Palladium-catalyzed arylation of linear and cyclic polyamines

FULL PAPER

Palladium-Catalyzed Arylation of Linear and Cyclic Polyamines

Irina P. Beletskaya,*^[a]Alla G. Bessmertnykh,^[a]Alexei D. Averin,^[a]Franck Denat,^[b]and

Roger Guilard*^[b]

Keywords: Amines / Amination / Aromatic substitution / Homogeneous catalysis / Palladium

The palladium-catalyzed arylation of polyamines is investi-

gated and it is shown that the C−N coupling reaction for a

given substrate is strongly dependent on the nature and the

concentration of the catalytic system, as well as the nature of

the base employed. The arylation of the primary amino group

is favored when both primary and secondary amines are pre-

sent; selective arylation is then possible without using any

without any significant formation of diamino compounds or

reduced derivatives, unlike what is observed when mono-

amines are used. The extent of polyarylation of polyamines

as a function of the excess of aryl halide and the nature and

the amount of catalyst is also studied. Finally, N-arylation of

a macrocyclic tetraamine (cyclam) is performed by using an

appropriate catalytic system.

protecting group. The reaction of dihalobenzenes with poly- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,

amines gives the monoamination products in good yields

Germany, 2005)

Introduction

reactions of aryl halides.^[9]Procedures involving nitration

followed by hydrogenation are not tolerated by many func-

tional groups and are often complicated due to the need for

protection and deprotection steps. The direct nucleophilic

substitution of aryl halides is a synthetic route dedicated

only to substrates that contain electron-withdrawing

groups, including perfluorinated compounds,^[10,11]and

Ullmann-type substitution reactions occur at high tempera-

tures, giving generally diarylation products, and depend

strongly on the nature of the substrate substituents.^[12]

These drawbacks are limiting factors for the synthesis of

aryl-substituted polyamines, especially nonsymmetrical de-

rivatives, as multistep syntheses are often required to pre-

pare even simple species.^[13]An indirect method comprising

several steps has been published recently for the preparation

of N-aryl-1,2-ethanediamines.^[14]A real breakthrough in the

amination of aryl halides using palladium catalysis has been

achieved in recent years on the basis of innovative work

conducted by the groups of Buchwald and Hartwig.^[15]This

soon became the most convenient method due to its obvi-

ous advantages, i.e. a wide choice of possible amines and

substrates with various substituents, high yields, and, in

many cases, mild conditions reactions. Over 150 publi-

cations dedicated to this field of synthesis have been pub-

lished during the last five years; these bear witness to the

real and urgent demand for this new synthetic method.

Polyamines are attracting a considerable and constant

interest due to their widespread use in pharmacology,^[1,2]

coordination chemistry,^[3]and supramolecular chemistry.^[4]

Alkyl- and benzyl-substituted linear polyamines have been

investigated as polydentate ligands for complexing pal-

ladium,^[5]copper,^[6]and other metals,^[7]and as fluorescence

sensors for detecting a variety of transition metals like Ni,

Zn, Cd, and Pb.^[8]Linking an aromatic moiety directly to

the nitrogen atom of the polyamine may favor the electronic

interaction between the complexing site of the molecule and

the arene moiety, which should induce a measurable re-

sponse and change the sensing properties of such systems.

A major area of interest is the investigation of the influence

of the aryl substituent on the sensing properties of poly-

amines. Convenient synthetic routes to alkyl- and benzyl-

substituted polyamines have already been described, but

their arylated derivatives are not yet readily available.

For decades, the synthesis of arylamines was achieved by

three main methods: nitration of arenes followed by the re-

duction of the nitro group, direct nucleophilic substitution

of activated arenes, and copper-mediated (Ullmann-type)

[a]

Department of Chemistry, Lomonosov Moscow State

University,

Moscow, 119899, Russia

Fax: (internat.) ϩ7-095-939-3618

We have explored the possibility of applying this tech-

nique to polyamines. Polyamines are a special class of

amines that are capable of forming stable chelates with a

metal atom, although their use as substrates in these

reactions is not obvious since the probable formation of

chelates might hinder the catalytic process. Here we report

E-mail: beletska@org.chem.msu.su

[b]

´

Laboratoire d’Ingenierie Moleculaire pour la Separation et les

´

Applications des Gaz (LIMSAG UMR 5633), Universite de

´

Bourgogne, Faculte des Sciences ‘‘Gabriel’’,

6, Bd Gabriel, 21100 Dijon, France

Fax: (internat.) ϩ33-3-80-39-61-17

E-mail: Roger.Guilard@u-bourgogne.fr

Eur. J. Org. Chem. 2005, 261Ϫ280

DOI: 10.1002/ejoc.200400456

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I. P. Beletskaya, A. G. Bessmertnykh, A. D. Averin, F. Denat, R. Guilard

FULL PAPER

our results on selective mono-, di-, and polyarylation of

polyamines. Some of the results described below have been

reported previously.^[16]

Monoarylation of Linear Polyamines with p-Bromobiphenyl

Various linear polyamines with different chain lengths

and different numbers of nitrogen atoms were successfully

arylated under the conditions mentioned above by p-

bromobiphenyl (2c) to give corresponding arylamines

14Ϫ20 in good to high yields (Scheme 2, Table 2). PdCl₂/

dppf and three equivalents of the polyamine were em-

ployed.

The selective formation of monoarylated polyamines was

observed in all these reactions as well as selective arylation

of the primary amino groups. Slightly lower yields were ob-

served when ethane-1,2-diamine (1b) and its derivative N-

(2-aminoethyl)ethane-1,2-diamine (1c) were used. However,

unsymmetrical N-(2-aminoethyl)propane-1,3-diamine (1e)

afforded a 1:1 mixture of the regioisomers 17 and 18 in high

yield (Table 2, entry 4).

Results

Monoarylation of 1,3-Propanediamine

A variety of aryl bromides and aryl iodides bearing

substituents with different electronic properties have been

reacted with a model propane-1,3-diamine (1a) using

Hartwig’s PdCl₂/dppf [dppf

ϭ 1,1Ј-bis(diphenylphos-

phanyl)ferrocene] catalytic system (Scheme 1).

The coupling of aryl bromides with α- and β-carbon-sub-

stituted primary diamines was also investigated (Scheme 3).

C_β-substitution did not affect the rate of the reaction

since the product 21 was obtained in high yield (Table 3,

entry 1). C_α-substitution, however, induced many changes,

in particular a strong decrease of the reaction rate and

lower yields (Table 3, entries 2,3). Moreover, even if a three-

fold excess of the amine was employed, diarylation became

notable. The use of 1-bromonaphthalene (2l), which is more

reactive than p-bromobiphenyl (2c), resulted in a higher

yield and better regioselectivity; no diarylated product was

observed (Table 3, entry 3). The presence of one methyl

group at the α carbon atom makes the reaction regioselec-

tive (Table 3, entries 2 and 3), and a double substitution

gives a total selectivity (Table 3, entry 4). As expected, the

1,2-disubstituted cyclohexane-1,2-diamine (1k) proved to be

less active than the diamine 1i since both amine groups are

sterically hindered (Table 3, entry 5).

Scheme 1

In a typical experimental procedure, aryl halides 2aϪm

were reacted with three equivalents of propane-1,3-diamine

in the presence of 0.5Ϫ2 mol % of [PdCl₂(dppf)] and twice

as much free dppf ligand (i.e. 1Ϫ4 mol %). Sodium tert-

butoxide (2 equiv.) was employed as a base and the reaction

mixtures were refluxed until full completion of the reactions

(Table 1). The monoarylated diamines 3Ϫ13 were obtained

in good to excellent yields in most cases. The best results

were obtained with 1-bromonaphthalene (2l) and 9-bromo-

anthracene (2m), which afforded the corresponding arylated

diamines 12 and 13 in high yields. While unsubstituted

bromobenzene (2a) led to N-phenylpropane-1,3-diamine in

60% yield after refluxing for 100 h, the presence of electron-

withdrawing groups in the para position of the benzene ring

(2c, 2k) gave higher yields with shorter reaction times and

lower catalyst loadings. On the other hand, the presence

N-Arylated Cyclams

Cyclic tetraazamacrocycles, and especially 1,4,8,11-tetra-

of some other electron-withdrawing groups led to lower azacyclotetradecane (cyclam, 1l), are among the most

yields of the desired products. This is the case for the easily widely used and studied polyamine derivatives due to their

enolizable p-bromoacetophenone (2g) and p-bromo(tri- remarkable abilities to coordinate metal cations and their

fluoromethyl)benzene (2f) — probably sensitive to sodium wide industrial and medicinal applications. Thus, the de-

tert-butoxide — which afforded the N-arylated compounds mand exists to elaborate a straightforward access to its N-

in 21 and 53% yields, respectively. In the case of p-bromo- arylated derivatives. Secondary acyclic amines are known to

benzonitrile (2h), which gave only the amidine product with be versatile substrates for catalytic amination reactions.^[15b]

PdCl₂/dppf, the desired product 10 was isolated in 95% As has been demonstrated above, the secondary amino

yield when Pd(dba)₂/dppf was used as the catalyst. As ex- groups of linear polyamines are unreactive in the presence

pected, the use of less-reactive aryl bromides substituted by of primary amino groups. Although some cyclic secondary

electron-donor groups (2b,d,e) resulted in lower yields and amines were found to be reactive derivatives in the aromatic

required higher catalyst loadings. Nevertheless, the presence CϪN coupling, our investigations proved that cyclam is re-

of a donor methoxy group in the ortho position appeared markably inert towards arylation.

to be more favorable and led to a reasonable yield (41%) of

Numerous attempts to carry out the arylation of cyclam

the target product 7. Surprisingly, the use of aryl iodides were unsuccessful. Different combinations of the catalyst

(2i,j) did not result in a substantial advantage over aryl bro- precursors with supporting ligands were used in the reac-

mides in terms of yields, reaction times, and amounts of tions of cyclam with aryl halides (bromo- and iodo-substi-

catalyst (Table 1, entries 9, 10). Selective substitution of the tuted benzenes, 1-bromonaphthalene, 4-bromobiphenyl and

bromine atom was observed when the bromochloro deriva- 9-bromoanthracene): Pd(dba)₂, Pd(OAc)₂, PdCl₂, dppf, bi-

tive 2k was used as the starting material (Table 1, entry 11). nap, P(tBu)₃, PCy₃, P(o-tol)₃but none of them led to the

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Palladium-Catalyzed Arylation of Linear and Cyclic Polyamines

FULL PAPER

Table 1. Palladium-catalyzed reactions of aryl halides with 1,3-diaminopropane^[a]

^[a]NaOtBu was used as the base and dioxane as solvent. ^[b]Yields of isolated compounds based on aryl halides. ^[c]The product of N¹,N³-

diamination was observed by NMR spectroscopy (Ͻ 7%). ^[d]1.2 Equiv. of NaOtBu was used. ^[e][Pd₂(dba)₃]/dppf catalytic system was used.

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I. P. Beletskaya, A. G. Bessmertnykh, A. D. Averin, F. Denat, R. Guilard

Table 2. Palladium-catalyzed reactions of 4-bromobiphenyl with polyamines^[a]

FULL PAPER

[a]

[b]

NaOtBu was used as the base and dioxane as solvent. Yields of isolated compounds based on aryl halides.

hoped-for derivatives — we observed only full or partial

reduction of the aryl halides into the corresponding arenes.

However, the reaction of cyclam with p-bromobiphenyl (2c)

and p-bromobenzonitrile (2h) using Pd(dba)₂/PPF-OMe^[17]

as catalyst afforded the corresponding N-arylated deriva-

tives 30 and 31 in rather modest 20% yield (Scheme 4). This

success opens the way to the catalytic preparation of N-

arylated cyclams, which are, to date, very rare.^[11,18]

Scheme 2

Monoamination of Dihalobenzenes by Polyamines

We have applied the standard procedure used for the

arylation of linear polyamines with dihalobenzenes as the

arylating agents; haloaryl-substituted polyamines, which

may serve as valuable precursors in organic synthesis, are

the target derivatives (Scheme 5).

Scheme 3

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Palladium-Catalyzed Arylation of Linear and Cyclic Polyamines

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Table 3. Palladium-catalyzed reactions of aryl halides with polyamines^[a]

[a]

[b]

[c]

NaOtBu was used as the base and dioxane as solvent.

catalytic system was used.

Yields of isolated compounds based on aryl halides.

[Pd(dba)₂]/dppf

Scheme 5

Scheme 4

substituted polyamines were obtained in good to excellent

The standard procedure employed 2Ϫ4 mol % Pd(dba)₂yields (Table 4). The results obtained in this series of reac-

with 2Ϫ6 mol % dppf as a catalyst, NaOtBu (2 equiv.) as a tions closely resemble those described in the case of the

base, and a 3:1 polyamine to dihalobenzene ratio. Various amination of aryl halides (Table 1). Again, ethane-1,2-di-

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I. P. Beletskaya, A. G. Bessmertnykh, A. D. Averin, F. Denat, R. Guilard

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Table 4. Palladium-catalyzed reactions of aryl dihalides with polyamines^[a]

^[a]NaOtBu was used as the base and dioxane as solvent. ^[b]Yields of isolated compounds based on aryl halides. ^[c]A minor amount (8%)

[d]

[e]

of tetrahydrobenzodiazepine 57 (diamination product) was observed.

65% conversion of p-diiodobenzene. A minor amount (15%)

[f]

[g]

of tetrahydrobenzodiazepine 57 was also obtained. Cs₂CO₃was employed as the base.

reaction proceeds slowly to give the desired product in 50% yield together with 15% of 1-bromo-3-nitrobenzene and 16% of 1,4-dibromo-

In the absence of palladium catalyst the

[h]

2-nitrobenzene. 60% conversion of p-diiodobenzene.

