listed in Table 1.

As before, fast conformational exchange means that diamides

5cec⁰having a secondary amide exhibit a sharp, clean spectrum.

After alkylation, the tertiary diamides 6cec⁰⁰were however present

in solution as a mixture of two major conformers in a ratio of 4:1 to

7.5:1 depending on solvent and temperature. In some cases, addi-

tional minor conformers were also detectable by ¹H NMR but could

not be quantiﬁed. All three diamides 6cec⁰⁰were found to have

Figure 5. X-ray crystal structure of 6c⁰.

Both amide bonds adopt a cis CeN conformation, in line with

precedent, and as we have previously observed, methyl groups on

each aromatic ring ﬂanking the benzanilide amide function are

aligned anti to avoid steric interaction.⁹The cis orientation of benz-

amides across the central aromatic ring can be explained by

a dipoleedipole interaction (shown in Fig. 5) between both amide

functions.²⁸Unfortunately, wewereunableto determinewhetherthe

conformation in the solid state is the same as the major conformation

in solutionddissolving a crystal of 6c⁰at low temperature (ꢁ50 ^ꢀC)

and acquiring a ¹H NMR spectrum immediately returned the same

mixture of conformers as that obtained on cooling a rt solution.

In an attempt to establish which of the conformational features

of 6c⁰are well controlled, and hence identify the second, minor,

conformer, we made analogues of 6c⁰lacking one or more of the

conformationally restricted amide NeCO, AreCO or AreN bonds.

Compounds 9, 12 and 13 were made by the methods shown in

Scheme 2.

1

broadened H NMR signals at 25 ^ꢀC, with diastereotopic benzylic

protons providing evidence of slow rotation on the NMR timescale

about the AreCO and/or AreN bonds. The results revealed that the

size of the R¹group (¼Me or Bn) has virtually no inﬂuence on the

conformational selectivity (compare 6c, 6c⁰). However, the selectivity

slightly increases when R²is increased in size from Me to Bn (cf. 6c⁰,

6c⁰⁰). At low temperature (ꢁ60 ^ꢀC, CDCl₃), ¹H NMR shows an im-

provement of conformational ratio to 88:12, but with signals still

remaining broadened. Solvent effects on the conformational ratio of

6c⁰were also studied at 25 ^ꢀC, with marginally better conformational

The ¹H NMR spectrum of 9 was revealing: it showed two con-

formers in a ratio of 90:10, which must be rotamers about the NeCO

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L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

The major conformer of 9, which presumably has the two aryl rings

cis about the NeCO bond as illustrated in Figure 6, has an AreCO

barrier too low to exhibit rotamers (enantiomeric in this case) at rt,

evenwith alarge2-iodo substituent. Thispresumably reﬂects the small

size of the NePh group, an effect, which has not been studied in detail

before.²²It seemed possible that the apparent conformational unifor-

mity of 6c⁰is likewise due to fast AreCO bond rotation, although the

fact that little change in the ratio of conformers is seen on lowering the

temperature to ꢁ60 ^ꢀC suggests this is unlikely.

Amide 12, which possesses the possibility of cis/trans isomerism

and also possibly syn/anti isomerism about a single NeCO bond

shows at 25 ^ꢀC only one conformer in the ¹H NMR spectrum, a re-

sult in accordance with previous work on 2,2⁰-disubstituted ben-

zanilides.⁹Low temperature (ꢁ65 ^ꢀC) NMR spectra of 12 however

showed much more complex behaviour, with at least four or ﬁve

conformers evident. We assume that, as in 9, this may be due to

AreCO rotamers becoming spectroscopically distinguishable only

at low temperature, and these spectra were not analysed further.

Compound 13 has the possibility of syn/anti conformational

isomerism, along with the possibility of cis/trans isomerism about

two amide bonds. At rt, only a single set of peaks is again observed,

but at temperatures below ꢁ50 ^ꢀC, four sets of signals arise in ratio

of 69:18:7:6. We assume that the major conformers (which both

have downﬁeld benzylic CH₂protons) arise from syn/anti isomer-

ism, as before with a barrier to AreCO rotation too low to allow

these diastereoisomeric structures to be distinguishable at ambient

temperature. The minor conformers (one of which has an upﬁeld

CH₂group) are presumably due to cis/trans isomerism.

2.5. Extending the oligomers: 7cec⁰⁰, 8cec⁰⁰

Although mixtures ofconformers wereobservedfor 6 in solution,

we decided to extend the investigation to triamides 7cec⁰⁰, 8cec⁰⁰.

These were made as before by reduction, amide formation and al-

kylation (Scheme 1). Addition of a secondary amide group, expected

to adopt a trans conformation and to show fast AreCO rotation, in-

troduces no new conformational complexity to these compounds,

and indeed the conformational ratio of secondary amides 7cec⁰⁰

(Table 1) is about the same as that of dimers 6cec⁰. However, on

alkylation, the possibility of further cis/trans isomerism and of slow

AreCO rotation arises, and the ¹H NMR spectrum of fully alkylated

compounds 8cec⁰⁰indicates that these tertiary triamides exist as

a mixture of at least four NMR-distinguishable conformers at 25 ^ꢀC

in CDCl₃, whatever the size of the nitrogen substituents.

Scheme 2. Synthesis and conformation of 9, 12 and 13.

bond (Fig. 6). The CH₂Ph group of minor rotamer appeared as a sharp

AB system (due to slow AreCO rotation) at ambient temperature.

However, the CH₂Ph group of the major conformer was a broadened

singlet at rt, which decoalesced to an AB system on cooling to ꢁ50 ^ꢀCin

CDCl₃. By variable temperature NMR, modelling the resulting line-

shapes, and ﬁtting the rates obtained to the Eyring equation (see

Supplementary data) we obtained a barrier to rotation about the

AreCO bond in the major (rings-cis) conformer of 50.1 kJ mol^ꢁ1at

25 ^ꢀC. The corresponding barrier to rotation in the minor (rings-trans)

conformer was 62.6 kJ mol^ꢁ1at 25 ^ꢀC; interestingly this also shows

that NeCO rotation must be slow, or otherwise a stepwise mechanism

for AreCO bond rotation of the minor conformer would exist by in-

terconversion with the major conformer.

2.6. Hybrid meta- and ortho- or para-substituted aromatic

amides

In view of the low conformational control in diamides 6cec⁰⁰and

triamides 8cec⁰⁰we decided to modify the substitution pattern of the

oligomers. It appeared that while some conformational control was

evident in the diamides, control breaks down in triamides 8cec⁰⁰.

Figure 6. Barriers to bond rotation in 9.

L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

6941

Thus, we decided to investigate the effect on the selectivity of the

substitution pattern of the second benzamide ring. We had already

studied the control evident in compounds with a benzamide AreCO

and an anilide AreN axis arranged ortho on a single ring.⁹Compounds

7d, eand 8d, ewere madebystandard methods asshown in Scheme 3.

Benzamides 5dee appear one conformer in solution by ¹H NMR

at 23 ^ꢀC in CDCl₃and display no diastereotopic benzylic protons.

Alkylation of 5d led to 6d, which appears to exists as an 84:16

mixture of conformers (CDCl₃, 25 ^ꢀC) much like the related struc-

tures 6cec⁰⁰having an ortho-methyl group. By contrast, compound

6e displays only one set of peaks by ¹H NMR at ambient tempera-

ture in solution.

on the same side of the aromatic ring.²⁹In solution, two major

conformers were observed arising from the syn/anti relationship

along the benzene ring. Shudo also investigated the conformational

behaviour of 1,2-bis(N-benzoyl-N-methylamino)benzene.³⁰This

compound displays broad ¹H NMR signals at rt, but exists as

a mixture of seven conformers in solution at ꢁ88 ^ꢀC (CD₂Cl₂) with

the anti (along the aromatic ring), cis/cis (amide) predominating.

We hoped to combine these two meta-substituted units into

oligomers containing alternating meta-phenylenediamine and

isophathalic acid units, and as a preliminary to this we made the

two amides 17a and 17b (Scheme 4). Although in this particular

example the ﬁnal compounds are symmetrical, we used 2-methyl-

3-nitrobenzenamine 16 as a precursor that would offer the op-

portunity to obtain non symmetrical oligomers.

M

Scheme 4. Synthesis and conformational studies of meta-diamidobenzene.

Unfortunately, at 25 ^ꢀC in CDCl₃a mixture of two conformers was

observed for both 17a and 17b in a 2:1 ratio. Proton NMR suggests

that both amides have cis geometry, so the conformers probably arise

from syn and anti isomerism at the central aromatic ring. In light of

these results, we did not extend this investigation to oligomers.

Scheme 3. Synthesis of hybrid meta and ortho- or para-substituted benzanilides.

2.8. More extended substituted oligo-m-benzamides

Trimer 8d bearing an ortho-substituted benzamide was then

synthesized. A mixture of several conformers was identiﬁed by ¹H

NMR, presumably due to poor conformational control through the

ortho-benzamide, as we previously observed for related com-

Although it seemed at this stage that increasing the number of

conformationally labile bonds was simply allowing more conformers

to be populated, it seemed possible that order would be regained

once a helical global secondary structure could be obtained: chain-

length dependence is a common feature of foldamer properties. We

therefore increased the length of the oligomer to encourage the

molecule to fold into awell-deﬁned structure, and exist mainlyas one

conformer in solution. Unfortunately, the pentamer (1c, R¹¼Bn,

R²¼Me, n¼3) and hexamer (1c, R¹¼Bn, R²¼Me, n¼4) were still

a mixture of conformers in solution at 25 ^ꢀC (CDCl₃).

1

pounds.⁹H NMR of 8e at 25 ^ꢀC in CDCl₃was uninformative:

a mixture of broad peaks was evident, and low temperature NMR at

ꢁ60 ^ꢀC failed to clarify the situation.

2.7. Oligomers from m-diaminobenzene and

m-benzenedicarboxylic acid

We have reported that tertiary benzene-1,3-dicarboxamides 14

with a methyl substituent interposed between the amides adopt an

anti orientation, driven by dipole interaction.²⁸Shudo et al. have

studied the conformation in solution and solid state of N,N⁰-

dimethylisophthalic dianilide 15, and found that it exists in the

solid state in the syn conformation, with N-phenyl groups located

2.9. Conformational studies of oligo-p-benzanilides

To test whether evidence of helicity in oligo-p-benzanilides^10,11

could be detected by diastereotopicity in a terminal CH₂Ph group

we constructed oligomers 19e22 by a similar route (Scheme 5).

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L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

Figure 8. X-ray crystal structure of 20a⁰.

After we had carried out this work, a report detailed circular

dichroism studies, which indicate that simple oligo-p-benzamides,

when capped with an enantiomerically pure ferrocenyl unit, adopt

helical conformations in solution.¹²However, our method, based on

observation of anisochronicity at diastereotopic methylene groups,

reports on the local chirality at the terminus of the potential helix,

and is therefore more sensitive than simple CD to helix breakdown.

2.10. Oligo-1,4-naphthanilides

Having seen evidence of helicity in oligo-p-benzanilides in the

solid state, we ﬁnally turned to more hindered analogues of these

compounds with the aim of slowing individual rotations to the point

where detailed conformational selectivity in solution could be

quantiﬁed. Oligo-1,4-naphthanilides were built by a similar strategy

of iterative amide formation with 4-nitronaphthalene-1-carbonyl

chloride 23,³³reduction and alkylation was used to build oligomers

27a and 27b. Scheme 6 shows the compounds made for this work.

Despite the presence of an AreCO bond likely to rotate slowly on

the NMR timescale,^22,23no diastereotopic peaks were observed for

24. However, in 25a and 25b diastereotopic peaks were observed,

which failed to coalesce at þ50 ^ꢀC in CDCl₃. This result is consistent

with either a good level of conformational control at the potentially

slowly rotating bonds in 25, or with unexpectedly fast rotation in the

AreCO bonds but not the AreN bond. The latter possibility was tested

by lowering the temperature to ꢁ75 ^ꢀC and running a spectrum in

toluenedno further decoalescences were observed, so we seem to be

attaining good conformational control. However, when further ter-

tiary amide units were added, to give 26 and 27, complex mixtures of

conformers were observed in the NMR spectra at ambient temper-

ature, and no further work was carried out on these oligomers.

Scheme 5. Synthesis of unsubstituted oligo-p-benzanilides.

As with the m-benzanilides, in no case we were able to observe

anything other than a 2H singlet for the CH₂groups of 19b⁰e22b⁰in

a variety of solvents even down to ꢁ85 ^ꢀC. However, we were able

to obtain crystal structures of 19a⁰³¹and 20a⁰³²and both com-

pounds showed evidence of helicity in the solid state (Figs. 7 and 8).

Compound 19a⁰is not long enough to generate a full turn of a helix

but the X-ray suggests the beginning of a helical conformation. 20a⁰

is long enough to generate more than one turn in what seems to be

more clearly a helix.

3. Conclusion

Building on conformational preferences evident in the solid

state, we studied the conformations adopted in solution by a series

of oligo-m-benzanilides and oligo-p-benzanilides hoping to ob-

serve limited conformational freedom and may be the formation of

helical structures. In the case of short dimers and trimers, some

degree of conformational control could be deduced from the sim-

plicity of the ¹H NMR spectra. However, invariably the degree of

control degraded signiﬁcantly as the oligomers were extended

further. The best performing of this wider class of non-hydrogen

bonded amide-type oligoarenes have turned out to be ureas de-

rived from oligo-m-phenylenediamine;^5,6,18none of the amides

presented here appear to have the same degree of more extended

control as those ureas.

Figure 7. X-ray crystal structure of 19a⁰.

L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

6943

Scheme 6. Synthesis of oligo-1,4-naphthanilides.

4. Experimental

25.2 mmol). The crude mixture was puriﬁed on silica gel (PE/EtOAc:

8/2) to afford a colourless solid (m¼2.36 g, 93%). IR (ﬁlm) 1648,

4.1. General procedure A: amide bond formation

1528 cm^ꢁ1. ¹H NMR (CDCl₃, 300 MHz)

d

5.18 (s, 2H), 6.96 (dd, J¼7.9,

1.6 Hz, 2H), 7.11e7.25 (m, 3H), 7.25e7.42 (m, 6H), 7.68 (m, 1H), 8.11

A solution of acid (1 equiv) in dry CH₂Cl₂(18 mL/mmol) was

cooled to 0 ^ꢀC. Oxalyl chloride (5 equiv) and one drop of DMF were

added. The solution was stirred for 3 h at rt. The solvent was re-

moved under reduced pressure. The resulting acid chloride or

commercially available acid chloride was dissolved in dry CH₂Cl₂

(5 mL/mmol acid). A solution of amine (2 equiv) and base (Et₃N or

pyridine) (2 equiv) in dry CH₂Cl₂(5 mL/mmol acid) was added at

0 ^ꢀC. The mixture was stirred at rt overnight. The organic layer was

washed with saturated NH₄Cl and brine, and dried over Na₂SO₄.

The solvent was removed under reduced pressure and the crude

mixture puriﬁed on silica gel to afford the amide.

(ddd, J¼8.2, 2.3, 1.1 Hz, 1H), 8.22 (t, J¼1.8 Hz, 1H). ¹³C NMR (CDCl₃,

75.5 MHz)

d 54.3 (CH₂), 124.2 (CH), 124.6 (CH), 127.2 (CH), 127.9

(CH), 128.3 (CH), 128.9 (CH), 128.9 (CH), 129.2 (CH), 129.7 (CH),

134.7 (CH), 136.6 (Cq), 137.9 (Cq), 142.7 (Cq), 147.8 (Cq), 168.2 (Cq).

MS (ESI^þ) m/z: 333 (67) [MþH]. HRMS calcd for C₂₀H₁₇N₂O₃:

333.1234, found: 333.1233.

4.3.2. N-(N⁰-Benzyl-N⁰-phenyl-3-carboxamidophenyl)-3-nitro-

benzamide 5a. Prepared according to general procedure B from

nitro compound 4a (1.10 g, 3.31 mmol) and SnCl₂$2H₂O (7.70 g,

34.1 mmol). The amine was obtained without further puriﬁcation

as a clear, foamy solid (m¼930 mg, 93%). IR (ﬁlm) 3355, 1633,

4.2. General procedure B: reduction of nitroarenes

1495 cm^ꢁ1. ¹H NMR (CDCl₃, 300 MHz)

d 3.48 (br s, 2H), 5.15 (s, 2H),

6.56 (ddd, J¼7.9, 2.4, 0.8 Hz, 2H), 6.64 (d, J¼7.7 Hz,1H), 6.80 (m, 1H),

SnCl₂$2H₂O (5 equiv) was added to a solution of nitro aryl

(1 equiv) in EtOAc ([SnCl₂]¼1 M). The mixture was stirred at rt

overnight. The solution was then washed with 2 M NaOH solution

and the aqueous layer was extracted with EtOAc (ꢂ3). The com-

bined organic layers were washed with water, brine and dried over

Na₂SO₄. The crude mixture was puriﬁed by ﬂash chromatography

on silica gel.

6.91 (t, J¼7.6 Hz, 1H), 6.96 (m, 1H), 7.09e7.21 (m, 3H), 7.26e7.37 (m,

5H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 54.1 (CH₂), 115.9 (CH), 116.6 (CH),

119.2 (CH), 126.9 (CH), 127.6 (CH), 127.8 (CH), 128.6 (CH), 128.7 (CH),

129.2 (CH), 137.3 (Cq), 137.9 (Cq), 143.9 (Cq), 146.4 (Cq), 171.1 (Cq).

MS m/z (ESI^þ): 303 (100) [MþH]. HRMS calcd for C₂₀H₁₉N₂O:

303.1492, found: 303.1489. Mp¼117e119 ^ꢀC.

The amine was used to make the amide 5a bygeneral procedure A

using amine (800 mg, 2.65 mmol), 3-nitrobenzoylchloride (490 mg,

2.65 mmol) and pyridine (0.71 mL, 8.75 mmol). The crude mixture

was puriﬁed through silica gel (PE/EtOAc: 8/2) to afford a creamy

4.3. General procedure C: amide alkylation

A solution of amide (1 equiv) in dry THF (9 mL/mmol amide)

was added dropwise at 0 ^ꢀC to a suspension of NaH (60%, 2 equiv) in

dry THF (4 mL/mmol NaH). The solution was stirred for 15 min at

0 ^ꢀC and methyl iodide or benzyl bromide (2 equiv) was added. The

resulting solution was stirred at rt for 3 h (or at 0 ^ꢀC with a p-

nitrobenzamide substrate, to avoid hydrolysis). After addition of

water, the aqueous layer was extracted with CH₂Cl₂. The combined

organic layers were washed with brine and dried over Na₂SO₄. The

crude mixture was puriﬁed by ﬂash chromatography on silica gel.

foam (m¼1.12 g, 94%). IR (ﬁlm) 1623, 1595, 1527 cm^ꢁ1

.

¹H NMR

(CDCl₃, 300 MHz)d5.06(s, 2H), 6.85e7.02(m, 3H), 7.03e7.33 (m, 9H),

7.61 (t, J¼7.9, 7.9 Hz, 1H), 7.79 (s, 1H), 7.93 (d, J¼8.3 Hz, 1H), 8.28 (d,

J¼7.6 Hz, 1H), 8.35 (dd, J¼8.1, 1.4 Hz, 1H), 8.77 (s, 1H), 9.47 (br s, 1H).

¹³C NMR (CDCl₃, 75.5 MHz)

d 54.2 (CH₂),120.6 (CH),122.2 (CH),122.6

(CH), 124.4 (CH), 126.4 (CH), 127.4 (CH), 127.8 (CH), 128.1 (CH),

128.5 (CH), 128.6 (CH), 128.8 (CH), 129.4 (CH), 129.9 (CH), 134.2

(CH), 136.7 (Cq), 136.8 (Cq), 137.1 (Cq), 138.5 (Cq), 142.8 (Cq), 148.3

(Cq), 163.9 (Cq), 171.1 (Cq). MS m/z (ESI^ꢁ): 450 (100) [MꢁH]. HRMS

calcd for C₂₇H₁₉N₃O₄: 466.1761, found: 452.1607. Mp¼143e145 ^ꢀC.

4.3.1. N-Benzyl-N-phenyl-3-nitrobenzamide 4a. Prepared according

to general procedure

A

from 3-nitrobenzoylchloride (1.42 g,

4.3.3. N-(N⁰-Benzyl-N⁰-phenyl-3⁰-carboxamidophenyl)-N-methyl-3-

7.65 mmol), benzylaniline (1.40 g, 7.65 mmol) and pyridine (2 mL,

nitrobenzamide 6a. Prepared according to general procedure C

6944

L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

from amide 5a (300 mg, 0.665 mmol), NaH (64.0 mg, 1.60 mmol)

and iodomethane (0.42 mL, 6.75 mmol). The crude mixture was

puriﬁed through silica gel (DCM then DCM/MeOH: 100/3) to afford

a creamy solid (m¼277 mg, 89%). IR (ﬁlm) 1647, 1521 cm^ꢁ1. ¹H NMR

0.144 mmol), NaH (6.00 mg, 0.150 mmol) and iodomethane

(0.09 mL, 1.44 mmol). The crude mixture was puriﬁed through sil-

ica gel (DCM then DCM/MeOH: 100/3) to afford a white solid

.

(m¼86 mg, 96%). IR (ﬁlm) 1644, 1602 cm^ꢁ^{1 1}H NMR (CDCl₃,

(CDCl₃, 300 MHz)

d

3.17 (s, 3H), 5.00 (s, 2H), 6.70e6.92 (m, 4H),

300 MHz)

d

3.20 (s, 3H), 3.40 (s, 3H), 5.15 (s, 2H), 6.54 (d, J¼8.0 Hz,

6.93e7.28 (m, 12H), 7.95 (d, J¼7.8 Hz, 1H), 8.10 (s, 1H). ¹³C NMR

1H), 6.74 (d, J¼7.6 Hz, 1H), 6.84e7.02 (m, 5H), 7.07e7.51 (m, 13H),

(CDCl₃, 75.5 MHz)

d

38.3 (CH₃), 54.2 (CH₂), 124.2 (CH), 124.7 (CH),

8.14 (dd, J¼10.5, 2.3 Hz, 2H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 38.6

127.2 (CH), 127.4 (CH), 127.8 (CH), 127.8 (CH), 128.1 (CH), 128.6 (CH),

128.8 (CH), 128. 9 (CH), 129.2 (CH), 129.3 (CH), 129.5 (CH), 134.6

(CH), 137.2 (Cq), 137.4 (Cq), 137.7 (Cq), 143.1 (Cq), 143.7 (Cq), 147.8

(Cq), 167.9 (Cq), 169.2 (Cq). MS m/z (ESI^þ): 466 (22) [MþH]. HRMS

calcd for C₂₈H₂₄N₃O₄: 466.1605, found: 466.1761.

(CH₃), 38.6 (CH₃), 54.3 (CH₂), 124.2 (CH), 124.7 (CH), 126.8 (CH),

127.4 (CH), 127.5 (CH), 127.6 (CH), 127.7 (CH), 127.9 (CH), 128.2 (CH),

128.8 (CH), 128.8 (CH), 128.9 (CH), 129.0 (CH), 129.4 (CH), 129.5

(CH), 134.7 (Cq), 137.3 (Cq), 137.4 (Cq), 137.8 (Cq), 143.4 (Cq), 144.0

(Cq), 144.1 (Cq), 147.8 (Cq), 168.0 (Cq), 168.9 (Cq), 169.2 (Cq). MS m/z

(ESI^þ) 621 (47) [MþNa]. HRMS calcd for C₃₆H₃₀N₄NaO₅: 621.2108,

found: 621.2101.

4.3.4. N-(N⁰-(N⁰⁰-Benzyl-N⁰⁰-phenyl-3⁰⁰-carboxamidophenyl)-

N⁰-methyl-3⁰-carboxamidophenyl)-3-nitrobenzamide 7a. Prepared

according to general procedure B from nitro compound 6a (318 mg,

0.684 mmol) and SnCl₂$2H₂O (1.58 g, 7.00 mmol). The title com-

pound was obtained without further puriﬁcation as a creamy foam

(m¼281 mg, 95%). IR (ﬁlm) 3353, 1632, 1496 cm^ꢁ1. ¹H NMR (CDCl₃,

4.3.7. N-(N⁰-(N⁰⁰-Benzyl-N⁰⁰-phenyl-3⁰⁰-carboxamidophenyl)-N⁰-

methyl-3⁰-carboxamidophenyl)-N-methyl-2-iodobenzamide 8a⁰.

Prepared according to general procedure C from amide 7a⁰

(82.0 mg, 0.123 mmol), NaH (60% solution in mineral oil) (7.00 mg,

0.175 mmol) and iodomethane (0.08 mL, 1.23 mmol). The crude

mixture was puriﬁed through silica gel (3% MeOH/DCM) to afford

300 MHz)

d

3.25 (s, 3H), 3.41 (br s, 2H), 5.14 (s, 2H), 6.31 (d, J¼7.5 Hz,

1H), 6.57 (ddd, J¼8.0, 2.4, 0.9 Hz,1H), 6.72 (t, J¼1.8 Hz,1H), 6.77e6.91

(m, 4H), 6.99 (t, J¼7.9 Hz, 1H), 7.10e7.24 (m, 5H), 7.24e7.39 (m, 5H).

an orange oil (m¼77 mg, 92%). ¹H NMR (CDCl₃, 300 MHz)

d ppm

¹³C NMR (CDCl₃, 75.5 MHz)

d

38.3 (CH₃), 54.1 (CH₂), 115.6 (CH), 116.6

7.62 (d, J¼7.6 Hz, 1H), 7.24e7.10 (m, 11H), 7.08e6.97 (m, 3H),

6.92e6.80 (m, 5H), 6.57 (d, J¼7.3 Hz, 1H), 6.40 (d, J¼6.9 Hz, 1H),

5.12 (s, 2H), 3.35 (s, 3H), 3.19 (s, 3H). ¹³C NMR (CDCl₃, 75.5 MHz)

(CH), 119.2 (CH), 126.9 (CH), 126.9 (CH), 127.2 (CH), 127.8 (CH), 128.1

(CH), 128.6 (CH), 128.7 (CH), 128.7 (CH), 128.7 (CH), 128.8 (CH), 129.4

(CH), 136.8 (Cq), 137.3 (Cq), 137.4 (Cq), 143.6 (Cq), 144.7 (Cq), 146.3

(Cq), 169.7 (Cq), 170.9 (Cq). MS m/z (ESI^þ): 436 (47) [MþH]. HRMS

calcd for C₂₈H₂₆N₃O₂: 436.2020, found: 436.2019. Mp¼102e106 ^ꢀC.

