Arylation of adamantanamines: II.* Palladium-catalyzed amination of dihalobenzenes with adamantylalkanamines

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 12, pp. 1790–1811. © Pleiades Publishing, Ltd., 2010.

Original Russian Text © A.D. Averin, M.A. Ulanovskaya, A.K. Buryak, E.N. Savel’ev, B.S. Orlinson, I.A. Novakov, I.P. Beletskaya, 2010, published in

Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 12, pp. 1779–1802.

Arylation of Adamantanamines: II.* Palladium-Catalyzed

Amination of Dihalobenzenes with Adamantylalkanamines

A. D. Averin^a, M. A. Ulanovskaya^a, A. K. Buryak^b, E. N. Savel’ev^c, B. S. Orlinson^c,

I. A. Novakov^c, and I. P. Beletskaya^a

^aFaculty of Chemistry, Moscow State University, Vorob’evy gory 1, Moscow, 119992 Russia

e-mail: averin@org.chem.msu.ru

^bFrumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Moscow, Russia

^cVolgograd State Technical University, Volgograd, Russia

Received February 17, 2010

Abstract—Palladium-catalyzed arylation of various (1-adamantyl)alkanamines with isomeric (ortho, meta, and

para) bromochloro- and dibromobenzenes was studied. Optimal catalytic systems were found for the synthesis

of mono- and diamination products, and the dependences of their yields on the nature of the initial amine and

dihalobenzene and on the amount of base were examined. Side amination products were isolated, and paths of

their formation were analyzed.

DOI: 10.1134/S1070428010120055

We previously reported on palladium-catalyzed

arylation of 1- and 2-aminoadamantanes, which may

be regarded as a convenient method for the synthesis

of the corresponding N-aryl derivatives [1]. In the

present work we tried to extend this procedure to more

complex amines of the adamantane series, in which the

amino group is separated from the adamantane frag-

ment by one or two methylene or methine units. The

simplest and most thoroughly studied amine of this

series is (1-adamantyl)methanamine (Ia). Compound

Ia was noted in more than 250 publications, whereas

only a few of them were concerned with the synthesis

of amine Ia. All other articles deal mostly with its bio-

chemical and pharmacological applications, synthesis

of ligands based thereon, and physicochemical studies.

For example, amine Ia was used to develop potential

P2X₇receptor antagonists (interleukin 1β inhibitors)

[2], modify 4-oxo-1,4-dihydroquinoline-3-carbox-

amides with a view to obtain SB₂-selective cannabioid

receptor ligands [3], and modify 8-azabicyclo[3.2.1]-

octane to prepare μ-opioid receptor agonists [4].

Amine Ia may be classed with 1-phenyl-2-amino-

ethanol derivatives that are β2-adrenoreceptor agonists

[5], transcription factor inhibitors that weaken protein–

DNA interactions [6], and metalloprotease [7] and

epoxide hydrolase inhibitors [8]; it was also used in the

synthesis of anticancer and antimalarial drugs (artemi-

sinin derivatives) [9]. Finally, (1-adamantyl)methan-

amine (Ia) was used in the synthesis of Schiff bases as

bidentate ligands for ruthenium complexes which cata-

lyzed olefin metathesis [10]. Only a few aryl deriva-

tives of aminomethyladamantane have been reported.

N-Phenylaminomethyladamantane was synthesized in

35% yield by heating a mixture of bromomethyl-

adamantane with aniline at the boiling point over

a period of 3 h [11]. N-(1-Adamantylmethyl)benzene-

1,2-diamine was obtained as intermediate product in

the synthesis of complex biologically active ligands

[12]. Another aryl derivative, N-(1-adamantylmethyl)-

4-bromoaniline was prepared by reaction of adaman-

tane-1-carbonyl chloride with 4-bromoaniline, fol-

lowed by reduction of the amide thus formed with

lithium tetrahydridoaluminate [13].

(1-Adamantyl)phenylmethanamine (Ib) was poorly

studied. We have found only one publication on the

synthesis of its N-phenyl derivative (yield 20%) via

electrochemical reduction of the product obtained by

reaction of the corresponding Schiff base with

1-bromoadamantane [14]. Biochemical and pharma-

ceutical applications of 1-(1-adamantyl)propan-1-

amine (Ic) were studied much better: it was noted in

40 publications. On the other hand, 1-(1-adamantyl)-

* For communication I, see [1].