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Palladium-Catalyzed Arylation of Linear and Cyclic Polyamines

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amine (1b) proved to be less reactive — the reaction led to the mono-, di-, and triarylated diamines 5, 46, 47, and 48

38 in only modest yield (Table 4, entry 8) — because poly- in high overall yields (87%; Table 5, entry 3). It is interesting

meric by-products were formed. p-Diiodobenzene appeared to note that replacement of the dppf ligand by binap led to

to be less efficient in the coupling — its conversion did not a highly selective reaction affording symmetrical diarylated

exceed 60Ϫ65% even with greater loadings of catalyst molecules 46, 49, and 50 in high yields (Table 5, entries

(Table 4, entries 5,12). A further increase of the amount of 4Ϫ6). The substituted diamine 1i appeared to be reluctant

catalyst favored the conversion but did not improve the to undergo diarylation (Table 5, entry 7), and neither the

yields of the target compounds. However, fully selective Pd/dppf nor the Pd/binap catalytic systems allowed us to

substitution of an iodine atom in the presence of a bromine avoid the formation of the monoarylated derivative 25.

atom (Table 4, entry 4), as well as of a bromine atom in the

Only monoarylation of primary amino groups has been

presence of a chlorine atom (Table 4, entry 6), was possible. discussed, although we also found that, with generous cata-

In the case of 1,4-dibromo-2-nitrobenzene (2t) selective lytic loadings and binap as a supporting ligand, arylation

substitution of the more-activated bromine atom took place of the secondary amino groups was also possible. Thus,

(Table 4, entry 7). As in the case of the previous experi- tetraarylated propane-1,3-diamine (51) and ethane-1,2-di-

ments, only the primary amino groups of the triamine 1d amine (52) were obtained in remarkable 95% yields

and the tetraamine 1f were selectively arylated (Table 4, (Table 5, entries 8,9), as well as the pentasubstituted tri-

entries 9Ϫ13).

amine 53 and the tetrasubstituted product 54. It is interesting

The reduction of the second halogen atom in the course to note that the reaction of the triamine 1d with four equiv-

of the amination of dihaloarenes is an usual side reaction. alents of p-bromobiphenyl resulted in the formation of a

Nevertheless, in the case of polyamines the reduced deriva- complex mixture of pentasubstituted 53, tetrasubstituted 54

tives were formed in much lower quantities than in the reac- and 55, and trisubstituted 56 triamines. The difference in

tions of dihalobenzenes with primary monoamines.^[16b]We the reactivity of both types (aliphatic and aniline-type) of

did not observe diamination of dihalobenzenes under these secondary amino groups present in the symmetrically diary-

conditions, which is not the case with secondary cyclic lated triamine 50 is significantly smaller than the difference

amines.^[19]When applied to substrates which contain more in the reactivity of the primary and secondary amino

than two bromine atoms, this reaction gave inseparable mix- groups in unsubstituted linear polyamines (Table 2).

tures of products.

Diamination of Dibromoarenes

Polyarylation of Polyamines

Previously published results on the diamination of di-

haloarenes deal mainly with secondary amines;^[19,20]the

main side-products were reported to be arylamines and

haloarylamines. We have described above (Table 4) the suc-

cessful monoamination of dihaloarenes by diamines with-

out reduction of the remaining halogen atom. Attempts to

conduct the double amination gave modest results: the reac-

tion of o-dibromobenzene (2p) with propane-1,3-diamine

(1a) required higher catalyst loadings and led to 75% yield

of a mixture of benzodiazepine (57), N-(2-bromophe-

nyl)propane-1,3-diamine (34), and N-phenylpropane-1,3-di-

amine (3) in a 1:1:1 ratio (Scheme 7).

The coupling of the same diamine 1a with m-dibromo-

benzene (2o) gave the desired diaminated product 58 in 23%

yield along with the reduced product 3 as the major com-

pound (Scheme 8). In both cases the substitution of the se-

cond bromine atom required prolonged heating, which may

also accelerate the reduction reaction. Indeed, independent

experiments revealed that heating the haloaryl diamines of

type 32Ϫ43 in the presence of the Pd catalyst resulted in a

slow formation of the reduction products.

The next step of our investigations was to find the appro-

priate conditions for di- and polyarylation of polyamines

(Scheme 6). The coupling of equimolar amounts of aryl

halides and polyamines led to different results depending

on the nature of the amine. Thus, the reaction of 1-bromo-

naphthalene with propane-1,3-diamine afforded a mixture

of mono- and diarylated products in a 14:1 ratio, which is

close to the ratio obtained with a threefold excess of the

diamine (18:1). However, in the case of N-(3-aminopropyl)-

propane-1,3-diamine the reaction with an equimolar

amount of the same bromide led to a 2:1 ratio of mono-

and diarylated compounds.

Scheme 6

Amination of Aryl Chlorides by Polyamines

Selective diarylation of polyamines was carried out suc-

Amination of aryl chlorides has been the topic of several

cessfully with the active 1-bromonaphthalene (2l) by using recent surveys.^[15a,15d,21]In a previous study we have found,

two equivalents of aryl halide (Table 5, entries 1,2), the cor- from many examples, that 1-bromonaphthalene is more re-

responding products 44 and 45 being obtained in excellent active in the amination coupling than p-bromobiphenyl.

yields (88Ϫ92%). Less-active p-bromobiphenyl (2c) re- Taking into account this observation, we decided to use 1-

quired a higher catalyst loading and provided a mixture of chloronaphthalene (2v) in the amination reaction with pro-

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I. P. Beletskaya, A. G. Bessmertnykh, A. D. Averin, F. Denat, R. Guilard

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Table 5. Palladium-catalyzed polyarylation of polyamines^[a]

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Palladium-Catalyzed Arylation of Linear and Cyclic Polyamines

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Table 5. (continued)

[a]

[b]

[c]

NaOtBu was used as the base and dioxane as solvent. Yields of isolated compounds based on aryl halides. [Pd(dba)₂]/dppf was

[d]

used as the catalytic system. [Pd(dba)₂]/binap was used as the catalytic system.

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I. P. Beletskaya, A. G. Bessmertnykh, A. D. Averin, F. Denat, R. Guilard

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diarylated products 12 and 44 in 83% total yield (Table 6,

entry 1). A lower selectivity of monoarylation is observed

when compared to the results obtained with 1-bromonaph-

thalene (Table 1, entry 12). This may be ascribed to the

lower reactivity of 2v, which requires a longer reaction time

and a greater amount of catalyst. The pure diarylated prod-

uct was obtained when 2.2 equivalents of aryl chloride were

used, and the target compound 44 was obtained in 84%

yield (Scheme 9, Table 6, entry 2).

Scheme 7

Scheme 9

It is clear that dppf is less efficient than binap in this

coupling reaction. The reaction of less-reactive p-chlorotol-

uene (2w) was also successful and produced the correspond-

ing product 4 in 31% yield. These results encouraged us to

use a monoamine in the coupling reaction with aryl chlo-

ride. The reaction of 1-chloronaphthalene (2v) with an ex-

Scheme 8

pane-1,3-diamine. The most efficient ligand for this purpose cess of n-hexylamine (1m) gave the corresponding 1-(N-hex-

proved to be binap, and a standard procedure with a three- yl)naphthylamine (59) in 76% yield (Table 6, entry 5). An

fold excess of amine afforded a 5:1 mixture of mono- and important feature of aryl chlorides is that they undergo re-

Table 6. Palladium-catalyzed reactions of aryl chlorides with polyamines^[a]

[a]

[b]

[c]

NaOtBu was used as the base and dioxane as solvent. Reported yields correspond to isolated compounds based on aryl halides.

60% conversion of o-dichlorobenzene.

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Palladium-Catalyzed Arylation of Linear and Cyclic Polyamines

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duction to arenes at a lower rate than the corresponding (77% with NaOtBu). Sodium carbonate was not efficient,

aryl bromides. Thus, the reaction of o-dichlorobenzene (2x) possibly due to its lower solubility in dioxane compared to

with propane-1,3-diamine gave the product 36 in 53% yield. that of cesium carbonate.

The substitution of chlorine was also observed in the reac-

tion of 1-bromo-2,6-dichlorobenzene (2u) with the same di-

amine. Indeed, the first step was the nucleophilic substi-

tution of the bromine atom, followed by chlorine substi-

tution and cyclization to give 6-chloro-2,3,4,5-tetrahydro-

1H-1,5-benzodiazepine (60) and N-(2,6-dichlorophe-

nyl)propane-1,3-diamine (61) as an 8:1 mixture in 80%

yield (Scheme 10).

The key factors acting on the CϪN coupling mentioned

above were observed for both mono- and polyamines, al-

though some particularities of the coupling of aryl halides

with polyamines have to be considered. For example, polya-

mines could have acted as strong chelating molecules

towards zero-valent palladium, thus diminishing its cata-

lytic activity. Fortunately this was not the case, and the

existence of intramolecular hydrogen bonds in polyamines

(structure A) probably explains why no stable chelates with

Pd⁰are formed; the chelating ligands in the catalytic process

during the oxidative-addition step are bidentate phosphorus

compounds such as dppf, or binap. The reaction of the un-

symmetrical triamine 1e with 2c, which led to an equimolar

mixture of the two regioisomers 17 and 18 (Table 2), also

supports the idea that no polyamine chelates are formed

during the catalytic cycle corresponding to oxidative ad-

dition. Indeed, intermediate five- and six-membered che-

lates would certainly produce two regioisomers in different

quantities due to their different stability.

Scheme 10

The synthesis of diaminoanthracenes and diami-

noanthraquinones starting from dichloro derivatives and

using a Pd catalyst will be published elsewhere.^[22]

Discussion

The experiments concerning the selective monoarylation

of propane-1,3-diamine (1a) with an equivalent amount

of 2c, as well as with perfluorinated aryl halides,^[11]show

that the second primary amino group is less reactive in the

arylation process. This may be explained by the fact that

the existing intramolecular hydrogen bond in the diamine

becomes stronger in the monoarylated derivative due to the

difference of the basicity of the two nitrogen atoms (struc-

ture B). The nitrogen atom of the remaining primary amino

group coordinates the hydrogen atom more strongly and its

participation in arylation reaction is therefore not favored.

Diarylation becomes possible either with the most active

aryl halides or in the presence of higher catalyst loadings.

Even exhaustive arylation, which leads to the formation of

tetra- and pentasubstituted diamines and triamines, is pos-

sible under these conditions (Table 5).

There are still some common features of the reactions of

polyamines with aryl halides which have to be reasonably

explained: a) the better efficiency of binap over dppf for the

selective di- and polyarylation of polyamines; b) the poorer

selectivity of less-reactive aryl halides (like p-bromobiphe-

nyl or 1-chloronaphthalene vs. 1-bromonaphthalene); and

c) the decrease of the selectivity of monoarylation with

higher catalyst loadings.

The compilation of a large amount of material dealing

with the arylation of polyamines by aryl halides leads us to

some general and distinctive features when different combi-

nations of starting molecules are used. The main character-

istic of all the studied reactions is the high selectivity for

the arylation of primary amino groups in the presence of

secondary amino groups, which is consistent with previous

results reported by Senanayake.^[23]Moreover, the selective

monoarylation of di- and polyamines proceeds smoothly

and no di- and polyarylation or reduction reactions are ob-

served. However, an appropriate catalytic system has to be

chosen for a given combination of aryl halide and poly-

amine in order to obtain the target product in the highest

yield. The amount of catalyst employed in the coupling is

strongly dependent on the nature of the starting com-

pounds — an excess of supporting ligand increases the yield

only in a few cases. Another important factor is the nature

of the base employed. Sodium tert-butoxide proved to be

efficient in all cases except when aryl halides containing

substituents sensitive to this strong base were used; cesium

carbonate was employed successfully in these latter cases.

Surprisingly, sodium hydroxide could also be used as a base

in this coupling reaction, alhtough lower yields were ob-

served; for example, the reaction of the triamine 1d with p-

The mechanism of the amination reaction is one of the

bromobiphenyl (2c) in the presence of sodium hydroxide most complicated among Pd-catalyzed carbonϪcarbon and

afforded the product 16 in a relatively moderate 53% yield carbonϪelement bond-formation processes. The currently

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I. P. Beletskaya, A. G. Bessmertnykh, A. D. Averin, F. Denat, R. Guilard

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accepted mechanism for the arylation of amines is pre- with p-dibromobenzene leads exclusively to the correspond-

sented in Scheme 11.^[15aϪ15c]

ing reduced product N-hexylaniline 62 (Scheme 12).

Scheme 12

A possible explanation may be as follows. We fully agree

with Hartwig’s opinion that the formation of the arene side-

product is due not only to the competing reductive elimi-

nation and β-hydride elimination,^[24d]but also to other re-

duction pathways. We suppose that dihaloarenes are es-

pecially prone to undergo reduction because the electron-

donating amino group hinders the second amination, and

that the prolonged heating required leads to reduction by

the excess of amine. The formation of the reduced product

could occur not only from the amidopalladium complex D,

but also from the amino, bisamino, and amino-amidopalla-

dium complexes C, E, and F respectively (Scheme 11). We

suppose that the formation of such complexes in the case

of polyamines includes substitution of one phosphorus

atom of the chelate phosphane by the second amino group

coordinated to palladium. While a PdϪP bond is stronger

than a PdϪN bond, this process is nevertheless possible, as

shown by Buchwald in the reaction of [ArPdX{P(o-tol)₃}]

with an excess of amine;^[25]formation of a complex contain-

ing two amines was observed. In our case this process is

favored by the formation of five- or six-membered chelates.

According to the hypothesis formulated by Whitesides,^[26]

β-hydride elimination from such chelate complexes is

thermodynamically unfavorable.

Scheme 11

It includes the following steps: (a) formation of the active

catalytic species, (b) oxidative addition of the aryl halide,

(c) coordination of the amine, (d) deprotonation, and (e)

reductive elimination of the product. Although detailed

mechanistic studies have been undertaken,^[24,25]several ex-

perimental results are not yet entirely clear. For example,

so far there is no exhaustive explanation of the influence of

the ligand nature and concentration, or the applicability of

a weak base like cesium carbonate. The true mechanism of

the competing reduction of the aryl halide to an arene is

also not clear, nor is the enhanced reduction of the second

halogen atom in the course of diamination of dihaloarenes.

Full information is also lacking concerning the com-

plexation with amine, the dissociation of the bidentate li-

gand in the catalytic cycle, and the coordination state of

palladium. Also the possible exchange of halogen by an al-

koxide group remains unclear. Many of these questions

have been discussed frequently in the literature but some

answers are still missing. The use of polyamines instead of

monoamines in the amination of aryl halides certainly can-

not be regarded as a convenient tool to solve some existing

mechanistical problems, but, nevertheless, we believe that

some particular features which make polyamines advan-

tageous over monoamines can be clarified. One of these

peculiarities is a dramatic decrease in the formation of the

arene by-product, which is the main side-reaction in the

amination reaction. As has already been demonstrated

(Table 4), polyamines form the corresponding haloaryl-sub-

stituted derivatives in good to excellent yields, while the re-

duction side-reaction of the remaining halogen atom is in-

Conclusion

In conclusion, the palladium-catalyzed arylation of poly-

amines has been shown to be a convenient one-pot pro-

cedure for the selective introduction of one or several aryl

moieties in polyamines without using any protecting

groups. This method is applicable for a wide range of poly-

amines.

Experimental Section

1

General Remarks: H and ¹³C NMR spectra were recorded at 200

and 50 MHz, respectively, on a Bruker AM200 spectrometer and

referenced to the residual protons of the deuterated solvent. Infra-

red spectroscopy was carried out on a PerkinϪElmer 1600 Series

FT-IR spectrometer. Elemental analyses were performed with a Fi-

sons EA 1108 CHNS. Gas chromatographic analyses were carried

out on a HewlettϪPackard HP-5890 Series II gas chromatograph

fitted with an HP-1 capillary column (25 m, 0.20 mm, 0.11 mm).

Thin-layer chromatography was carried out on E. Merck Silica Gel

significant. On the contrary, the reaction of n-hexylamine 60F-254 TLC plates.