The amine was used to make the title compound according to

general procedure A using amine (100 mg, 0.229 mmol), 3-nitro-

benzoylchloride (300 mg, 2.30 mmol) and pyridine (0.6 mL,

7.59 mmol). The crude mixture was puriﬁed through silica gel (DCM

to DCM/MeOH: 100/3) to afford a white, foamy solid (m¼130 mg,

d

ppm 37.4, 38.3, 54.3, 93.7, 94.7, 127.3, 127.4, 127.7, 127.9, 128.2,

128.3, 128.6, 128.8, 129.0, 129.5, 130.2, 131.2, 131.8, 133.2, 136.5,

137.3, 137.3, 139.3, 141.8, 142.4, 143.4, 144.1. MS m/z (ESI^þ) 702

(100%). HRMS calcd for C₃₆H₃₀IN₃NaO₃: 702.1230, found:

702.2056.

4.3.8. N-Benzyl-4-methyl-3-nitro-N-phenylbenzamide 4b. Prepared

according to general procedure A from the acid 2b (1.83 g,

10.1 mmol), oxalyl chloride (2.17 mL, 25.2 mmol), amine (925 mg,

5.05 mmol) and Et₃N (0.84 mL, 5.05 mmol). The crude mixture was

puriﬁed through silica gel (PE/EtOAc: 6/4) to afford a white solid

(1.91 g, 91%). IR (ﬁlm) 1647, 1525 cm^ꢁ1. ¹H NMR (CDCl₃, 300 MHz)

97%). IR (ﬁlm) 1624, 1596, 1525 cm^ꢁ^{1 1}H NMR (CDCl₃, 300 MHz)

.

d

3.20 (s, 3H), 5.10 (s, 2H), 6.58 (d, J¼7.7 Hz, 1H), 6.87 (dd, J¼7.9,

1.4 Hz, 3H), 6.98 (dt, J¼7.8, 5.1 Hz, 2H), 7.06e7.31 (m, 9H), 7.55e7.72

(m, 3H), 7.95 (dd, J¼8.2, 1.2 Hz, 1H), 8.24e8.29 (m, 1H), 8.35 (ddd,

J¼8.3, 2.2, 1.0 Hz, 1H), 8.71 (t, J¼1.8 Hz, 1H), 9.66 (s, 1H). ¹³C NMR

d

2.47 (s, 3H), 5.09 (s, 2H), 6.89 (m, 2H), 7.09 (d, J¼7.9 Hz, 1H),

(CDCl₃, 75.5 MHz)

d

38.3 (CH₃), 54.2 (CH₂), 120.8 (CH), 122.1 (CH),

7.20e7.11 (m, 3H), 7.29e7.12 (m, 5H), 7.40 (dd, J¼7.9, 1.8 Hz, 1H),

122.6 (CH), 124.4 (CH), 126.3 (CH), 127.1 (CH), 127.2 (CH), 127.3 (CH),

127.7 (CH), 128.1 (CH), 128.6 (CH), 128.7 (CH), 128.9 (CH), 129.4 (CH),

129.9 (CH), 134.3 (CH), 136.1 (CH), 136.7 (Cq), 137.1 (Cq), 134.4 (Cq),

137.4 (Cq), 138.6 (Cq), 143.1 (Cq), 144.0 (Cq), 148.2 (Cq), 163.9 (Cq),

169.8 (Cq), 170.7 (Cq). MS m/z (ESI^þ): 585 (33) [MþH]. HRMS calcd

for C₃₆H₃₀IN₃NaO₃: 585.2132, found: 585.2144. Mp¼151e153 ^ꢀC.

7.94 (d, J¼1.8 Hz, 1H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 20.4 (CH₃), 54.0

(CH₂), 125.3 (CH), 127.3 (CH), 127.5 (CH), 127.8 (CH), 128.5 (CH),

128.6 (CH), 129.4 (CH), 132.2 (CH), 132.9 (CH), 134.9 (Cq), 135.1 (Cq),

136.8 (Cq), 142.6 (Cq), 148.3 (Cq), 167.7 (Cq). HRMS calcd for

C₂₁H₁₈N₂Na O₃: 369.1210, found: 369.1220. Mp¼62e64 ^ꢀC.

4.3.9. 1-N-Benzyl-4-methyl-3-N-(4-methyl-3-nitrobenzene)-1-N-

phenylbenzene-1,3-diamide 5b. Prepared according to general pro-

cedure B from nitroarene 4b (1.71 g, 4.94 mmol), SnCl₂$2H₂O

(11.1 g, 49.4 mmol). The crude mixture was puriﬁed through silica

gel (PE/EtOAc: 6/4) to afford a white solid (1.53 g, 98%). IR (ﬁlm)

4.3.5. N-(N⁰-(N⁰⁰-Benzyl-N⁰⁰-phenyl-3⁰⁰-carboxamidophenyl)-N⁰-

methyl-3⁰-carboxamidophenyl)-2-iodobenzamide

7a⁰. Prepared

according to general procedure A from amine derived from 6a

(263 mg, 0.600 mmol), iodobenzoylchloride (160 mg, 0.601 mmol)

and pyridine (0.24 mL, 1.98 mmol). The crude mixture was puriﬁed

through silica gel (3% MeOH/DCM) to afford a beige foamy solid

3363,1634 cm^ꢁ1. ¹H NMR (CDCl₃, 300 MHz)

d 2.05 (s, 3H), 3.54 (br s,

2H), 5.11 (s, 2H), 6.54 (dd, J¼7.7, 1.7 Hz, 1H), 6.76 (d, J¼7.7 Hz, 1H),

(m¼351 mg, 88%). ¹H NMR (CDCl₃, 300 MHz)

d ppm 9.17 (s, 1H),

6.80 (d, J¼1.8 Hz,1H), 6.93 (m, 2H), 7.18e7.06 (m, 3H), 7.32e7.21 (m,

7.92 (d, J¼7.7 Hz, 1H), 7.82 (d, J¼8.0 Hz, 1H), 7.68 (s, 1H), 7.40e7.04

(m, 13H), 6.98 (q, J¼8.0, 7.9, 7.9 Hz, 1H), 6.85 (d, J¼6.9 Hz, 2H), 6.76

(d, J¼7.7 Hz, 3H), 6.53 (d, J¼7.5 Hz, 1H), 5.07 (s, 1H), 3.01 (s, 3H). ¹³C

5H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 17.2 (CH₃), 53.8 (CH₂), 115.5 (CH),

119.3 (CH), 124.1 (CH), 126.4 (CH), 127.2 (CH), 127.4 (CH), 128.2 (CH),

128.4 (CH), 128.8 (CH), 129.4 (CH), 134.5 (Cq), 137.7 (Cq), 144.8 (Cq),

144.0 (Cq), 144.1 (Cq), 170.6 (Cq). MS (ESI^þ) m/z: 317 (62) [MþH],

339 (52) [MþNa]. HRMS calcd for C₂₁H₂₁N₂O: 317.1648, found:

317.1647. Mp¼104e105 ^ꢀC.

NMR (CDCl₃, 75.5 MHz) d ppm 38.4, 53.9, 120.9, 121.9, 124.3, 126.9,

127.2, 127.4, 127.8, 128.0, 128.1, 128.2, 128.4, 128.6, 129.0, 129.5,

131.4, 132.6, 132.9,134.5, 135.3,135.9,137.3, 137.3,138.7,139.9, 141.5,

142.4, 143.2, 144.2, 161.5, 168.0, 168.3, 169.7, 170.4. MS m/z (ESI^þ)

689 (23%). HRMS calcd for C₃₅H₂₈I N₃NaO₃: 688.1068, found:

688.1065. Mp 123e125 ^ꢀC.

The amine was used to make the title compound by general

procedure A using the acid (114 mg, 0.629 mmol), oxalyl chloride

(0.27 mL, 3.16 mmol), amine (100 mg, 0.316 mmol) and pyridine

(0.08 mL, 0.948 mmol). The crude mixture was puriﬁed through

silica gel (PE/EtOAc: 7/3) to afford a white solid (142 mg, 91%). IR

4.3.6. N-(N⁰-(N⁰⁰-Benzyl-N⁰⁰-phenyl-3⁰⁰-carboxamidophenyl)-N⁰-

methyl-3⁰-carboxamidophenyl)-N-methyl-3-nitrobenzamide

8a.

Prepared according to general procedure C from amide 7a (84.0 mg,

(ﬁlm) 3278, 1622 cm^ꢁ1

.

¹H NMR (CDCl₃, 300 MHz, High concen-

2.17 (s, 3H), 2.70 (s, 3H), 5.12 (s, 2H), 6.83 (m, 2H), 6.98 (m,

tration)

d

L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

6945

2H), 7.22e7.09 (m, 3H), 7.31e7.24 (m, 5H), 7.44 (d, J¼8.1 Hz, 1H),

7.52 (s, 1H), 8.16 (dd, J¼7.9, 1.7H, 1H), 8.63 (d, J¼1.7 Hz, 1H), 9.02 (br

0.441 mmol), NaH (88.0 mg, 2.20 mmol), methyl iodide (0.137 mL,

2.20 mmol). The crude mixture was puriﬁed through silica gel (PE

to PE/EtOAc: 5/5) to afford a white foam (230 mg, 81%). ¹H NMR and

¹³C NMR show mixture of multiple conformers resulting impossible

to any ratio. MS (ESI^þ) m/z: 663 (100) [MþNa]. HRMS calcd for

C₃₉H₃₆N₄NaO₅: 663.2578, found: 663.2571.

s, 1H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 17.8 (CH₃), 20.5 (CH₃), 53.9

(CH₂), 123.8 (CH), 125.3 (CH), 125.8 (CH), 126.9 (CH), 127.4 (CH),

127.7 (CH), 128.3 (CH), 128.4 (CH), 129.1 (CH), 129.7 (CH), 131.9 (CH),

133.0 (CH), 133.7 (Cq), 133.7 (Cq), 133.8 (Cq), 135.2 (Cq), 136.9 (Cq),

137.0 (Cq),142.7 (Cq),149.0 (Cq),163.6 (Cq), 170.7 (Cq). MS (ESI^þ) m/

z: 502 (100) [MþNa]. HRMS calcd for C₂₉H₂₅N₃NaO₄: 502.1737,

found: 502.1744. Mp¼126e130 ^ꢀC.

4.3.13. 1-N,3-N-Dibenzyl-4-methyl-3-N-(4-methyl-3-nitrobenzene)-

1-N-phenylbenzene-1,3-diamido 6b⁰. Prepared according to general

procedure C from amide 5b (103 mg, 0.209 mmol), NaH (33.0 mg,

0.835 mmol), benzyl bromide (0.25 mL, 2.09 mmol). The crude

mixture was puriﬁed through silica gel (PE then PE/EtOAc: 7/3) to

4.3.10. 1-N-Benzyl-3-N,4-dimethyl-3-N-(4-methyl-3-nitrobenzene)-

1-N-phenylbenzene-1,3-diamido 6b. Prepared according to general

procedure C from amide 5b (765 mg, 1.60 mmol), NaH (319 mg,

7.98 mmol), methyl iodide (0.5 mL, 7.98 mmol). The crude mixture

was puriﬁed through silica gel (PE then PE/EtOAc: 7/3) to afford

afford a white solid (110 mg, 92%). IR (ﬁlm) 3064, 1648, 1528 cm^ꢁ1

.

Ratio: >95/5. ¹H NMR (CDCl₃, 300 MHz)

d 1.50 (s, 3H), 2.50 (s, 3H),

4.55 (d, J¼13.7 Hz, 1H), 5.01 (d, J¼13.7 Hz, 1H), 5.07 (d, J¼14.5 Hz,

1H), 5.11 (d, J¼14.5 Hz, 1H), 6.82 (d, J¼7.9 Hz, 1H), 6.87e6.92 (m,

2H), 7.01 (d, J¼7.9 Hz, 1H), 7.05e7.32 (m, 16H), 7.99 (m, 1H). ¹³C

a white solid (733 mg, 93%). IR (ﬁlm) 3061e2931, 1644, 1528 cm^ꢁ1

.

Ratio: >95/5. ¹H NMR (CDCl₃, 500 MHz)

d 2.04 (s, 3H), 2.52 (s, 3H),

3.17 (s, 3H), 5.08 (m, 2H), 6.83 (m, 2H), 6.97 (d, J¼8.0 Hz, 1H), 7.07

NMR (CDCl₃, 75.5 MHz) d 17.3 (CH₃), 20.3 (CH₃), 53.9 (CH₂), 54.0

(d, J¼8.0 Hz, 1H), 7.09e7.15 (m, 4H), 7.16e7.19 (m, 2H), 7.23e7.32

(CH₂), 125.2 (CH), 127.0 (CH), 127.4 (CH), 127.8 (CH), 127.9 (CH),

128.3 (CH), 128.4 (CH), 128.4 (CH), 128.7 (CH), 129.1 (CH), 129.3

(CH), 129.4 (CH), 131.0 (CH), 131.9 (CH), 132.4 (CH), 134.6 (Cq), 134.9

(Cq), 135.2 (Cq), 135.7 (Cq), 137.0 (Cq), 137.7 (Cq), 140.1 (Cq), 143.3

(Cq), 148.3 (Cq), 167.0 (Cq), 168.7 (Cq). MS (ESI^þ) m/z: 592 (100)

[MþNa]. HRMS calcd for C₃₆H₃₁N₃NaO₄: 592.2207, found: 592.2217.

Mp¼56e58 ^ꢀC.

(m, 5H), 7.92 (d, J¼1.6 Hz, 1H). ¹³C NMR (CDCl₃, 125 MHz)

d 17.5

(CH₃), 20.4 (CH₃), 37.6 (CH₃), 54.0 (CH₂), 125.0 (CH), 126.8 (CH),

127.4 (CH),127.6 (CH),128.3 (CH),128.4 (CH),128.7 (CH), 128.9 (CH),

129.0 (CH), 131.1 (CH), 132.1 (CH), 132.4 (CH), 134.4 (Cq), 135.1 (Cq),

135.3 (Cq), 136.6 (Cq), 137.0 (Cq), 142.1 (Cq), 143.1 (Cq), 148.2 (Cq),

167.5 (Cq), 168.6 (Cq). MS (ESI^þ) m/z: 516 [MþNa]. HRMS calcd for

C₃₀H₂₇N₃NaO₄: 516.1899, found: 516.1887. Mp¼65e66 ^ꢀC.

4.3.14. 1-N,3-N-Dibenzyl-4-methyl-3-N-{4-methyl-3-[(4-methyl-3-

nitrobenzene)amido]benzene}-1-N-phenylbenzene-1,3-diamido 7b⁰.

Prepared according to general procedure B from nitro 6b⁰(580 mg,

1.02 mmol), SnCl₂$2H₂O (2.30 g, 10.2 mmol). The crude mixture was

puriﬁed through silica gel (PE/EtOAc: 6/4) to afford a yellow solid

(512 mg, 93%). IR (ﬁlm) 3454e3359, 1637, 1590 cm^ꢁ1. Ratio: >95/5.

4.3.11. 1-N-Benzyl-3-N,4-dimethyl-3-N-{4-methyl-3-[(4-methyl-3-

nitrobenzene)amido]benzene}-1-N-phenylbenzene-1,3-diamido 7b.

Prepared according to general procedure B from nitro 6b (346 mg,

0.702 mmol), SnCl₂$2H₂O (789 mg, 3.50 mmol). The crude mixture

was puriﬁed through silica gel (PE/EtOAc: 6/4) to afford a yellow

foam (321 mg, 99%). Ratio: >95/5. IR (ﬁlm) 3458, 3357, 3059e2926,

¹H NMR (CDCl₃, 300 MHz)

d 1.48 (s, 3H), 2.02 (s, 3H), 3.50 (br s, 2H),

1641 cm^ꢁ1.¹H NMR (CDCl₃, 500 MHz)

d

2.00 (s, 6H), 3.11 (s, 3H), 3.58

4.50 (d, J¼13.9 Hz, 1H), 4.94 (d, J¼13.9 Hz, 1H), 5.05 (d, J¼14.5 Hz,

1H), 5.11 (d, J¼14.5 Hz, 1H), 6.18 (dd, J¼7.7, 1.4 Hz, 1H), 6.64 (d,

J¼7.8 Hz,1H), 6.72 (d, J¼1.5 Hz,1H), 6.76 (d, J¼7.8 Hz,1H), 6.84e6.89

(br s, 2H), 5.07 (m, 2H), 6.02 (d, J¼7.6 Hz, 1H), 6.66 (d, J¼7.8 Hz, 1H),

6.70 (s, 1H), 6.79 (m, 2H), 6.86. (d, J¼7.8 Hz, 1H), 7.06 (d, J¼8.0 Hz,

1H), 7.08e7.15 (m, 4H), 7.22e7.29 (m, 5H). ¹³C NMR (CDCl₃,

(m, 2H), 7.04e7.33 (m,15H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 17.2 (CH₃),

125 MHz)

d

17.2 (CH₃), 17.7 (CH₃), 37.5 (CH₃), 53.9 (CH₂), 115.1 (CH),

17.6 (CH₃), 53.8 (CH₂), 53.9 (CH₂), 115.4 (CH), 119.0 (CH), 124.3 (Cq),

126.9 (CH), 127.3 (CH), 127.4 (CH), 127.8 (CH), 127.9 (CH), 128.2 (CH),

128.3 (CH), 128.4 (CH), 129.1 (CH), 129.2 (CH) 129.3 (CH), 130.7 (CH),

134.2 (Cq), 134.4 (Cq), 136.6 (Cq), 137.2 (Cq), 138.1 (Cq), 141.2 (Cq),

143.4 (Cq),143.8 (Cq),169.3 (Cq),169.8 (Cq). MS (ESI^þ) m/z: 562 (100)

[MþNa]. HRMS calcd for C₃₆H₃₄N₃O₂: 540.2651, found: 540.2640.

The amine was used to make the title compound by general

procedure A from the acid (134 mg, 0.740 mmol), oxalyl chloride

(0.32 mL, 3.71 mmol), amine (200 mg, 0.371 mL) and pyridine

(0.09 mL, 1.11 mmol). The crude mixture was puriﬁed through silica

gel (PE/EtOAc: 6/4) to afford a white solid (202 mg, 77%). IR (ﬁlm)

3435, 1641, 1526 cm^ꢁ1. Ratio: >95/5. ¹H NMR (CDCl₃, 300 MHz)

118.6 (CH), 124.1 (Cq), 126.7 (CH), 127.4 (CH), 127.7 (CH), 127.8 (CH),

128.4 (CH),128.5 (CH),129.0 (CH),129.2 (CH), 130.7 (CH),134.2 (Cq),

134.6 (Cq), 136.7 (Cq), 137.2 (Cq), 143.2 (Cq), 143.3 (Cq), 144.0 (Cq),

169.3 (Cq), 170.6 (Cq). MS (ESI^þ) m/z: 486 (40) [MþNa]. HRMS calcd

for C₃₀H₂₉N₃NaO₂: 486.2152, found: 486.2152.

This amine was used to make the title compound according to

general procedure A from acid (247.7 mg, 1.36 mmol), oxalyl

chloride (0.59 mL, 6.82 mmol), amine (316 mg, 0.682 mL) and

pyridine (0.28 mL, 3.41 mmol). The crude mixture was puriﬁed

through silica gel (PE/EtOAc: 8/2 to 5/5) to afford a white foam

(373 mg, 87%). IR (ﬁlm) 3281, 3061e2928, 1644, 1527 cm^ꢁ1. Ratio:

90/10. ¹H NMR (CDCl₃, 500 MHz)

d

2.01 (s, 3H), 2.13 (s, 3H), 2.67 (s,

d

1.48 (s, 3H), 2.12 (s, 3H), 2.67 (s, 3H), 4.41 (d, J¼13.8 Hz,1H), 5.03 (d,

3H), 3.12 (s, 3H) 5.08 (m, 2H), 6.41 (d, J¼7.8, 1H), 6.70 (d, J¼7.9 Hz,

1H), 6.84e6.92 (m, 2H), 7.09 (d, J¼8.4 Hz, 1H), 7.11e7.17 (m, 4H),

7.19 (s, 1H), 7.22e7.29 (m, 5H), 7.40 (s, 1H), 7.41 (d, J¼8.4 Hz, 1H),

8.09 (d, J¼7.9 Hz, 1H), 8.58 (s, 1H), 9.19 (br s, 1H). ¹³C NMR (CDCl₃,

J¼13.8 Hz, 1H), 5.07 (d, J¼14.5 Hz, 1H), 5.11 (d, J¼14.5 Hz, 1H), 6.39

(dd, J¼7.9, 1.6 Hz, 1H), 6.67 (d, J¼8.1 Hz, 1H), 6.74 (d, J¼8.1 Hz, 1H),

6.92 (m, 2H), 7.02 (m, 2H), 7.13 (m, 3H), 7.16e7.23 (m, 6H), 7.25e7.31

(m, 4H), 7.42 (m, 2H), 8.11 (dd, J¼8.0, 1.6 Hz, 1H), 8.57 (d,

125 MHz)

d

17.5 (CH₃), 17.8 (CH₃), 20.4 (CH₃), 37.3 (CH₃), 54.8 (CH₂),

J¼1.6 Hz,1H), 9.01 (br s,1H).¹³C NMR (CDCl₃, 75.5 MHz)

d 17.7 (CH₃),

123.7 (CH), 124.8 (CH),125.9 (CH), 126.8 (CH),127.3 (CH), 127.8 (CH),

128.1 (CH), 128.3 (CH), 128.4 (CH), 128.8 (CH), 129.0 (CH), 129.3

(CH), 130.9 (CH), 132.1 (CH), 132.9 (CH), 133.3 (Cq), 133.6 (Cq), 134.1

(Cq), 134.6 (Cq), 135.2 (Cq), 136.8 (Cq), 136.9 (Cq), 137.1 (Cq), 142.1

(Cq), 143.2 (Cq), 148.9 (Cq), 163.6 (Cq), 169.2 (Cq), 170.5 (Cq). MS

(ESI^þ) m/z: 649 (100) [MþNa]. HRMS calcd for C₃₈H₃₄N₄NaO₅:

649.2421, found: 649.2416.

18.1 (CH₃), 20.8 (CH₃), 54.0 (CH₂), 54.3 (CH₂), 123.7 (CH), 125.1

(CH), 126.5 (CH), 126.9 (CH), 127.4 (CH), 127.7 (CH), 128.0 (CH), 128.1

(CH), 128.3 (CH), 128.4 (CH), 129.1 (CH), 129.2 (CH), 129.3 (CH),

129.4 (CH), 131.0 (CH), 132.0 (CH), 133.0 (CH), 133.4 (Cq), 133.6 (Cq),

134.1 (Cq), 134.4 (Cq), 135.0 (Cq), 136.0 (Cq), 136.9 (Cq), 137.1

(Cq), 138.3 (Cq), 140.2 (Cq), 143.4 (Cq), 149.0 (Cq), 163.7 (Cq), 169.4

(Cq), 170.0 (Cq). MS (ESI^þ) m/z: 725 (100) [MþNa]. HRMS calcd for

C₄₄H₃₈N₄NaO₅: 725.2740, found: 725.2744. Mp¼118e124 ^ꢀC.

4.3.12. N-(N⁰-(N⁰⁰-Benzyl-N⁰⁰-phenyl-3⁰⁰-carboxamidophenyl)-N⁰-

methyl-3⁰-carboxamidophenyl)-N-methyl-3-nitrobenzamide 8b. Pre-

pared according to general procedure C from amide 7b (276 mg,

4.3.15. 1-N,3-N-Dibenzyl-3-N-{3-[benzyl(4-methyl-3-nitrobenzene)

amido]-4-methylbenzene}-4-methyl-1-N-phenylbenzene-1,3-

6946

L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

diamido 8b⁰. Prepared according to general procedure C from amide

7b⁰(50.0 mg, 0.071 mmol), NaH (12.0 mg, 0.284 mmol), benzyl

bromide (0.085 mL, 0.716 mmol). The crude mixture was puriﬁed

through silica gel (PE to PE/EtOAc: 7/3) to afford a colourless oil

(55 mg, 98%). ¹H NMR and ¹³C NMR show mixture of multiple con-

formers resulting impossible to any ratio. MS (ESI^þ) m/z: 815 (100)

[MþNa]. HRMS calcd for C₅₁H₄₄N₄NaO₅: 815.3204, found: 815.3193.

general procedure B

from nitro 4c⁰(200 mg, 0.578 mmol),

SnCl₂$2H₂O (1.30 g, 5.78 mmol). The crude mixture was puriﬁed

through silica gel (PE/EtOAc: 6/4) to afford a colourless oil

(m¼177 mg, 97%). IR (ﬁlm) 3360, 3062e2857, 1643, 1591 cm^ꢁ1. ¹H

NMR (CDCl₃, 300 MHz) d 2.14 (s, 3H), 3.71 (br s, 2H), 5.13 (br s, 2H),

6.50 (m, 2H), 6.77 (m, 1H), 6.84 (m, 2H), 6.98e7.12 (m, 3H),

7.20e7.34 (m, 5H). ¹³C NMR (CDCl₃, 75.5 MHz)

d

14.0 (CH₃), 52.4

(CH₂), 114.7 (CH), 117.2 (CH), 118.4 (Cq), 125.5 (CH), 126.5 (CH), 127.0

(CH), 127.3 (CH), 128.1 (CH), 128.2 (CH), 128.3 (CH), 137.0 (Cq), 137.3

(Cq), 141.9 (Cq), 144.7 (Cq), 171.1 (Cq). MS (EI) m/z: 317 (100) [MþH].

HRMS calcd for C₂₁H₂₀N₂O: 317.1648, found: 317.1646.