1790

ARYLATION OF ADAMANTANAMINES: II.

1791

NH₂

Me

NH₂

Me

Ph

NH₂

Ia

Ib

Ic

Id

propan-2-amine (Id) which is isomeric to Ic, was

studied to a considerably lesser extent; moreover, no its

N-aryl derivatives were reported prior to our studies.

dibromobenzenes (Scheme 1). The reactions were

carried out using equimolar amounts of the initial com-

pounds in dioxane at concentrations of 0.1 M. Initially,

standard Pd(dba)₂/BINAP system was selected as

catalyst [15]. The results are collected in Table 1. First

of all we made sure that no reaction occurred in the

absence of catalyst. For this purpose, amine Ia was

heated with bromobenzene in the presence of 1.5 equiv

of sodium tert-butoxide in boiling dioxane over a peri-

od of 7 h. The reaction mixture contained only the

initial reactants, and even traces of the expected prod-

uct were not detected. When the reaction was carried

out in the presence of Pd(dba)₂/BINAP (4/4.5 mol %)

as catalytic system, N-phenyl derivative IV was

formed in 82% yield (Table 1, run no. 1). The reactions

of Ia with isomeric bromochlorobenzenes smoothly

occurred under standard conditions [Pd(dba)₂/BINAP

Taking the above stated into account, it seemed

reasonable to examine palladium-catalyzed arylation

of adamantyl-containing amines Ia–Id with isomeric

dihalo benzenes with a view to obtain the corre-

sponding N-(halophenyl) derivatives which were ex-

pected to possess a significant pharmacological poten-

tial. It was also interesting to elucidate how the nature

of initial amines and dihalo benzenes (i.e., nature of

the halogen atoms and their mutual position) affect the

mono- and diamination processes, as well as reduction.

Arylation of (1-adamantyl)methanamine. We ex-

amined palladium-catalyzed arylation of (1-adaman-

tyl)methanamine (Ia) with isomeric bromochloro- and

Scheme 1.

Pd(dba)₂/L

t-BuONa, dioxane

H

N

+

NH₂

Br

Ia

IV

Br

H

N

H

N

Pd(dba)₂/L

t-BuONa, dioxane

Hlg

NH

NH₂

+

IV

Hlg

Ia

IIa–IIf

IIIa–IIIc

NMe₂

L =

,

PCy₂

DavePHOS (PCy₂NMe₂)

P(Bu-t)₂

PCy₂

P(Bu-t)₂

P(Bu-t)₂NMe₂

PCy₂

Fe

Me

NMe

,

₂, dppe, dppp, dppf.

PPh₂

O

PPh₂

PCy₂

Xantphos

Cy-Xantphos

PPFNMe₂

II, Hlg = p-Cl (a), m-Cl (b), o-Cl (c), p-Br (d), m-Br (e), o-Br (f); III, para isomer (a), meta isomer (b), ortho isomer (c).

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

AVERIN et al.

1792

Table 1. Synthesis of N-aryl 1-aminomethyladamantane derivatives IIa–IIf (dihaloarene–amine ratio 1:1)

Run no.

Halobenzene

Pd/L (mol %)

Product (yield, %)

01

Bromobenzene

p-Br,Cl

m-Br,Cl

o-Br,Cl

p-Br,Br

m-Br,Br

o-Br,Br

Pd(dba)₂/BINAP (4/4.5)

Pd(dba)₂/BINAP (2/2.5)

Pd(dba)₂/BINAP (4/4.5)

Pd(dba)₂/DavePHOS (4/5)

Pd(dba)₂/PCy₂(4/8)

IV (82)

IIa (79)

IIa (71)

IIb (81)

IIc (93)

02

03

04

05

06

IId (23), IV (11)

07

IId (11), IIIa (30), IV (13)

IId (13), IIIa (24), IV (15)

IId (42), IIIa (33)

IId (0)