Eur. J. Org. Chem. 2005, 261Ϫ280

Palladium-Catalyzed Arylation of Linear and Cyclic Polyamines

FULL PAPER

Reactions under argon atmosphere were carried out using standard

Schlenk techniques. All reagents were used directly as obtained

commercially, unless otherwise noted. Dioxane was distilled under

argon from sodium benzophenone ketyl. 1,8-Dichloroanthraqui-

none was purchased from Acros Chemical Co. Sodium tert-butox-

ide was purchased from Aldrich Chemical Co. and stored under

nitrogen. Small amounts were taken as needed, stored in a Schlenk

tube for up to two weeks, and quickly weighed in the air. Propane-

1,3-diamine (1a), ethane-1,2-diamine (1b), N-(2-aminoethyl)ethane-

1,2-diamine (1c), N-(3-aminopropyl)propane-1,3-diamine (1d), N-

(2-aminoethyl)propane-1,3-diamine (1e), N¹-2-[(3-aminopropyl)a-

mino]ethylpropane-1,3-diamine (1f), N¹-(3-aminopropyl)-N¹-meth-

ylpropane-1,3-diamine (1g), 2,2-dimethylpropane-1,3-diamine (1h),

1,2-propanediamine (1i), 2-methyl-1,2-propanediamine (1j), trans-

1,2-diaminocyclohexane (1k), bromobenzene (2a), 4-bromotoluene

(2b), 4-bromobiphenyl (2c), p-bromoanisole (2d), o-bromoanisole

(2e), 1-bromo-4-(trifluoromethyl)benzene (2f), 4-bromoaceto-

phenone (2g), 4-bromobenzonitrile (2h), iodobenzene (2i), 4-iodo-

toluene (2j), 4-bromo-4Ј-chlorobenzophenone (2k), 1-bromonaph-

thalene (2l), 9-bromoanthracene (2m), o-dibromobenzene (2n), m-

dibromobenzene (2o), p-dibromobenzene (2p), 4-bromo-1-iodoben-

zene (2q), p-diiodobenzene (2r), o-bromochlorobenzene (2s), 1,4-

dibromo-3-nitrobenzene (2t), 1-bromo-2,6-dichlorobenzene (2u), 1-

chloronaphthalene (2v), 4-chlorotoluene (2w), o-dichlorobenzene

(2x), [PdCl₂(dppf)], dppf, and PPF-OMe were purchased from Ald-

rich Chemical Co.; binap was purchased from Strem Chemical

Company and used as supplied. Pd(dba)₂and [Pd₂(dba)₃]·CHCl₃

were synthesized by a literature procedure.^[27]Cyclam (1l) was also

synthesized by a literature procedure.^[28]

H), 3.17 (t, J ϭ 6.6 Hz, 2 H), 6.52 (AAЈ, J ϭ 8.3 Hz, 2 H), 6.96

(BBЈ, J ϭ 8.9 Hz, 2 H) ppm. ¹³C NMR (CDCl₃): δ ϭ 20.9 (1 C),

33.6 (1 C), 40.9 (1 C), 42.9 (1 C), 113.5 (2 C), 126.9 (1 C), 130.3 (2

C), 146.8 (1 C) ppm. IR (KBr): ν˜ ϭ 3317 cm^Ϫ1, 1617, 1523, 1303,

1123, 804. MS (EI): m/z ϭ 165 (5), 164 (40) [M^ϩ], 140 (17), 132

(22), 120 (100), 107 (27), 91 (24), 77 (13).

N¹-[(1,1Ј-Biphenyl)-4-yl]propane-1,3-diamine (5): See Table 1, entry

3. The reaction mixture was chromatographed with CH₂Cl₂and

then with CH₂Cl₂/CH₃OH/NH₃(10:3:1) to yield a white solid. M.p.

72Ϫ76 °C. Yield: 170 mg (75%). ¹H NMR [CD₃OD ϩ NH₃(1

drop)]: δ ϭ 2.08 (q, J ϭ 6.8 Hz, 2 H), 3.07 (t, J ϭ 7.2 Hz, 2 H),

3.47 (t, J ϭ 6.8 Hz, 2 H), 7.02 (d, J ϭ 8.8 Hz, 2 H), 7.47 (t, J ϭ

8.8 Hz, 1 H), 7.71 (m, 6 H) ppm; NH signals are not given. ¹³C

NMR [CD₃OD ϩ NH₃(1 drop)]: δ ϭ 32.6 (1 C), 39.9 (1 C), 42.0

(1 C), 113.8 (2 C), 126.6 (3 C), 128.2 (2 C), 129.3 (2 C), 130.3 (1

C), 142.0 (1 C), 149.1 (1 C) ppm. IR (KBr): ν˜ ϭ 3419 cm^Ϫ1, 3267,

1611, 824, 764. MS (EI): m/z ϭ 227 (17), 226 (100) [M^ϩ], 209 (11),

208 (18), 196 (12), 183 (16), 182 (91), 169 (46), 154 (13), 153 (17),

152 (40), 141 (13), 115 (15). C₁₅H₁₈N₂(226.32): calcd. C 79.61, H

8.02, N 12.38; found C 79.41, H 8.03, N 12.14.

N¹-(4-Methoxyphenyl)propane-1,3-diamine (6):^[30]See Table 1, entry

4. The reaction mixture was chromatographed with CH₂Cl₂and

then with CH₂Cl₂/CH₃OH/NH₃(4:2:1) to yield a brown oil. Yield:

34 mg (19%). ¹H NMR (CDCl₃): δ ϭ 1.73 (q, J ϭ 6.8 Hz, 2 H),

2.81 (t, J ϭ 6.8 Hz, 2 H), 3.03 (t, J ϭ 6.6 Hz, 2 H), 3.66 (s, 3 H),

4.05 (br. s, 3 H), 6.52 (AAЈ, J ϭ 9.0 Hz, 2 H), 6.70 (BBЈ, J ϭ

9.0 Hz, 2 H) ppm. ¹³C NMR (CDCl₃): δ ϭ 31.9 (1 C), 40.2 (1 C),

43.3 (1 C), 56.4 (1 C), 114.9 (2 C), 115.5 (2 C), 143.3 (1 C), 152.7

(1 C) ppm. MS (EI): m/z ϭ 181 (5), 180 (43) [M^ϩ], 162 (9), 148

(13), 137 (10), 136 (100), 134 (10), 123 (28), 122 (10), 121 (14), 120

(10), 107 (22). C₁₀H₁₆N₂O·0.33CH₂Cl₂(180.25·0.33CH₂Cl₂): calcd.

C 59.58, H 8.07, N 13.46; found C 60.09, H 8.04, N 13.10.

General Procedure for the Palladium-Catalyzed Monoarylation of

Polyamines using the [PdCl₂(dppf)]/dppf Catalytic System: Dioxane

(10 mL), the indicated amount of [PdCl₂(dppf)] with dppf ligand,

and the amine (3 mmol) were added to an argon-flushed, two-

necked flask and stirred for 2 min. The aryl halide (1 mmol) and

sodium tert-butoxide (2 mmol) were then added to the reaction

mixture. The vial was flushed with argon and the mixture was re-

fluxed whilst stirring. After the indicated period of time the mixture

was cooled down to room temperature, 1 mL of water was added,

and the reaction mixture was concentrated under reduced pressure.

The residue was taken up with CH₂Cl₂and the product was ex-

tracted from the organic layer with aqueous HCl (ca. 10%). After

addition of NaOH aqueous solution until pH 12, the product was

extracted with CH₂Cl₂. The organic layers were dried over anhy-

drous Na₂SO₄and the solvents evaporated in vacuo. The crude

material was purified by column chromatography on silica gel. The

following compounds were prepared by the described procedure,

and the results are summarized in Tables 1Ϫ3.

N¹-(2-Methoxyphenyl)propane-1,3-diamine (7): See Table 1, entry 5.

The reaction mixture was chromatographed with CH₂Cl₂and then

with CH₂Cl₂/CH₃OH/NH₃(12:4:1) to yield a brown oil. Yield:

74 mg (41%). ¹H NMR (CDCl₃): δ ϭ 1.77 (br. q, J ϭ 6.6 Hz, 2 H),

2.81 (br. t, J ϭ 6.6 Hz, 2 H), 3.17 (br. t, J ϭ 6.6 Hz, 2 H), 3.81 (s,

3 H), 6.71 (m, 4 H) ppm; NH signals are not given. ¹³C NMR

(CDCl₃): δ ϭ 33.6 (1 C), 40.7 (1 C), 42.1 (1 C), 56.0 (1 C), 110.0

(1 C), 110.4 (1 C), 116.9 (1 C), 121.9 (1 C), 139.0 (1 C), 147.4 (1

C) ppm. MS (EI): m/z ϭ 181 (7), 180 (59) [M^ϩ], 162 (12), 133

(17), 132 (15), 136 (100), 131 (15), 123 (54), 121 (58), 120 (72).

C₁₀H₁₆N₂O·0.33CH₃OH (180.25·0.33CH₃OH): calcd. C 65.00, H

9.15, N 14.67; found C 65.27, H 8.66, N 15.13.

N¹-[4-(Trifluoromethyl)phenyl]propane-1,3-diamine (8): See Table 1,

entry 6. The reaction mixture was chromatographed with CH₂Cl₂

and then with CH₂Cl₂/CH₃OH/NH₃(12:4:1) to yield a yellow solid.

N¹-Phenylpropane-1,3-diamine^[29](3): See Table 1, entries 1 and 9.

The reaction mixture was chromatographed with CH₂Cl₂and then

with CH₂Cl₂/CH₃OH/NH₃(10:3:1) to yield a yellow oil. Yield:

1

Yield: 116 mg (53%). H NMR (CDCl₃): δ ϭ 1.67 (q, J ϭ 6.6 Hz,

2 H), 1.94 (br. s, 2 H), 2.76 (t, J ϭ 6.6 Hz, 2 H), 3.11 (t, J ϭ 6.6 Hz,

2 H), 4.73 (br. s, 1 H), 6.53 (AAЈ, J ϭ 8.4 Hz, 2 H), 7.34 (BBЈ, J ϭ

8.4 Hz, 2 H) ppm. ¹³C NMR (CDCl₃): δ ϭ 32.8 (1 C), 40.9 (1 C),

42.5 (1 C), 112.3 (2 C), 118.4 (q, J ϭ 33 Hz, 1 C), 125.9 (q, J ϭ

273 Hz, 1 C), 127.2 (br. s, 2 C), 151.7 (1 C) ppm. IR (KBr): ν˜ ϭ

3406 cm^Ϫ1, 3326, 1620, 1331, 1066, 823. MS (EI): m/z ϭ 219 (5),

218 (37) [M^ϩ], 201 (53), 200 (49), 199 (12), 188 (9), 175 (13), 174

(100), 172 (25), 161 (14), 145 (30), 132 (12), 127 (13).

C₁₀H₁₃F₃N₂·H₂O (218.22·H₂O): calcd. C 50.82, H 6.40, N 11.86;

found C 51.01, H 5.57, N 11.50.

1

90 mg (60%). H NMR (CDCl₃): δ ϭ 1.98 (br. m, 2 H), 2.82 (br.

t, J ϭ 8.4 Hz, 2 H), 3.39 (br. t, J ϭ 8.4 Hz, 2 H), 6.62 (d, J ϭ

8.4 Hz, 2 H), 7.37 (m, 1 H), 7.88 (m, 2 H) ppm; NH signals are

not given. ¹³C NMR (CDCl₃): δ ϭ 33.9 (1 C), 41.1 (1 C), 42.9 (1

C), 113.6 (2 C), 117.9 (1 C), 129.9 (2 C), 149.5 (1 C) ppm. MS (EI):

m/z ϭ 151 (4), 150 (35) [M^ϩ], 133 (27), 132 (37), 120 (10), 118 (8),

107 (11), 106 (100), 104 (15), 93 (25), 77 (35).

N¹-(4-Methylphenyl)propane-1,3-diamine^[30](4): See Table 1, entries

2 and 10. The reaction mixture was chromatographed with CH₂Cl₂

and then with CH₂Cl₂/CH₃OH/NH₃(12:4:1) to yield a yellow oil. 1-[4-(3-Aminopropyl)aminophenyl]ethanone (9): See Table 1, entry 7.

Yield: 84 mg (51%). ¹H NMR (CDCl₃): δ ϭ 1.73 (q, J ϭ 6.8 Hz, 2 The reaction mixture was chromatographed with CH₂Cl₂and then

H), 2.21 (s, 3 H), 2.81 (t, J ϭ 6.6 Hz, 2 H), 2.85 (s, 2 H), 2.92 (s, 1 with CH₂Cl₂/CH₃OH/NH₃(12:4:1) to yield an orange solid. M.p.

Eur. J. Org. Chem. 2005, 261Ϫ280

www.eurjoc.org

273

I. P. Beletskaya, A. G. Bessmertnykh, A. D. Averin, F. Denat, R. Guilard

FULL PAPER

1

80 to 82 °C. Yield: 40 mg (21%). H NMR (CDCl₃): δ ϭ 1.47 (br. 136 mg (64%). H NMR (CDCl₃): δ ϭ 1.41 (br. s, 2 H), 2.95 (br.

s, 2 H), 1.73 (q, J ϭ 6.6 Hz, 2 H), 2.45 (s, 3 H), 2.82 (t, J ϭ 6.6 Hz, t, J ϭ 5.8 Hz, 2 H), 3.21 (br. t, J ϭ 5.8 Hz, 2 H), 4.20 (br. s, 1 H),

2 H), 3.21 (br. m, 2 H), 4.92 (br. s, 1 H), 6.51 (d, J ϭ 8.8 Hz, 2 H),

7.79 (d, J ϭ 8.8 Hz, 2 H) ppm. ¹³C NMR (CDCl₃): δ ϭ 26.6 (1 C), H) ppm. ¹³C NMR (CDCl₃): δ ϭ 41.9 (1 C), 47.2 (1 C), 113.9 (2

32.8 (1 C), 40.8 (1 C), 42.2 (1 C), 111.8 (2 C), 131.5 (2 C), 131.8 (1 C), 126.9 (1 C), 127.0 (2 C), 128.6 (2 C), 129.4 (2 C), 130.9 (1 C),

C), 153.3 (1 C), 197.0 (1 C) ppm. IR (KBr): ν˜ ϭ 3356 cm^Ϫ1, 3027, 141.9 (1 C), 148.6 (1 C) ppm. IR (KBr): ν˜ ϭ 3380 cm^Ϫ1, 3226,

6.71 (d, J ϭ 10 Hz, 2 H), 7.26 (m, 1 H), 7.44 (m, 4 H), 7.56 (m, 2

1665, 1598, 1477, 1426, 1307, 1281, 1179, 824. MS (EI): m/z ϭ 193

1610, 1531, 1494, 1475, 771. MS (EI): m/z ϭ 170 (14), 169 (100),

(7), 192 (50) [M^ϩ], 175 (32), 174 (16), 160 (61), 148 (100), 146 (13), 168 (24), 167 (14), 152 (3), 141 (8), 139 (5), 115 (9).