4.3.16. N,2-Dimethyl-3-nitro-N-phenylbenzamide 4c. Prepared acc-

ording to general procedure A from acid (2.00 g, 11.0 mmol), oxalyl

chloride (4.72 mL, 55.8 mmol), N-methylaniline (2.38 mL,

22.0 mmol) and Et₃N (3.06 mL, 21.9 mmol). The crude mixture was

puriﬁed through silica gel (PE/EtOAc: 8/2) to afford a colourless

solid (m¼3.1 g, 99%). IR (ﬁlm) 3064e2937,1649,1528 cm^ꢁ1. ¹H NMR

This amine was used to make the title compound according to

general procedure A from acid (203 mg, 1.12 mmol), oxalyl chloride

(0.48 mL, 5.67 mmol), amine (177 mg, 0.560 mmol) and pyridine

(0.14 mL,1.68 mmol). The crude mixture was puriﬁed through silica

gel (PE/EtOAc: 6/4) to afford a white solid (m¼250 mg, 93%). IR

(CDCl₃, 300 MHz) d 2.50 (s, 3H), 3.53 (s, 3H), 6.60 (m, 2H), 7.29e7.09

(m, 5H), 7.69 (d, J¼7.9 Hz, 1H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 16.8

(CH₃), 37.3 (CH₃), 124.5 (CH), 126.1 (CH), 126.6 (CH), 127.5 (CH),

129.3 (CH), 129.9 (Cq), 131.6 (CH), 139.9 (Cq), 142.9 (Cq), 150.0 (Cq),

168.8 (Cq). MS (EI) m/z: 271 (100) [MþH]. HRMS calcd for

C₁₅H₁₅N₂O₃: 271.1077, found: 271.1077. Mp¼78e79 ^ꢀC.

(ﬁlm) 3433, 1643, 1526 cm^ꢁ1. ¹H NMR (CDCl₃, 300 MHz)

d 2.12 (s,

3H), 2.57 (s, 3H), 4.98 (s, 2H), 6.79 (m, 3H), 6.94 (t, J¼7.8 Hz, 1H),

7.03e7.13 (m, 3H), 7.16e7.23 (m, 2H), 7.24e7.30 (m, 3H), 7.35 (t,

J¼7.9 Hz, 1H), 7.47 (d, J¼7.9 Hz, 1H), 7.65 (d, J¼7.5 Hz, 1H), 7.85 (d,

J¼8.0 Hz, 1H), 8.30 (br s, 1H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 14.9

4.3.17. N-Benzyl-2-methyl-3-nitro-N-phenylbenzamide 4c⁰. Prepared

according to general procedure A from acid (2.00 g, 11.0 mmol),

oxalyl chloride (4.72 mL, 55.8 mmol), N-benzylaniline (4.08 mL,

23.6 mmol) and Et₃N (3.06 mL, 21.9 mmol). The crude mixture was

puriﬁed through silica gel (PE/EtOAc: 9/1 then 8/2) to afford a white

(CH₃),16.1 (CH₃), 52.9 (CH₂),124.7 (CH),124.8 (CH),125.3 (CH),125.8

(CH), 126.7 (CH), 127.4 (CH), 127.5 (CH), 127.6 (CH), 127.9 (Cq), 128.4

(CH), 128.5 (CH), 129.0 (CH), 130.6 (Cq), 130.8 (CH), 135.6 (Cq), 136.9

(Cq), 137.4 (Cq), 139.8 (Cq), 141.5 (Cq), 150.8 (Cq), 166.4 (Cq), 170.5

(Cq). MS (ESI^þ) m/z: 497 (40) [MþNH₄], 502 (100) [MþNa]. HRMS

calcd for C₂₉H₂₉N₄O₄: 497.2183, found: 497.2195. Mp¼185e190 ^ꢀC.

solid (m¼3.72 g, 98%). IR (ﬁlm) 1649, 1527 cm^ꢁ1

.

¹H NMR (CDCl₃,

d 2.52 (s, 3H), 5.12 (s, 2H), 6.85e6.79 (m, 2H), 7.15e7.05

300 MHz)

(m, 4H), 7.32e7.22 (m, 6H), 7.67 (d, J¼8.2 Hz, 1H). ¹³C NMR (CDCl₃,

4.3.20. 1-N-Benzyl-2-methyl-3-N-(2-nitrobenzene)-1-N-phenyl-

benzene-1,3-dicarboxamide 5d. Prepared according to general pro-

cedure A from acid (210 mg, 1.26 mmol), oxalyl chloride (0.54 mL,

6.33 mmol), amine derived from 4c⁰(200 mg, 0.633 mmol) and

pyridine (0.15 mL, 1.85 mmol). The crude mixture was puriﬁed

through silica gel (PE/EtOAc: 6/4 then EtOAc) to afford a white solid

(275 mg, 95%). IR (ﬁlm) 3436, 1640, 1527 cm^ꢁ1. ¹H NMR (DMSO-d₆,

75.5 MHz)

d 16.8 (CH₃), 53.1 (CH₂), 124.4 (CH), 126.0 (CH), 127.8

(CH), 127.9 (CH), 128.6 (CH), 128.9 (CH), 129.2 (CH), 129.9 (Cq), 131.5

(CH),136.8 (Cq), 139.7 (Cq), 141.3 (Cq), 150.0 (Cq), 168.7 (Cq). MS (EI)

m/z: 347 (51) [MþH]. HRMS calcd for C₂₁H₁₉N₂O₃: 347.1390, found:

347.1398. Mp¼104e105 ^ꢀC.

4.3.18. 1-N,2-Dimethyl-3-N-(2-methyl-3-nitrobenzene)-1-N-phenyl-

benzene-1,3-dicarboxamide 5c. Prepared according to general pro-

cedure B from nitro 4c (100 mg, 0.370 mmol), SnCl₂$2H₂O (652 mg,

2.89 mmol). The crude mixture was puriﬁed through silica gel (PE/

EtOAc: 6/4) to afford a colourless oil (m¼81 mg, 91%). IR (ﬁlm) 3357,

300 MHz) d 2.27 (s, 3H), 5.14 (s, 2H), 7.18e7.00 (m, 7H), 7.37e7.23

(m, 6H), 7.92e7.70 (m, 3H), 8.14 (d, J¼7.9 Hz, 1H), 10.1 (br s, 1H). ¹³C

NMR (DMSO-d₆, 75.5 MHz)

d 14.9 (CH₃), 51.9 (CH₂), 124.2 (CH),

125.0 (CH), 125.2 (CH), 125.9 (CH), 127.0 (CH), 127.2 (CH), 127.7 (CH),

127.9 (CH), 128.4 (CH), 128.8 (CH), 129.3 (CH), 129.6 (Cq), 130.8

(CH), 132.7 (Cq), 134.0 (CH), 135.8 (Cq), 137.4 (Cq), 137.9 (Cq), 141.7

(Cq), 146.5 (Cq), 164.4 (Cq), 169.5 (Cq). MS (ESI^þ) m/z: 466 (100)

[MþH]. HRMS calcd for C₂₈H₂₄N₃O₄: 466.1761, found: 466.1757.

3059e2929, 1636, 1589 cm^ꢁ1. ¹H NMR (CDCl₃, 300 MHz)

d 2.09 (br

s, 3H), 3.50 (br s, 3H), 3.61 (br s, 2H), 6.49 (br m, 2H), 6.79 (br t,

J¼7.0 Hz, 1H), 6.94e7.21 (br m, 5H). ¹³C NMR (CDCl₃, 75.5 MHz)

d

14.2 (CH₃), 37.1 (CH₃), 115.1 (CH), 117.9 (CH), 118.8 (Cq), 125.9 (CH),

126.4 (CH), 126.5 (CH), 128.7 (CH), 137.6 (Cq), 143.8 (Cq), 144.4 (Cq),

171.4 (Cq). MS (EI) m/z: 241 (100) [MþH]. HRMS calcd for

C₁₅H₁₇N₂O: 241.1335, found: 241.1331.

This amine was used to make the title compound according to

general procedure A from acid (307 mg, 1.69 mmol), oxalyl chloride

(0.73 mL, 8.63 mmol), amine (204 mg, 0.850 mmol) and Et₃N

(0.24 mL, 1.72 mmol). The crude mixture was puriﬁed through silica

gel (PE/EtOAc: 6/4) to afford a white solid (m¼201 mg, 82%). IR (ﬁlm)

3243, 3055,1645,1528 cm^ꢁ1. Ratio 85/15: ¹H NMR (CDCl₃, 500 MHz)

4.3.21. 1-N-Benzyl-2-methyl-3-N-(4-nitrobenzene)-1-N-phenyl-

benzene-1,3-dicarboxamide 5e. Prepared according to general pro-

cedure A from acid chloride (265 mg, 1.43 mmol), amine derived

from 4c⁰(226 mg, 0.715 mmol) and pyridine (0.17 mL, 2.14 mmol).

The crude mixture was puriﬁed through silica gel (PE/EtOAc: 6/4) to

afford a white solid (284 mg, 86%). IR (ﬁlm) 3437, 1639, 1527 cm^ꢁ1

.

¹H NMR (CDCl₃, 300 MHz)

d 2.12 (s, 3H), 5.11 (s, 2H), 6.89e6.81 (m,

2H), 6.94 (t, J¼7.8 Hz, 1H), 7.13e7.04 (m, 3H), 7.18 (br s, 1H), 7.29 (m,

4H), 7.41 (br s, 1H), 8.09 (br s, 1H), 8.30e8.19 (m, 3H), 8.38 (m, 1H),

d

major conformer 2.19 (s, 3H), 2.60 (s, 3H), 3.44 (s, 3H), 6.84 (d,

8.70 (br s, 1H). ¹³C NMR (DMSO-d₆, 125 MHz)

d 15.1 (CH₃), 51.9

J¼7.4 Hz,1H), 6.98 (m, 3H), 7.11 (m, 1H), 7.19 (t, J¼7.4 Hz, 2H), 7.42 (t,

J¼7.7 Hz, 1H), 7.66 (m, 2H), 7.71 (br s, 1H), 7.90 (d, J¼8.0 Hz, 1H).

Minorconformer 1.61 (br s, 3H), 2.65 (s, 3H), 3.17 (s, 3H), other signals

(CH₂), 123.6 (CH), 123.7 (CH), 125.2 (CH), 125.4 (CH), 126.8 (CH),

126.9 (CH), 127.2 (CH), 127.7 (CH), 127.9 (CH), 128.4 (CH), 128.8 (CH),

129.2 (CH), 130.7 (CH), 136.1 (Cq), 137.4 (Cq), 137.8 (Cq), 139.9 (Cq),

141.7 (Cq), 149.2 (Cq), 150.0 (Cq), 163.7 (Cq), 169.5 (Cq). MS (ESI^þ)

m/z: 483 (90) [MþNH₄], 488 (100) [MþNa]. HRMS calcd for

C₂₈H₂₇N₄O₄: 483.2027, found: 483.2022. Mp¼224e226 ^ꢀC.

masked by major conformer. ¹³C NMR (CDCl₃, 125 MHz)

d 14.9 (CH₃),

16.1 (CH₃), 37.2 (CH₃), 124.6 (CH), 124.9 (CH), 125.3 (CH), 125.8 (CH),

126.4 (CH), 126.7 (CH), 127.1 (CH), 127.8 (Cq), 129.2 (CH), 130.5 (Cq),

130.8 (CH), 135.6 (Cq), 137.5 (Cq), 139.9 (Cq), 143.2 (Cq), 150.8 (Cq),

166.4 (Cq), 170.6 (Cq). MS (ESI^þ) m/z: 426 (90) [MþNa]. HRMS calcd

for C₂₃H₂₁N₃NaO₄: 426.1424, found: 426.1417. Mp¼89e94 ^ꢀC.

4.3.22. 1-N,2,3-N-Trimethyl-1-N-(2-methyl-3-nitrobenzene)-3-N-

phenylbenzene-1,3-dicarboxamide 6c. Prepared according to gen-

eral procedure C from amide 5c (81.0 mg, 0.201 mmol), NaH

(32.0 mg, 0.800 mmol) and MeI (0.13 mL, 2.09 mmol). The crude

mixture was puriﬁed through silica gel (PE then PE/EtOAc 9/1, 6/4,

4.3.19. 1-N-Benzyl-2-methyl-3-N-(2-methyl-3-nitrobenzene)-1-N-

phenylbenzene-1,3-dicarboxamide 5c⁰. Prepared according to

L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

6947

4/6) to afford a white solid (m¼66 mg, 79%). IR (ﬁlm) 2932, 1647,

1528 cm^ꢁ1. Ratio: 80/20. ¹H NMR (CDCl₃, 300 MHz)

major con-

(m, 9H), 7.90 (dd, J¼7.8, 1.1 Hz, 1H). Minor conformer

d

2.41 (s, 3H),

d

2.97 (s, 3H), 5.27 (d, J¼14.5 Hz, 1H), 7.52 (d, J¼7.7 Hz, 1H), 7.71

(t, J¼7.7 Hz, 1H), 7.77 (t, J¼7.4 Hz, 1H), 8.25 (d, J¼8.2 Hz, 1H), other

signals masked by major conformer. ¹³C NMR (CDCl₃, 75.5 MHz)

former: 2.25 (s, 3H), 2.48 (s, 3H), 3.25 (s, 3H), 3.46 (s, 3H), 6.74e6.93

(m, 4H), 6.95e7.12 (m, 6H), 7.68 (dd, J¼2.3, 6.9 Hz, 1H). Minor

conformer: 2.32 (s, 3H), 2.59 (s, 3H), 2.97 (s, 3H), 3.53 (s, 3H),

7.13e7.23 (m, 4H), 7.33e7.57 (m, 4H), 7.92 (d, J¼7.7 Hz, 1H), other

signals masked by major conformer. ¹³C NMR (CDCl₃, 75.5 MHz)

major conformer

d 15.2 (CH₃), 36.6 (CH₃), 52.9 (CH₂), 124.4 (CH),

126.3 (CH), 127.1 (CH), 127.4 (CH), 127.5 (CH), 127.5 (CH), 127.6

(CH), 128.1 (CH), 128.5 (CH), 128.6 (CH), 128.7 (CH), 129.4 (CH), 131.9

(Cq), 132.8 (Cq), 133.3 (CH), 137.0 (Cq), 138.5 (Cq), 141.6 (Cq),

d

major conformer: 15.2 (CH₃), 16.9 (CH₃), 36.8 (CH₃), 37.3 (CH₃),

124.5 (CH), 125.9 (CH), 126.3 (CH), 126.4 (CH), 126.9 (CH), 127.7

(CH), 128.4 (CH), 128.8 (CH), 130.2 (CH), 131.7 (Cq), 138.9 (Cq), 139.2

(Cq), 142.1 (Cq), 143.1 (Cq), 150.1 (Cq), 168.7 (Cq), 169.5 (Cq). MS

(ESI^þ) m/z: 440 (100) [MþNa]. HRMS calcd for C₂₄H₂₃N₃NaO₄:

440.1581, found: 440.1583. Mp¼232e240 ^ꢀC.

142.0 (Cq), 145.6 (Cq), 167.2 (Cq),169.5 (Cq). Minor conformer d 39.0

(CH₃), 52.3 (CH₂), 126.6 (CH), 127.2 (CH), 128.0 (CH), 128.4 (CH),

128.8 (CH), 129.9 (CH), 134.7 (CH), other signals masked by major

conformer. MS (ESI^þ) m/z: 502 (100) [MþNa]. HRMS calcd for

C₂₉H₂₅N₃NaO₄: 502.1737, found: 502.1745. Mp¼98e100 ^ꢀC.

4.3.23. 1-N-Benzyl-2,3-N-dimethyl-3-N-(2-methyl-3-nitrobenzene)-

1-N-phenylbenzene-1,3-dicarboxamide 6c⁰. Prepared according to

general procedure C from amide 5c⁰(75.0 mg, 0.156 mmol), NaH

(25.0 mg, 0.625 mmol) and MeI (0.1 mL, 1.56 mmol). The crude

mixture was puriﬁed through silica gel (PE then PE/EtOAc 9/1, 8/2,

6/4) to afford a pale yellow solid (m¼57 mg, 74%). IR (ﬁlm) 3062,

4.3.26. 1-N-Benzyl-2,3-N-dimethyl-3-N-(4-nitrobenzene)-1-N-phe-

nylbenzene-1,3-dicarboxamide 6e. Prepared according to general

procedure C from amide 5e (100 mg, 0.215 mmol), NaH (34.4 mg,

0.860 mmol), methyliodide (0.13 mL, 2.15 mmol). The crude mix-

ture was puriﬁed through silica gel (PE then PE/EtOAc: 6/4) to af-

ford a white solid (80 mg, 78%). IR (ﬁlm) 3061, 1646, 1527 cm^ꢁ1

.

1646, 1528 cm^ꢁ1. Ratio: 80/20. ¹H NMR (CDCl₃, 300 MHz)

d

major

Ratio: 95/5. ¹H NMR (CDCl₃, 300 MHz)

d 2.29 (s, 3H), 3.30 (s, 3H),

conformer: 2.30 (s, 3H), 2.49 (s, 3H), 3.26 (s, 3H), 5.05 (d, J¼14.3 Hz,

1H), 5.09 (d, J¼14.3 Hz, 1H), 6.68e6.77 (m, 2H), 6.80 (t, J¼7.5 Hz,

1H), 6.90 (dd, J¼7.5, 1.1 Hz, 1H), 6.96e7.07 (m, 6H), 7.26e7.35 (m,

5H), 7.66 (dd, J¼6.9, 2.6 Hz, 1H). Minor conformer: 2.35 (s, 3H), 2.59

(s, 3H), 2.96 (s, 3H), 5.26 (d, J¼14.5, 1H), 7.92 (d, J¼8.1 Hz, 1H), other

signals masked by major conformer. ¹³C NMR (CDCl₃, 75.5 MHz)

5.07 (d, J¼14.2 Hz, 1H), 5.12 (d, J¼14.2 Hz, 1H), 6.79 (m, 3H), 6.92 (t,

J¼7.7 Hz, 1H), 7.06 (m, 3H), 7.14 (m, 1H), 7.24 (d, J¼8.8 Hz, 2H), 7.31

(m, 5H), 7.91 (d, J¼8.8 Hz, 2H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 15.0

(CH₃), 37.4 (CH₃), 53.1 (CH₂), 122.8 (CH), 126.5 (CH), 127.4 (CH),

127.5 (CH), 127.6 (CH), 127.9 (CH), 128.5 (CH), 128.7 (CH), 128.8 (CH),

128.9 (CH), 129.0 (CH), 131.5 (Cq), 136.9 (Cq), 139.2 (Cq), 141.4 (Cq),

141.5 (Cq), 142.8 (Cq), 147.8 (Cq), 168.3 (Cq), 169.4 (Cq). MS (ESI^þ) m/

z: 497 (38) [MþNH₄], 502 (100) [MþNa]. HRMS calcd for

C₂₉H₂₉N₄O₄: 497.2183, found: 497.2179. Mp¼100e102 ^ꢀC.

d

major conformer: 15.3 (CH₃), 16.9 (CH₃), 36.8 (CH₃), 53.0 (CH₂),

124.4 (CH), 125.9 (CH), 126.3 (CH), 127.3 (CH), 127.5 (CH), 127.6 (CH),

127.6 (CH), 128.3 (CH), 128.4 (CH), 128.6 (CH), 128.8 (CH), 130.2

(CH), 130.3 (Cq), 131.7 (Cq), 137.0 (Cq), 138.8 (Cq), 139.2 (Cq), 141.6

(Cq),142.2 (Cq),150.1 (Cq),168.8 (Cq),169.4 (Cq). MS (ESI^þ) m/z: 511

(62) [MþNH₄], 516 (100) [MþNa]. HRMS calcd for C₃₀H₃₁N₄O₄:

511.2340, found: 511.2347. Mp¼156e157 ^ꢀC.

4.3.27. 1-N,2,3-N-Trimethyl-1-N-{2-methyl-3-[(2-methyl-3-nitroben-

zene)amido]benzene}-3-N-phenylbenzene-1,3-dicarboxamide 7c. Pre-

pared according to general procedure B from nitro 6c (129 mg,

0.309 mmol), SnCl₂$2H₂O (349 mg, 1.55 mmol). The crude mixture

was puriﬁed through silica gel (toluene/EtOAc: 4/6) to afford

4.3.24. 1-N,3-N-Dibenzyl-2-methyl-1-N-(2-methyl-3-nitrobenzene)-

3-N-phenylbenzene-1,3-dicarboxamide 6c’. Prepared according to

general procedure C from amide 5c⁰(60.0 mg, 0.125 mmol), NaH

(20.0 mg, 0.500 mmol), benzyl bromide (0.15 mL, 1.25 mmol). The

crude mixture was puriﬁed through silica gel (PE then PE/EtOAc: 7/

3) to afford a colourless oil (m¼71 mg, 100%). IR (ﬁlm) 3064, 1648,

a white solid (m¼100 mg, 84%). IR (ﬁlm) 3370, 1645, 1528 cm^ꢁ1

.

Ratio 78/22. ¹H NMR (CDCl₃, 500 MHz)

d major conformer: 2.12 (s,

3H), 2.29 (s, 3H), 3.23 (s, 3H), 3.47 (s, 3H), 3.61 (br s, 2H), 6.28 (d,

J¼7.4 Hz, 1H), 6.48 (d, J¼7.7 Hz, 1H), 6.69 (t, J¼7.7 Hz, 1H),

6.73e6.82 (m, 4H), 6.99e7.11 (m, 3H), 7.16 (m, 1H). Minor con-

former 2.19 (s, 3H), 2.33 (s, 3H), 2.95 (s, 3H), 3.53 (s, 3H), other

signals masked by major conformer. ¹³C NMR (CDCl₃, 125 MHz)

1528 cm^ꢁ1. Ratio 85/15. ¹H NMR (CDCl₃, 300 MHz)

d major con-

former: 2.28 (s, 3H), 2.42 (s, 3H), 3.98 (d, J¼13.5 Hz, 1H), 5.07 (br s,

2H), 5.66 (d, J¼13.5 Hz, 1H), 6.23 (d, J¼7.9 Hz, 1H), 6.62 (t, J¼7.9 Hz,

1H), 6.73 (m, 2H), 6.87 (d, J¼7.5 Hz, 1H), 7.36e6.93 (m, 15H), 7.64

(dd, J¼7.5, 1.4 Hz, 1H). Minor conformer: 2.22 (s, 3H), 2.36 (s, 3H),

7.96 (d, J¼7.8 Hz, 1H), other signals masked by major conformer. ¹³C

d

major conformer: 14.4 (CH₃), 15.2 (CH₃), 36.5 (CH₃), 37.0 (CH₃),

115.2 (CH), 116.5 (CH), 119.0 (Cq), 125.9 (CH), 126.2 (CH), 126.6 (CH),

126.9 (CH), 127.1 (CH), 128.6 (CH), 128.9 (CH), 131.9 (Cq), 137.0 (Cq),

138.1 (Cq), 143.2 (Cq), 144.9 (Cq), 145.1 (Cq), 169.8 (Cq), 171.4 (Cq).

MS (ESI^þ) m/z: 388 (100) [MþH]. HRMS calcd for C₂₄H₂₆N₃O₂:

388.2020, found: 388.2030. Mp¼241e242 ^ꢀC.

NMR (CDCl₃, 75.5 MHz)

d major conformer: 15.2 (CH₃), 16.7 (CH₃),

52.0 (CH₂), 53.0 (CH₂), 124.5 (CH), 125.7 (CH), 126.0 (CH),127.3 (CH),

127.6 (CH), 127.6 (CH), 127.9 (CH), 128.4 (CH), 128.5 (CH), 128.7 (CH),

128.8 (CH), 129.5 (CH), 129.8 (CH), 129.9 (CH), 130.2 (Cq), 131.9 (Cq),

136.2 (Cq), 137.1 (Cq), 138.7 (Cq), 139.1 (Cq), 139.9 (Cq), 141.7 (Cq),

150.1 (Cq), 168.5 (Cq), 169.5 (Cq). MS (ESI^þ) m/z: 592 (100) [MþNa].

HRMS calcd for C₃₆H₃₁N₃NaO₄: 592.2207, found: 592.2201.

Mp¼60e62 ^ꢀC.

This amine was used to make the title compound according to

general procedure A from acid (49.0 mg, 0.268 mmol), oxalyl

chloride (0.11 mL, 1.34 mmol), amine (52.0 mg, 0.134 mmol) and

Et₃N (0.037 mL, 0.268 mmol). The crude mixture was puriﬁed

through silica gel (PE/EtOAc: 1/9) to afford a colourless oil (65 mg,

88%). IR (ﬁlm) 3249, 3056, 1627 cm^ꢁ1. Ratio: 77/23. ¹H NMR (CDCl₃,

300 MHz) d major conformer: 2.16 (s, 3H), 2.21 (s, 3H), 2.55 (s, 3H),

4.3.25. 1-N-Benzyl-2,3-N-dimethyl-3-N-(2-nitrobenzene)-1-N-phe-

nylbenzene-1,3-dicarboxamide 6d. Prepared according to general

procedure C from amide 5d (200 mg, 0.430 mmol), NaH (69.0 mg,

1.72 mmol), methyl iodide (0.27 mL, 4.34 mmol). The crude mix-

ture was puriﬁed through silica gel (PE then PE/EtOAc: 6/4) to af-

3.10 (s, 3H), 3.43 (s, 3H), 6.51 (d, J¼7.2 Hz, 1H), 6.69e7.18 (m, 9H),

7.37 (t, J¼7.8 Hz, 1H), 7.51e7.70 (m, 2H), 7.86 (d, J¼7.8 Hz, 1H), 8.20

(br s, 1H). Minor conformer: 2.17 (s, 3H), 2.59 (s, 3H), 2.88 (s, 3H)

3.50 (s, 3H), 8.72 (br s, 1H), other signals masked by major con-

former. ¹³C NMR (CDCl₃, 125 MHz)

d major conformer: 15.1 (CH₃),

ford a yellow solid (177 mg, 86%). IR (ﬁlm) 3060, 1644, 1526 cm^ꢁ1

.