08

09^a

10^b

11^b

12^c

13^d

14^a

15^e

16^f

17

Pd(dba)₂/P(Bu-t)₂(4/8)

Pd(OAc)₂/dppe (5/10)

Pd(OAc)₂/dppf (5/10)

IId (traces)

Pd(OAc)₂/dppp (5/10)

Pd(dba)₂/dppp (5/7.5)

IId (9)

IId (7)

Pd(dba)₂/Xantphos (10/10)

Pd(dba)₂/Cy-Xantphos (10/10)

Pd(dba)₂/BINAP (4/4.5)

IId (34)

IId (17), IV (7)

IIe (47, 39^g), IIIb (10), 4^g), IV (17, 7^g)

IIe (38, 30^g), IIIc (38, 34^g), IV (19, 5^g)

a

b

c

d

e

f

Joint chromatographic separation of the products obtained in run nos. 9 and 14; yield of IId 33%.

Conversion of p-dibromobenzene 100%.

Conversion of p-dibromobenzene 55%.

Conversion of p-dibromobenzene 65%.

Conversion of p-dibromobenzene 78%.

Adamantane-1-carbaldehyde (12%).

After chromatographic separation.

g

4/4.5 mol %, 1.5 equiv of t-BuONa, c = 0.1 M] and

were complete in 5–7 h; target compounds IIa–IIc

were obtained in high yields, and only in the reaction

with m-bromochlorobenzene an insignificant amount

of side diamination product was detected. Consider-

ably lower reactivity of chlorine atom compared to

bromine in catalytic amination ensured selective

formation of just chloro-substituted anilines IIa–IIc.

a more active amination catalyst containing P-donor

ligand DavePHOS [16] led to formation of an appreci-

able amount of p-diamino-substituted benzene IIIa,

whereas the yield of compound IId was even smaller

(Table 1, run no. 7). The results were not improved

when another donor ligand, 2-(dicyclohexylphosphino)-

biphenyl (PCy₂), was used (Table 1, run no. 8), while

in the presence of structurally related ligand, 2-(di-tert-

butylphosphino)biphenyl [P(t-Bu₂)] the yield of IId

increased to 45%, though the amount of diamination

product IIIa remained significant (Table 1, run no. 9).

The catalytic system including Xantphos as ligand

was also quite successful for the formation of target

compound IId (Table 1, run no. 14), while the yield of

IId decreased in the presence of a Xantphos analog

containing dicyclohexylphosphino groups (Cy-Xant-

phos); in addition, the conversion of initial dibromo-

benzene was not complete (Table 1, run no. 15).

Reduction of the amount of catalyst to 2 mol %

resulted in slight decrease of the yield (Table 1, run

no. 3). The reaction mixtures were analyzed by ¹H and

¹³C NMR spectroscopy and treated with water, and

the products were extracted into methylene chloride. If

several products were formed, they were isolated as

individual substances by chromatography on silica gel.

The reactions with isomeric dibromobenzenes fol-

lowed a considerably more complex pattern. Surpris-

ingly, the strongest difficulties were encountered in the

reaction with p-dibromobenzene, and the yield of com-

pound IId in the presence of standard catalytic system

did not exceed 23% (Table 1, run no. 6). The use of

Other bidentate phosphine ligands, such as dppe,

dppp, and dppf, turned out to be completely ineffective

(Table 1; run nos. 10–13). In some cases, poor yield of

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

ARYLATION OF ADAMANTANAMINES: II.

1793

Scheme 2.

R

P

H

N

(1)

R

Pd

Ad

R

P

Pd

Hlg

(2) t-BuONa (–NaHlg)

P

NH

NH₂

P

–

Pd

R

+

Ia

Ad

NH

~β-H

SiO₂/H₂O

AdCHO

IId was observed together with incomplete conversion

of initial p-dibromobenzene (Table 1; run nos. 12, 13),

whereas in other cases the conversion of p-dibromo-

benzene was complete, but even traces of the amina-

tion product were not detected (Table 1, run nos. 10,

11). The main side processes in the reactions with

dibromobenzenes are reduction and double amination.