136 (33), 132 (48), 120 (36), 119 (14), 106 (22), 105 (28), 104 (12),

N¹-(2-Aminoethyl)-N²-[(1,1Ј-biphenyl)-4-yl]ethane-1,2-diamine (15):

91 (19).

See Table 2, entry 2. The reaction mixture was chromatographed

4-[(3-Aminopropyl)amino]benzonitrile (10): See Table 1, entry 8. The

reaction mixture was chromatographed with CH₂Cl₂and then with

with CH₂Cl₂and then with CH₂Cl₂/CH₃OH/NH₃(2:2:1) to yield

1

a white solid. M.p. 145 to 150 °C. Yield: 166 mg (65%). H NMR

CH₂Cl₂/CH₃OH/NH₃(10:3:1) to yield a yellow oil. Yield: 166 mg

(CDCl₃): δ ϭ 1.73 (br. s, 3 H), 2.66 (m, 2 H), 2.75 (m, 2 H), 2.85

1

(95%). H NMR (CDCl₃): δ ϭ 1.43 (br. s, 2 H), 1.56 (br. m, 2 H),

(m, 2 H), 3.21 (m, 2 H), 4.40 (br. s, 1 H), 6.70 (d, J ϭ 8.6 Hz, 2

2.78 (br. s, 2 H), 3.14 (br. s, 2 H), 5.22 (br. s, 1 H), 6.47 (d, J ϭ

H), 7.28 (m, 1 H), 7.43 (m, 4 H), 7.57 (m, 2 H) ppm. ¹³C NMR

8.6 Hz, 2 H), 7.30 (d, J ϭ 8.6 Hz, 2 H) ppm. ¹³C NMR (CDCl₃):

(CDCl₃): δ ϭ 42.4 (1 C), 44.2 (1 C), 49.2 (1 C), 52.8 (1 C), 113.9

δ ϭ 31.7 (1 C), 40.1 (1 C), 41.5 (1 C), 97.3 (1 C), 111.9 (2 C), 120.8

(1 C), 133.5 (2 C), 151.7 (1 C) ppm.

(2 C), 126.7 (1 C), 126.9 (2 C), 128.6 (2 C), 129.4 (2 C), 130.7 (1

C), 141.9 (1 C), 148.7 (1 C) ppm. IR (KBr): ν˜ ϭ 3380 cm^Ϫ1, 2930,

1608, 1531, 1303, 1183, 826. MS (EI): m/z ϭ 256 (5), 255 (19) [M^ϩ],

4-[(3-Aminopropyl)amino]phenyl(4-chlorophenyl)methanone

(11):

196 (27), 195 (41), 183 (100), 182 (96), 181 (16), 154 (15), 153 (21),

152 (59), 151 (14), 141 (14), 115 (16), 73 (86). C₁₆H₂₁N₃·0.5CHCl₃

(255.18·0.5CHCl₃): calcd. C 64.88, H 7.51, N, 12.28; found C 65.09,

H 7.80, N 12.24.

See Table 1, entry 11. The reaction mixture was chromatographed

with CH₂Cl₂and then with CH₂Cl₂/CH₃OH/NH₃(12:4:1) to yield

a yellow oil. Yield: 221 mg (77%). H NMR (CDCl₃): δ ϭ 1.79 (q,

1

J ϭ 6.6 Hz, 2 H), 2.24 (br. s, 2 H), 2.89 (t, J ϭ 6.4 Hz, 2 H), 3.26

(t, J ϭ 6.6 Hz, 2 H), 5.10 (br. s, 1 H), 6.54 (d, J ϭ 8.6 Hz, 2 H),

7.38 (d, J ϭ 8.6 Hz, 2 H), 7.64 (m, 4 H) ppm. ¹³C NMR (CDCl₃):

δ ϭ 32.6 (1 C), 40.8 (1 C), 42.2 (1 C), 111.8 (2 C), 125.5 (1 C),

129.0 (2 C), 131.6 (2 C), 133.6 (2 C), 137.9 (1 C), 138.2 (1 C), 153.4

(1 C), 194.4 (1 C) ppm. MS (EI): m/z ϭ 290 (20), 289 (12), 288

(56) [M^ϩ], 271 (40), 244 (90), 232 (37), 180 (7), 160 (31), 141 (33),

139 (100), 132 (58). C₁₆H₁₇ClN₂O·CHCl₃(288.10·CHCl₃): calcd. C

59.71, H 8.53, N 5.39; found C 59.10, H 9.01, N 5.32.

N¹-(3-Aminopropyl)-N³-[(1,1Ј-biphenyl)-4-yl]propane-1,3-diamine

(16): See Table 2, entry 3. The reaction mixture was chromato-

graphed with CH₂Cl₂and then with CH₂Cl₂/CH₃OH/NH₃(2:1:1)

to yield a creamy white solid. Yield: 218 mg (77%). ¹H NMR

(CDCl₃): δ ϭ 1.61 (br. q, J ϭ 6.8 Hz, 2 H), 1.78 (br. q, J ϭ 6.4 Hz,

2 H), 2.68 (m, 6 H), 3.19 (br. t, J ϭ 6.4 Hz, 2 H), 6.66 (d, J ϭ

8.4 Hz, 2 H), 7.28 (m, 1 H), 7.39 (m, 4 H), 7.56 (m, 2 H) ppm; NH

signals are not given. ¹³C NMR (CDCl₃): δ ϭ 30.0 (1 C), 34.3 (1

C), 41.2 (1 C), 43.6 (1 C), 48.6 (1 C), 49.2 (1 C), 113.6 (2 C), 126.7

(1 C), 126.9 (2 C), 128.6 (2 C), 129.4 (2 C), 130.4 (1 C), 142.0 (1

C), 148.8 (1 C) ppm. IR (KBr): ν˜ ϭ 3359 cm^Ϫ1, 1612, 1560, 1528,

1489, 1323, 826. MS (EI): m/z ϭ 284 (30), 283 (100) [M^ϩ], 209 (38),

196 (29), 183 (21), 182 (68), 169 (52), 152 (34), 84 (45), 71 (35).

N¹-Naphthalen-1-ylpropane-1,3-diamine (12): See Table 1, entry 12.

The reaction mixture was chromatographed with CH₂Cl₂and then

with CH₂Cl₂/CH₃OH/NH₃(12:4:1) to yield a white solid. M.p.

1

95Ϫ98 °C. Yield: 178 mg (89%). H NMR (CDCl₃): δ ϭ 1.87 (q,

J ϭ 6.4 Hz, 2 H), 2.92 (t, J ϭ 6.4 Hz, 2 H), 3.34 (t, J ϭ 6.5 Hz, 2

H), 6.59 (br. d, J ϭ 7.5 Hz, 1 H), 7.40 (m, 4 H), 7.81 (m, 2 H)

ppm; NH signals are not given. ¹³C NMR (CDCl₃): δ ϭ 32.7 (1

C), 41.7 (1 C), 43.8 (1 C), 104.5 (1 C), 117.5 (1 C), 121.0 (1 C),

124.1 (1 C), 125.2 (1 C), 126.4 (1 C), 127.4 (1 C), 129.3 (1 C), 134.4

(1 C), 144.1 (1 C) ppm. IR (KBr): ν˜ ϭ 3405 cm^Ϫ1, 1580, 1519,

1469, 1407, 1388, 764. MS (EI): m/z ϭ 201 (14), 200 (92) [M^ϩ], 183

(11), 182 (30), 168 (19), 167 (17), 166 (13), 165 (13), 157 (33), 156

(100), 143 (80), 129 (53), 128 (51), 127 (42), 126 (16), 115 (50).

C₁₃H₁₆N₂·CH₃OH (200.13·CH₃OH): calcd. C 72.38, H 8.68, N

12.06; found C 71.66, H 8.16, N 12.34.

N¹-{2-[(1,1Ј-Biphenyl)-4-yl]aminoethyl}propane-1,3-diamine (17) and

N¹-(2-Aminoethyl)-N³-[(1,1Ј-biphenyl)-4-yl]propane-1,3-diamine

(18): See Table 2, entry 4. These compounds were separated by col-

umn chromatography on SiO₂with CH₂Cl₂and then with CH₂Cl₂/

CH₃OH/NH₃(8:2:1) as eluent. Yield: 229 mg (85%).

17: Obtained as a white solid. ¹H NMR [CDCl₃ϩ CD₃OD ϩ NH₃

(1 drop)]: δ ϭ 1.89 (q, J ϭ 6.8 Hz, 2 H), 2.87 (t, J ϭ 7.2 Hz, 2 H),

2.96 (t, J ϭ 7.0 Hz, 2 H), 3.01 (t, J ϭ 6.8 Hz, 2 H), 3.45 (br. t, J ϭ

6.4 Hz, 2 H), 6.90 (d, J ϭ 8.6 Hz, 2 H), 7.36 (m, 1 H), 7.54 (m, 6

H) ppm; NH signals are not given. ¹³C NMR [CDCl₃ϩ CD₃OD

ϩ NH₃(1 drop)]: δ ϭ 30.9 (1 C), 40.1 (1 C), 43.7 (1 C), 47.8 (1 C),

49.1 (1 C), 114.1 (2 C), 126.8 (3 C), 128.5 (2 C), 129.5 (2 C), 130.8

N¹-Anthracen-9-ylpropane-1,3-diamine (13): See Table 1, entry 13.

The crude product was crystallized from CH₂Cl₂/hexane (1:1).

1

Yield: 212 mg (85%). H NMR (CDCl₃): δ ϭ 1.88 (q, J ϭ 6.6 Hz,

(1 C), 142.2 (1 C), 149.2 (1 C) ppm. IR (KBr): ν˜ ϭ 3421 cm^Ϫ1

,

2 H), 2.50 (br. s, 3 H), 2.91 (t, J ϭ 6.6 Hz, 2 H), 3.42 (t, J ϭ 6.8 Hz,

2 H), 7.48 (m, 4 H), 8.00 (m, 2 H), 8.15 (s, 1 H), 8.28 (m, 2 H)

ppm. ¹³C NMR (CDCl₃): δ ϭ 35.3 (1 C), 41.4 (1 C), 51.2 (1 C),

122.0 (2 C), 122.1 (1 C), 123.9 (2 C), 125.5 (2 C), 125.9 (2 C), 129.7

3275, 1611, 1528, 1489, 828, 762. MS (EI): m/z ϭ 269 (15) [M^ϩ],

196 (54), 195 (18), 184 (13),183 (100), 182 (81), 181 (16), 169 (17),

154 (11), 153 (15), 152 (33), 99 (22), 98 (120), 87 (50), 70 (12).

C₁₇H₂₃N₃·CH₃OH (269.19·CH₃OH): calcd. C 71.72, H 9.03, N

13.96; found C 71.37, H 8.68, N 14.24.

(2 C), 133.0 (2 C), 142.7 (1 C) ppm. IR (KBr): ν˜ ϭ 3331 cm^Ϫ1

,

1610, 1530, 1489, 820, 759. MS (EI): m/z ϭ 251 (18), 250 (94) [M^ϩ],

220 (10), 217 (10), 215 (22), 207 (14), 206 (52), 205 (26), 204 (52),

193 (75), 192 (35), 191 (18), 179 (39), 178 (100), 176 (29), 165 (63),

164 (25), 163(14).

18: ¹H NMR [CDCl₃ϩ CD₃OD ϩ NH₃(1 drop)]: δ ϭ 1.80 (q,

J ϭ 6.8 Hz, 2 H), 2.65 (m, 4 H), 2.75 (t, J ϭ 6.8 Hz, 2 H), 3.16 (t,

J ϭ 6.8 Hz, 2 H), 6.69 (d, J ϭ 8.8 Hz, 2 H), 7.23 (m, 1 H), 7.45

(m, 4 H), 7.72 (m, 2 H) ppm; NH signals are not given. ¹³C NMR

[CDCl₃ϩ CD₃OD ϩ NH₃(1 drop)]: δ ϭ 29.3 (1 C), 40.9 (1 C),

42.3 (1 C), 47.7 (1 C), 51.7 (1 C), 113.5 (2 C), 126.4 (3 C), 128.1 (2

C), 129.0 (2 C), 130.0 (1 C), 141.6 (1 C), 148.5 (1 C) ppm.

N¹-[(1,1Ј-Biphenyl)-4-yl]ethane-1,2-diamine (14):^[29]See Table 2, en-

try 1. The reaction mixture was chromatographed with CH₂Cl₂and

then with CH₂Cl₂/CH₃OH/NH₃(12:4:1) to yield a yellow oil. Yield:

274

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Eur. J. Org. Chem. 2005, 261Ϫ280

Palladium-Catalyzed Arylation of Linear and Cyclic Polyamines

FULL PAPER

C₁₇H₂₃N₃·CH₃OH (269.19·CH₃OH): calcd. C 71.72, H 9.03, N

13.96; found C 71.41, H 8.03, N 12.14.

s, 2 H), 2.84 (m, 2 H), 3.47 (m, 1 H), 4.20 (br. s, 1 H), 6.69 (d, J ϭ

8.4 Hz, 2 H), 7.27 (m, 1 H), 7.41 (m, 4 H), 7.51 (m, 2 H) ppm. ¹³C

NMR (CDCl₃): δ ϭ 18.7 (1 C), 47.5 (1 C), 50.9 (1 C), 113.7 (2 C),

126.2 (2 C), 126.4 (1 C), 128.1 (2 C), 128.8 (2 C), 130.3 (1 C), 141.4

(1 C), 147.3 (1 C) ppm.

N¹-2-[(3-Aminopropyl)amino]ethyl-N³-[(1,1Ј-biphenyl)-4-yl]propane-

1,3-diamine (19): See Table 2, entry 5. The reaction mixture was

chromatographed with CH₂Cl₂and then with CH₂Cl₂/CH₃OH/

1

N¹,N²-Bis[(1,1Ј-biphenyl)-4-yl]propane-1,2-diamine (24): Yield:

14 mg (4%). ¹H NMR (CDCl₃): δ ϭ 1.31 (d, J ϭ 6.2 Hz, 3 H), 1.60

(br. s, 1 H), 3.20 (m, 1 H), 3.38 (m, 1 H), 3.85 (m, 2 H), 6.71 (d,

J ϭ 8.8 Hz, 2 H), 6.73 (d, J ϭ 8.8 Hz, 2 H), 7.24 (m, 2 H), 7.43

(m, 8 H), 7.59 (m, 4 H) ppm. ¹³C NMR (CDCl₃): δ ϭ 19.45 (1 C),

48.8 (1 C), 49.8 (1 C), 113.4 (2 C), 114.0 (2 C), 126.4 (2 C), 126.4

(4 C), 128.1 (2 C), 128.2 (2 C), 128.8 (4 C), 130.7 (1 C), 130.9 (1

C), 141.2 (1 C), 141.2 (1 C), 146.9 (1 C), 147.7 (1 C) ppm. MS (EI):

m/z ϭ 379 (12), 378 (28) [M^ϩ], 197 (40), 196 (40), 196 (100), 195

(14), 184 (20), 183 (87), 182 (25), 181 (11), 180 (12), 154 (13), 153

(14), 152 (29).