15.1 (CH₃), 16.1 (CH₃), 36.7 (CH₃), 37.2 (CH₃), 123.6 (CH), 124.6 (CH),

125.3 (CH), 125.6 (CH), 126.2 (CH), 126.7 (CH), 126.8 (CH), 127.3

(CH), 128.4 (CH), 129.0 (CH), 130.4 (Cq), 130.7 (CH), 130.9 (CH), 131.7

(Cq), 136.0 (Cq), 136.9 (Cq), 138.6 (Cq), 139.6 (Cq), 139.8 (Cq), 142.6

(Cq), 143.1 (Cq), 150.8 (Cq), 166.3 (Cq), 169.7 (Cq), 170.5 (Cq). MS

Ratio: 84/16. ¹H NMR (DMSO-d₆, 300 MHz) major conformer

d 2.33

(s, 3H), 3.26 (s, 3H), 5.04 (d, J¼14.2 Hz, 1H), 5.13 (d, J¼14.2 Hz, 1H),

6.77e6.69 (m, 2H), 6.86 (d, J¼7.3 Hz, 1H), 6.97 (d, J¼7.8 Hz,

1H), 7.04e7.00 (m, 2H), 7.07 (dd, J¼7.3, 1.4 Hz, 1H), 7.43e7.19

6948

L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

(ESI^þ) m/z: 551 (80) [MþH], 573 (57) [MþNa]. HRMS calcd for

C₃₂H₃₁N₄O₅: 551.2289, found: 551.2292. Mp¼156e158 ^ꢀC.

(0.08 mL, 0.945 mmol), amine (49 mg, 0.091 mmol) and Et₃N

(0.026 mL, 0.186 mmol). The crude mixture was puriﬁed through

silica gel (PE/EtOAc: 5/5) to afford a white solid (43 mg, 67%). IR

4.3.28. 1-N-Benzyl-2,3-N-dimethyl-3-N-{2-methyl-3-[(2-methyl-3-

nitrobenzene)amido]benzene}-1-N-phenylbenzene-1,3-dicarbox-

amide 7c⁰. Prepared according to general procedure B from nitro

6c⁰(514 mg, 1.04 mmol), SnCl₂$2H₂O (2.34 g, 10.4 mmol). The crude

mixture was puriﬁed through silica gel (PE/EtOAc: 2/8) to afford

.

(ﬁlm) 3257, 1645, 1527 cm^ꢁ1Ratio: 83/17. ¹H NMR (CDCl₃,

300 MHz)

d

major conformer: 2.14 (s, 3H), 2.28 (s, 3H), 2.59 (s, 3H),

3.95 (d, J¼13.5 Hz, 1H), 5.01e5.21 (br m, 2H), 5.55 (d, J¼13.5 Hz,

1H), 6.26 (d, J¼6.8 Hz, 1H), 6.59e6.68 (m, 2H), 6.72e6.79 (m, 2H),

6.80e6.93 (m, 2H), 6.98e7.06 (m, 2H), 7.07e37 (m, 11H), 7.41 (t,

J¼7.8 Hz, 1H), 7.57 (d, J¼7.4 Hz, 1H), 7.67 (d, J¼7.9 Hz, 1H), 7.91 (d,

a white solid (460 mg, 96%). IR (ﬁlm) 3455e3360, 1640, 1592 cm^ꢁ1

.

Ratio: 75/25. ¹H NMR (CDCl₃, 300 MHz)

d

major conformer: 2.17 (s,

J¼7.8 Hz, 1H), 7.98 (s, 1H). ¹³C NMR (CDCl₃, 75.5 MHz)

d major

3H), 2.32 (s, 3H), 3.22 (s, 3H), 5.05 (d, J¼14.2 Hz, 1H), 5.14 (d,

J¼14.6 Hz, 1H), 6.31 (d, J¼7.2 Hz, 1H), 6.57 (d, J¼7.7 Hz, 1H),

6.75e6.67 (m, 3H), 6.80 (m, 1H), 6.86 (m, 1H), 7.02 (m, 3H), 7.11 (m,

1H), 7.35e7.26 (m, 5H). Minor conformer: 2.23 (s, 3H), 2.35 (s, 3H),

2.95 (s, 3H), 5.26 (d, J¼14.1 Hz, 1H), other signals masked by major

conformer: 15.3 (CH₃), 15.5 (CH₃), 16.4 (CH₃), 52.3 (CH₂), 53.3 (CH₂),

123.6 (CH), 124.5 (CH), 124.6 (CH), 125.7 (CH), 125.8 (CH), 125.9

(CH), 126.1 (CH), 127.1 (CH), 127.5 (CH), 127.9 (CH), 128.1 (CH), 128.6

(CH), 128.8 (CH), 128.9 (CH), 129.2 (CH), 129.7 (CH), 130.5 (CH),

130.9 (Cq), 131.0 (CH), 132.3 (Cq), 136.0 (Cq), 136.6 (Cq), 137.2 (Cq),

137.5 (Cq), 138.7 (Cq), 140.1 (Cq), 140.6 (Cq), 142.1 (Cq), 151.2 (Cq),

166.5 (Cq), 169.9 (Cq), 170.5 (Cq). MS (ESI^þ) m/z: 725 (100) [MþNa].

HRMS calcd for C₄₄H₃₈N₄NaO₅: 725.2734, found: 725.2734.

conformer. ¹³C NMR (CDCl₃, 75.5 MHz)

d major conformer: 14.4

(CH₃), 15.2 (CH₃), 36.4 (CH₃), 52.6 (CH₂), 115.1 (CH), 116.1 (CH), 118.9

(Cq), 125.6 (CH), 126.8 (CH), 127.1 (CH), 127.3 (CH), 127.4 (CH), 128.3

(CH), 128.3 (CH), 128.4 (CH), 128.6 (CH), 128.7 (CH), 131.7 (Cq), 136.8

(Cq), 137.1 (Cq), 137.9 (Cq), 141.6 (Cq), 143.0 (Cq), 144.7 (Cq), 169.6

(Cq), 171.4 (Cq). MS (ESI^þ) m/z: 464 (100) [MþH], 481 (78)

[MþNH₄]. HRMS calcd for C₃₀H₃₀N₃O₂: 464.2333, found: 464.2342.

Mp¼70e71 ^ꢀC.

4.3.30. 1-N-Benzyl-2,3-N-dimethyl-3-N-{2-[(2-methyl-3-nitroben-

zene)amido]benzene}-1-N-phenylbenzene-1,3-dicarboxamide 7d. Pre-

pared according to general procedure B from nitro 6d (100 mg,

0.209 mmol), SnCl₂$2H₂O (470 mg, 2.09 mmol). The crude mixture

was puriﬁed through silica gel (PE/EtOAc: 6/4) to afford a yellow

This amine was used to make the title compound according to

general procedure A from acid (78.0 mg, 0.432 mmol), oxalyl

chloride (0.19 mL, 2.16 mmol), amine (100 mg, 0.216 mmol) and

Et₃N (0.06 mL, 0.432 mmol). The crude mixture was puriﬁed

through silica gel (PE/EtOAc: 3/7) to afford a white solid (127 mg,

94%). IR (ﬁlm) 3253, 3061, 1630 cm^ꢁ1. Ratio: 75/25. ¹H NMR (CDCl₃,

foam (91 mg, 97%). IR (ﬁlm) 3457, 3356, 3032, 1641, 1591 cm^ꢁ1

.

Ratio: 94/6. ¹H NMR (CDCl₃, 300 MHz)

d 2.29 (s, 3H), 3.20 (s, 3H),

4.62 (br s, 2H), 5.03 (d, J¼14.3 Hz, 1H), 5.16 (d, J¼14.3 Hz, 1H), 6.15

(m, 1H), 6.43 (m, 1H), 6.57 (d, J¼8.1 Hz, 1H), 6.76e6.69 (m, 2H),

6.88e6.79 (m, 3H), 6.93 (m,1H), 7.04 (m, 3H), 7.36e7.23 (m, 5H). ¹³C

300 MHz)

d

major conformer: 2.20 (s, 3H), 2.29 (s, 3H), 2.57 (s, 3H),

NMR (CDCl₃, 75.5 MHz) d 15.0 (CH₃), 37.2 (CH₃), 52.9 (CH₂), 116.4

3.16 (s, 3H), 5.05 (d, J¼14.4 Hz, 1H), 5.08 (d, J¼14.4 Hz, 1H), 6.55 (d,

J¼7.2 Hz, 1H), 6.66e6.89 (m, 5H), 6.94e7.12 (m 4H), 7.28 (m, 4H),

7.40 (t, J¼8.1 Hz, 1H), 7.62e772 (m, 2H), 7.77 (br s, 1H), 7.89 (d,

J¼7.8 Hz, 1H). Minor conformer 2.16 (s, 3H), 2.24 (s, 3H), 2.62 (s,

3H), 2.91 (s, 3H), other signals masked by major conformer. ¹³C

(CH), 116.5 (CH), 118.7 (CH), 126.1 (CH), 126.5 (CH), 127.0 (CH), 127.5

(CH), 128.4 (CH), 128.6 (CH), 128.8 (CH), 130.4 (Cq), 130.5 (Cq), 131.8

(CH), 137.2 (Cq), 138.4 (Cq), 141.8 (Cq), 144.3 (Cq), 146.8 (Cq), 169.9

(Cq), 171.1 (Cq). MS (ESI^þ) m/z: 472 (100) [MþNa]. HRMS calcd for

C₂₉H₂₇N₃NaO₂: 472.1995, found: 472.2003. Mp¼128e130 ^ꢀC.

This amine was used to make the title compound according to

general procedure A from acid (73.0 mg, 0.403 mmol), oxalyl chlo-

ride (0.17 mL, 2.01 mmol), amine (90.0 mg, 0.200 mmol) and pyri-

dine (0.048 mL, 0.593 mmol). The crude mixture was puriﬁed

through silica gel (PE/EtOAc: 6/4 to EtOAc) to afford a white solid

(89 mg, 73%). IR (ﬁlm) 3032, 1641, 1526 cm^ꢁ1. Ratio: 95/5. ¹H NMR

NMR (CDCl₃, 125 MHz)

d major conformer: 15.2 (CH₃), 15.3 (CH₃),

16.1 (CH₃), 36.8 (CH₃), 52.9 (CH₂), 123.9 (CH), 124.3 (CH), 125.8 (CH),

126.1 (CH), 126.5 (CH), 127.2 (CH), 127.4 (CH), 127.5 (CH), 127.8 (CH),

127.9 (CH), 128.7 (CH), 128.6 (CH), 128.9 (CH), 129.2 (CH), 130.9

(CH), 131.8 (Cq), 135.8 (Cq), 135.9 (Cq), 137.0 (Cq), 137.1 (Cq), 137.4

(Cq), 138.6 (Cq), 139.8 (Cq), 141.7 (Cq), 142.7 (Cq), 151.0 (Cq), 166.2

(Cq), 169.6 (Cq), 170.5 (Cq). MS (ESI^þ) m/z: 644 (21) [MþNH₄], 649

(100) [MþNa]. HRMS calcd for C₃₈H₃₈N₅O₅: 644.2867, found:

644.2876. Mp¼100e102 ^ꢀC.

(CDCl₃, 300 MHz)

d 2.22 (s, 3H), 2.63 (s, 3H), 3.20 (s, 3H), 5.05 (d,

J¼14.6 Hz, 1H), 5.09 (d, J¼14.6 Hz, 1H), 6.60 (m, 2H), 6.71 (m, 2H),

6.78 (d, J¼7.6 Hz, 1H), 6.84e6.96 (m, 2H), 7.01e7.10 (m, 4H),

7.18e7.37 (m, 5H), 7.45 (t, J¼7.8 Hz,1H), 7.73 (d, J¼7.5 Hz,1H), 7.91 (d,

J¼7.8 Hz, 1H), 8.39 (d, J¼8.4 Hz, 1H), 10.1 (br s, 1H). ¹³C NMR (CDCl₃,

4.3.29. 1-N,3-N-Dibenzyl-2-methyl-1-N-{2-methyl-3-[(2-methyl-3-

nitrobenzene)amido]benzene}-3-N-phenylbenzene-1,3-dicarbox-

amide 7c’. Prepared according to general procedure B from nitro 6c’

(53.0 mg, 0.093 mmol), SnCl₂$2H₂O (210 mg, 0.931 mmol). The

crude mixture was puriﬁed through silica gel (PE/EtOAc: 5/5) to af-

ford a white solid (49 mg, 98%). IR (ﬁlm) 3460e3360, 1643, 1592,

75.5 MHz) d 14.9 (CH₃), 16.1 (CH₃), 37.8 (CH₃), 53.0 (CH₂), 122.0 (CH),

122.9 (CH), 125.6 (CH), 126.5 (CH), 127.0 (CH), 127.1 (CH), 127.2 (CH),

127.6 (CH), 128.4 (CH), 128.5 (CH), 128.6 (CH), 128.9 (CH), 129.0 (CH),

130.7 (CH), 130.7 (Cq), 130.9 (CH), 131.4 (Cq), 137.0 (Cq), 137.2 (Cq),

138.9 (Cq), 139.8 (Cq), 141.6 (Cq), 143.6 (Cq), 151.1 (Cq), 170.1 (Cq),

169.5 (Cq), 165.9 (Cq). MS (ESI^þ) m/z: 630 (100) [MþNH₄]. HRMS

calcd for C₃₇H₃₆N₅O₅: 630.2711, found: 630.2720. Mp¼144e145 ^ꢀC.

1391, 730 cm^ꢁ1. Ratio: 95/5. ¹H NMR (CDCl₃, 300 MHz)

d major

conformer: 2.01 (s, 3H), 2.27 (s, 3H), 3.39 (br s, 2H), 3.92 (br m, 1H),

5.01 (d, J¼14.4 Hz, 1H), 5.05 (d, J¼14.4 Hz, 1H), 5.64 (d, J¼13.9 Hz,

1H), 6.22 (br m,1H), 6.28 (d, J¼7.6 Hz,1H), 6.39 (d, J¼7.9 Hz,1H), 6.51

(t, J¼7.6 Hz, 1H), 6.64 (t, J¼7.9 Hz, 1H), 6.66e6.71 (m, 2H), 6.73 (d,

J¼7.5 Hz, 1H), 6.98e7.11 (m, 5H), 7.14e7.20 (m, 2H), 7.22e7.31 (m,

4.3.31. 1-N-Benzyl-2,3-N-dimethyl-3-N-{4-[(2-methyl-3-nitroben-

zene)amido]benzene}-1-N-phenylbenzene-1,3-dicarboxamide 7e. Pre-

pared according to general procedure B from nitro 6e (79.0 mg,

0.164 mmol), SnCl₂$2H₂O (370 mg, 1.64 mmol) in DMF (3 mL). The

crude mixture was puriﬁed through silica gel (PE/EtOAc: 4/6) to

afford a white foam (65.5 mg, 89%). IR (ﬁlm) 3351, 3047, 1633,

6H). ¹³C NMR (CDCl₃, 125 MHz)

d major conformer: 14.4 (CH₃), 15.4

(CH₃), 51.8 (CH₂), 52.9 (CH₂), 115.3 (CH), 119.0 (Cq), 125.3 (CH), 125.9

(CH), 127.0 (CH), 127.1 (CH), 127.5 (CH), 127.6 (CH), 127.6 (CH), 128.3

(CH), 128.6 (CH), 128.7 (CH), 129.2 (CH), 129.6 (CH), 130.3 (CH), 132.3

(Cq), 136.7 (Cq), 136.9 (Cq), 137.3 (Cq), 138.0 (Cq), 140.9 (Cq), 141.9

(Cq), 144.8 (Cq), 169.8 (Cq), 171.2 (Cq). MS (ESI^þ) m/z: 562 (100)

[MþNa]. HRMS calcd for C₃₆H₃₃N₃NaO₂: 562.2465, found: 562.2469.

This method was used to make the title compound by general

procedure A from acid (34.0 mg, 0.188 mmol), oxalyl chloride

1605 cm^ꢁ1. Ratio: >95/5. ¹H NMR (CDCl₃, 500 MHz)

d 2.20 (s, 3H),

3.12 (s, 3H), 3.63 (br s, 2H), 5.02 (d, J¼14.2 Hz, 1H), 5.12 (d,

J¼14.2 Hz,1H), 6.23 (d, J¼7.9 Hz, 2H), 6.73 (d, J¼7.0 Hz, 2H), 6.77 (m,

1H), 6.83 (m, 1H), 6.91 (m, 3H), 7.04 (m, 3H), 7.22e7.28 (m, 5H). ¹³C

NMR (CDCl₃, 125 MHz)

d 15.2 (CH₃), 37.9 (CH₃), 53 (CH₂), 113.6 (CH),

124.6 (Cq), 126.3 (CH), 126.5 (CH), 127.2 (CH), 127.6 (CH), 127.7 (CH),

L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

6949

128.5 (CH), 128.7 (CH), 128.9 (CH), 129.0 (CH), 130.5 (CH), 131.2 (Cq),

137.2 (Cq), 138.8, (Cq), 141.8 (Cq), 144.9 (Cq), 148.0 (Cq), 170.1 (Cq),

170.5 (Cq). MS (ESI^þ) m/z: 472 (30) [MþNa]. HRMS calcd for

C₂₉H₂₇N₃NaO₂: 472.1995, found: 472.2001.

8e. Prepared according to general procedure C from amide 7e

(77.0 mg, 0.125 mmol), NaH (20.0 mg, 0.500 mmol), methyl iodide

(0.08 mL, 1.25 mmol). The crude mixture was puriﬁed through sil-

ica gel (PE to PE/EtOAc: 6/4) to afford a yellow solid (56 mg, 72%). ¹H

The title compound was made using general procedure A from

acid (59.4 mg, 0.328 mmol), oxalyl chloride (0.14 mL,1.64 mmol), this

amine (65.5 mg, 0.145 mmol) and pyridine (0.03 mL, 0.371 mmol).

The crude mixture was puriﬁed through silica gel (PE/EtOAc: 4/6) to

afford a white solid (80 mg, 90%). IR (ﬁlm) 3255, 3057, 1643,

NMR (CDCl₃, 300 MHz) d 2.24 (br s, 3H), 2.34 (br s, 3H), 3.09 (br s,

3H), 3.42 (br s, 3H), 5.11 (br m, 2H), 6.48 (br m, 1H), 6.69 (br m, 3H),

6.84 (br m, 2H), 6.94 (br m, 3H), 7.03e7.15 (br m, 5H), 7.26e7.34 (br

m, 5H), 7.69 (br m, 1H). MS (ESI^þ) m/z: 649 [MþNa]. HRMS calcd for

C₃₈H₃₄N₄NaO₅: 649.2421, found: 649.2434.

1528 cm^ꢁ1. Ratio: 90/10. ¹H NMR (DMSO-d₆, 300 MHz)

d 2.22 (s, 3H),

2.51 (s, 3H), 3.08 (s, 3H), 5.00 (br m, 2H), 6.79 (m, 3H), 6.91 (m, 2H),

7.00 (d, J¼8.1 Hz, 2H), 7.20e7.10 (m, 3H), 7.37e7.23 (m, 6H), 7.83 (d,

J¼7.8 Hz, 1H), 7.60 (d, J¼7.6 Hz, 1H), 7.41 (d, J¼8.4 Hz, 2H), 9.27 (br s,

4.3.37. tert-Butyl 3-(N-benzyl-2-methyl-3-nitrobenzamido)-2-meth-

ylbenzoate 12. Pyridine (2 mL) and t-BuOH (2 mL) were added to

a ﬂask containing the acid chloride (200 mg, 1.00 mmol). The so-

lution was then stirred overnight at rt. After addition of DCM, the

resulting solution was washed with water, 5% HCl then brine. The

organic layer was dried over Na₂SO₄and the solvent removed un-

der vacuo. Puriﬁcation of the crude mixture through silica gel (PE/

EtOAc: 9/1) affords the product as a colourless oil (m¼54 mg, 23%).

1H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 15.1 (CH₃), 16.0 (CH₃), 37.6 (CH₃),

52.8 (CH₂), 118.5 (CH), 125.2 (CH), 126.4 (CH), 126.6 (CH), 126.9 (CH),

127.6 (CH), 127.6 (CH), 128.5 (CH), 128.5 (CH), 128.9 (CH), 129.3 (CH),

130.4 (Cq), 130.5 (Cq), 130.8 (CH), 131.5 (Cq), 136.9 (Cq), 138.6 (Cq),

139.6 (Cq), 139.9 (Cq), 141.2 (Cq), 143.8 (Cq), 150.6 (Cq), 166.4 (Cq),

169.8 (Cq), 169.9 (Cq). MS (ESI^þ) m/z: 635 (100) [MþNa]. HRMS calcd

for C₃₇H₃₂N₄NaO₅: 635.2265, found: 635.2267. Mp¼104e106 ^ꢀC.

¹H NMR (CDCl₃, 300 MHz)

d

1.60 (s, 9H), 2.59 (s, 3H), 7.35 (t,

J¼7.8 Hz, 1H), 7.81 (dd, J¼8.1, 1.1 Hz, 1H), 7.86 (dd, J¼7.8, 1.1 Hz, 1H).

¹³C NMR (CDCl₃, 75 MHz)

166.0 (Cq), 151.7 (Cq), 135.7 (Cq), 133.0

d

4.3.32. 1-N,2,3-N-Trimethyl-1-N-{2-methyl-3-[methyl(2-methyl-3-

nitrobenzene)amido]benzene}-3-N-phenylbenzene-1,3-dicarbox-

amide 8c. Prepared according to general procedure C from amide 7c

(65.0 mg, 0.118 mmol), NaH (19.0 mg, 0.475 mmol) and MeI (0.07 mL,

1.18 mmol). The crude mixture was puriﬁed through silica gel (PE

then PE/EtOAc 8/2 to 1/9) to afford a colourless foam(m¼48 mg, 72%).

¹H NMR and ¹³C NMR show mixture of multiple conformers resulting

impossible to determine any ratio. MS (CI) m/z: 565 (30) [MþH].

HRMS calcd for C₃₃H₃₃N₄O₅: 565.2445, found: 565.2436.

(CH), 132.0 (Cq), 126.3 (CH), 126.0 (CH), 82.7 (Cq), 28.1 (CH₃), 16.2

(CH₃). MS (ESI^þ) m/z: 255 (50) [MþH]. HRMS calcd for C₁₂H₁₉N₂O₄:

255.1339, found: 255.1340.

Nitro compound was reduced according to general procedure B

from nitroarene (32.0 mg, 0.135 mmol), SnCl₂$2H₂O (304 mg,

1.35 mmol). The crude mixture was used without further puriﬁca-

tion. Secondary amide was prepared according to general procedure

A

from acid (49.0 mg, 0.270 mmol), oxalyl chloride (0.12 mL,

1.35 mmol), previous amine (0.135 mmol) and Et₃N (0.04 mL,

0.287 mmol). Benzylation was made according to procedure C from

amide (40.0 mg, 0.108 mmol), NaH (18.0 mg, 0.432 mmol) and BnBr

(0.13 mL, 1.08 mmol). The crude mixture was puriﬁed through silica

gel (PE then PE/EtOAc 9/1) to afford a colourless oil (m¼42 mg, 63%

4.3.33. 1-N-Benzyl-2,3-N-dimethyl-3-N-{2-methyl-3-[methyl(2-

methyl-3-nitrobenzene)amido]benzene}-1-N-phenylbenzene-1,3-di-

carboxamide 8c⁰. Prepared according to general procedure C from

amide 7c⁰(46.0 mg, 0.073 mmol), NaH (12.0 mg, 0.300 mmol) and

MeI (0.046 mL, 0.739 mmol). The crude mixture was puriﬁed

through silica gel (PE then PE/EtOAc 9/1 to 2/8) to afford a colour-

less foam (m¼36 mg, 77%). ¹H NMR and ¹³C NMR show mixture of

multiple conformers resulting impossible to determine any ratio.

MS (ESI^þ) m/z: 663 (100) [MþNa]. HRMS calcd for C₃₉H₃₆N₄NaO₅:

663.2578, found: 663.2577.

over three steps). IR (ﬁlm) 3067e2933, 1714, 1650 cm^ꢁ^{1 1}H NMR

.

(CDCl₃, 300 MHz)

d 1.54 (s, 9H), 2.45 (s, 3H), 2.47 (s, 3H), 4.16 (d,

J¼13.7 Hz, 1H), 5.75 (d, J¼13.7 Hz, 1H), 6.86 (t, J¼7.8 Hz, 1H), 7.04 (t,

J¼7.8 Hz, 1H), 7.14 (m, 1H), 7.21e7.30 (m, 6H), 7.55 (dd, J¼7.8, 1.3 Hz,

1H), 7.62 (dd, J¼8.0,1.3 Hz,1H).¹³C NMR (CDCl₃, 75 MHz)

d 16.0 (CH₃),

16.7 (CH₃), 28.2 (CH₃), 52.4 (CH₂), 81.9 (Cq), 124.6 (CH), 125.8 (CH),

126.1 (CH), 128.0 (CH), 128.5 (CH), 129.6 (CH), 129.7 (CH), 130.1 (Cq),

130.3 (CH), 132.6 (CH), 133.9 (Cq), 136.1 (Cq), 136.2 (Cq), 139.2 (Cq),

140.6 (Cq), 150.2 (Cq), 166.3 (Cq), 168.7 (Cq). MS (ESI^þ) m/z: 483 (60)

[MþNa]. HRMS calcd for C₂₇H₂₈N₂NaO₅: 483.1890, found: 483.1897.

4.3.34. 1-N,3-N-Dibenzyl-1-N-{3-[benzyl(2-methyl-3-nitrobenzene)

amido]-2-methylbenzene}-2-methyl-3-N-phenylbenzene-1,3-di-

carboxamide 8c’. Prepared according to general procedure C from

amide 7c’ (40.0 mg, 0.057 mmol), NaH (9.00 mg, 0.225 mmol),

benzyl bromide (0.07 mL, 0.589 mmol). The crude mixture was

puriﬁed through silica gel (PE to PE/EtOAc: 6/4) to afford a white

solid (m¼42 mg, 93%). ¹H NMR and ¹³C NMR show mixture of

multiple conformers resulting impossible to determine any ratio.

MS (ESI^þ) m/z: 810 (62) [MþNH₄], 815 (100) [MþNa]. HRMS calcd

for C₅₁H₄₄N₄NaO₅: 815.3204, found: 815.3182.