The reaction of Ia with o-dibromobenzene gave com-

parable amounts of the target monoamination product

IIf and o-phenylenediamine derivative IIIc. The reac-

tion was also accompanied by formation of reduction

product IV (Table 1, run no. 17). The yield of com-

pound IIe obtained from m-dibromobenzene was

higher, while the yield of by-product IIIb decreased;

reduction product IV was also formed (Table 1, run

no. 16). Presumably, compound IV is formed accord-

ing to a catalytic mechanism which involves β-hydride

shift in intermediate palladium complex (Scheme 2).

Schiff base formed during the reduction process is

hydrolytically unstable, and it decomposes into ada-

mantane-1-carbaldehyde and amine IV upon chroma-

tography on silica gel. Furthermore, reduction of one

bromine atom in the initial dihalobenzene could give

chloro- or bromobenzene. However, the yields of these

compounds were not determined, for they were readily

removed from the reaction mixture under reduced

pressure together with dioxane (the boiling points of

chlorobenzene and bromobenzene are 132 and 156°C,

respectively).

On the whole, the reactions with bromochloroben-

zenes provide better results than those obtained in

analogous reactions with dibromobenzenes (the same

applies to reactions with other amines; see below),

which is consistent with the higher reactivity of

bromine atom in other catalytic reactions. The conver-

sion of dibromobenzenes is generally higher than the

conversion of the amine; this means that the reactions

are accompanied by other side processes which do not

involve amines. By special experiment we showed that

m-dibromobenzene under standard amination condi-

tions but in the absence of amine in 7 h largely under-

goes transformation into a complex mixture of uniden-

tifiable compounds.

We have become interested in relatively ready

formation of diaminobenzene derivatives IIIa–IIIc,

specifically of ortho-diamination product IIIc. In order

to synthesize compounds containing two adamantane

fragments as potential physiologically active sub-

stances [12], we performed reactions of isomeric

Table 2. Synthesis of diaminobenzene derivatives IIIa–IIIc (dibromobenzene–amine ratio 1:3)

Run no.

Dibromobenzene

Pd/L (mol %)

Product (yield, %)

1

^a2^a

^a3^a

4

para

meta

ortho

Pd(dba)₂/BINAP (4/4.5)

Pd(dba)₂/DavePHOS (8/16)

Pd(dba)₂/P(t-Bu)₂(8/16)

Pd(dba)₂/BINAP (8/9)

IV (96)

IIIa (43), IV (30)

IIIa (90), IV (9)

IIIb (99)

5

Pd(dba)₂/BINAP (8/9)

IIIc (66), IV (15), IIf (15), IIIb (2)

IIIc (36), IV (33), IIf (12), IIIb (2)

IIIc (24), IV (21)

6

Pd(dba)₂/ DavePHOS (8/10)

Pd(dba)₂/P(t-Bu)₂(8/16)

7

a

Joint chromatographic separation of the products obtained in run nos. 2 and 3; yield of IIIa 50%.

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

AVERIN et al.

1794

dibromobenzenes with 3 equiv of amine Ia. The use of

Pd(dba)₂/BINAP as catalytic system in the reaction

with p-dibromobenzene led to exclusive formation of

reduction product IV (Table 2, run no. 1). Donor phos-

phine ligands DavePHOS and especially P(t-Bu)₂

favored considerable increase in the yield of diamina-

tion product IIIa (up to 90%; Table 2, run nos. 2, 3),

and the yield of reduction product IV decreased. Com-

ment of bromine by the second amino group, becomes

more facile. This may be responsible for relatively

easy formation of o-diamino derivative IIIc even in the

presence of an equimolar amount of amine Ia.

Arylation of (1-adamantyl)phenylmethanamine

(Ib). The arylation of sterically hindered amine Ib

(Scheme 3) with p-bromochlorobenzene was success-

ful in the presence of 4 mol % of standard catalytic

system, and the yield of arylation product Va was 65%

(Table 3, run no. 1). Likewise, compound Ib reacted

with m-bromochlorobenzene, yielding 75% of mono-

amination product Vc. The yield of compound Vc in

the reaction with more sterically hindered o-bromo-

chlorobenzene was 48%, and it increased to 56% in the

presence of a larger amount of the catalyst (8 mol %)

(Table 3; run nos. 2–4). The lower yields of com-

pounds Va–Vc as compared to the yields of IIa–IIc in

the reactions with amine Ia should be attributed to

stronger steric hindrances at the nitrogen atom in

amine Ib.