NH₃(2:1:1) to yield a white solid. Yield: 287 mg (88%). H NMR

[CDCl₃ϩ CD₃OD ϩ NH₃(1 drop)]: δ ϭ 1.65 (m, 2 H), 1.81 (m,

2 H), 2.65 (m, 10 H), 3.53 (t, J ϭ 7.9 Hz, 2 H), 6.71 (d, J ϭ 10.7 Hz,

2 H), 7.58 (m, 1 H), 7.75 (m, 4 H), 7.90 (m, 2 H) ppm; NH signals

are not given. ¹³C NMR (CDCl₃ϩ CD₃OD): δ ϭ 30.0 (1 C), 32.5

(1 C), 40.5 (1 C), 43.0 (1 C), 48.2 (1 C), 48.5 (1 C), 50.0 (2 C),

114.3 (2 C), 127.0 (3 C), 128.8 (2 C), 129.9 (2 C), 130.5 (1 C), 142.4

(1 C), 149.6 (1 C) ppm. IR (KBr): ν˜ ϭ 3386 cm^Ϫ1, 1611, 1528, 780.

MS (EI): m/z ϭ 327 (11), 326 (26) [M^ϩ], 252 (11), 240 (28), 239

(27), 238 (27), 226 (27), 196 (100), 182 (42), 169 (17), 152 (18), 87

(44), 71 (11).

N¹-(3-Aminopropyl)-N³-[(1,1Ј-biphenyl)-4-yl]-N¹-methylpropane-

1,3-diamine (20): See Table 2, entry 6. The reaction mixture was

chromatographed with CH₂Cl₂and then with CH₂Cl₂/CH₃OH/

N¹-(Naphthalen-1-yl)propane-1,2-diamine (25): See Table 3, entry 3.

This compound was separated from N²-[1-naphthyl]-1,2-propanedi-

amine (26) and N¹,N²-bis(1-naphthyl)-1,2-propanediamine (27) by

column chromatography on SiO₂using, successively, CH₂Cl₂,

CH₂Cl₂/CH₃OH (9:1), and CH₂Cl₂/CH₃OH/NH₃(30:4:1) as el-

1

NH₃(2:1:1) to yield a white solid. Yield: 247 mg (83%). H NMR

(CDCl₃): δ ϭ 1.26 (br. s, 2 H), 1.62 (m, 2 H), 1.78 (m, 2 H), 2.25

(s, 3 H), 2.40 (t, J ϭ 8.0 Hz, 2 H), 2.45 (t, J ϭ 8.0 Hz, 2 H), 2.75

(br. t, J ϭ 7.7 Hz, 2 H), 3.20 (br. t, J ϭ 7.7 Hz, 2 H), 4.75 (br. s, 1

H), 6.66 (d, J ϭ 10.0 Hz, 2 H), 7.25 (m, 1 H), 7.43 (m, 4 H), 7.58

(m, 2 H) ppm. ¹³C NMR (CDCl₃): δ ϭ 27.1 (1 C), 31.9 (1 C), 41.3

(1 C), 42.9 (1 C), 44.0 (1 C), 56.4 (1 C), 57.4 (1 C), 113.6 (2 C),

126.6 (1 C), 126.9 (2 C), 128.6 (2 C), 129.4 (2 C), 130.3 (1 C), 142.0

(1 C), 148.9 (1 C) ppm. IR (KBr): ν˜ ϭ 3410 cm^Ϫ1, 3299, 1611,

1526, 1477, 765, 700. MS (EI): m/z ϭ 298 (22), 297 (100) [M^ϩ], 209

(31), 208 (22), 182 (61), 169 (15), 153 (16), 152 (38),141 (11), 115

(13), 98 (21), 85 (28), 84 (15), 72 (34), 71 (21). C₁₉H₂₇N₃·CH₃OH

(297.22·CH₃OH): calcd. C 72.89, H 9.49, N 12.76; found C 72.46,

H 9.23, N 13.15.

1

uents. Yield: 107 mg (53%). H NMR (CDCl₃): δ ϭ 1.21 (d, J ϭ

6.0 Hz, 3 H), 1.82 (br. s, 2 H), 2.99 (m, 1 H), 3.29 (m, 2 H), 4.94

(br. s, 1 H), 6.59 (d, J ϭ 7.4 Hz, 1 H), 7.31 (m, 4 H), 7.84 (m, 2

H) ppm. ¹³C NMR (CDCl₃): δ ϭ 22.5 (1 C), 46.1 (1 C), 51.9 (1

C), 104.4 (1 C), 117.3 (1 C), 120.2 (1 C), 123.6 (1 C), 124.7 (1 C),

125.8 (1 C), 126.7 (1 C), 128.6 (1 C), 134.4 (1 C), 143.7 (1 C) ppm.

MS (EI): m/z ϭ 202 (27), 201 (42), 200 (100) [M^ϩ], 158 (22), 157

(88), 156 (83), 155 (20), 154 (28), 143 (10), 129 (30), 128 (25), 127

(24), 115 (12), 44 (64).

N²-(Naphthalen-1-yl)propane-1,2-diamine (26): Yield: 15 mg (8%).

¹H NMR (CDCl₃): δ ϭ 1.28 (d, J ϭ 6.2 Hz, 3 H), 1.56 (br. s, 2 H),

2.85 (m, 1 H), 3.68 (m, 2 H), 4.95 (br. s, 1 H), 6.65 (d, J ϭ 7.6 Hz,

1 H), 7.34 (m, 4 H), 7.81 (m, 2 H) ppm. ¹³C NMR (CDCl₃): δ ϭ

18.4 (1 C), 47.1 (1 C), 50.5 (1 C), 105.0 (1 C), 117.2 (1 C), 120.1 (1

C), 123.7 (1 C), 124.7 (1 C), 125.8 (1 C), 126.7 (1 C), 128.7 (1 C),

134.5 (1 C), 142.8 (1 C) ppm. MS (EI): m/z ϭ 186 (17), 185 (35),

175 (15), 173 (100), 141 (100), 128 (13), 116 (18), 105 (13), 104 (45),

100 (12), 99 (38), 98 (9), 97 (9), 87 (33), 86 (12), 85 (71), 71 (19),

70 (12), 58 (31), 56 (36), 44 (62).

N¹-[(1,1Ј-Biphenyl)-4-yl]-2,2-dimethylpropane-1,3-diamine (21): See

Table 3, entry 1. The crude product was crystallized from CH₂Cl₂/

Et₂O/hexane (2:1:1) to yield a white solid. M.p. 78 to 80 °C. Yield:

1

191 mg (75%). H NMR (CDCl₃): δ ϭ 1.02 (s, 6 H), 2.66 (s, 2 H),

3.06 (s, 2 H), 6.74 (d, J ϭ 8.6 Hz, 2 H), 7.28 (m, 1 H), 7.47 (m, 4

H), 7.60 (m, 2 H) ppm; NH signals are not given. ¹³C NMR

(CDCl₃): δ ϭ 24.6 (2 C), 36.1 (1 C), 52.1 (1 C), 53.9 (1 C), 113.6

(2 C), 126.7 (1 C), 126.9 (2 C), 128.6 (2 C), 129.4 (2 C), 130.3 (1

C), 142.1 (1 C), 149.4 (1 C) ppm. IR (KBr): ν˜ ϭ 3353 cm^Ϫ1, 3310,

1613, 1530, 1488, 1277, 1252, 829, 761. MS (EI): m/z ϭ 255 (14),

254 (100) [M^ϩ], 224 (7), 183 (18), 182 (100), 181 (7), 169 (22), 152

(20), 141 (9), 73 (14). C₁₇H₂₂N₂·0.5CH₃OH (254.18·0.5CH₃OH):

calcd. C 71.73, H 8.95, N 10.36; found C 71.36, H 8.45, N 10.29.

N¹,N²-Di(naphthalen-1-yl)propane-1,2-diamine (27): Yield: 10 mg

1

(3%). H NMR (CDCl₃): δ ϭ 1.53 (d, J ϭ 6.2 Hz, 3 H), 3.51 (m,

2 H), 4.20 (m, 1 H), 4.44 (br. s, 1 H), 4.89 (br. s, 1 H), 6.84 (d, J ϭ

7.2 Hz, 1 H), 6.93 (d, J ϭ 7.2 Hz, 1 H), 7.41 (m, 8 H), 7.89 (m, 4

H) ppm. ¹³C NMR (CDCl₃): δ ϭ 19.3 (1 C), 48.7 (1 C), 50.0 (1

C), 104.7 (1 C), 105.8 (1 C), 117.8 (1 C), 118.0 (1 C), 120.1 (2 C),

123.7 (2 C), 124.0 (2 C), 124.9 (2 C), 125.9 (1 C), 126.7 (1 C), 128.6

(1 C), 128.8 (1 C), 134.4 (1 C), 134.6 (1 C), 142.6 (1 C), 143.6 (1

C) ppm. MS (EI): m/z ϭ 327 (5), 326 (19) [M^ϩ], 170 (100), 171

(16), 157 (75), 154 (12), 128 (18), 127 (14).

N¹-[(1,1Ј-Biphenyl)-4-yl]propane-1,2-diamine (22): See Table 3, en-

try 2. This compound was separated from N²-[(1,1Ј-biphenyl)-4-yl]-

1,2-propanediamine (23) and N¹,N²-bis[(1,1Ј-biphenyl)-4-yl]-1,2-

propanediamine (24) by column chromatography on SiO₂using,

successively CH₂Cl₂, CH₂Cl₂/CH₃OH (9:1), and CH₂Cl₂/CH₃OH/

NH₃(30:4:1) as eluents. Yield: 74 mg (33%). ¹H NMR (CDCl₃):

δ ϭ 1.16 (d, J ϭ 6.2 Hz, 3 H), 1.34 (br. s, 2 H), 2.90 (m, 1 H), 3.18

(m, 2 H), 4.53 (br. s, 1 H), 6.69 (d, J ϭ 8.4 Hz, 2 H), 7.27 (m, 1

H), 7.45 (m, 4 H), 7.49 (m, 2 H) ppm. ¹³C NMR (CDCl₃): δ ϭ

22.0 (1 C), 46.3 (1 C), 52.0 (1 C), 113.2 (2C), 126.1 (1 C), 126.3 (2

C), 128.0 (2 C), 128.7 (2 C), 130.2 (1 C), 141.3 (1 C), 147.9 (1 C)

ppm. MS (EI): m/z ϭ 227 (8), 226 (24) [M^ϩ], 184 (200), 183 (100),

182 (83), 181 (11), 153 (11), 152 (30), 44 (75).

N¹-[(1,1Ј-Biphenyl)-4-yl]-2-methylpropane-1,2-diamine (28): See

Table 3, entry 4. The reaction mixture was chromatographed with

CH₂Cl₂and then with CH₂Cl₂/CH₃OH/NH₃(30:6:1) to yield a

white solid. M.p. 116 to 118 °C. Yield: 202 mg (84%). ¹H NMR

(CDCl₃): δ ϭ 1.22 (s, 6 H), 1.77 (br. s, 2 H), 3.05 (s, 2 H), 4.28 (br.

s, 1 H), 6.74 (d, J ϭ 8.6 Hz, 2 H), 7.28 (m, 1 H), 7.44 (m, 4 H),

7.57 (m, 2 H) ppm. ¹³C NMR (CDCl₃): δ ϭ 28.9 (2 C), 50.5 (1 C),

55.4 (1 C), 113.1 (2 C), 126.0 (1 C), 126.2 (2 C), 127.9 (2 C), 128.7

(2 C), 130.0 (1 C), 141.3 (1 C), 148.4 (1 C) ppm. MS (EI): m/z ϭ

N²-[(1,1Ј-Biphenyl)-4-yl]propane-1,2-diamine (23): Yield: 12 mg

1

(5%). H NMR (CDCl₃): δ ϭ 1.19 (d, J ϭ 6.2 Hz, 3 H), 1.49 (br. 241 (4), 240 (17) [M^ϩ], 184 (14), 183 (68), 182 (28), 152 (22), 58

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275

I. P. Beletskaya, A. G. Bessmertnykh, A. D. Averin, F. Denat, R. Guilard

FULL PAPER

(100). C₁₆H₂₀N₂·0.5H₂O (240.35·0.5H₂O): calcd. C 77.07, H 8.49,

N 11.23; found C 76.56, H 8.16, N 11.02.

¹³C NMR (CDCl₃): δ ϭ 26.1 (1 C), 26.5 (1 C), 46.8 (1 C), 47.0 (1

C), 47.5 (1 C), 48.3 (1 C), 48.9 (1 C), 50.1 (1 C), 50.9 (1 C), 50.6

(1 C), 118.7 (2 C), 126.1 (1 C), 126.6 (2 C), 128.1 (2 C), 128.8 (2

C), 133.5 (1 C), 140.7 (1 C), 148.9 (1 C) ppm.

N¹-(Naphthalen-1-yl)cyclohexane-1,2-diamine (29): See Table 3, en-

try 5. The reaction mixture was chromatographed with CH₂Cl₂and

then with CH₂Cl₂/CH₃OH/NH₃(30:6:1) to yield a yellow oil. Yield:

4-(1,4,8,11-Tetraazacyclotetradec-1-yl)benzonitrile (31): This com-

pound was prepared from cyclam and 4-bromobenzonitrile

(91 mg). Yield: 33 mg (22%). ¹H NMR (CDCl₃): δ ϭ 1.73 (m, 4

H), 2.40 (br. s, 3 H), 2.85 (m, 12 H), 3.50 (m, 4 H), 6.62 (d, J ϭ

8.6 Hz, 2 H), 7.39 (d, J ϭ 8.6 Hz, 2 H) ppm. ¹³C NMR (CDCl₃):

δ ϭ 27.9 (1 C), 29.1 (1 C), 45.6 (1 C), 47.6 (1 C), 48.2 (2 C), 48.5

(2 C), 48.9 (1 C), 51.7 (1 C), 97.5 (1 C), 112.2 (2 C), 120.8 (1 C),

133.7 (2 C), 151.7 (1 C) ppm.