4.3.38. 3-N-Benzene-1-N-benzyl-2-methyl-1-N-phenylbenzene-1,3-

dicarboxamide 13. Prepared according to general procedure A from

benzoyl chloride (0.15 mL, 1.26 mmol), amine derived from 4c⁰

(209 mg, 0.661 mL) and Et₃N (0.18 mL, 1.26 mmol). The crude mix-

ture was puriﬁed through silica gel (PE/EtOAc: 6/4) to afford a white

solid (256 mg, 93%). IR (ﬁlm) 3288, 3062e3032,1649 cm^ꢁ1. ¹H NMR

(CDCl₃, 300 MHz)

J¼7.8 Hz, 1H), 7.08 (m, 3H), 7.34e7.27 (m, 4H), 7.48 (m, 2H), 7.55 (m,

1H), 7.62 (m, 1H), 7.83 (m, 3H). ¹³C NMR (CDCl₃, 75.5 MHz)

14.7

d 2.32 (s, 3H), 5.14 (s, 2H), 6.86 (m, 3H), 7.00 (t,

4.3.35. 1-N-Benzyl-2,3-N-dimethyl-3-N-{2-[methyl(2-methyl-3-ni-

trobenzene)amido]benzene}-1-N-phenylbenzene-1,3-dicarboxamide

8d. Prepared according to general procedure C from amide 7d

(56.0 mg, 0.091 mmol), NaH (14.6 mg, 0.365 mmol), methyl iodide

(0.06 mL, 0.963 mmol). The crude mixture was puriﬁed through

silica gel (PE to PE/EtOAc: 6/4) to afford a white solid (41 mg, 72%).

¹H NMR and ¹³C NMR show mixture of multiple conformers

resulting impossible to determine any ratio. MS (ESI^þ) m/z: 649

(100) [MþNa]. HRMS calcd for C₃₈H₃N₄NaO₅: 649.2421, found:

649.2415.

d

(CH₃), 52.9 (CH₂),124.2 (CH),124.4 (CH),125.6 (CH),127.2 (CH),127.4

(CH), 127.5 (CH), 127.7 (Cq), 128.4 (CH), 128.5 (CH), 128.5 (CH), 128.8

(CH), 131.6 (CH), 134.5 (Cq), 136.2 (Cq), 137.1 (Cq), 141.7 (Cq), 166.7

(Cq), 170.7 (Cq). MS (ESI^þ) m/z: 443 (100) [MþNa]. HRMS calcd for

C₂₈H₂₄N₂NaO₂: 443.1730, found: 443.1732. Mp¼152e154 ^ꢀC.

The secondary amide was alkylated according to general pro-

cedure

C using amide (57.0 mg, 0.136 mmol), NaH (22.0 mg,

0.550 mmol), methyl iodide (0.084 mL, 1.36 mmol). The crude

mixture was puriﬁed through silica gel (PE then PE/EtOAc: 6/4) to

afford a white solid (50 mg, 85%). IR (ﬁlm) 3062, 1644, 1593 cm^ꢁ1

.

4.3.36. 1-N-Benzyl-2,3-N-dimethyl-3-N-{4-[methyl(2-methyl-3-ni-

trobenzene)amido]benzene}-1-N-phenylbenzene-1,3-dicarboxamide

Ratio: >95/5. ¹H NMR (CDCl₃, 300 MHz)

5.03 (d, J¼14.4 Hz,1H), 5.14 (d, J¼14.4 Hz,1H), 6.73 (m, 2H), 6.81 (m,

d 2.27 (s, 3H), 3.21 (s, 3H),

6950

L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

2H), 6.90 (m, 1H), 7.13e7.01 (m, 7H), 7.20 (m, 1H), 7.28 (m, 5H). ¹³

NMR (CDCl₃, 75.5 MHz) 15.1 (CH₃), 37.5 (CH₃), 52.9 (CH₂), 126.1

(CH), 126.8 (CH), 127.1 (CH), 127.5 (CH), 127.6 (CH), 127.6 (CH), 128.1

(CH) 128.5 (CH), 128.6 (CH), 128.9 (CH), 129.0 (CH), 129.6 (CH), 131.8

(Cq), 135.3 (Cq), 137.1 (Cq), 138.7 (Cq), 141.7 (Cq), 144.0 (Cq), 169.8

(Cq), 170.5 (Cq). MS (ESI^þ) m/z: 457 (100) [MþNa]. HRMS calcd for

C₂₉H₂₆N₂NaO₂: 457.1886, found: 457.1900. Mp¼114e116 ^ꢀC.

C

conformer d 13.5 (CH₃), 37.2 (CH₃), 132.2 (Cq), 135.4 (Cq), 145.0 (Cq),

d

170.3 (Cq) other signals masked by major conformer. MS (ESI^þ) m/z:

359 (100) [MþH], 376 (84) [MþNH₄], 381 (57) [MþNa]. HRMS calcd

for C₂₃H₂₆N₃O₂: 376.2020, found: 376.2027. Mp¼128e130 ^ꢀC.

4.3.40. N-{3-[Benzene(benzyl)amido]-2-methylphenyl}-N-benzyl-

benzamide 17b. Prepared according to general procedure C from the

benzamide derived from 16 (150 mg, 0.586 mmol), NaH (93.0 mg,

2.32 mmol), benzyl bromide (0.69 mL, 5.81 mmol). The crude mix-

ture was puriﬁed through silica gel (PE then PE/EtOAc: 8/2) to afford

4.3.39. N-{3-[Benzene(methyl)amido]-2-methylphenyl}-N-methyl-

benzamide 17a. Prepared according to general procedure A from

benzoyl chloride (1.68 mL, 13.1 mmol), amine 16 (1.00 g,

6.57 mmol) and pyridine (1.6 mL, 19.7 mmol). The crude mixture

was puriﬁed through silica gel (PE/EtOAc: 7/3 then EtOAc) to afford

a white solid (1.49 g, 89%). IR (ﬁlm) 3266, 1645, 1522 cm^ꢁ1. ¹H NMR

a colourless oil (112 mg, 56%). ¹H NMR (CDCl₃, 300 MHz)

d 2.23 (s,

3H), 4.63 (d, J¼14.0 Hz, 1H), 5.51 (d, J¼14.0 Hz, 1H), 7.22e7.06 (m,

4H), 7.35e7.24 (m, 8H), 7.74 (d, J¼7.6 Hz, 1H). ¹³C NMR (CDCl₃,

75.5 MHz) d 14.4 (CH₃), 53.0 (CH₂), 123.7 (CH),126.4 (CH),127.8 (CH),

(DMSO-d₆, 300 MHz)

d

2.31 (s, 3H), 7.48 (m, 1H), 7.58e7.52 (m, 2H),

127.8 (CH), 127.9 (CH), 128.5 (CH), 129.3 (CH), 130.0 (CH), 131.0 (Cq),

134.5 (CH), 135.1 (Cq), 135.9 (Cq), 143.4 (Cq), 150.8 (Cq), 170.3 (Cq).

MS (ESI^þ) m/z: 347 (46) [MþH], 364 (48) [MþNH₄], 369 (70)

[MþNa]. HRMS calcd for C₂₁H₁₉N₂O₃: 347.1390, found: 347.1382.

This nitro compound was reducedaccording to general procedure

7.65e7.59 (m, 1H), 7.69 (dd, J¼7.9, 1.1 Hz, 1H), 7.82 (dd, J¼8.1, 1.2 Hz,

1H), 8.03 (m, 2H), 10.3 (br s, 1H). ¹³C NMR (DMSO-d₆, 75.5 MHz)

d

14.0 (CH₃), 121.5 (CH), 126.6 (CH), 127.7 (CH), 128.3 (Cq), 128.4

(CH), 131.3 (CH), 131.8 (CH), 133.8 (Cq), 138.4 (Cq), 150.8 (Cq), 165.6

(Cq). MS (ESI^þ) m/z: 257 (100) [MþH], 279 (15) [MþNa]. HRMS

calcd for C₁₄H₁₃N₂O₃: 257.0921, found: 257.0924. Mp¼164e165 ^ꢀC.

The amide was alkylated according to general procedure C using

amide (150 mg, 0.586 mmol), NaH (93.0 mg, 2.32 mmol), methyl

iodide (0.36 mL, 5.78 mmol). The crude mixture was puriﬁed

through silica gel (PE then PE/EtOAc: 8/2) to afford a yellow solid

B

using nitro (112 mg, 0.323 mmol), SnCl₂$2H₂O (722 mg,

3.20 mmol). The crude mixture was puriﬁed through silica gel (PE/

EtOAc: 7/3) to afford a white solid (93 mg, 92%). IR (ﬁlm) 3469,

1631 cm^ꢁ1. ¹H NMR (CDCl₃, 300 MHz)

d 1.67 (s, 3H), 3.40 (br s, 2H),

4.76 (d, J¼13.9 Hz,1H), 5.25 (d, J¼13.9 Hz,1H), 6.41 (dd, J¼7.8, 0.8 Hz,

1H), 6.48 (dd, J¼7.9, 0.8 Hz,1H), 6.84 (dt, J¼7.9, 0.4 Hz,1H), 7.15e7.08

(m, 2H), 7.19 (m, 1H), 7.28e7.24 (m, 3H), 7.36e7.29 (m, 4H). ¹³C NMR

(143 mg, 92%). ¹H NMR (CDCl₃, 300 MHz)

d 2.44 (s, 3H), 3.38 (s, 3H),

7.29e7.13 (m, 7H), 7.74 (d, J¼7.6 Hz, 1H). ¹³C NMR (CDCl₃, 75.5 MHz)

(CDCl₃, 75.5 MHz) d 11.9 (CH₃), 53.5 (CH₂), 114.0 (CH), 119.4 (CH),

d

14.5 (CH₃), 37.5 (CH₃), 123.5 (CH), 127.0 (CH), 127.8 (CH), 127.9

119.9 (Cq), 126.5 (CH), 127.3 (CH), 128.0 (CH), 128.1 (CH), 129.3 (CH),

129.4 (CH),136.1 (Cq),136.9 (Cq),142.1 (Cq),145.6 (Cq),170.3 (Cq). MS

(ESI^þ) m/z: 317 (28) [MþH], 339 (61) [MþNa]. HRMS calcd for

C₂₁H₂₀N₂NaO₁: 339.1468, found: 339.1473. Mp¼136e138 ^ꢀC.

This amine was acylated according to general procedure A using

benzoyl chloride (0.089 mL, 0.767 mmol), amine (84.0 mg,

0.265 mmol) and pyridine (0.085 mL, 1.05 mmol). The crude mix-

ture was puriﬁed through silica gel (PE/EtOAc: 8/2) to afford a white

(CH), 130.1 (CH), 130.3 (Cq), 133.3 (CH), 134.9 (Cq), 146.6 (Cq), 150.9

(Cq), 170.8 (Cq). MS (ESI^þ) m/z: 271 (100) [MþH]. HRMS calcd for

C₁₅H₁₅N₂O₃: 271.1077, found: 271.1068. Mp¼70e71 ^ꢀC.

This nitro compound was reduced according to general pro-

cedure B using nitro (142 mg, 0.526 mmol), SnCl₂$2H₂O (1.17 g,

5.18 mmol). The crude mixture was puriﬁed through silica gel (PE/

EtOAc: 7/3) to afford a white solid (112 mg, 90%). IR (ﬁlm) 3356,

1628, 1574 cm^ꢁ1. ¹H NMR (CDCl₃, 300 MHz)

d

2.00 (s, 3H), 3.37 (s,

3H), 3.62 (br s, 2H), 6.52 (m, 2H), 6.89 (t, J¼7.9 Hz,1H), 7.27e7.11 (m,

3H), 7.35e7.30 (m, 2H). ¹³C NMR (CDCl₃, 75.5 MHz)

11.8 (CH₃), 37.6

foam (132 mg, 90%). IR (ﬁlm) 3293, 3060, 1647 cm^ꢁ1

.

¹H NMR

(CDCl₃, 300 MHz)

d

1.92 (s, 3H), 4.77 (d, J¼13.9 Hz, 1H), 5.35 (d,

d

J¼14.3 Hz, 1H), 6.85 (d, J¼7.9 Hz, 1H), 7.20e7.09 (m, 3H), 7.24 (m,

1H), 7.38e7.29 (m, 7H), 7.49 (m, 2H), 7.58 (m, 1H), 7.68 (br s, 1H),

(CH₃), 113.9 (CH), 118.3 (CH), 118.9 (Cq), 126.8 (CH), 127.3 (CH), 127.9

(CH), 129.4 (CH), 135.9 (Cq), 143.9 (Cq), 145.8 (Cq), 170.8 (Cq). MS

(ESI^þ) m/z: 263 (10) [MþNa]. HRMS calcd for C₁₅H₁₆N₂NaO₁:

263.1155, found: 263.1157. Mp¼130e131 ^ꢀC.

7.85 (m, 3H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 12.6 (CH₃), 53.5 (CH₂),

122.4 (CH), 126.3 (CH), 126.7 (CH), 126.9 (CH), 127.2 (Cq), 127.6 (CH),

128.1 (CH), 128.3 (CH),128.7 (CH),129.4 (CH), 129.7 (CH),131.9 (CH),

134.5 (Cq), 135.7 (Cq), 136.6 (Cq), 137.0 (Cq), 142.1 (Cq), 165.5 (Cq),

170.4 (Cq). MS (ESI^þ) m/z: 443 (100) [MþNa]. HRMS calcd for

C₂₈H₂₄N₂NaO₂: 443.1730, found: 443.1727.

This amide was benzylated according to general procedure C

using amide (76.0 mg, 0.181 mmol), NaH (29.0 mg, 0.724 mmol),

benzyl bromide (0.22 mL, 1.81 mmol). The crude mixture was pu-

riﬁed through silica gel (PE then PE/EtOAc: 8/2) to afford a white

solid (73 mg, 79%). IR (ﬁlm) 3061, 1644, 1381 cm^ꢁ1. Ratio: 2/1. ¹H

This amine was acylated according to general procedure A using

benzoyl chloride (0.112 mL, 0.874 mmol), amine (105 mg,

0.437 mmol) and pyridine (0.106 mL, 1.31 mmol). The crude mixture

was puriﬁed through silica gel (PE/EtOAc: 7/3) to afford a white foam

(142 mg, 95%). IR (ﬁlm) 3287, 3059e2926,1647 cm^ꢁ1.¹H NMR (CDCl₃,

300 MHz)

d

2.15 (s, 3H), 3.29 (s, 3H), 6.87 (d, J¼7.7 Hz, 1H), 7.12e7.02

(m, 3H), 7.16 (d, J¼7.1 Hz, 1H), 7.23 (m, 2H), 7.40 (m, 2H), 7.51 (t,

J¼7.3 Hz, 1H), 7.61 (d, J¼7.9 Hz, 1H), 7.83 (d, J¼7.3 Hz, 2H), 8.10 (br s,

1H). ¹³C NMR (CDCl₃, 75.5 MHz)

d

12.7 (CH₃), 37.6 (CH₃), 123.3

NMR (CDCl₃, 300 MHz) d 1.70 (s, 3H, maj), 1.72 (s, 3H, min), 4.23 (d,

(CH), 125.6 (CH), 126.8 (CH), 127.0 (CH), 127.5 (CH), 127.8 (Cq), 127.9

(CH), 128.6 (CH), 129.6 (CH), 131.8 (CH), 134.3 (Cq), 135.4 (Cq), 137.1

(Cq), 143.9 (Cq), 165.7 (Cq), 170.8 (Cq). MS (ESI^þ) m/z: 367 (100)

[MþNa]. HRMS calcd for C₂₂H₂₀N₂NaO₂: 367.1417, found: 367.1429.

Mp¼52e54 ^ꢀC.

J¼4.3 Hz, 1H, maj), 4.51 (d, J¼13.9 Hz, 1H, min), 5.18 (d, J¼13.8 Hz,

1H, maj), 5.26 (d, J¼13.9 Hz, 1H, min), 6.64 (d, J¼7.9 Hz, 1H, maj),

6.69 (d, J¼7.8 Hz, 1H, min), 6.82 (m, 1H, min), 7.15e7.02 (m, 4H,

majþmin), 7.38e7.18 (m, 12H, majþmin). ¹³C NMR (CDCl₃,

75.5 MHz) major conformer

d 13.5 (CH₃), 52.6 (CH₂), 126.4 (CH),

This amide was alkylated according to general procedure C using

amide (142 mg, 0.413 mmol), NaH (66.0 mg, 1.65 mmol), methyl

iodide (0.26 mL, 4.13 mmol). The crude mixture was puriﬁed

through silica gel (PE then PE/EtOAc: 6/4) to afford a white solid

(123 mg, 83%). IR (ﬁlm) 3060e2929, 1644, 1574,1362 cm^ꢁ1. Ratio: 2/

127.5 (CH), 127.6 (CH), 128.1 (CH), 128.2 (CH), 129.3 (CH), 129.5 (CH),

129.8 (CH), 133.7 (Cq), 135.8 (Cq), 136.2 (Cq), 142.7 (Cq), 170.0 (Cq).

Minor conformer

d 13.2 (CH₃), 53.1 (CH₂), 127.7 (CH), 128.0 (CH),

128.2 (CH), 129.7 (CH), 129.7 (CH), 134.1 (Cq), 135.4 (Cq), 136.3 (Cq),

142.6 (Cq), other signals masked by major conformer. MS (ESI^þ) m/

z: 511 (100) [MþH], 528 (43) [MþNH₄], 533 (22) [MþNa]. HRMS

calcd for C₃₅H₃₁N₂O₂: 511.2380, found: 511.2392. Mp¼169e170 ^ꢀC.

1. ¹H NMR (CDCl₃, 300 MHz)

d 1.98 (s, 3H, min), 2.19 (s, 3H, maj), 3.12

(s, 6H, min), 3.29 (s, 6H, maj), 7.62e6.81 (m,13H, majþmin).¹³C NMR

(CDCl₃, 75.5 MHz) major conformer

d 13.1 (CH₃), 37.7 (CH₃), 127.1

(CH), 127.2 (CH), 127.5 (CH), 127.6 (CH), 127.9 (CH), 128.0 (CH), 128.3

(CH), 129.7 (CH), 132.1 (Cq), 135.2 (Cq), 145.1 (Cq), 170.5 (Cq). Minor

4.3.41. N-Methyl-4-nitro-N-phenylbenzamide 18a. Prepared acc-

ording to general procedure A from 4-nitrobenzoyl chloride (1.50 g,

L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

6951

8.08 mmol), pyridine (2.2 mL, 27.2 mmol) and N-methylaniline

(0.86 mL, 7.94 mmol), 18a was obtained without further puriﬁca-

J¼8.5 Hz, 2H), 6.94 (d, J¼7.5 Hz, 2H), 7.12 (t, J¼7.5 Hz, 1H), 7.17

(d, J¼8.5 Hz, 2H), 7.18 (d, J¼7.5 Hz, 2H), 7.31 (d, J¼9.0 Hz, 2H), 7.96

tion (2.03 g, 98%). ¹H NMR (CDCl₃, 300 MHz)

d

3.55 (s, 3H), 7.06 (d,

(d, J¼9.0 Hz, 2H). ¹³C NMR (CDCl₃, 75,5 MHz)

d 38.2 (CH₃), 38.5

J¼7.2 Hz, 2H), 7.23 (t, J¼6.9 Hz, 1H), 7.27 (dd, J¼7.2, 6.9 Hz, 2H), 7.48

(CH₃), 123.3 (CH), 126.3 (CH), 127.0 (CH), 127.2 (CH), 129.5 (CH),

129.7 (CH), 130.1 (CH), 135.2 (Cq), 142.0 (Cq), 144.7 (Cq), 144.9 (Cq),

148.2 (Cq), 168.4 (Cq), 169.6 (Cq). IR (ﬁlm) 1648, 1522, 1360,

1310 cm^ꢁ1. HRMS calcd for C₂₂H₂₀N₃O₄: 390.1448, found: 390.1450.

(d, J¼8.7 Hz, 2H), 8.04 (d, J¼8.7 Hz, 2H). ¹³C NMR (CDCl₃, 75.5 MHz)

d

38.2 (CH₃), 122.9 (CH), 126.9 (CH), 127.3 (CH), 129.5 (CH), 142.1

(Cq), 143.7 (Cq), 147.9 (Cq), 168.3 (Cq). IR (ﬁlm) 1651, 1520 cm^ꢁ1

.

HRMS calcd for C₁₄H₁₃N₂O₃: 257.0921, found: 257.0925. Anal. Calcd

for C₁₄H₁₂N₂O₃$¼H₂O (260.76): C, 64.49; H, 4.83; N, 10.74. Found:

C, 64.79; H, 4.62; N, 10.74.

4.3.44. 2-Iodo-N-methyl-N-(4-(N⁰-methyl-N⁰-(4-(N⁰⁰-methyl-N⁰⁰-

phenyl)carbamoyl)phenyl)carbamoyl)phenylbenzamide

pared according to general procedure from 19a (1.20 g,

3.08 mmol) the amine was obtained (860 mg, 78%). ¹H NMR (CDCl₃,

300 MHz) 3.38 (s, 3H), 3.47 (s, 3H), 3.84 (br s, 2H), 6.35 (d,

20a⁰. Pre-

B

4.3.42. 2-Iodo-N-methyl-N-(4-(N⁰-methyl-N⁰-phenyl)carbamoyl)

phenylbenzamide 19a⁰. Prepared according to general procedure B

from 18a (2.00 g, 7.81 mmol) and SnCl₂$2H₂O (17.5 g, 77.5 mmol),

the amine was obtained without further puriﬁcation (1.7 g, 96%). ¹H

d

J¼8.4 Hz, 2H), 6.81 (d, J¼8.4 Hz, 2H), 6.99 (dd, J¼8.1, 1.2 Hz, 2H),

7.02 (dd, J¼8.4, 1.8 Hz, 2H), 7.14e7.23 (m, 5H). Minor conformer

NMR (CDCl₃, 300 MHz)

d

3.38 (br s, 2H), 3.46 (s, 3H), 6.40 (d,

d

3.40 (s, 3H), 3.50 (s, 3H), 6.66 (d, J¼8.7 Hz, 2H), 7.45 (d, J¼8.7 Hz,

J¼8.7 Hz, 2H), 7.04 (dd, J¼7.5, 1.5 Hz, 2H), 7.11e7.15 (m, 1H), 8.13 (d,

2H), 7.66 (d, J¼8.4 Hz, 2H), other signals masked by major con-

J¼8.7 Hz, 2H), 7.24 (dd, J¼7.5, 7.2 Hz, 2H). ¹³C NMR (CDCl₃,

former. Ratio 10:1. ¹³C NMR (CDCl₃, 75.5 MHz)

d

38.2 (CH₃), 28.4

75.5 MHz)

d

38.6 (CH₃), 113.6 (CH), 125.3 (Cq), 126.0 (CH), 127.8

(CH₃), 113.5 (CH), 124.7 (Cq), 125.6 (CH), 126.5 (CH), 126.8 (CH),

129.1 (CH), 129.7 (CH), 131.0 (CH), 133.1 (Cq), 144.7 (Cq), 146.8 (Cq),

(CH), 129.1 (CH), 131.1 (CH), 145.8 (Cq), 147.8 (Cq), 170.5 (Cq). IR

(ﬁlm) 3350, 1630 cm^ꢁ1. HRMS calcd for C₁₄H₁₄N₂NaO: 249.0998,

found: 249.1002. Anal. Calcd for C₁₄H₁₄N₂O$¼H₂O (230.78): C,

72.86; H, 6.33; N, 12.14. Found: C, 73.21; H, 6.15; N, 12.16.

Prepared according to general procedure A from this amine

(102 mg, 0.451 mmol), pyridine (0.2 mL, 2.47 mmol) and 2-iodo-

benzoyl chloride (97%, 142 mg, 0.517 mmol) the amide was

obtained without further puriﬁcation (202 mg, quantitative). ¹H

148.1 (Cq), 169.7 (Cq), 170.4 (Cq). IR (ﬁlm) 3357, 1632, 1601 cm^ꢁ1

.

HRMS calcd for C₂₂H₂₁N₃NaO₂: 382.1526, found: 382.1533.

Prepared according to general procedure A from this amine

(1.600 g, 7.08 mmol) and 2-iodobenzoyl chloride (97%, 77.0.0 mg,

0.2800 mmol) the amide was obtained without further puriﬁcation

(162 mg, quantitative). ¹H NMR (CDCl₃, 300 MHz) major conformer

d

1.87 (br s, 1H), 3.38 (s, 3H), 3.44 (s, 3H), 6.85 (d, J¼8.4 Hz, 2H), 6.98

NMR (CDCl₃, 300 MHz)

d

3.44 (s, 3H), 7.04 (d, J¼7.2 Hz, 1H),

(dd, J¼7.2, 1.2 Hz, 2H), 7.14e7.19 (m, 5H), 7.24 (d, J¼7.2 Hz, 1H), 7.30

(d, J¼8.7 Hz, 1H), 7.40 (t, J¼7.5 Hz, 1H), 7.48e7.52 (m, 3H), 7.90 (d,

7.07e7.45 (m, 11H), 7.86 (d, J¼7.8 Hz, 1H), 7.94 (br s, 1H). ¹³C NMR

(CDCl₃, 75,5 MHz)

d

38.6 (CH₃), 92.4 (Cq), 118.8 (CH), 126.6 (CH),

J¼7.5 Hz, 1H), 8.40 (s, 1H). Minor conformer

d 3.33 (s, 3H), 7.63 (d,

126.8 (CH),128.2 (CH),128.4 (CH),128.3 (CH),130.0 (CH),131.4 (CH),

131.5 (Cq), 139.0 (Cq), 139.9 (CH), 141.7 (Cq), 144.8 (Cq), 167.3 (Cq),

169.9 (Cq). IR (ﬁlm) 3240, 1624, 1594 cm^ꢁ1. HRMS calcd for

C₂₁H₁₈IN₂O₂: 457.0407 found: 457.0408.