1

101 mg (42%). H NMR (CDCl₃): δ ϭ 0.85 (m, 1 H), 1.20 (m, 3

H), 1.61 (m, 2 H), 1.93 (m, 1 H), 2.18 (m, 1 H), 2.47 (m, 1 H), 3.27

(br. s, 1 H), 4.04 (br. s, 2 H), 4.27 (br. s, 1 H), 6.70 (d, J ϭ 6.8 Hz,

1 H), 7.44 (m, 4 H), 7.74 (m, 1 H), 7.96 (m, 1 H) ppm. ¹³C NMR

(CDCl₃): δ ϭ 25.3 (1 C), 25.5 (1 C), 32.1 (1 C), 34.6 (1 C), 55.9 (1

C), 58.9 (1 C), 106.2 (1 C), 118.1 (1 C), 121.4 (1 C), 124.6 (1 C),

125.4 (1 C), 126.5 (1 C), 127.3 (1 C), 129.4 (1 C), 135.2 (1 C), 143.5

(1 C) ppm. MS (EI): m/z ϭ 241 (11), 240 (55) [M^ϩ], 197 (5), 194

(6), 183 (9), 182 (43), 168 (56), 167 (42), 144 (47), 143 (100), 127

(41), 97 (27), 43 (22). C₁₆H₂₀N₂·0.5CH₂Cl₂(240.35·0.5CH₂Cl₂):

calcd. C 70.07, H 9.91, N 7.48; found C 69.40, H 10.16, N 7.54.

General Procedure for the Palladium-Catalyzed Reactions of Aryl

Dihalides with Polyamines using the [Pd₂(dba)₃]/dppf Catalytic Sys-

tem: Dioxane (10 mL), the indicated amount of [Pd₂(dba)₃]·CHCl₃

{or [Pd(dba)₂]}, dppf, and the amine (3 mmol) were added to an

argon-flushed, two-necked flask and the mixture was stirred for

10 min. The aryl halide (1 mmol) and sodium tert-butoxide

(2 mmol) were then added, the vial was flushed with argon, and

the mixture was refluxed with stirring. After the indicated period

of time it was cooled down to room temperature, 1 mL of water

was added, and the reaction mixture was concentrated in vacuo.

The residue was taken up with CH₂Cl₂(30 mL). The organic layer

was washed with water, dried over anhydrous Na₂SO₄, and the sol-

vents evaporated in vacuo. The crude material was purified by col-

umn chromatography on silica gel. The following compounds were

prepared by the described procedure; the results are summarized

in Table 4.

Attempts at the Pd-Catalyzed Arylation of Cyclam (1l). Typical Pro-

cedure: dioxane (15 mL) and the catalyst precursor were placed in

an argon-flushed, two-necked flask. The reaction mixture was

stirred for 5 min. The aryl halide (1 mmol), 1.0 equiv. of cyclam

(1l), and 2.0 equiv. of NaOtBu were then added and the mixture

was refluxed for 24Ϫ72 h. After cooling down to room temperature

and concentrating in vacuo, the residue was taken up with CH₂Cl₂

(30 mL), washed with water, dried over Na₂SO₄, and the solvents

evaporated in vacuo. The residue was analysed by ¹H and ¹³C

NMR spectroscopy. Arylation of cyclam was carried out with the

following aryl halides:

1) 1-Bromonaphthalene in the presence of: a) 4 mol % Pd(dba)₂

and 6 mol % P(tBu)₃; b) 5 mol % Pd(OAc)₂and 20 mol % P(tBu)₃;

c) 2 mol % [PdCl₂(dppf)] and 4 mol % dppf; d) 2 mol % Pd(dba)₂

and 3 mol % P(PPF-OMe)₃.

2) 4-Bromobiphenyl in the presence of: a) 4 mol % Pd(OAc)₂and

6 mol % P(tBu)₃; b) 4 mol % Pd(dba)₂and 5 mol % binap; c) 2

N¹-(4-Bromophenyl)propane-1,3-diamine (32): See Table 4, entries

1,4. The reaction mixture was chromatographed with CH₂Cl₂and

then with CH₂Cl₂/CH₃OH/NH₃(8:2:1) to yield a white solid. Yield:

1

213 mg (93%). H NMR (CDCl₃): δ ϭ 1.73 (q, J ϭ 6.6 Hz, 2 H),

2.82 (t, J ϭ 6.6 Hz, 2 H), 3.14 (t, J ϭ 6.9 Hz, 2 H), 6.46 (AAЈ, J ϭ

8.6 Hz, 2 H), 7.15 (BBЈ, J ϭ 8.6 Hz, 2 H) ppm; NH signals are not

given. ¹³C NMR (CDCl₃): δ ϭ 32.0 (1 C), 39.9 (1 C), 41.9 (1 C),

108.3 (1 C), 114.2 (2 C), 131.0 (2 C), 147.5 (1 C) ppm. IR (nujol):

ν˜ ϭ 3342 cm^Ϫ1, 3050, 820, 777. C₉H₁₃BrN₂(229.12): calcd. C

47.18, H 5.72, Br 34.87, N 12.23; found C 47.43, H 6.08, Br 34.41,

N 12.38.

mol % [PdCl₂(dppf)] and

[Pd₂(dba)₃[·CHCl₃and 4 mol % P(o-tol)₃.

3) p-Tolyl bromide in the presence of 5 mol % Pd(OAc)₂and 30

mol % P(tBu)₃.

4) p-Tolyl chloride in the presence of 4 mol % Pd(dba)₂and 16

mol % P(cy)₃.

5) 1,3-Dibromobenzene in the presence of 4 mol % Pd(dba)₂and

16 mol % P(o-tol)₃.

No aryl-substituted cyclams were formed in any of these reactions:

either the reaction did not occur at all or only partial or complete

reduction of the aryl halide to the corresponding arene was ob-

served.

4

mol % dppf; d)

1

mol %

N¹-(3-Bromophenyl)propane-1,3-diamine (33): See Table 4, entry 2.

The reaction mixture was chromatographed with CH₂Cl₂and then

with CH₂Cl₂/CH₃OH/NH₃(8:2:1) to yield a white solid. Yield:

1

212 mg (93%). H NMR (CDCl₃): δ ϭ 1.67 (q, J ϭ 6.6 Hz, 2 H),

2.75 (br. s, 2 H), 3.09 (t, J ϭ 6.6 Hz, 2 H), 6.43 (d, J ϭ 8.5 Hz, 1

H), 6.74 (d, J ϭ 6.3 Hz, 2 H), 6.94 (t, J ϭ 7.4 Hz, 1 H) ppm; NH

signals are not given. ¹³C NMR (CDCl₃): δ ϭ 31.6 (1 C), 39.5 (1

C), 41.2 (1 C), 110.8 (1 C), 114.3 (1 C), 118.8 (1 C), 122.6 (1 C),

129.9 (1 C), 149.3 (1 C) ppm. IR (nujol): ν˜ ϭ 3300 cm^Ϫ1, 3055,

910, 842, 760, 733. C₉H₁₃BrN₂(229.12): calcd. C 47.18, H 5.72, Br

34.87, N 12.23; found C 47.34, H 5.92, Br 34.49, N 12.42.

General Procedure for the Palladium-Catalyzed Arylation of Cyclam

(1l) using the Pd(dba)₂/PPF-OMe Catalytic System: Dioxane (15

mL), Pd(dba)₂(6 mg, 0.01 mmol), and PPF-OMe (6 mg,

0.014 mmol) were added to an argon-flushed, two-necked flask.

The reaction mixture was stirred for 5 min. Cyclam (100 mg,

0.5 mmol), the aryl halide (0.5 mmol), and NaOtBu (96 mg,

1 mmol) were then added and the mixture was refluxed for 100 h.

After cooling down to room temperature and concentrating in va-

cuo, the residue was taken up with CH₂Cl₂(30 mL), washed with

water, dried over Na₂SO₄, and the solvents evaporated in vacuo.

The residue was chromatographed on silica using, successively,

CH₂Cl₂and CH₂Cl₂/MeOH/NH₃(16:4:1) as eluents.

N¹-(2-Bromophenyl)propane-1,3-diamine (34): See Table 4, entry 3.

The reaction mixture was chromatographed with CH₂Cl₂and then

with CH₂Cl₂/CH₃OH/NH₃(8:2:1) to yield a yellow oil. Yield:

1

163 mg (71%). H NMR (CDCl₃): δ ϭ 1.74 (q, J ϭ 6.8 Hz, 2 H),

2.18 (br. s, 2 H), 2.79 (t, J ϭ 6.7 Hz, 2 H), 3.16 (t, J ϭ 6.8 Hz, 2

H), 4.57 (br. s, 1 H), 6.51 (dt, J ϭ 7.5, 1.0 Hz, 1 H), 6.59 (dd, J ϭ

8.5, 1.0 Hz, 1 H), 7.13 (dt, J ϭ 7.6, 1.0 Hz, 1 H), 7.38 (dd, J ϭ 8.5,

1-[(1,1Ј-Biphenyl)-4-yl]-1,4,8,11-tetraazacyclotetradecane (30): This

compound was prepared from cyclam and 4-bromobiphenyl 1.0 Hz, 1 H) ppm. ¹³C NMR (CDCl₃): δ ϭ 29.3 (1 C), 38.6 (1 C),

1

(117 mg). Yield: 35 mg (20%). H NMR (CDCl₃): δ ϭ 1.73 (m, 4

40.9 (1 C), 109.6 (1 C), 111.2 (1 C), 117.6 (1 C), 128.4 (1 C), 132.3

H), 3.10 (m, 19 H), 7.06 (d, J ϭ 8.5 Hz, 2 H), 7.45 (m, 7 H) ppm. (1 C), 145.1 (1 C) ppm. IR (nujol): ν˜ ϭ 3392 cm^Ϫ1, 3080, 791, 745.

Eur. J. Org. Chem. 2005, 261Ϫ280

Palladium-Catalyzed Arylation of Linear and Cyclic Polyamines

C₉H₁₃BrN₂(229.12): calcd. C 47.18, H 5.72, Br 34.87, N 12.23; (nujol): ν˜ ϭ 3333 cm^Ϫ1, 3050, 912, 852, 764, 735. C₁₂H₂₀BrN₃

FULL PAPER

found C 47.51, H 5.48, Br 34.61, N 11.88.

(285.08): calcd. C 50.36, H 7.04, Br 27.92, N 14.68; found C 50.19,

H 6.91, Br 27.73, N 14.61.

N¹-(4-Iodophenyl)propane-1,3-diamine (35): See Table 4, entry 5.

The reaction mixture was chromatographed with CH₂Cl₂and then

with CH₂Cl₂/CH₃OH/NH₃(12:3:1) to yield a brown oil. Yield:

N¹-(3-Aminopropyl)-N³-(2-bromophenyl)propane-1,3-diamine (41):

See Table 4, entry 11. The reaction mixture was chromatographed

with CH₂Cl₂and then with CH₂Cl₂/CH₃OH/NH₃(8:3:1) to yield

1

157 mg (57%). H NMR (CDCl₃): δ ϭ 1.73 (q, J ϭ 6.6 Hz, 2 H),

1

2.82 (t, J ϭ 6.6 Hz, 2 H), 3.15 (t, J ϭ 6.5 Hz, 2 H), 6.65 (AAЈ, J ϭ

8.6 Hz, 2 H), 7.38 (BBЈ, J ϭ 8.6 Hz, 2 H) ppm; NH signals are not

given. ¹³C NMR (CDCl₃): δ ϭ 32.3 (1 C), 40.1 (1 C), 41.9 (1 C),

88.1 (1 C), 114.5 (2 C), 137.6 (2 C), 147.9 (1 C) ppm.

a yellow oil. Yield: 212 mg (74%). H NMR (CDCl₃): δ ϭ 1.55 (q,

J ϭ 6.6 Hz, 2 H), 1.74 (q, J ϭ 6.4 Hz, 2 H), 2.01 (br. s, 3 H), 2.66

(m, 6 H), 3.13 (br. t, J ϭ 6.2 Hz, 2 H), 4.80 (br. s, 1 H), 6.46 (d,

J ϭ 7.6 Hz, 1 H), 6.53 (t, J ϭ 8.2 Hz, 1 H), 7.08 (d, J ϭ 8.2 Hz, 1

H), 7.32 (d, J ϭ 7.6 Hz, 1 H) ppm. ¹³C NMR (CDCl₃): δ ϭ 28.5

(1 C), 33.1 (1 C), 39.9 (1 C), 42.1 (1 C), 47.3 (1 C), 47.6 (1 C),

108.9 (1 C), 110.4 (1 C), 116.6 (1 C), 127.8 (1 C), 131.6 (1 C), 144.7

(1 C) ppm. IR (nujol): ν˜ ϭ 3392 cm^Ϫ1, 3084, 795, 747. C₁₂H₂₀BrN₃

(285.08): calcd. C 50.36, H 7.04, Br 27.92, N 14.68; found C 50.10,

H 7.10, Br 27.67, N 14.65.

N¹-(2-Chlorophenyl)propane-1,3-diamine (36): See Table 4, entry 6.

The reaction mixture was chromatographed with CH₂Cl₂and then

with CH₂Cl₂/CH₃OH/NH₃(30:6:1) to yield a yellow oil. Yield:

1

139 mg (75%). H NMR (CDCl₃): δ ϭ 1.40 (br. s, 2 H), 1.76 (br.

t, J ϭ 6.8 Hz, 2 H), 2.82 (br. s, 2 H), 3.20 (br. t, J ϭ 6.8 Hz, 2 H),

4.60 (br. s, 1 H), 6.58 (t, J ϭ 8.6 Hz, 1 H), 6.62 (d, J ϭ 7.3 Hz, 1

H), 7.10 (t, J ϭ 7.3 Hz, 1 H), 7.20 (t, J ϭ 8.5 Hz, 1 H) ppm. ¹³C

NMR (CDCl₃): δ ϭ 32.6 (1 C), 40.1 (1 C), 41.7 (1 C), 111.0 (1 C),

116.9 (1 C), 119.0 (1 C), 127.8 (1 C), 129.0 (1 C), 144.2 (1 C) ppm.

N¹-(3-Aminopropyl)-N³-(4-iodophenyl)propane-1,3-diamine (42): See

Table 4, entry 12. The reaction mixture was chromatographed with

CH₂Cl₂and then with CH₂Cl₂/CH₃OH/NH₃(12:3:1) to yield a

1

yellow oil. Yield: 160 mg (48%). H NMR (CDCl₃): δ ϭ 1.58 (br.

N¹-(4-Bromo-2-nitrophenyl)propane-1,3-diamine (37): See Table 4,

entry 7. The reaction mixture was chromatographed with CH₂Cl₂/

CH₃OH (4:1) to yield an orange solid. Yield: 216 mg (79%). ¹H

NMR (CDCl₃): δ ϭ 1.26 (br. s, 2 H), 1.85 (q, J ϭ 6.8 Hz, 2 H),

2.85 (t, J ϭ 6.8 Hz, 2 H), 3.40 (t, J ϭ 6.8 Hz, 2 H), 6.76 (d, J ϭ

8.5 Hz, 1 H), 7.44 (dd, J ϭ 8.5, 2.5 Hz, 1 H), 8.20 (br. s, 1 H), 8.26

(d, J ϭ 2.5 Hz, 1 H) ppm. ¹³C NMR (CDCl₃): δ ϭ 32.1 (1 C), 39.7

(1 C), 41.2 (1 C), 106.3 (1 C), 115.6 (1 C), 128.9 (1 C), 132.1 (1 C),

138.9 (1 C), 144.5 (1 C) ppm.

s, 2 H), 1.68 (br. s, 2 H), 2.71 (br. s, 6 H), 3.08 (br. s, 2 H), 6.34

(AAЈ, J ϭ 8.5 Hz, 2 H), 7.33 (BBЈ, J ϭ 8.5 Hz, 2 H) ppm; NH

signals are not given. ¹³C NMR (CDCl₃): δ ϭ 28.8 (1 C), 33.4 (1

C), 40.1 (1 C), 42.6 (1 C), 47.5 (1 C), 48.2 (1 C), 89.1 (1 C), 114.8

(2C), 138.4 (2 C), 148.0 (1 C) ppm. IR (nujol): ν˜ ϭ 3382 cm^Ϫ1

,

3080, 798, 755.

N¹-2-[(3-Aminopropyl)amino]ethyl-N³-(2,6-dichlorophenyl)propane-

1,3-diamine (43): See Table 4, entry 13. The reaction mixture was

chromatographed with CH₂Cl₂and then with CH₂Cl₂/CH₃OH/

NH₃(8:3:1) to yield a yellow oil. Yield: 271 mg (85%). ¹H NMR

(CDCl₃): δ ϭ 1.25 (m, 8 H), 2.45 (m, 10 H), 3.15 (m, 2 H), 4.20

(br. s, 1 H), 6.48 (t, J ϭ 8.5 Hz, 1 H), 6.92 (d, J ϭ 8.5 Hz, 2 H)

ppm. ¹³C NMR (CDCl₃): δ ϭ 30.4 (1 C), 33.1 (1 C), 39.9 (1 C),

45.5 (1 C), 47.3 (2 C), 49.0 (2 C), 120.7 (1 C), 125.3 (2 C), 128.3 (2

C), 142.4 (1 C) ppm. MS (EI): m/z ϭ 174 (10), 173 (100), 171 (95),

149 (13), 145 (5), 143 (5), 92 (60), 84 (20), 65 (70).

N¹-(4-Bromophenyl)ethane-1,2-diamine (38): See Table 4, entry 8.

The reaction mixture was chromatographed with CH₂Cl₂and then

with CH₂Cl₂/CH₃OH/NH₃(8:3:1) to yield a yellow oil. Yield:

1

97 mg (45%). H NMR (CDCl₃): δ ϭ 2.81 (br. s, 3 H), 3.03 (br. s,

4 H), 6.41 (d, J ϭ 7.9 Hz, 2 H), 7.15 (d, J ϭ 7.9 Hz, 2 H) ppm.

¹³C NMR (CDCl₃): δ ϭ 40.5 (1 C), 45.7 (1 C), 108.6 (1 C), 114.4

(2 C), 131.8 (2 C), 147.3 (1 C) ppm. C₈H₁₁BrN₂(215.09): calcd. C

44.67, H 5.15; found C 45.26, H 4.77.

N¹-(3-Aminopropyl)-N³-(4-bromophenyl)propane-1,3-diamine (39):

See Table 4, entry 9. The reaction mixture was chromatographed

with CH₂Cl₂and then with CH₂Cl₂/CH₃OH/NH₃(8:3:1) to yield

2,3,4,5-Tetrahydro-1H-1,5-benzodiazepine (57): The reaction of o-

dibromobenzene (2p; 472 mg, 2 mmol) with 1,3-diaminopropane

(1a; 148 mg, 2 mmol) was carried out using the general procedure

for the amination of aryl dibromides, in the presence of 8 mol %

Pd(dba)₂and 12 mol % dppf. The reaction mixture was refluxed

for 4 days. The product 57 (25% yield) was separated from the

compounds 3 and 34 by chromatography on SiO₂using CH₂Cl₂/

CH₃OH (10:1) and then CH₂Cl₂/CH₃OH/NH₃(12:4:1) as eluents.

¹H NMR (CDCl₃): δ ϭ 1.76 (m, 2 H), 3.01 (m, 4 H), 3.80 (br. s, 2

H), 6.70 (m, 4 H) ppm. ¹³C NMR (CDCl₃): δ ϭ 32.6 (1 C), 47.3

(2 C), 120.0 (2 C), 121.0 (2 C), 140.6 (2 C) ppm. MS (EI): m/z ϭ

149 (6), 148 (53) [M^ϩ], 147 (8), 134 (2), 133 (4), 132 (8), 130 (4),

120 (15), 119 (12), 107 (2), 106 (2), 92 (14), 77 (6), 65 (15).

1

a yellow oil. Yield: 272 mg (95%). H NMR (CDCl₃): δ ϭ 1.54 (q,

J ϭ 6.9 Hz, 2 H), 1.68 (q, J ϭ 6.6 Hz, 2 H), 2.57 (t, J ϭ 6.9 Hz, 2

H), 2.64 (t, J ϭ 6.6 Hz, 2 H), 2.68 (t, J ϭ 6.9 Hz, 2 H), 3.04 (t,

J ϭ 6.6 Hz, 2 H), 6.37 (AAЈ, J ϭ 8.5 Hz, 2 H), 7.14 (BBЈ, J ϭ

8.5 Hz, 2 H) ppm; NH signals are not given. ¹³C NMR (CDCl₃):

δ ϭ 28.8 (1 C), 33.4 (1 C), 40.1 (1 C), 42.6 (1 C), 47.5 (1 C), 48.2

(1 C), 107.9 (1 C), 113.8 (2 C), 131.5 (2 C), 147.3 (1 C) ppm. IR

(nujol): ν˜ ϭ 3305 cm^Ϫ1, 3037, 815, 764, 699. C₁₂H₂₀BrN₃(285.08):

calcd. C 50.36, H 7.04, Br 27.92, N 14.68; found C 50.09, H 6.91,

Br 28.07, N 14.52.

N¹-(3-Aminopropyl)-N³-(3-bromophenyl)propane-1,3-diamine (40):

N¹,N³-Bis(3-aminopropyl)benzene-1,3-diamine (58): The reaction of

See Table 4, entry 10. The reaction mixture was chromatographed m-dibromobenzene (2o; 236 mg, 1 mmol) with 1,3-diaminopropane

with CH₂Cl₂and then with CH₂Cl₂/CH₃OH/NH₃(8:2:1) to yield (1a; 296 mg, 4 mmol) was carried out using the general procedure

1

a yellow oil. Yield: 266 mg (93%). H NMR (CDCl₃): δ ϭ 1.54 (q,

for the amination of aryl dibromides, in the presence of 2 mol %

J ϭ 6.9 Hz, 2 H), 1.68 (q, J ϭ 6.5 Hz, 2 H), 2.57 (t, J ϭ 6.9 Hz, 2 [PdCl₂(dppf)] and 2 mol % dppf. The reaction mixture was refluxed

H), 2.63 (t, J ϭ 6.6 Hz, 2 H), 2.68 (t, J ϭ 6.9 Hz, 2 H), 3.05 (t,

J ϭ 6.6 Hz, 2 H), 6.40 (d, J ϭ 7.9 Hz, 1 H), 6.62 (t, J ϭ 1.7 Hz, 1

for 1 day. The product 58 (23% yield) was separated from com-

pound 3 by column chromatography on SiO₂using CH₂Cl₂/

H), 6.68 (d, J ϭ 7.6 Hz, 1 H), 6.90 (t, J ϭ 8.2 Hz, 1 H) ppm; NH CH₃OH/NH₃(12:3:1) as eluent. ¹H NMR (CDCl₃): δ ϭ 1.73 (q,

signals are not given. ¹³C NMR (CDCl₃): δ ϭ 28.7 (1 C), 33.3 (1

C), 40.2 (1 C), 42.5 (1 C), 47.6 (1 C), 48.2 (1 C), 111.1 (1 C), 114.6 (br. s, 1 H), 5.97 (d, J ϭ 7.7 Hz, 2 H), 6.95 (t, J ϭ 7.7 Hz, 1 H)

(1 C), 119.1 (1 C), 122.9 (1 C), 130.1 (1 C), 149.7 (1 C) ppm. IR

ppm; NH signals are not given. ¹³C NMR (CDCl₃): δ ϭ 32.7 (2

J ϭ 6.6 Hz, 4 H), 2.75 (br. s, 4 H), 3.09 (t, J ϭ 6.6 Hz, 4 H), 5.83

Eur. J. Org. Chem. 2005, 261Ϫ280

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277

I. P. Beletskaya, A. G. Bessmertnykh, A. D. Averin, F. Denat, R. Guilard

FULL PAPER

C), 39.9 (2 C), 41.6 (2 C), 96.7 (1 C), 102.3 (2 C), 129.6 (1 C), 149.4

(2 C) ppm.

(4 C), 128.6 (2 C), 129.7 (4 C), 130.6 (4 C), 136.6 (2 C), 142.6 (2

C), 149.1 (2 C) ppm.

N¹,N¹,N²-Tris[(1,1Ј-biphenyl)-4-yl]propane-1,3-diamine (48): Yield:

77 mg (15%). ¹H NMR (CDCl₃): δ ϭ 2.09 (q, J ϭ 6.6 Hz, 2 H),

3.31 (t, J ϭ 6.6 Hz, 2 H), 3.74 (br. s, 1 H), 3.97 (t, J ϭ 6.6 Hz, 2

H), 6.68 (d, J ϭ 8.8 Hz, 2 H), 7.18 (d, J ϭ 8.8 Hz, 4 H), 7.28 (m,

3 H), 7.48 (m, 18 H) ppm. ¹³C NMR (CDCl₃): δ ϭ 27.7 (1 C), 41.9

(1 C), 50.1 (1 C), 113.3 (2 C), 121.4 (4 C), 126.3 (1 C), 126.4 (2 C),

126.8 (4 C), 126.9 (2 C), 128.2 (6 C), 128.9 (6 C), 130.5 (1 C), 134.4

(2 C), 140.7 (2 C), 141.2 (1 C), 147.2 (2 C), 147.7 (1 C) ppm. MS

(EI): m/z ϭ 532 (11), 531 (45), 530 (100) [M^ϩ], 360 (11), 335 (22),

334 (50), 322 (20), 321 (75), 265 (14), 209 (13), 208 (13), 207 (18),

193 (16), 182 (32), 181 (14), 180 (17), 169 (18), 167 (20), 154 (12),

153 (29), 152 (31), 115 (9). C₃₉H₃₄N₂·H₂O (530.70·H₂O): calcd. C

84.88, H 7.19, N 4.69; found C 85.37, H 6.61, N 5.11.

General Procedure for the Palladium-Catalyzed Double Arylation

and Polyarylation of Polyamines using the Pd/dppf and Pd/binap

Catalytic Systems: Dioxane (10 mL), the indicated amount of

Pd(dba)₂, dppf or binap, and the amine (1 mmol) were added to

an argon-flushed, two-necked flask and the mixture was stirred for

10 min. The aryl halide (2Ϫ5 mmol) and sodium tert-butoxide

(2 mmol) were then added to the reaction mixture, the vial was

flushed with argon, and the mixture was refluxed whilst stirring.

After cooling down to room temperature, 1 mL of water was added

and the reaction mixture was concentrated in vacuo. The residue

was taken up with CH₂Cl₂(30 mL). The organic layer was washed

with water, dried over anhydrous Na₂SO₄, and the solvents evapo-

rated in vacuo. The crude material was purified by column chroma-

tography on silica gel. The following compounds were prepared by

the above procedure, and the results are summarized in Table 5.

N¹,N²-Bis[(1,1Ј-biphenyl)-4-yl]ethane-1,2-diamine (49): See Table 5,

entry 5. The reaction mixture was chromatographed with CH₂Cl₂/

toluene (1:1) to yield a white solid. M.p. 190Ϫ192 °C. Yield: 273 mg

N¹,N³-Di(naphthalen-1-yl)propane-1,3-diamine (44): See Table 5,

1

(75%). H NMR (CDCl₃): δ ϭ 3.47 (s, 4 H), 3.96 (br. s, 2 H), 6.73

entry 1. The reaction mixture was chromatographed with CH₂Cl₂

(d, J ϭ 8.8 Hz, 4 H), 7.24 (m, 8 H), 7.48 (m, 6 H) ppm. ¹³C NMR

(CDCl₃): δ ϭ 43.5 (2 C), 113.4 (4 C), 125.4 (2 C), 126.4 (4 C), 128.2

(4 C), 129.2 (4 C), 130.9 (2 C), 141.2 (2 C), 146.9 (2 C) ppm. MS

(EI): m/z ϭ 366 (14), 365 (23), 364 (75) [M^ϩ], 194 (28), 184 (95),

183 (100), 182 (18), 181 (19), 154 (17), 153 (19), 152 (41), 151 (12).

1

to yield a brown solid. M.p. 115Ϫ117 °C. Yield: 287 mg (88%). H

NMR (CDCl₃): δ ϭ 2.19 (q, J ϭ 6.8 Hz, 2 H), 3.48 (t, J ϭ 6.8 Hz,

4 H), 4.65 (br. s, 2 H), 6.72 (dd, J ϭ 7.5, 1.2 Hz, 2 H), 7.49 (m, 8

H), 7.88 (m, 4 H) ppm. ¹³C NMR (CDCl₃): δ ϭ 29.7 (1 C), 43.9

(2 C), 105.8 (2 C), 118.7 (2 C), 120.8 (2 C), 124.7 (2 C), 125.6 (2

C), 126.5 (2 C), 127.4 (2 C), 129.5 (2 C), 135.4 (2 C), 144.1 (2 C)

ppm. IR (KBr): ν˜ ϭ 3358 cm^Ϫ1, 1628, 1581, 1522, 1471, 1262, 788.

MS (EI): m/z ϭ 327 (26), 326 (100) [M^ϩ], 182 (37), 156 (71), 143

(49), 129 (48), 128 (57), 127 (45), 115 (56).

N¹-[(1,1Ј-biphenyl)-4-yl]-N³-[3-([(1,1Ј-biphenyl)-4-yl]amino)propyl]-

propane-1,3-diamine (50): See Table 5, entry 6. The reaction mixture

was chromatographed with CH₂Cl₂/MeOH (9:1) and then with

CH₂Cl₂/CH₃OH/NH₃(16:3:1) to yield a white solid. M.p. 95Ϫ97

°C. Yield: 524 mg (89%). ¹H NMR (CDCl₃): δ ϭ 1.85 (q, J ϭ

6.5 Hz, 4 H), 2.79 (t, J ϭ 6.5 Hz, 4 H), 3.28 (t, J ϭ 6.6 Hz, 4 H),

6.70 (d, J ϭ 8.2 Hz, 4 H), 7.29 (m, 2 H), 7.43 (m, 8 H), 7.58 (m, 4

H) ppm; NH signals are not given. ¹³C NMR (CDCl₃): δ ϭ 29.6

(2 C), 43.0 (2 C), 48.5 (2 C), 113.1 (4 C), 126.2 (2 C), 126.3 (4 C),

128.0 (4 C), 128.8 (4 C), 130.0 (2 C), 141.4 (2 C), 148.1 (2 C) ppm.