Prepared according to general procedure C from NaH (60%,

79.0 mg, 1.97 mmol), the amide (224 mg, 0.491 mmol) and iodo-

methane (0.3 mL, 4.82 mmol). The crude product was puriﬁed by

ﬂash chromatography (DCM to DCM/MeOH 1%) to yield 19a⁰

(201 mg, 96%). Mp 210e212 ^ꢀC. ¹H NMR (CDCl₃, 300 MHz) major

J¼7.8 Hz, 2H), 7.69 (d, J¼8.7 Hz, 1H), 7.84 (d, J¼8.4 Hz, 1H), other

signals masked by major conformer. Ratio 10:1. ¹³C NMR (CDCl₃,

75.5 MHz) d 38.5 (CH₃), 38.6 (CH₃), 92.9 (Cq), 119.0 (CH), 126.2 (CH),

127.1 (CH), 127.2 (CH), 128.5 (CH), 128.7 (CH), 129.6 (CH), 130.0 (CH),

130.3 (CH), 131.3 (Cq), 131.7 (CH), 134.1 (Cq), 139.7 (Cq), 140.2 (CH),

142.2 (Cq), 144.7 (Cq), 146.2 (Cq), 167.7 (Cq), 169.9 (Cq), 170.0 (Cq).

IR (ﬁlm) 3257, 1632, 1596 cm^ꢁ1. HRMS calcd for C₂₉H₂₅IN₃O₃:

590.0935, found: 590.0929.

Prepared according to general procedure C from this amide

(162 mg, 0.275 mmol) and iodomethane (0.2 mL, 3.21 mmol), after

ﬂash chromatography puriﬁcation (DCM to DCM/MeOH 2%) the

title compound was obtained (157 mg, 95%). Mp 138e140 ^ꢀC. ¹H

conformer

(m, 6H), 7.59 (d, J¼7.7 Hz, 1H), Minor conformer

other signals masked by major conformer. Ratio 16:1. ¹³C NMR

(CDCl₃, 75.5 MHz) 37.0 (CH₃), 38.2 (CH₃), 93.4 (Cq), 126.1 (CH),

d

3.41 (s, 3H), 3.42 (s, 3H), 6.83e6.93 (m, 6H), 7.05e7.15

d

3.09 (br s, 6H),

d

NMR (CDCl₃, 300 MHz) d 3.97 (s, 3H), 3.49 (s, 3H), 3.52 (s, 3H), 6.72

126.5 (CH),126.7 (CH),127.3 (CH),128.5 (CH),129.1 (CH),129.4 (CH),

129.9 (CH), 134.3 (Cq), 139.0 (CH), 141.9 (Cq), 143.9 (Cq), 144.4 (Cq),

169.5 (Cq), 169.9 (Cq). IR (ﬁlm) 1643, 1603 cm^ꢁ1. HRMS calcd for

C₂₂H₂₀IN₂O₂: 471.0564, found: 471.0576.

(br s, 1H), 6.91e7.06 (m, 8H), 7.14 (br s, 1H), 7.11e7.18 (m, 2H),

7.21e7.31 (m, 4H), 7.70 (br d, J¼8.1 Hz, 1H). ¹³C NMR (CDCl₃,

75.5 MHz) d 37.4 (CH₃), 38.3 (CH₃), 38.7 (CH₃), 93.5 (Cq), 125.5 (CH),

126.0 (CH), 126.7 (CH), 126.8 (CH), 127.4 (CH), 128.5 (CH), 129.2

(CH), 129.5 (CH), 129.8 (CH), 130.1 (CH), 133.6 (Cq), 139.0 (Cq), 139.1

(CH), 141.8 (Cq), 144.3 (Cq), 144.6 (Cq), 145.4 (Cq), 169.1 (Cq), 169.3

(Cq), 169.8 (Cq). IR (ﬁlm) 1643, 1603 cm^ꢁ1. HRMS calcd for

C₃₀H₂₆IN₃NaO₃: 626.0911, found: 626.0924.

4.3.43. N-Methyl-N-(4-(N⁰-methyl-N⁰-phenyl)carbamoyl)phenyl-4-

nitrobenzamide 19a. Prepared according to general procedure A

from the amine derived from 18a (1.60 g, 7.08 mmol) and 4-nitro-

benzoyl chloride (1.33 g, 7.17 mmol) a very insoluble amide was

obtained without further puriﬁcation (2.65 g, quantitative). ¹H

4.3.45. N-Methyl-N-(4-(N⁰-methyl-N⁰-(4-(N⁰⁰-methyl-N⁰⁰-phenyl)car-

bamoyl)phenyl)carbamoyl)phenyl-4-nitrobenzamide 20a. Prepared

according to general procedure A from the amine derived from 19a

(750 mg, 2.09 mmol) and 4-nitrobenzoyl chloride (388 mg,

2.09 mmol) the amide was obtained without further puriﬁcation

(959 mg, 90%). Mp 228e230 ^ꢀC. ¹H NMR (CDCl₃, 300 MHz) major

NMR (DMSO-d₆, 300 MHz)

d 3.39 (s, 3H), 7.18e7.21 (m, 3H),

7.26e7.34 (m, 4H), 7.67 (d, J¼8.7 Hz, 2H), 8.19 (d, J¼8.7 Hz, 2H), 8.37

(d, J¼8.7 Hz, 2H), 10.75 (s, 1H). IR (ﬁlm) 3360, 1635 cm^ꢁ1. HRMS

calcd for C₂₁H₁₈N₃O₄: 376.1292, found: 376.1294.

To a solution of this amide (1.15 g, 3.07 mmol) in THF (100 mL) at

0 ^ꢀC, NaH (480 mg, 12.0 mmol) was added followed by immediate

addition of iodomethane (2 mL, 32.1 mmol). The mixture was stir-

red at 0 ^ꢀC under nitrogen overnight. HCl (1.5 N) was added to the

solution at 0 ^ꢀC and it was extracted with AcOEt. The organic layer

was washed with water, dried, ﬁltered and the solvent was re-

moved under reduced pressure. The crude product was puriﬁed by

ﬂash chromatography (DCM to DCM/MeOH 10%) to yield 19a

conformer

d

3.40 (s, 3H), 3.44 (s, 3H), 6.82 (d, J¼8.7 Hz, 2H), 6.97

(dd, J¼7.2, 1.5 Hz, 2H), 7.14 (d, J¼8.7 Hz, 2H), 7.15 (d, J¼9.0 Hz, 2H),

7.16 (d, J¼7.2 Hz, 1H), 7.24 (d, J¼9.0 Hz, 2H), 7.45 (d, J¼8.7 Hz, 2H),

8.05 (d, J¼8.7 Hz, 2H), 8.30 (d, J¼9.0 Hz, 2H), 8.51 (s, 1H). Minor

conformer

d

3.33 (s, 3H), 3.38 (s, 3H), 6.75 (d, J¼9.0 Hz, 2H), 6.90 (d,

J¼8.4 Hz, 2H), 7.38 (d, J¼8.4 Hz, 2H), 7.98 (d, J¼8.4 Hz, 2H), 8.24 (d,

J¼9.0 Hz, 2H), 8.44 (s, 1H), other signals masked by the major

(1.01 g, 85%). ¹H NMR (CDCl₃, 500 MHz)

d

3.44 (s, 6H), 6.81 (d,

conformer. Ratio 10:1. ¹³C NMR (CDCl₃, 75.5 MHz)

d 38.2 (CH₃), 38.4

6952

L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

(CH₃), 119.1 (CH), 123.9 (CH), 125.9 (CH), 126.8 (CH), 128.5 (CH),

129.3 (CH), 129.7 (CH), 129.9 (CH), 131.5 (Cq), 133.8 (Cq), 139.1 (Cq),

140.3 (Cq), 144.5 (Cq), 145.8 (Cq), 149.8 (Cq), 163.8 (Cq), 169.6 (Cq),

169.8 (Cq). IR (ﬁlm) 3368, 1641, 1600 cm^ꢁ1. HRMS calcd for

C₂₉H₂₄N₄NaO₅: 531.1639, found: 531.1639.

Prepared according to general procedure C from this amide

(268 mg, 0.527 mmol) and iodomethane (0.4 mL, 6.42 mmol) after

ﬂash chromatography puriﬁcation (DCM to DCM/MeOH 6%) the

title compound was obtained (266 mg, 97%). ¹H NMR (CDCl₃,

(ﬁlm) 1643, 1603 cm^ꢁ1. HRMS calcd for C₃₈H₃₃IN₄NaO₄: 759.1439,

found: 759.1439.

4.3.47. N-Methyl-N-(4-(N⁰-methyl-N⁰-(4-(N⁰⁰-methyl-N⁰⁰-(4-(N⁰⁰⁰-

methyl-N⁰⁰⁰-phenyl)carbamoyl)phenyl)carbamoyl)phenyl)carbamoyl)

phenyl-4-nitrobenzamide 21a. Prepared according to general pro-

cedure A from the amine derived from 20a (689 mg, 1.40 mmol) and

4-nitrobenzoyl chloride (282 mg, 1.52 mmol) after ﬂash chroma-

tography puriﬁcation (DCM to DCM/MeOH 4%) the amide was

obtained (813 mg, 90%). ¹H NMR (CDCl₃, 300 MHz) major conformer

300 MHz) major conformer

d 3.40 (s, 3H), 3.47 (s, 3H), 3.53 (s, 3H),

6.76 (d, J¼8.7 Hz, 2H), 6.82 (d, J¼8.7 Hz, 2H), 7.04 (dd, J¼8.1, 1.5 Hz,

2H), 7.09e7.26 (m, 2H), 7.13 (t, J¼8.7 Hz, 4H), 7.22 (d, J¼7.5 Hz, 1H),

7.35 (d, J¼9.0 Hz, 2H), 8.03 (d, J¼9.0 Hz, 2H), minor conformer

d

3.36 (s, 6H), 3.48 (s, 3H), 6.82 (d, J¼8.4 Hz, 2H), 6.86 (d, J¼8.7 Hz,

2H), 6.99 (d, J¼7.5 Hz, 2H), 7.09e7.15 (m, 6H), 7.25e7.30 (m, 4H), 7.55

(d, J¼8.7 Hz, 2H), 8.32e8.34 (m, 3H), 10.16 (s, 1H). Minor conformer

d

3.33 (s, 3H), 5.26 (s, 2H), 6.70 (d, J¼8.4 Hz, 1H), 6.97 (d, J¼7.5 Hz,

d

3.30 (s, 3H), 3.44 (s, 3H), 7.48 (d, J¼8.7 Hz, 1H), 8.05 (d, J¼9.0 Hz,

2H), 7.96 (d, J¼8.7 Hz, 1H), 8.24 (d, J¼9.0 Hz, 1H), 8.32 (d, J¼9.0 Hz,

2H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 37.7 (CH₃), 37.8 (CH₃), 38.5 (CH₃),

1H), other signals masked by major conformer. Ratio: 10:1. ¹³C NMR

118.9 (CH), 123.1 (CH), 125.9 (CH), 126.1 (CH), 126.5 (CH), 126.9 (CH),

128.7 (CH), 128.9 (CH), 129.1 (CH), 129.4 (CH), 129.7 (CH), 130.1 (Cq),

133.1 (Cq), 133.9 (Cq), 139.9 (Cq), 140.3 (Cq), 143.7 (Cq), 145.4 (Cq),

145.7 (Cq), 149.2 (Cq), 164.1 (Cq), 169.1 (Cq), 169.6 (Cq), 169.9 (Cq). IR

(ﬁlm) 3329, 1642, 1601, 1526, 1368, 1348 cm^ꢁ1. HRMS calcd for

C₃₇H₃₂N₅O₆: 642.2347, found: 642.2354.

Prepared according to general procedure C from this amide

(813 mg, 1.27 mmol) and iodomethane (0.8 mL, 12.8 mmol) after

ﬂash chromatography puriﬁcation (DCM to DCM/MeOH 2%) the

title compound was obtained (731 mg, 88%). ¹H NMR (CDCl₃,

(CDCl₃, 75.5 MHz)

d 38.3 (CH₃), 38.4 (CH₃), 38.7 (CH₃), 123.4 (CH),

126.2 (CH), 126.4 (CH), 127.0 (CH), 127.2 (CH), 129.5 (CH), 129.87

(CH),129.93 (CH),130.3 (CH),134.5 (Cq),134.8 (Cq),141.8 (Cq),144.9

(Cq), 145.2 (Cq), 145.6 (Cq), 148.4 (Cq), 168.4 (Cq), 169.2 (Cq), 169.6

(Cq). IR (ﬁlm) 1678, 1601, 1522, 1366, 1348 cm^ꢁ1. HRMS calcd for

C₃₀H₂₇N₄O₅: 523.1976, found: 523.1974.

4.3.46. 2-Iodo-N-methyl-N-(4-(N⁰-methyl-N⁰-(4-(N⁰⁰-methyl-N⁰⁰-(4-

(N⁰⁰⁰-methyl-N⁰⁰⁰-phenyl)carbamoyl)phenyl)carbamoyl)phenyl)carba-

moyl)phenylbenzamide 21a⁰. Prepared according to general pro-

cedure B from 20a (847 mg, 1.62 mmol) the amine was obtained

without further puriﬁcation (702 mg, 88%). ¹H NMR (CDCl₃,

300 MHz) major conformer

d 3.42 (s, 3H), 3.44 (s, 3H), 3.47 (s, 3H),

3.49 (s, 3H), 6.72 (d, J¼8.4 Hz, 2H), 6.81 (d, J¼8.4 Hz, 2H), 6.86 (d,

J¼8.4 Hz, 2H), 6.99 (dd, J¼7.5, 1.8 Hz, 2H), 7.03 (d, J¼8.7 Hz, 2H), 7.11

(d, J¼8.7 Hz, 2H), 7.15 (d, J¼8.4 Hz, 2H), 7.16e7.19 (m, 1H), 7.21 (d,

J¼7.5 Hz, 2H), 7.35 (d, J¼9.0 Hz, 2H), 8.00 (d, J¼9.0 Hz, 2H). Minor

300 MHz) d 3.40 (s, 3H), 3.31 (s, 3H), 3.36 (s, 3H), 4.28 (br s, 2H), 6.29

(d, J¼8.7 Hz, 2H), 6.73 (d, J¼8.7 Hz, 2H), 6.76 (d, J¼8.7 Hz, 2H), 6.87

(dd, J¼7.5, 1.2 Hz, 2H), 6.93 (d, J¼8.7 Hz, 2H), 7.01 (d, J¼8.7 Hz, 2H),

conformer

75.5 MHz)

d

3.38 (s, 3H), 3.39 (s, 3H), 5.26 (s, 2H). ¹³C NMR (CDCl₃,

37.97 (CH₃), 38.07 (CH₃), 38.12 (CH₃), 38.4 (CH₃), 123.0

7.10e7.14 (m, 5H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 37.66 (CH₃), 37.79

(CH₃), 37.82 (CH₃), 112.9 (CH), 125.3 (CH), 125.4 (CH), 126.4 (CH),

126.47 (Cq), 126.52 (CH), 128.8 (CH), 129.1 (CH), 129.4 (CH), 130.8

(CH), 132.4 (Cq), 133.2 (Cq), 144.2 (Cq), 145.3 (Cq), 146.7 (Cq), 148.9

(Cq), 169.2 (Cq), 169.3 (Cq), 170.0 (Cq). IR (ﬁlm) 3351, 1634,

1602 cm^ꢁ1. HRMS calcd for C₃₀H₂₉N₄O₃: 493.2234, found: 493.2229.

Prepared according to general procedure A from this amine

(50.0 mg, 0.101 mmol) and 2-iodobenzoyl chloride (97%, 30.0 mg,

0.109 mmol) after ﬂash chromatography puriﬁcation (DCM to DCM/

MeOH 4%) the amide was obtained (66 mg, 90%). ¹H NMR (CDCl₃,

(CH), 125.82 (CH), 125.85 (CH), 126.2 (CH), 126.6 (CH), 126.8 (CH),

129.1 (CH), 129.50 (CH), 129.54 (CH), 129.7 (CH), 130.0 (CH), 133.8

(Cq), 133.9 (Cq), 134.2 (Cq), 141.5 (Cq), 144.6 (Cq), 145.0 (Cq), 145.4

(Cq), 145.5 (Cq), 147.9 (Cq), 168.0 (Cq), 168.9 (Cq), 169.0 (Cq), 169.3

(Cq). IR (ﬁlm) 1645, 1602, 1521, 1367 cm^ꢁ1. HRMS calcd for

C₃₈H₃₄N₆O₅: 656.2504, found: 656.2511.

4.3.48. N-Benzyl-4-nitro-N-phenylbenzamide 18b. Prepared accord-

ing to general procedure A from 4-nitrobenzoyl chloride (5.09 g,

27.4 mmol), pyridine (7.5 mL, 92.8 mmol) and N-benzylaniline

(5.02 g, 27.4 mmol), the title compound was obtained without fur-

300 MHz) major conformer

d 2.93 (s, 3H), 3.33 (s, 3H), 3.46 (s, 3H),

6.76 (d, J¼8.4 Hz, 2H), 6.85 (d, J¼8.7 Hz, 2H), 6.92 (dd, J¼8.1, 1.5 Hz,

2H), 7.08e7.23 (m, 10H), 7.46 (ddd, J¼7.5, 7.2, 0.9 Hz, 1H), 7.56 (d,

J¼7.5 Hz, 2H), 7.60 (dd, J¼7.5, 15 Hz, 1H), 7.96 (dd, J¼8.1, 0.9 Hz, 1H),

ther puriﬁcation (9.04 g, 99%). ¹H NMR (CDCl₃, 300 MHz)

d 3.17 (s,

2H), 6.91e6.94 (m, 2H), 7.18e7.21 (m, 3H), 7.31e7.35 (m, 5H), 7.51 (d,

9.66 (s, 1H). Minor conformer

d

3.41 (s, 3H), 7.89 (dd, J¼7.8, 0.9 Hz,

J¼8.7 Hz, 2H), 8.05 (d, J¼8.7 Hz, 2H). ¹³C NMR (CDCl₃, 75.5 MHz)

1H), other signals masked by major conformer. ¹³C NMR (CDCl₃,

75.5 MHz) 37.8 (CH₃), 37.9 (CH₃), 38.0 (CH₃), 92.8 (Cq), 118.7 (CH),

d 54.2 (CH₂), 123.3 (CH), 127.8 (CH), 128.0 (CH), 128.2 (CH), 128.9 (CH),

d

129.7 (CH), 129.8 (CH), 137.1 (Cq), 142.5 (Cq), 142.6 (Cq), 148.2 (Cq),

168.6 (Cq). IR (ﬁlm) 1647, 1522, 1400, 1390 cm^ꢁ1. HRMS calcd for

C₂₀H₁₇N₃O₂: 333.1234, found: 333.1236. Anal. calcd for C₂₀H₁₆N₂O₃

(332.3): C, 72.28; H, 4.85; N, 8.43. Found: C, 72.03; H, 4.86; N, 8.40.

125.8 (CH), 126.1 (CH), 126.7 (CH), 127.0 (CH), 128.0 (CH), 128.5

(CH), 128.9 (CH), 129.2 (CH), 129.5 (CH), 129.9 (Cq), 130.1 (CH), 130.9

(CH), 133.6 (Cq), 133.8 (Cq), 139.6 (CH), 140.1 (Cq), 142.7 (Cq),

143.9 (Cq), 145.6 (Cq), 146.2 (Cq), 168.2 (Cq), 169.6 (Cq), 170.0 (Cq),

170.6 (Cq). IR (ﬁlm) 3256, 1642, 1632, 1601 cm^ꢁ1. HRMS calcd for

C₃₇H₃₁IN₄NaO₄: 745.1282, found: 745.1293.

Prepared according to general procedure C from this amide

(66.0 mg, 0.091 mmol) and iodomethane (0.1 mL, 1.60 mmol), after

ﬂash chromatography puriﬁcation (DCM to DCM/MeOH 2%) the

title compound was obtained (58 mg, 86%). ¹H NMR (CDCl₃,

4.3.49. N-(4-(N⁰-Benzyl-N⁰-phenyl)carbamoyl)phenyl-2-iodo-N-

methylbenzamide 19b⁰. Prepared according to general procedure B

from 18b (9.04 g, 27.2 mmol) the amine was obtained (7.5 g, 91%).

¹H NMR (CDCl₃, 300 MHz) major conformer

d 4.10 (br s, 2H), 5.16 (s,

2H), 6.41 (d, J¼8.7 Hz, 2H), 6.98 (dd, J¼8.4, 1.5 Hz, 2H), 7.18 (d,

J¼7.5 Hz, 2H), 7.22 (d, J¼8.7 Hz, 2H), 7.09e7.38 (m, 6H). Minor

300 MHz)

d

3.40 (s, 3H), 3.42 (s, 3H), 3.45 (s, 3H), 3.48 (s, 3H), 6.62

conformer

d

5.09 (s, 2H), 6.34 (dd, J¼8.7, 1.5 Hz, 2H), 6.92 (d,

(br d, J¼7.8 Hz, 1H), 6.78 (d, J¼8.4 Hz, 2H), 6.85e7.02 (m, 9H),

J¼8.7 Hz, 2H). Ratio 20:1. ¹³C NMR (CDCl₃, 75.5 MHz)

d 54.4 (CH₂),

7.11e7.23 (m, 8H), 7.63 (br d, J¼7.8 Hz, 1H). ¹³C NMR (CDCl₃,

125.2 (CH), 126.5 (Cq), 127.5 (CH), 127.7 (CH), 128.5 (CH), 128.7 (CH),

129.3 (CH), 131.4 (CH), 138.2 (Cq), 144.8 (Cq), 148.6 (Cq), 170.8 (Cq).

IR (ﬁlm) 3358, 1632 cm^ꢁ1. HRMS calcd for C₂₀H₁₉N₂O: 303.1492,

found: 303.1495.

75.5 MHz) d 37.4 (CH₃), 38.3 (CH₃), 38.5 (CH₃), 38.8 (CH₃), 93.8 (Cq),

125.8 (CH), 126.0 (CH), 126.4 (CH), 127.0 (CH), 127.1 (Cq), 127.2 (CH),

127.8 (CH),128.9 (CH),129.5 (CH), 129.9 (CH),130.1 (CH),130.2 (CH),

130.4 (CH), 133.1 (Cq), 133.9 (Cq), 134.3 (Cq), 139.4 (CH), 142.2 (Cq),

144.9 (Cq), 145.9 (Cq), 169.3 (Cq), 169.5 (Cq), 16.7 (Cq), 175.5 (Cq). IR

Prepared according to general procedure A from this amine

(100 mg, 0.331 mmol) and 2-iodobenzoyl chloride (97%, 83.0 mg,

L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

6953

0.302 mmol) the amide was obtained without further puriﬁcation

(176 mg, quantitative). ¹H NMR (CDCl₃, 300 MHz)

5.07 (s, 2H), 6.94

0.098 mmol) after ﬂash chromatography puriﬁcation (DCM to

d

DCM/MeOH 4%) the amide was obtained (51 mg, 67%). ¹H NMR

(d, J¼6.9 Hz, 2H), 7.05 (ddd, J¼8.1, 7.2, 1.5 Hz,1H), 7.14e7.35 (m, 12H),

(CDCl₃, 300 MHz) d 3.36 (s, 3H), 5.07 (s, 2H), 6.82e6.87 (m, 4H),

7.45 (d, J¼8.7 Hz, 2H), 7.81 (d, J¼7.8 Hz, 1H), 8.70 (s, 1H). ¹³C NMR

7.12e7.22 (m, 9H), 7.26e7.31 (m, 4H), 7.40 (ddd, J¼7.5, 6.9, 1.2 Hz,

(CDCl₃, 75.5 MHz) d 54.4 (CH₂), 92.2 (Cq),119.2 (CH),127.1 (CH),127.7

1H), 7.46e7.50 (m, 3H), 7.89 (d, J¼7.8 Hz, 1H), 8.42 (s, 1H). ¹³C NMR

(CH), 127.9 (CH), 128.3 (CH), 128.6 (CH), 128.8 (CH), 129.5 (CH), 130.2

(CH), 131.6 (CH), 137.7 (Cq), 139.7 (Cq), 140.2 (CH), 142.0 (Cq), 143.7

(Cq), 167.9 (Cq), 170.2 (Cq). IR (ﬁlm) 3258, 1626, 1594 cm^ꢁ1. HRMS

calcd for C₂₇H₂₂IN₂O₂: 533.0720, found: 533.0720.

Prepared according to general procedure C from this amide

(175 mg, 0.329 mmol) and iodomethane (0.2 mL, 3.21 mmol), after

ﬂash chromatography puriﬁcation (DCM to DCM/MeOH 2%) the

title compound was obtained (163 mg, 91%). ¹H NMR (CDCl₃,

(CDCl₃, 75.5 MHz) d 38.5 (CH₃), 54.1 (CH₂), 92.8 (Cq), 119.0 (CH),

126.1 (CH), 127.4 (CH), 127.7 (CH), 127.9 (CH), 128.5 (CH), 128.7

(CH), 128.8 (CH), 129.5 (CH), 130.1 (CH), 130.3 (CH), 131.2 (Cq), 131.7

(CH), 134.1 (Cq), 137.5 (Cq), 139.7 (Cq), 140.3 (CH), 142.2 (Cq), 143.3

(Cq), 146.2 (Cq), 167.7 (Cq), 169.8 (Cq), 170.0 (Cq). IR (ﬁlm) 3257,

1632, 1599 cm^ꢁ1. HRMS calcd for C₃₅H₂₉IN₃O₃: 666.1248, found:

666.1261.

Prepared according to general procedure C from this amide

(51.0 mg, 0.077 mmol) and iodomethane (0.1 mL, 1.61 mmol), after

ﬂash chromatography puriﬁcation (DCM to DCM/MeOH 2%) the

title compound was obtained (47 mg, 90%). ¹H NMR (CDCl₃,

300 MHz)

d 3.43 (s, 3H), 5.09 (s, 2H), 6.76e6.98 (m, 6H), 7.07e7.18

(m, 5H), 7.23e7.32 (m, 6H), 7.61 (d, J¼7.8 Hz, 1H). ¹³C NMR (CDCl₃,

75.5 MHz)

d 37.4 (CH₃), 54.0 (CH₂), 126.4 (CH), 127.1 (CH), 127.7

(CH), 127.9 (CH), 128.68 (CH), 128.73 (CH), 128.9 (Cq), 129.3 (CH),

129.7 (CH), 130.2 (CH), 134.7 (Cq), 137.5 (Cq), 139.4 (CH), 142.2 (Cq),

300 MHz) d 3.36 (s, 3H), 3.45 (s, 3H), 5.12 (s, 2H), 6.66 (br d,

J¼7.2 Hz,1H), 6.84e6.92 (m, 5H), 7.00 (br d, J¼7.2 Hz, 2H), 8.11e7.20

143.3 (Cq), 144.3 (Cq), 169.8 (Cq), 170.3 (Cq). IR (ﬁlm) 1643 cm^ꢁ1

.

(m, 6H), 7.27e7.32 (m, 7H), 7.53 (br d, J¼7.8 Hz, 1H). ¹³C NMR

HRMS calcd for C₂₈H₂₃IN₂NaO₂: 569.0696, found: 569.0697.

(CDCl₃, 75.5 MHz) d 37.0 (CH₃), 38.0 (CH₃), 54.0 (CH₂), 93.6 (Cq),

125.4 (CH), 126.0 (CH), 126.9 (CH), 127.5 (CH), 127.7 (CH), 128.47

(CH), 128.52 (CH), 129.1 (CH), 129.6 (CH), 129.8 (CH), 130.1 (CH),

133.60 (Cq), 133.62 (Cq), 137.1 (Cq), 139.2 (CH), 141.7 (Cq), 143.2

(Cq), 144.4 (Cq), 145.5 (Cq), 169.10 (Cq), 169.12 (Cq), 169.9 (Cq). IR

(ﬁlm) 1643, 1603 cm^ꢁ1. HRMS calcd for C₃₆H₃₁IN₃O₃: 680.1405,

found: 680.1394.

4.3.50. N-(4-(N⁰-Benzyl-N⁰-phenyl)carbamoyl)phenyl-N-methyl-4-

nitrobenzamide 19b. Prepared according to general procedure A

from the amine derived from 18b (8.80 g, 29.1 mmol) and 4-

nitrobenzoyl chloride (5.40 g, 29.1 mmol) the amide was obtained

without further puriﬁcation (11.7 g, 89%). ¹H NMR (CDCl₃,

300 MHz)

d

major conformer 5.12 (s, 2H), 7.97 (dd, J¼8.1, 1.5 Hz,

2H), 7.14e7.26 (m, 5H), 7.27e7.31 (m, 5H), 7.46 (d, J¼8.7 Hz, 2H),

8.01 (d, J¼9.0 Hz, 2H), 8.15 (d, J¼9.0 Hz, 2H), 9.08 (s, 1H). Minor

4.3.52. N-Methyl-N-(4-(N⁰-methyl-N⁰-(4-(N⁰⁰-benzyl-N⁰⁰-phenyl)car-

bamoyl)phenyl)carbamoyl)phenyl-4-nitrobenzamide 20b. Prepared

according to general procedure A from the amine derived from 19b

(1.10 g, 2.53 mmol) and 4-nitrobenzoyl chloride (470 mg,

2.53 mmol) followed by general procedure C using iodomethane

(1.6 mL, 25.7 mmol) after ﬂash chromatography puriﬁcation (DCM to

DCM/MeOH 4%) the title compound was obtained (1.25 g, 83%). ¹H

conformer

d

5.05 (s, 2H), 7.95 (d, J¼8.4 Hz, 2H), 8.08 (d, J¼9.0 Hz,

2H), other signals masked by the major conformer. Ratio 20:1. ¹³C

NMR (CDCl₃, 75.5 MHz) 54.5 (CH₂), 119.9 (CH), 123.9 (CH), 127.3

d

(CH), 127.79 (CH), 127.82 (CH), 128.3 (CH), 128.8 (CH), 128.9 (CH),

129.5 (CH), 129.9 (CH), 132.0 (Cq), 137.4 (Cq), 139.5 (Cq), 140.5 (Cq),

143.5 (Cq), 149.8 (Cq), 164.3 (Cq), 170.6 (Cq). IR (ﬁlm) 1623, 1595,

1527 cm^ꢁ1. HRMS calcd for C₂₇H₂₂N₃O₄: 452.1605, found: 452.1610.

Anal. Calcd for C₂₇H₂₁O₄N₃$¼H₂O (456.0): C, 71.83; H, 4.69; N, 9.31.

Found: C, 70.87; H, 4.68; N, 9.20.

Prepared according to general procedure C from this amide

(11.7 g, 25.9 mmol) and iodomethane (17 mL, 273 mmol) after ﬂash

chromatography puriﬁcation (DCM to DCM/MeOH 10%) the title

compound was obtained (6.23 g, 52%). ¹H NMR (CDCl₃, 300 MHz)

NMR (CDCl₃, 500 MHz) major conformer

d 3.18 (s, 3H), 3.27 (s, 3H),

4.95 (s, 2H), 6.57 (d, J¼8.5 Hz, 2H), 6.63 (d, J¼8.5 Hz, 2H), 6.72 (d,

J¼7.0 Hz, 2H), 6.90e6.96 (m, 5H), 7.00 (d, J¼8.5 Hz, 2H), 7.03e7.13

(m, 5H), 7.16 (d, J¼8.5 Hz, 2H), 7.85 (d, J¼9.0 Hz, 2H). Minor con-

former

d

3.22 (s, 3H), 3.25 (s, 3H), 4.95 (s, 3H), 7.37 (d, J¼8.5 Hz, 2H),

7.91 (d, J¼9.0 Hz, 2H). Ratio 20:1. ¹³C NMR (CDCl₃, 75.5 MHz)

d 38.3

(CH₃), 38.4 (CH₃), 54.2 (CH₂),123.4 (CH),126.1 (CH),126.4 (CH),127.1

(CH), 127.7 (CH), 128.1 (CH), 128.7 (CH), 128.8 (CH), 129.3 (CH), 129.8

(CH), 129.9 (CH), 130.3 (CH), 134.4 (Cq), 134.7 (Cq), 137.4 (Cq), 141.8

(Cq), 143.3 (Cq), 145.2 (Cq), 145.6 (Cq), 148.4 (Cq), 168.4 (Cq), 169.2

(Cq),169.5 (Cq). IR (ﬁlm) 1643,1601,1522,1349 cm^ꢁ1. HRMS calcd for

C₃₆H₃₀N₄NaO₅: 621.2108, found: 621.2108.

d

3.46 (s, 3H), 5.08 (s, 2H), 6.80e6.84 (m, 2H), 6.83 (d, J¼8.4 Hz, 2H),

7.10e7.12 (m, 3H), 7.23 (d, J¼8.1 Hz, 2H), 7.25e7.30 (m, 5H), 7.32 (d,

J¼8.7 Hz, 2H), 7.97 (d, J¼8.4 Hz, 2H). ¹³C NMR (CDCl₃, 75.5 MHz)

d

38.2 (CH₃), 54.1 (CH₂), 123.3 (CH), 126.3 (CH), 127.2 (CH), 127.8

(CH), 128.2 (CH), 128.77 (CH), 128.79 (CH), 129.3 (CH), 129.7 (CH),

130.2 (CH), 135.3 (Cq), 137.3 (Cq), 141.9 (Cq), 143.2 (Cq), 144.9 (Cq),

148.1 (Cq), 168.4 (Cq), 169.5 (Cq). IR (ﬁlm) 1647, 1521 cm^ꢁ1. HRMS

calcd for C₂₈H₂₃N₃O₄: 488.1581, found: 488.1576.

4.3.53. 2-Iodo-N-methyl-N-(4-(N⁰-methyl-N⁰-(4-(N⁰⁰-methyl-N⁰⁰-(4-

(N⁰⁰⁰-benzyl-N⁰⁰⁰-phenyl)carbamoyl)phenyl)carbamoyl)phenyl)carba-

moyl)phenylbenzamide 21b⁰. Prepared according to general pro-

cedure B from 20b (1.20 g, 2.00 mmol) the amine was obtained

without further puriﬁcation (1.14 g, quantitative). ¹H NMR (CDCl₃,

4.3.51. 2-Iodo-N-methyl-N-(4-(N⁰-methyl-N⁰-(4-(N⁰⁰-benzyl-N⁰⁰-phe-

nyl)carbamoyl)phenyl)carbamoyl)phenylbenzamide 20b⁰. Prepared

according to general procedure B from 19b (6.20 g, 13.3 mmol) the

amine was obtained without further puriﬁcation (5.8 g, quantita-

300 MHz) major conformer

d 3.36 (s, 3H), 3.41 (s, 3H), 3.96 (br s,

2H), 5.09 (s, 2H), 6.25 (d, J¼8.7 Hz, 2H), 6.74e6.83 (m, 6H), 6.98 (d,

J¼8.7 Hz, 2H), 7.06 (d, J¼8.7 Hz, 2H), 7.11e7.14 (m, 3H), 7.18 (d,

tive). ¹H NMR (CDCl₃, 300 MHz) major conformer

d

3.38 (s, 3H), 3.91

J¼8.4 Hz, 2H), 7.28e7.31 (m, 5H). Minor conformer

d 3.30 (s, 3H),

(br s, 2H), 5.11 (s, 2H), 6.36 (d, J¼8.4 Hz, 2H), 6.82 (d, J¼8.7 Hz, 2H),

3.40 (s, 3H), 6.58 (d, J¼8.4 Hz, 2H), 7.51 (d, J¼8.7 Hz, 2H), 7.71 (d,

6.86e6.90 (m, 2H), 7.02 (d, J¼8.7 Hz, 2H), 7.13e7.17 (m, 3H), 7.21 (d,

J¼8.7 Hz, 2H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 37.88 (CH₃), 37.91 (CH₃),

J¼8.4 Hz, 2H), 7.26e7.31 (m, 5H). Minor conformer

d

3.46 (s, 3H),

54.0 (CH₂), 113.0 (CH), 123.3 (Cq), 125.5 (CH), 125.6 (CH), 126.8 (CH),

127.4 (CH),127.5 (CH),128.3 (CH),128.4 (CH),128.9 (CH),129.4 (CH),

129.6 (CH), 130.9 (CH), 132.9 (Cq), 133.8 (Cq), 137.4 (Cq), 143.6 (Cq),

146.1 (Cq),147.4 (Cq),149.2 (Cq),169.7 (Cq),169.8 (Cq),170.6 (Cq). IR

(ﬁlm) 3352, 1642, 1632, 1599 cm^ꢁ1. HRMS calcd for C₃₆H₃₃N₄O₃:

569.2547, found: 569.2543.

5.09 (s, 2H), 6.30 (d, J¼8.7 Hz, 2H). Ratio 20:1. ¹³C NMR (CDCl₃,

75.5 MHz)

d 38.1 (CH₃), 53.8 (CH₂), 125.9 (CH), 127.0 (CH), 127.7

(CH), 127.9 (CH), 128.6 (CH), 128.7 (CH), 129.3 (CH), 130.0 (CH), 131.3

(CH), 133.4 (Cq), 137.6 (Cq), 143.6 (Cq), 147.1 (Cq), 148.2 (Cq), 148.3

(Cq), 169.6 (Cq), 170.4 (Cq). IR (ﬁlm) 3352, 1632, 1600 cm^ꢁ1

.

Prepared according to general procedure A from this amine

(50.0 mg, 0.115 mmol) and 2-iodobenzoyl chloride (97%, 27.0 mg,

Prepared according to general procedure A from this amine

(300 mg, 0.528 mmol) and 2-iodobenzoyl chloride (97%, 123 mg,

6954

L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

0.448 mmol) the amide was obtained without further puriﬁcation

(421 mg, quantitative). ¹H NMR (CDCl₃, 300 MHz)

3.28 (s, 3H),

(m, 2H), 6.97 (d, J¼8.7 Hz, 2H), 7.05 (d, J¼8.7 Hz, 2H), 7.07 (d, J¼8.7 Hz,

2H), 7.19 (d, J¼8.7 Hz, 1H), 7.12e7.31 (m, 12H). ¹³C NMR (CDCl₃,

d

3.44 (s, 3H), 4.52 (s, 2H), 6.31e6.76 (m, 4H), 6.82 (d, J¼8.4 Hz, 2H),

6.96e6.99 (m, 2H), 7.01 (dd, J¼7.8, 1.5 Hz, 2H), 7.07e7.14 (m, 7H),

7.18e7.24 (m, 4H), 7.32 (ddd, J¼8.4, 7.5, 0.9 Hz, 1H), 7.49 (d,

J¼8.7 Hz, 2H), 7.54 (dd, J¼7.5,1.5 Hz,1H), 7.82 (dd, J¼8.1, 0.9 Hz,1H),

75.5 MHz) d 37.8 (CH₃), 38.0 (CH₃), 38.2 (CH₃), 53.9 (CH₂), 113.2 (CH),

123.6 (Cq), 125.6 (CH), 126.8 (CH), 127.4 (CH), 127.6 (CH), 128.29 (CH),

128.33 (CH),128.4 (CH),128.9 (CH),129.0 (CH),129.4 (CH),129.6 (CH),

129.8 (CH), 131.0 (CH), 132.5 (Cq), 132.6 (Cq), 134.0 (Cq), 137.0 (Cq),

143.0 (Cq), 145.5 (Cq), 145.8 (Cq), 147.1 (Cq), 148.7 (Cq), 169.0 (Cq),

9.69 (s, 1H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 38.2 (CH₃), 38.3 (CH₃),

53.8 (CH₂), 93.1 (Cq), 119.1 (CH), 126.3 (CH), 127.5 (CH), 127.8 (CH),

128.1 (CH), 128.3 (CH), 128.6 (CH), 129.2 (CH), 129.3 (CH), 129.9

(CH), 130.1 (CH), 130.3 (CH), 131.3 (Cq), 133.6 (Cq), 134.1 (Cq), 136.7

(Cq), 139.9 (CH), 140.5 (Cq), 142.2 (Cq), 142.9 (Cq), 145.9 (Cq), 146.4

(Cq), 168.3 (Cq), 169.5 (Cq), 169.9 (Cq), 170.4 (Cq). IR (ﬁlm) 3256,

1642, 1632, 1603 cm^ꢁ1. HRMS calcd for C₄₃H₃₆IN₄O₄: 799.1776,

found: 799.1767.

169.2 (Cq), 169.6 (Cq), 170.1 (Cq). IR (ﬁlm) 3351, 1641, 1602 cm^ꢁ1

.

HRMS calcd for C₄₄H₃₉N₅NaO₄: 724.2894, found: 724.2887.

Prepared according to general procedure A from this amine

(93.0 mg, 0.132 mmol) and 2-iodobenzoyl chloride (97%, 40.0 mg,

0.146 mmol) after ﬂash chromatography puriﬁcation (DCM to

DCM/MeOH 2%) the amide was obtained (113 mg, 91%). ¹H NMR

(CDCl₃, 300 MHz)

d 3.38 (s, 6H), 3.47 (s, 6H), 5.10 (s, 2H), 6.70

Prepared according to general procedure C from this amide

(435 mg, 0.544 mmol) and iodomethane (0.3 mL, 4.82 mmol), after

ﬂash chromatography puriﬁcation (DCM to DCM/MeOH 3%) the title

compound was obtained (47 mg, 79%). ¹H NMR (CDCl₃, 300 MHz)

(d, J¼8.4 Hz, 2H), 6.74 (d, J¼8.4 Hz, 2H), 6.85e6.90 (m, 6H), 7.01 (d,

J¼8.4 Hz, 2H), 7.11e7.31 (m, 10H), 7.42 (d, J¼7.5 Hz, 1H), 7.45

(d, J¼8.1 Hz, 1H), 7.52 (d, J¼8.7 Hz, 1H), 7.60 (dd, J¼7.5, 1.5 Hz, 1H),

7.92 (d, J¼7.8 Hz, 1H), 9.48 (s, 1H). ¹³C NMR (CDCl₃, 75.5 MHz)

d

3.31 (s, 3H), 3.33 (s, 3H), 5.37 (s, 3H), 5.02 (s, 2H), 6.54 (br d,

d 37.8 (CH₃), 38.0 (CH₃), 38.1 (CH₃), 53.4 (CH₂), 92.8 (Cq), 118.7

J¼7.8 Hz, 1H), 6.70 (d, J¼8.4 Hz, 2H), 6.78e7.81 (m, 3H), 7.85e7.90

(CH), 125.7 (CH), 125.9 (CH), 126.1 (CH), 126.9 (CH), 127.5 (CH),

127.7 (CH), 128.0 (CH), 128.38 (CH), 128.42 (CH), 128.46 (CH),

128.50 (CH), 128.9 (CH), 129.0 (CH), 129.7 (CH), 129.9 (CH), 130.1

(CH), 131.0 (Cq), 132.4 (Cq), 133.8 (Cq), 134.39 (Cq), 134.40 (Cq),

137.0 (Cq), 139.7 (CH), 140.0 (Cq), 143.1 (Cq), 145.0 (Cq), 145.9 (Cq),

146.3 (Cq), 167.8 (Cq), 162.2 (Cq), 169.3 (Cq), 170.2 (Cq). IR (ﬁlm)

1642, 1633, 1602 cm^ꢁ1. HRMS calcd for C₅₁H₄₃IN₅O₅: 932.2303,

found: 932.2291.

Prepared according to general procedure C from this amide

(113 mg, 0.121 mmol) and iodomethane (0.2 mL, 3.21 mmol), after

ﬂash chromatography puriﬁcation (DCM to DCM/MeOH 4%) the

title compound was obtained (70 mg, 61%). ¹H NMR (CDCl₃,

(m, 6H), 7.00e7.06 (m, 5H), 7.15e7.20 (m, 8H), 7.52 (br d, J¼7.5 Hz,

1H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 36.8 (CH₃), 37.6 (CH₃), 37.9 (CH₃),

53.6 (CH₂), 93.3 (Cq), 125.1 (CH), 125.4 (CH), 125.8 (CH), 126.5 (CH),

127.1 (CH), 127.4 (CH), 128.0 (CH), 128.1 (CH), 128.3 (CH), 128.7 (CH),

129.2 (CH), 129.4 (CH), 129.5 (CH), 129.8 (CH), 132.4 (Cq), 133.3 (Cq),

133.7 (Cq), 136.8 (Cq), 138.7 (CH), 141.6 (Cq), 142.8 (Cq), 144.1 (Cq),

145.3 (Cq),169.2 (Cq),169.3 (Cq),169.5 (Cq),170.0 (Cq). IR (ﬁlm) 1642,

1603 cm^ꢁ1. HRMS calcd for C₄₄H₃₈IN₄O₄: 813.1932, found: 813.1945.

4.3.54. N-Methyl-N-(4-(N⁰-methyl-N⁰-(4-(N⁰⁰-methyl-N⁰⁰-(4-(N⁰⁰⁰-

benzyl-N⁰⁰⁰-phenyl)carbamoyl)phenyl)carbamoyl)phenyl)carbamoyl)

phenyl-4-nitrobenzamide 21b. To a solution of S5 (see below)

(504 mg, 1.68 mmol) in dry DCM (7 mL) was added oxalyl chloride

(0.18 mL, 2.06 mmol) followed by a drop of DMF. After the effer-

vescence stop the solution was stirred at rt under nitrogen for 2 h.

The solvent was removed to dryness under reduced pressure and

the residue was redissolved in DCM (10 mL). The amide derived

from 19b (366 mL, 0.84 mmol) and pyridine (0.50 mL, 6.18 mmol)

were added and the mixture was stirred at rt overnight. The solu-

tion was partitioned between DCM and NaHCO₃aqueous saturated

solution and the organic phase was washed with NaHCO₃aqueous

saturated solution and HCl 3 N, and then it was dried, ﬁltered and

the solvent was removed under reduced pressure. The residue was

redissolved in THF (30 mL) and iodomethane (0.6 mL, 9.64 mmol)

following method C after ﬂash chromatography puriﬁcation (DCM

to DCM/MeOH 5%) the title compound was obtained (256 mg, 42%).

500 MHz)

d 3.23 (s, 6H), 3.37 (s, 6H), 4.96 (s, 2H), 6.55 (br d,

J¼7.0 Hz, 1H), 6.60 (d, J¼8.5 Hz, 2H), 6.62 (d, J¼8.5 Hz, 2H), 6.69 (d,

J¼7.0 Hz, 2H), 6.78e6.80 (m, 4H), 6.87 (d, J¼7.0 Hz, 4H), 6.94e6.97

(m, 6H), 7.03 (d, J¼8.5 Hz, 2H), 7.09e7.13 (m, 6H), 7.47 (br d,

J¼7.0 Hz, 1H). ¹³C NMR (CDCl₃, 125 MHz)

d 37.0 (CH₃), 37.1 (CH₃),

38.0 (CH₃), 38.2 (CH₃), 53.9 (CH₂), 94.0 (Cq), 125.70 (CH), 125.72

(CH), 126.1 (CH), 126.8 (CH), 127.4 (CH), 127.6 (CH), 128.3 (CH), 128.4

(CH), 129.0 (CH), 129.5 (CH), 129.7 (CH), 129.8 (CH), 130.0 (CH),

132.9 (Cq), 133.4 (Cq), 133.7 (Cq), 134.0 (Cq), 137.0 (Cq), 139.1 (CH),

141.9 (Cq), 143.1 (Cq), 144.4 (Cq), 145.5 (Cq), 145.7 (Cq), 145.8 (Cq),

169.1 (Cq), 169.82 (Cq), 169.83 (Cq). IR (ﬁlm) 1642, 1603 cm^ꢁ1

.

HRMS calcd for C₅₂H₄₅IN₅O₅: 946.2460, found: 946.2480.

4.3.56. N-Benzyl-4-nitro-N-phenyl-1-naphthamide

24. Prepared

according to general procedure C from 4-nitro-1-naphthoic acid

(1.00 g, 4.61 mmol), thionyl chloride (10 mL), pyridine (1.3 mL,

16.1 mmol) and N-phenylbenzamine (857 mg, 4.68 mmol). The

crude product was puriﬁed by ﬂash chromatography (Petrol to

petrol/AcOEt 40%) to yield 24 (1.6 g, 90%). ¹H NMR (CDCl₃, 300 MHz)

¹H NMR (CDCl₃, 300 MHz)

d 3.43 (s, 3H), 3.49 (s, 3H), 3.48 (s, 3H),

5.12 (s, 2H), 6.72 (d, J¼8.4 Hz, 1H), 6.80e6.89 (m, 6H), 7.04 (d,

J¼8.7 Hz, 1H), 7.10e7.22 (m, 8H), 7.21 (d, J¼8.4 Hz, 1H), 7.28e7.34

(m, 7H), 7.35 (d, J¼8.7 Hz, 1H), 7.99 (d, J¼9.0 Hz, 1H). ¹³C NMR

(CDCl₃, 75.5 MHz)

d

38.0 (CH₃), 38.1 (CH₃), 38.2 (CH₃), 54.0 (CH₂),

d 5.25 (s, 2H), 6.34e6.80 (m, 2H), 7.00e6.97 (m, 3H), 7.26 (d,

123.0 (CH),125.8 (CH), 125.9 (CH),126.2 (CH),127.4 (CH), 127.6 (CH),

128.3 (CH), 128.41 (CH), 128.44 (CH), 129.0 (CH), 129.5 (CH), 129.8

(CH), 129.9 (CH), 130.9 (CH), 133.8 (Cq), 134.0 (Cq), 134.2 (Cq), 137.1

(Cq), 141.6 (Cq), 143.2 (Cq), 145.0 (Cq), 145.4 (Cq), 145.5 (Cq), 147.9

(Cq), 168.0 (Cq), 168.9 (Cq), 169.0 (Cq), 169.0 (Cq). IR (ﬁlm) 1644,

1602 cm^ꢁ1. HRMS calcd for C₄₄H₃₈N₅O₆: 732.2817, found: 732.2815.

J¼7.8 Hz, 1H), 7.41e7.33 (m, 5H), 7.67 (dd, J¼7.2, 1.5 Hz, 1H), 7.69 (dd,

J¼7.2,1.5 Hz,1H), 7.91 (d, J¼7.8 Hz,1H), 8.22e8.18 (m,1H), 8.46e8.43

(m, 1H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 53.2 (CH₂), 122.4 (CH), 123.2

(CH), 123.4 (CH), 125.0 (Cq), 125.9 (CH), 127.6 (CH), 127.7 (CH), 127.8

(CH), 128.1 (CH), 128.6 (CH), 128.8 (CH), 129.0 (CH), 129.4 (CH), 131.2

(Cq), 136.8 (Cq), 140.6 (Cq), 141.3 (Cq), 146.3 (Cq), 168.4 (Cq), IR (ﬁlm)

1651 cm^ꢁ1HRMS calcd for C₂₄H₁₉N₂O₃: 383.1390, found 383.1395.