MS (EI): m/z ϭ 436 (38), 435 (100) [M^ϩ], 237 (20), 226 (23), 209

(28), 208 (22), 196 (43), 195 (18), 183 (29), 182 (74), 181 (21), 180

(16), 169 (38), 167 (100), 154 (11), 153 (17), 152 (28).

N¹-(Naphthalen-1-yl)-N³-[3-(naphthalen-1-ylamino)propyl]propane-

1,3-diamine (45): See Table 5, entry 2. The crude product was crys-

tallized from CH₂Cl₂/Et₂O/hexane (2:1:1) to yield a brown solid.

1

Yield: 353 mg (92%). H NMR (CDCl₃): δ ϭ 1.97 (q, J ϭ 6.1 Hz,

4 H), 2.83 (t, J ϭ 6.1 Hz, 4 H), 3.37 (t, J ϭ 6.1 Hz, 4 H), 5.10 (br.

s, 3 H), 6.61 (d, J ϭ 7.3 Hz, 2 H), 7.41 (m, 8 H), 7.85 (m, 4 H)

ppm. ¹³C NMR (CDCl₃): δ ϭ 29.8 (2 C), 44.3 (2 C), 49.7 (2 C),

104.6 (2 C), 117.6 (2 C), 121.1 (2 C), 124.3 (2 C), 125.3 (2 C), 126.5

(2 C), 127.5 (2 C), 129.4 (2 C), 135.1 (2 C), 144.7 (2 C) ppm. IR

(KBr): ν˜ ϭ 3375 cm^Ϫ1, 1581, 1528, 1479, 1409, 1129, 786, 768. MS

(EI): m/z ϭ 384 (31), 383 (100) [M^ϩ], 200 (15), 170 (33), 157 (31),

156 (44), 143 (22), 128 (18), 127 (12), 84 (16). C₂₆H₂₉N₃·CH₃OH

(383.24·CH₃OH): calcd. C 78.02, H 8.01, N 10.12; found C 77.84,

H 7.42, N 10.43.

N¹,N¹,N³,N³-Tetrakis[(1,1Ј-biphenyl)-4-yl]propane-1,3-diamine (51):

See Table 5, entry 8. The reaction mixture was chromatographed

with CH₂Cl₂/toluene (1:1) to yield a white solid. M.p. 198 to 200

°C. Yield: 648 mg (95%). ¹H NMR (CDCl₃): δ ϭ 2.21 (q, J ϭ

6.5 Hz, 2 H), 3.97 (t, J ϭ 6.5 Hz, 4 H), 7.11 (d, J ϭ 8.2 Hz, 8 H),

7.48 (m, 28 H) ppm. ¹³C NMR (CDCl₃): δ ϭ 25.5 (1 C), 49.9 (2

C), 121.4 (8 C), 126.6 (8 C), 126.8 (4 C), 128.0 (8 C), 128.8 (8 C),

134.2 (4 C), 140.7 (4 C), 147.0 (4 C) ppm. MS (EI): m/z ϭ 669

(10), 668 (13), 530 (2), 335 (40), 334 (100), 322 (5), 243 (2), 181 (3),

180 (7), 154 (4), 153 (18), 152 (12), 151 (5).

N¹,N³-Bis[(1,1Ј-biphenyl)-4-yl]propane-1,3-diamine

(46):

See

Table 5, entry 3,4. Compound 46 was separated from N¹,N¹-

bis[(1,1Ј-biphenyl)-4-yl]propane-1,3-diamine (47) and N¹,N¹,N²-

tris[(1,1Ј-biphenyl)-4-yl]ethane-1,2-diamine (48) by chromatogra-

phy on SiO₂using CH₂Cl₂/CH₃OH (20:1) as eluent as a white solid.

1

N¹,N¹,N²,N²-Tetrakis[(1,1Ј-biphenyl)-4-yl]ethane-1,2-diamine (52):

See Table 5, entry 9. The reaction mixture was chromatographed

with CH₂Cl₂/toluene (1:1) to yield a white solid. M.p. Ͼ 250 °C

M.p. 120 to 122 °C. Yield: 137 mg (35%). H NMR (CDCl₃): δ ϭ

1.98 (q, J ϭ 6.6 Hz, 2 H), 3.32 (t, J ϭ 6.6 Hz, 4 H), 3.68 (br. s, 2

H), 6.71 (d, J ϭ 8.4 Hz, 4 H), 7.30 (m, 2 H), 7.47 (m, 12 H) ppm.

¹³C NMR (CDCl₃): δ ϭ 29.3 (1 C), 42.1 (2 C), 113.2 (4 C), 126.4

(6 C), 128.1 (4 C), 128.8 (4 C), 130.5 (2 C), 141.3 (2 C), 147.7 (2

C) ppm. MS (EI): m/z ϭ 380 (14), 379 (99), 378 (100) [M^ϩ], 209

(41), 208 (36), 196 (10), 195 (10), 192 (10), 189 (10), 169 (38), 168

(10), 167 (10), 154 (11), 153 (11), 152 (21), 132 (11).

1

(dec.). Yield: 635 mg (95%). H NMR (CDCl₃): δ ϭ 4.15 (s, 4 H),

7.08 (d, J ϭ 8.8 Hz, 8 H), 7.44 (m, 28 H) ppm. ¹³C NMR (CDCl₃):

δ ϭ 50.1 (2 C), 121.2 (8 C), 126.8 (8 C), 126.8 (4 C), 128.2 (8 C),

128.9 (8 C), 134.5 (4 C), 140.8 (4 C), 146.9 (4 C) ppm. MS (EI):

m/z ϭ 669 (11), 668 (18) [M^ϩ], 336 (11), 335 (67), 334 (100), 321

(10), 180 (17), 167 (17), 153 (41), 152 (27).

N¹,N¹-Bis[(1,1Ј-biphenyl)-4-yl]propane-1,3-diamine (47): Yield:

1

55 mg (15%). H NMR (CD₃OD): δ ϭ 2.04 (br. q, 2 H), 3.30 (br.

N¹,N¹,N³-Tris[(1,1Ј-biphenyl)-4-yl]-N³-[3-(bis[(1,1Ј-biphenyl)-4-yl]-

t, 2 H), 3.30 (br. t, 2 H), 7.08 (d, J ϭ 8.8 Hz, 4 H), 7.25 (m, 2 H), amino)propyl]propane-1,3-diamine (53): See Table 5, entry 10.

7.34 (m, 12 H) ppm; NH signals are not given. ¹³C NMR

Compound 53 (white crystals. M.p. 158 to 160 °C) was separated

(CD₃OD): δ ϭ 28.2 (1 C), 31.4 (1 C), 39.7 (1 C), 123.3 (4 C), 128.2 from N¹,N¹-bis[(1,1Ј-biphenyl)-4-yl]-N³-[3-(bis[(1,1Ј-biphenyl)-4-

278

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Eur. J. Org. Chem. 2005, 261Ϫ280

Palladium-Catalyzed Arylation of Linear and Cyclic Polyamines

FULL PAPER

yl]amino)propyl]propane-1,3-diamine (54) by column chromatog-

The organic layer was separated, washed with water, dried over

raphy on SiO₂using CH₂Cl₂/hexane (1:1) as eluent. Yield: 463 mg

(52%). H NMR (CDCl₃): δ ϭ 2.05 (q, J ϭ 6.6 Hz, 4 H), 3.45 (t, crude material was purified by column chromatography on silica

anhydrous Na₂SO₄, and the solvents evaporated in vacuo. The

1

J ϭ 6.6 Hz, 4 H), 3.92 (t, J ϭ 6.6 Hz, 4 H), 6.68 (d, J ϭ 8.9 Hz, 2

H), 7.12 (d, J ϭ 8.8 Hz, 8 H), 7.48 (m, 35 H) ppm. ¹³C NMR

(CDCl₃): δ ϭ 25.5 (2 C), 49.1 (2 C), 49.8 (2 C), 113.2 (2 C), 121.5

(8 C), 126.1 (1 C), 126.2 (2 C), 126.5 (br. s, 12 C), 128.1 (br. s, 10

C), 128.9 (br. s, 10 C), 139.5 (1 C), 140.4 (4 C), 140.7 (4 C), 141.5

(1 C), 147.2 (4 C), 148.1 (1 C) ppm. MS (EI): m/z ϭ 531 (2), 530

(4), 361 (6), 335 (12), 321 (23), 196 (26), 193 (12), 182 (11), 180

(16), 166 (17), 153 (36), 152 (22), 115 (14), 97 (10), 91 (12), 77 (21).

C₆₆H₅₇N₃·H₂O (891.46·H₂O): calcd. C 87.09, H 6.53, N 4.62; found

C 87.17, H 6.70, N 4.82.

gel. The results are summarized in Table 6.

N-Hexylnaphthalen-1-ylamine (59): See Table 6, entry 5. The reac-

tion mixture was chromatographed with CH₂Cl₂/pentane (1:1) to

yield a yellow oil. Yield: 173 mg (76%). ¹H NMR (CDCl₃): δ ϭ

1.06 (t, J ϭ 7.0 Hz, 3 H), 1.48 (m, 6 H), 1.82 (q, J ϭ 7.0 Hz, 2 H),

3.32 (t, J ϭ 6.9 Hz, 2 H), 4.28 (br. s, 1 H), 6.70 (d, J ϭ 7.6 Hz, 1

H), 7.34 (d, J ϭ 8.2 Hz, 1 H), 7.50 (m, 3 H), 7.85 (m, 2 H) ppm.

¹³C NMR (CDCl₃): δ ϭ 14.2 (1 C), 22.8 (1 C), 27.1 (1 C), 29.5 (1

C), 31.8 (1 C), 44.3 (1 C), 104.2 (1 C), 117.1 (1 C), 119.9 (1 C),

123.4 (1 C), 124.6 (1 C), 125.7 (1 C), 126.8 (1 C), 128.7 (1 C), 134.4

(1 C), 143.7 (1 C) ppm.

N¹,N¹-Bis[(1,1Ј-biphenyl)-4-yl]-N³-[3-(bis[(1,1Ј-biphenyl)-4-

1

yl]amino)propyl]propane-1,3-diamine (54): Yield: 274 mg (37%). H

NMR (CDCl₃): δ ϭ 1.96 (br. q, 4 H), 2.75 (br. t, 4 H), 3.90 (br. t,

4 H), 7.15 (d, J ϭ 8.2 Hz, 8 H), 7.48 (m, 28 H) ppm; NH signals

are not given. ¹³C NMR (CDCl₃): δ ϭ 27.9 (2 C), 47.4 (2 C), 50.2

(2 C), 121.3 (8 C), 126.6 (8 C), 126.8 (4 C), 128.0 (8 C), 128.8 (8

C), 134.2 (4 C), 140.7 (4 C), 147.1 (4 C) ppm.

6-Chloro-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (60): The reac-

tion of 1-bromo-2,6-dichlorobenzene (2u; 225 mg, 1 mmol) with

1,3-propanediamine (1a; 220 mg, 3 mmol) was carried out using

the general procedure for the amination of aryl chlorides in the

presence of 2 mol % Pd(dba)₂and 3 mol % dppf. The reaction mix-

ture was refluxed for 4 days. The products 60 (132 mg, 72%) and

61 (7 mg, 8%) were separated by column chromatography on SiO₂

Reaction of N-(3-Aminopropyl)propane-1,3-diamine (1d) with Four

Equivalents of 4-Bromobiphenyl (2c): See Table 5, entry 11. The

reaction was carried out using the general procedure for the poly-

arylation of polyamines. Compounds 53Ϫ56 were separated by

column chromatography on SiO₂using, successively, CH₂Cl₂/

hexane (1:1), CH₂Cl₂, and CH₂Cl₂/CH₃OH (10:1) as eluents.

1

using CH₂Cl₂/hexane (1:1) as eluent. H NMR (CDCl₃): δ ϭ 1.82

(m, 2 H), 3.11 (m, 4 H), 4.50 (br. s, 2 H), 6.60 (m, 2 H), 6.88 (m,

1 H) ppm. ¹³C NMR (CDCl₃): δ ϭ 31.9 (1 C), 46.5 (1 C), 46.9 (1

C), 118.4 (1 C), 120.4 (1 C), 121.4 (1 C), 123.8 (1 C), 137.2 (1 C),

141.7 (1 C) ppm.

N¹,N¹,N³-Tris[(1,1Ј-biphenyl)-4-yl]-N³-[3-([(1,1Ј-biphenyl)-4-

yl]amino)propyl]propane-1,3-diamine (55): This compound was ob-

N¹-(2,6-Dichlorophenyl)propane-1,3-diamine (61): ¹H NMR

(CDCl₃): δ ϭ 1.41 (br. s, 2 H), 1.67 (q, J ϭ 6.9 Hz, 2 H), 2.77 (t,

J ϭ 6.9 Hz, 2 H), 3.35 (br. t, J ϭ 6.9 Hz, 2 H), 4.10 (br. s, 1 H),

7.16 (d, J ϭ 8.2 Hz, 2 H), 6.70 (d, J ϭ 8.2 Hz, 1 H) ppm. ¹³C

NMR (CDCl₃): δ ϭ 34.5 (1 C), 40.0 (1 C), 45.5 (1 C), 121.7 (1 C),

126.2 (2 C), 128.9 (2 C), 142.9 (1 C) ppm.

1

tained as white crystals. M.p. 116Ϫ118 °C. Yield: 58 mg (8%). H

NMR (CDCl₃): δ ϭ 1.94 (br. q, J ϭ 6.6 Hz, 2 H), 2.10 (br. q, J ϭ

6.6 Hz, 2 H), 3.22 (t, J ϭ 6.6 Hz, 2 H), 3.48 (br. q, J ϭ 6.6 Hz, 4

H), 3.92 (br. t, J ϭ 6.6 Hz, 2 H), 6.68 (d, J ϭ 8.6 Hz, 2 H), 6.76

(d, J ϭ 8.8 Hz, 2 H), 7.14 (d, J ϭ 8.8 Hz, 4 H), 7.38 (m, 28 H)

ppm; NH signals are not given. ¹³C NMR (CDCl₃): δ ϭ 25.4 (1

C), 27.4 (1 C), 41.9 (1 C), 49.3 (2 C), 49.8 (1 C), 113.3 (4 C), 121.5

(4 C), 126.3 (br. s, 6 C), 126.7 (br. s, 6 C), 128.1 (br. s, 8 C), 128.8

(4 C), 128.9 (4 C), 129.7 (1 C), 130.5 (1 C), 134.4 (2 C), 140.7 (2

C), 141.0 (1 C), 141.3 (1 C), 147.1 (3 C), 147.7 (1 C) ppm. MS (EI):

m/z ϭ 362 (7), 361 (17), 348 (10), 347 (33), 346 (9), 335 (33), 322

(23), 321 (100), 243 (10), 180 (16), 167 (12), 153 (17), 152 (43), 115

(12), 77 (22).

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Received July 1, 2004

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Palladium-catalyzed arylation of linear and cyclic polyamines

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