4.3.55. 2-Iodo-N-methyl-N-(4-(N⁰-methyl-N⁰-(4-(N⁰⁰-methyl-N⁰⁰-(4-

(N⁰⁰⁰-methyl-N⁰⁰⁰-(4-(N⁰⁰⁰⁰-benzyl-N⁰⁰⁰⁰-phenyl)carbamoyl)phenyl)car-

bamoyl)phenyl)carbamoyl)phenyl)carbamoyl)phenylbenzamide

22b⁰. Prepared according to general procedure B from 21b (262 mg,

0.358 mmol) the amine was obtained without further puriﬁcation

4.3.57. N-(4-(N⁰-Benzyl-N⁰-phenyl)carbamoyl)-1-naphthyl-N-

methyl-4-nitronaphthamide 25a. Prepared according to general

procedure B from 24 (1.60 g, 4.19 mmol) the amine was obtained

without further puriﬁcation (1.23 g, 83%). ¹H NMR (CDCl₃,

(227 mg, 90%). ¹H NMR (CDCl₃, 300 MHz)

d

3.40 (s, 3H), 3.42 (s, 3H),

300 MHz)

d

4.19 (br s, 2H), 5.23 (s, 2H), 6.34 (d, J¼7.8 Hz, 1H), 6.88

3.43 (s, 3H), 4.16 (br s, 2H), 5.11 (s, 2H), 6.32 (d, J¼8.7 Hz, 1H), 6.70 (d,

(d, J¼8.1 Hz, 2H), 6.93e6.97 (m, 3H), 7.02 (d, J¼7.8 Hz, 1H),

7.26e7.41 (m, 6H), 7.51 (ddd, J¼8.1 Hz, 7.2, 1.5, 1H), 7.67 (d, J¼8.1 Hz,

J¼8.4 Hz,1H), 6.72 (d, J¼8.7 Hz,1H), 6.82 (d, J¼8.7 Hz, 2H), 6.86e6.89

L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

6955

1H), 8.22 (d, J¼8.4 Hz, 1H). ¹³C NMR (CDCl₃, 75.5 MHz)

d

53.2 (CH₂),

J¼7.8 Hz, 1H), 6.60 (d, J¼7.2 Hz, 2H), 6.68 (d, J¼7.8 Hz, 1H),

6.72e6.81 (m, 4H), 6.90 (d, J¼7.2 Hz, 1H), 7.30e7.40 (m, 6H), 7.48

(dd, J¼7.8, 7.2 Hz, 1H), 7.56e7.65 (m, 3H), 8.03 (d, J¼7.5 Hz, 1H), 8.13

(d, J¼7.5 Hz, 1H), 8.23 (d, J¼8.4 Hz, 1H). ¹³C NMR (CDCl₃, 75.5 MHz)

107.4 (CH), 120.9 (CH), 122.9 (Cq), 124.0 (Cq), 124.7 (CH), 125.8 (CH),

126.2 (CH), 126.6 (CH), 127.0 (CH), 127.2 (CH), 127.4 (CH), 128.3 (CH),

128.4 (CH), 128.5 (CH), 131.6 (Cq), 137.7 (Cq), 143.2 (Cq), 143.4 (Cq),

170.9 (Cq). IR (ﬁlm) 1628 cm^ꢁ1HRMS calcd for C₂₄H₂₁N₂O:

353.1648, found 353.1655.

d

37.6 (CH₃), 52.6 (CH₂), 107.1 (CH), 120.8 (CH), 122.6 (CH), 123.0

(CH), 123.4 (Cq), 123.7 (CH), 124.3 (CH), 125.1 (CH), 125.4 (CH), 125.7

(CH), 125.8 (CH), 126.3 (CH), 126.4 (CH), 126.9 (CH), 127.0 (CH), 127.1

(CH), 127.3 (CH), 128.3 (CH), 129.3 (Cq), 131.2 (Cq), 133.6 (Cq), 137.0

(Cq), 141.5 (Cq), 143.3 (Cq), 170.0 (Cq), 172.5 (Cq). IR (ﬁlm)

1632 cm^ꢁ1. HRMS calcd for C₃₆H₃₀N₃O₂: 536.2333, found: 536.2336.

Prepared according to general procedure A from this amine

(233 mg, 0.435 mmol) and 4-nitro-1-naphthoyl chloride (118 mg,

0.501 mmol) the amide was obtained without further puriﬁcation

Prepared according to general procedure A from this amine

(294 mg, 0.835 mmol) and 4-nitro-1-naphthoyl chloride (203 mg,

0.861 mmol) after ﬂash chromatography puriﬁcation (petrol to

AcOEt) the amide was obtained (446 mg, 97%). ¹H NMR (CDCl₃,

300 MHz)

d 4.94 (s, 2H), 6.65e6.74 (m, 2H), 6.84e6.94 (m, 4H),

7.09e7.15 (m, 2H), 7.18e7.26 (m, 3H), 7.31 (dd, J¼7.5, 7.0 Hz, 1H),

7.41 (dd, J¼8.0, 7.0 Hz, 1H), 7.46 (d, J¼7.0 Hz, 1H), 7.57 (d, J¼7.5 Hz,

1H), 7.66 (dd, J¼7.5, 7.0 Hz, 1H), 7.74 (dd, J¼8.0, 7.0 Hz, 1H), 7.79 (d,

J¼7.5 Hz, 1H), 7.86 (d, J¼8.5 Hz, 1H), 8.08 (d, J¼8.0 Hz, 1H), 8.37 (d,

J¼7.5 Hz, 1H), 8.48 (d, J¼9.0 Hz, 1H). ¹³C NMR (CDCl₃, 75.5 MHz)

(127 mg, 40%). ¹H NMR (CDCl₃, 300 MHz)

d 3.33 (s, 3H), 5.01 (s, 2H),

6.43e6.53 (m, 2H), 6.61e6.85 (m, 5H), 6.91e7.05 (m, 1H), 7.14e7.29

(m, 7H), 7.38 (d, J¼7.8 Hz, 1H), 7.40 (d, J¼7.2 Hz, 1H), 7.48 (d,

J¼7.2 Hz, 1H), 7.53 (d, J¼7.2 Hz, 1H), 7.61e7.70 (m, 4H), 7.75e7.89

(m, 2H), 7.94 (d, J¼8.4 Hz, 1H), 8.16 (d, J¼8.4 Hz, 1H), 8.39 (d,

d

53.6 (CH₂), 119.9 (CH), 122.0 (CH), 122.8 (CH), 123.6 (CH), 124.0

(CH), 125.6 (CH), 126.5 (CH), 127.0 (CH), 127.3 (CH), 127.7 (CH), 127.9

(CH), 128.5 (CH), 128.6 (CH), 128.8 (CH), 129.3 (CH), 129.8 (CH),

130.8 (Cq), 131.3 (Cq), 131.8 (Cq), 133.0 (Cq), 137.0 (Cq), 140.5 (Cq),

142.1 (Cq), 148.0 (Cq), 167.1 (Cq), 170.8 (Cq), IR (ﬁlm) 3237,

1625 cm^ꢁ1HRMS calcd for C₃₅H₂₆N₃O₂: 552.1918, found 552.1909.

Prepared according to general procedure C from the amide

(223 mg, 0.404 mmol) and methyl iodide (0.25 mL, 4.01 mmol), after

ﬂash chromatography puriﬁcation (petrol to AcOEt) the title com-

pound was obtained (231 mg, quantitative). ¹H NMR (CDCl₃,

J¼8.4 Hz, 1H), 9.46 (br s, 1H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 37.4

(CH₃), 52.7 (CH₂), 119.3 (CH), 121.8 (CH), 122.1 (CH), 122.8 (CH),

122.9 (CH), 123.2 (CH), 123.3 (CH), 123.4 (CH), 123.8 (CH), 124.9

(CH), 125.1 (Cq), 125.6 (CH), 125.8 (CH), 126.1 (CH), 126.2 (CH), 126.7

(CH), 126.8 (CH), 127.0 (CH), 127.5 (CH), 128.1 (CH), 128.4 (CH), 128.5

(CH), 129.3 (Cq), 129.4 (CH), 130.4 (Cq), 131.0 (Cq), 131.1 (Cq), 131.4

(Cq), 132.8 (Cq), 134.4 (Cq), 136.8 (Cq), 139.5 (Cq), 140.3 (Cq), 141.4

(Cq), 166.5 (Cq), 169.2 (Cq), 171.0 (Cq). IR (ﬁlm) 3239, 1623 cm^ꢁ1

.

500 MHz)

d

3.50 (s, 3H), 4.98 (d, J¼14.3 Hz, 1H), 5.10 (d, J¼14.3 Hz,

HRMS calcd for C₄₇H₃₄N₄NaO₅: 757.2421, found 757.2411.

Prepared according to general procedure C from this amide

(127 mg, 0.173 mmol) and methyl iodide (0.2 mL, 3.21 mmol), after

ﬂash chromatography puriﬁcation (DCM to DCM/MeOH 2%) the

title compound was obtained (116 mg, 90%). ¹H NMR and ¹³C NMR

show mixture of multiple conformers. IR (ﬁlm) 1644 cm^ꢁ1. HRMS

calcd for C₄₈H₃₇N₄NaO₅: 749.2758, found: 749.2754.

1H), 6.44 (d, J¼7.2 Hz, 2H), 6.59e6.63 (m, 2H), 6.67e6.70 (m, 2H),

6.75 (dd, J¼7.2, 7.0 Hz, 1H), 6.83 (d, J¼7.2 Hz, 1H), 7.22e7.18 (m, 5H),

7.48 (d, J¼7.8 Hz,1H), 7.52 (d, J¼7.2 Hz, 1H), 7.55 (d, J¼7.5 Hz,1H), 7.58

(d, J¼7.0 Hz, 1H), 7.61 (d, J¼7.5 Hz, 1H), 7.91 (d, J¼8.2 Hz, 1H), 7.99 (d,

J¼8.2 Hz, 1H), 8.15 (d, J¼7.8 Hz, 1H), 8.37 (d, J¼8.8 Hz, 1H). ¹³C NMR

(CDCl₃, 75.5 MHz)

d 37.8 (CH₃), 52.8 (CH₂), 121.4 (CH), 122.2 (CH),

122.5 (CH),123.1 (CH),124.1 (CH),124.77 (CH),124.81(Cq),126.0 (CH),

126.2 (CH), 126.8 (CH), 127.2 (CH), 127.5 (CH), 127.6 (CH), 127.8 (CH),

128.0 (CH), 128.3 (CH), 128.4 (CH), 128.6 (CH), 129.2 (Cq), 129.3 (CH),

130.9 (Cq), 131.3 (Cq), 135.2 (Cq), 136.9 (Cq), 139.5 (Cq), 140.1 (Cq),

4.3.60. N-Benzyl-N-(4-(N⁰-benzyl-N⁰-(4-(N⁰⁰-benzyl-N⁰⁰-phenyl)car-

bamoyl)-1-naphtyl)carbamoyl)-1-naphtyl-4-nitronapthamide 26b.

Prepared according to general procedure B from 25b (280 mg,

0.437 mmol) the amine was obtained without further puriﬁcation

141.4 (Cq), 146.2 (Cq), 169.06 (Cq), 169.10 (Cq). IR (ﬁlm) 1646 cm^ꢁ1

.

HRMS calcd for C₃₆H₂₈N₃O₄: 566.2074, found 566.2078.

(195 mg, 73%). ¹H NMR (CDCl₃, 300 MHz)

d 3.98 (br s, 2H), 4.27 (d,

J¼13.5 Hz,1H), 5.18 (s, 2H), 6.94 (d, J¼7.8 Hz,1H), 6.03 (d, J¼13.5 Hz,

1H), 6.27 (d, J¼7.5 Hz, 1H), 6.60e6.65 (m, 3H), 6.74 (d, J¼7.8 Hz, 1H),

6.79.6.88 (m, 2H), 6.99 (dd, J¼7.5, 7.2 Hz, 1H), 7.12e7.40 (m, 11H),

7.45 (dd, J¼7.8, 7.5 Hz, 1H), 7.57e7.64 (m, 3H), 8.10 (d, J¼8.1 Hz, 1H),

4.3.58. N-Benzyl-N-(4-(N⁰-Benzyl-N⁰-phenyl)carbamoyl)-1-naphtyl-

4-nitronaphtamide 25b. Prepared according to general procedure C

from the same amide (221 mg, 0.401 mmol) and benzyl bromide

(0.2 mL, 1.67 mmol), after ﬂash chromatography puriﬁcation (pet-

rol to petrol/AcOEt 50%) the title compound was obtained (257 mg,

8.05e8.17 (m, 2H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 52.4 (CH₂), 52.7

(CH₂),107.3 (CH),120.8 (CH),122.7 (Cq),123.0 (CH),123.8 (Cq),124.4

(CH),124.8 (CH),124.9 (CH),125.6 (CH),125.8 (CH),125.9 (CH),126.4

(CH), 126.5 (CH), 127.0 (CH), 127.2 (CH), 127.4 (CH), 128.0 (CH), 128.2

(CH), 128.4 (CH), 129.5 (CH), 131.2 (Cq), 133.7 (Cq), 137.1 (Cq), 137.2

(Cq),138.7 (Cq), 141.8 (Cq),143.1 (Cq), 170.0 (Cq),171.9 (Cq). IR (ﬁlm)

1633 cm^ꢁ1. HRMS calcd for C₄₂H₃₄N₃O₂: 612.2646, found: 612.2647.

Prepared according to general procedure A from this amine

(195 mg, 0.319 mmol) and 4-nitro-1-naphthoyl chloride (86.0 mg,

0.365 mmol) the amide was obtained without further puriﬁcation

quantitative). ¹H NMR (CDCl₃, 500 MHz)

d

4.15 (d, J¼14.0 Hz, 1H),

4.99 (d, J¼14.0 Hz, 1H), 5.06 (d, J¼14.0 Hz, 1H), 5.96 (d, J¼14.0 Hz,

1H), 6.12e6.12 (m, 1H), 6.39e6.46 (m, 2H), 6.51 (d, J¼7.5 Hz, 1H),

6.59e6.68 (m, 1H), 6.75e6.83 (m, 1H), 6.85e6.90 (m, 1H), 7.07e7.13

(m, 1H), 7.17e7.25 (m, 12H), 7.48 (d, J¼8.0 Hz, 1H), 7.50 (d, J¼7.5 Hz,

1H), 7.54 (d, J¼7.0 Hz, 1H), 7.57 (d, J¼7.0 Hz, 1H), 7.93e7.97 (m, 1H),

8.01 (d, J¼9.0 Hz, 1H), 8.34 (d, J¼8.5 Hz, 1H). ¹³C NMR (CDCl₃,

75.5 MHz)

d 52.5 (CH₂), 52.8 (CH₂), 121.0 (CH), 122.3 (CH), 122.4

(CH), 123.0 (CH),124.4 (CH),124.7 (Cq), 125.6 (CH), 126.0 (CH),126.2

(CH), 126.7 (CH), 127.2 (CH), 127.4 (CH), 127.7 (CH), 127.9 (CH), 128.2

(CH), 128.4 (CH), 128.5 (CH), 129.2 (CH), 129.6 (CH), 130.9 (Cq), 131.3

(Cq), 135.0 (Cq), 136.4 (Cq), 136.8 (Cq), 136.9 (Cq), 140.0 (Cq), 141.5

(Cq), 146.1 (Cq), 168.8 (Cq), 169.1 (Cq). IR (ﬁlm) 1646 cm^ꢁ1. HRMS

calcd for C₄₂H₃₅N₄O₄: 659.2653, found 659.2644. (MþNH₄).

(258 mg, quantitative). ¹H NMR (CDCl₃, 300 MHz)

d 4.10 (d,

J¼13.2 Hz, 1H), 4.99 (br s, 2H), 5.83 (d, J¼13.2 Hz, 1H), 6.14

(d, J¼7.2 Hz, 1H), 6.31 (d, J¼6.9 Hz, 1H), 6.52 (d, J¼6.9 Hz, 2H), 6.63

(d, J¼8.1 Hz, 1H), 6.75 (d, J¼7.2 Hz, 1H), 6.84e7.07 (m, 7H),

7.12e7.33 (m, 7H), 7.38 (d, J¼7.8 Hz, 1H), 7.41 (d, J¼7.2 Hz, 1H), 7.46

(d, J¼7.2 Hz, 1H), 7.49 (d, J¼7.5 Hz, 1H), 7.60e7.69 (m, 4H), 7.86 (d,

J¼9.0 Hz, 1H), 7.90 (d, J¼9.0 Hz, 1H), 7.98 (d, J¼8.1 Hz, 1H), 8.10 (d,

J¼8.4 Hz, 1H), 8.36 (d, J¼8.4 Hz, 1H), 9.44 (br s, 1H). ¹³C NMR (CDCl₃,

4.3.59. N-Methyl-N-(4-(N⁰-methyl-N⁰-(4-(N⁰⁰-benzyl-N⁰⁰-phenyl)car-

bamoyl)-1-naphtyl)carbamoyl)-1-naphtyl-4-nitronapthamide 26a.

Prepared according to general procedure B from 25a (231 mg,

0.409 mmol) the amine was obtained without further puriﬁcation

75.5 MHz)

d 52.7 (CH₂), 52.4 (CH₂), 119.9 (CH), 122.0 (CH), 122.1

(CH),122.8 (CH), 123.3 (CH),124.6 (Cq), 124.8 (CH), 125.3 (CH), 125.8

(CH),125.9 (CH),126.0 (CH),126.2 (CH),126.7 (CH),126.8 (CH),127.2

(CH), 127.4 (CH), 127.5 (CH), 127.8 (CH), 128.1 (CH), 128.3 (CH), 128.4

(CH), 129.2 (Cq), 129.3 (CH), 129.5 (CH), 130.5 (Cq), 131.0 (Cq), 131.1

(219 mg, quantitative). ¹H NMR (CDCl₃, 300 MHz)

d

3.52 (s, 3H), 4.19

(br s, 2H), 5.15 (d, J¼14.0 Hz, 1H), 5.24 (d, J¼14.0 Hz, 1H), 5.90 (d,

6956

L. Chabaud et al. / Tetrahedron 66 (2010) 6936e6957

(Cq), 131.7 (Cq), 132.8 (Cq), 134.3 (Cq), 136.5 (Cq), 136.7 (Cq), 137.5

(Cq), 139.3 (Cq), 141.5 (Cq), 147.5 (Cq), 147.6 (Cq), 166.4 (Cq), 169.3

(Cq), 170.5 (Cq). IR (ﬁlm) 3240, 1630 cm^ꢁ1. HRMS calcd for

C₅₃H₄₂N₅O₅: 828.3180, found 828.3163.

3.32 mmol) and iodomethane (2.2 mL, 35.3 mmol) after ﬂash

chromatography puriﬁcation (DCM to DCM/MeOH 2%) the title

compound was obtained (658 mg, 63%). ¹H NMR (CDCl₃, 300 MHz)

d

3.57 (s, 3H), 3.90 (s, 3H), 7.11 (d, J¼8.7 Hz, 2H), 7.47 (d, J¼9.0 Hz,

Prepared according to general procedure C from this amide

(257 mg, 0.310 mmol) and benzyl bromide (0.2 mL,1.67 mmol), after

ﬂash chromatography puriﬁcation (petrol to petrol/AcOEt 20%) the

title compound was obtained (235 mg, 82%). ¹H NMR and ¹³C NMR

2H), 7.94 (d, J¼8.7 Hz, 2H), 8.06 (d, J¼9.0 Hz, 2H). ¹³C NMR (CDCl₃,

75.5 MHz)

d 38.4 (CH₃), 52.6 (CH₃), 123.5 (CH), 126.8 (CH), 129.0

(Cq), 129.9 (CH), 131.2 (CH), 141.8 (Cq), 148.0 (Cq), 148.5 (Cq), 166.1

(Cq), 168.5 (Cq). IR (ﬁlm) 1720, 1655, 1523 cm^ꢁ1. HRMS calcd for

C₁₆H₁₄N₅O₂: 314.0897, found: 314.0899.

show a complex mixture of multiple conformers. IR (ﬁlm) 1645 cm^ꢁ1

.

HRMS calcd for C₆₀H₄₄N₄NaO₅: 923.3204, found: 923.3215.

4.3.65. tert-Butyl 4-(4-nitro-benzoylamino)benzoate S3. Prepared

according to general procedure A from tert-butyl 4-aminobenzoate

(1.04 g, 5.37 mmol) and 4-nitrobenzoyl chloride (960 mg,

5.17 mmol) the title compound was obtained without further

4.3.61. N-Methyl-N-(4-(N⁰-methyl-N⁰-(4-(N⁰⁰-methyl-N⁰⁰-(4-(N⁰⁰⁰-

benzyl-N⁰⁰⁰-phenyl)carbamoyl)-1-naphtyl)carbamoyl)-1-naphtyl)car-

bamoyl)-1-naphtyl-4-nitronapthamide 27a. Prepared according to

general procedure B from 26a (116 mg, 0.159 mmol) the amine was

obtained without further puriﬁcation (111 mg, quantitative). ¹H

NMR and ¹³C NMR show a mixture of multiple conformers. IR (ﬁlm)

1642, 1632 cm^ꢁ1. HRMS calcd for C₄₈H₃₉N₄O₃: 719.3032, found:

719.3017.

Prepared according to general procedure A from this amine

(133 mg, 0.185 mmol) and 4-nitro-1-naphthoyl chloride (52.0 mg,

0.221 mmol) the amide was obtained without further puriﬁcation

(130 mg, 76%). ¹H NMR and ¹³C NMR show mixture of multiple

conformers. IR (ﬁlm)1641,1633 cm^ꢁ1. HRMS calcd for C₅₉H₄₃N₅NaO₆:

940.3106, found: 940.3108.

Prepared according to general procedure C from this amide

(130 mg, 0.142 mmol) and methyl iodide (0.15 mL, 2.41 mmol), af-

ter ﬂash chromatography puriﬁcation (Petrol to AcOEt) the title

compound was obtained (70 mg, 53%). ¹H NMR and ¹³C NMR show

mixture of multiple conformers. IR (ﬁlm) 1643, 1588 cm^ꢁ1. HRMS

calcd for C₆₀H₄₅N₅NaO₆: 954.3262, found: 954.3258.

puriﬁcation (741 mg, 42%). ¹H NMR (DMSO-d₆, 300 MHz)

d

1.57 (s,

9H), 7.94 (s, 4H), 8.22 (d, J¼9.0 Hz, 2H), 8.40 (d, J¼9.0 Hz, 2H),10.87 (s,

1H).¹³C NMR (DMSO-d₆, 75.5 MHz)

28.5 (CH₃), 81.1 (Cq),120.3 (CH),

d

124.3 (CH), 127.3 (Cq), 130.1 (CH), 130.7 (CH), 140.9 (Cq), 143.5 (Cq),

150.0 (Cq), 165.0 (Cq), 165.3 (Cq). IR (ﬁlm) 3385, 1678, 1526, 1310,

1298 cm^ꢁ1. HRMS calcd for C₁₈H₁₈N₂O₅: 342.1210, found: 342.1213.

4.3.66. tert-Butyl 4-(N-methyl-N-(4-nitro-benzoyl)amino)benzoate

S4. Prepared according to general procedure C from S3 (700 mg,

2.05 mmol) and iodomethane (4.27 mL, 68.6 mmol) after ﬂash

chromatography puriﬁcation (DCM to DCM/MeOH 2%) the title

compound was obtained (697 mg, 96%). ¹H NMR (CDCl₃, 300 MHz)

d

1.56 (s, 9H), 3.53 (s, 3H), 7.09 (d, J¼8.7 Hz, 2H), 7.47 (d, J¼9.0 Hz,

2H), 7.87 (d, J¼8.7 Hz, 2H), 8.05 (d, J¼9.0 Hz, 2H). ¹³C NMR (CDCl₃,

75.5 MHz) d 28.3 (CH₃), 81.8 (Cq), 123.5 (CH), 126.6 (CH), 129.8 (CH),

131.0 (CH), 131.5 (Cq), 141.9 (Cq), 147.6 (Cq), 148.4 (Cq), 164.7 (Cq),

168.5 (Cq). IR (ﬁlm) 1711, 1650, 1524, 1368, 1347 cm^ꢁ1. HRMS calcd

for C₁₉H₂₁N₂O₅: 357.1445, found: 357.1452.

4.3.62. N-Benzyl-N-(4-(N⁰-benzyl-N⁰-(4-(N⁰⁰-benzyl-N⁰⁰-(4-(N⁰⁰⁰-ben-

zyl-N⁰⁰⁰-phenyl)carbamoyl)-1-naphtyl)carbamoyl)-1-naphtyl)carba-

moyl)-1-naphtyl-4-nitronapthamide 27b. Prepared according to

general procedure B from 26b (235 mg, 0.261 mmol) the amine was

obtained without further puriﬁcation (227 mg, quantitative). ¹H

NMR and ¹³C NMR show mixture of multiple conformers. IR (ﬁlm)

1642, 1632 cm^ꢁ1. HRMS calcd for C₆₀H₄₆N₄NaO₃: 893.3449, found:

893.3462.

4.3.67. 4-(N-Methyl-N-(4-nitro-benzoyl)amino)benzoic acid S5. To

a solution of S4 (103 mg, 0.289 mmol) in dry DCM (5 mL) at 0 ^ꢀC

TFA (1 mL) was added. The mixture was stirred at 0 ^ꢀC for 2.5 h. The

organics were removed under reduced pressure to yield S5 (87 mg,

quantitative). ¹H NMR (CDCl₃, 300 MHz)

d 3.59 (s, 3H), 7.19 (d,

J¼8.4 Hz, 2H), 7.47 (d, J¼8.7 Hz, 2H), 8.01 (d, J¼8.4 Hz, 2H), 8.08 (d,

J¼8.7 Hz, 2H), 8.37 (s, 1H). ¹³C NMR (CDCl₃, 75.5 MHz)

d 39.0 (CH₃),

Prepared according to general procedure A from this amine

(240 mg, 0.276 mmol) and 4-nitro-1-naphthoyl chloride (77.0 mg,

0.327 mmol) the amide was obtained without further puriﬁcation

(248 mg, 84%). ¹H NMR and ¹³C NMR show mixture of multiple

conformers. IR (ﬁlm) 1641,1630 cm^ꢁ1. MS (ESI^þ) 1093 (MþNa, 50),

1124 (MþNaþMeOH, 100).

123.9 (CH), 127.2 (CH), 128.3 (Cq), 129.8 (CH), 132.2 (CH), 140.2 (Cq),

148.1 (Cq), 148.9 (Cq), 170.6 (Cq), 170.9 (Cq).

Acknowledgements

We are grateful to the Leverhulme Trust and to the EU (Marie

Curie programme) for support of the work, to the EPSRC and

GlaxoSmithKline for a studentship (to AP), and to Gemma Roberts

for assistance with the synthesis of 8a⁰.

Prepared according to general procedure C from this amide

(248 mg, 0.232 mmol) and benzyl bromide (0.15 mL, 1.25 mmol),

after ﬂash chromatography puriﬁcation (petrol to AcOEt) the title

compound was obtained (61 mg, 23%). ¹H NMR and ¹³C NMR show

mixture of multiple conformers. IR (ﬁlm) 1647,1587 cm^ꢁ1. MS (ESI^þ)

1182 (MþNa).

Supplementary data

Supplementary data associated with this article can be found in

the online version, at doi:10.1016/j.tet.2010.06.037.

4.3.63. Methyl 4-(4-nitro-benzoylamino)benzoate S1. Prepared

according to general procedure A from methyl 4-aminobenzoate

(1.25 g, 8.26 mmol) and 4-nitrobenzoyl chloride (2.02 g, 10.9 mmol)

the title compound was obtained without further puriﬁcation

References and notes

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Article Doi

Conformational studies of tertiary oligo-m-benzanilides and oligo-p-benzanilides in solution

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