1

pound IIIa displayed in the H NMR spectrum of the

reaction mixture narrow signals at δ 2.71 (d, 2H,

CH₂N) and 6.54 ppm (s, 4H, H_arom). The corresponding

carbon signals appeared in the ¹³C NMR spectrum at

δ_C58.0 (2C), 114.5 (4C), and 141.4 ppm (2C). How-

1

ever, the H NMR spectrum of the product isolated by

chromatography contained very broad lines (about

500 Hz), whereas signals from the corresponding

carbon atoms were not observed at all. As will be

shown below, such pattern is typical of all p-diamino-

substituted benzenes synthesized in this work.

Diamination of m-dibromobenzene was character-

ized by almost quantitative yield (Table 2, run no. 4)

when Pd(dba)₂/BINAP was used as catalytic system.

This system turned out to ensure the best results in the

reaction with o-dibromobenzene: the yield of target

diaminobenzene IIIc was 66% (Table 2, run no. 5).

Catalytic systems based on donor phosphine ligands

were less effective (Table 2; run nos. 6, 7). In these

cases, monoamino derivative IId and reduced com-

pound IV were formed as by-products. In addition,

a small amount of isomeric m-diamino derivative IIIb

was detected in two experiments (Table 2; run nos. 5,

6). Compound IIIb was formed following the elimina-

tion–addition pattern (benzyne mechanism) rather than

the catalytic path.

Fairly high yield of amination product Vd (60%)

was obtained in the reaction with p-dibromobenzene

(Table 3, run no. 5). Analogous reaction with m-di-

bromobenzene gave N-substituted bromoaniline Ve in

a lower yield (44%; Table 3, run no. 6). The yield

further decreased when Xantphos was used as ligand

instead of BINAP (Table 3, run no. 7), and in the pres-

ence of donor phosphine ligand DavePHOS the major

product was diaminobenzene VIb (Table 3, run no. 8).

The reaction of Ib with o-dibromobenzene afforded

40% of amination product Vf and 22% of reduction

product VII. Raising the amount of the catalyst did not

increase the yield of Vf (Table 3; run nos. 9, 10). In

this case, DavePHOS also favored formation of di-

amination product VIc, while the yield of Vf was

several times lower (Table 3, run no. 11). It should be

noted that the conversion of o-dibromobenzene did not

exceed 90%. In some cases, oxidation product of

amine Ib, 1-adamantyl phenyl ketone, was isolated by

chromatography (Table 3; run nos. 3, 6, 9).

We previously studied diamination of isomeric di-

bromobenzenes with linear polyamines and found that

meta-diamination products can be obtained in high

yield [17] and that ortho- or para-diamination almost

does not occur; in almost no cases reduction products

were formed. As follows from the above data, a differ-

ent pattern is observed in the reactions with (1-ada-

mantyl)methanamine (Ia). According to PM3 calcula-

tions,** lone electron pair on the nitrogen atom in

molecule IIf (N-substituted o-bromoaniline) is partly

forced out from conjugation with π-electron system of

the benzene ring; therefore, positive mesomeric effect

of the amino group is weakened, and oxidative addi-

tion at the C–Br bond to Pd(0), followed by replace-

With a view to synthesize the corresponding di-

amino derivatives, isomeric dibromobenzenes were

reacted with 3 equiv of amine Ib in the presence of

different catalytic systems. No diaminobenzene VIa

was formed in the reaction of p-dibromobenzene

catalyzed by palladium complex with BINAP. Instead,

monoamination product Vd and reduction product VII

were obtained in approximately similar yields (Table 4,

run no. 1). A more effective ligand was DavePHOS; in

this case, the yield of VIa was 33%. As in the reaction

** In collaboration with Prof. T.V. Magdesieva and post-graduate

student A.V. Dolganov (Lomonosov Moscow State University).

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

ARYLATION OF ADAMANTANAMINES: II.

1795

Scheme 3.

Ph

Hlg

HN

Br

Ph

Pd(dba)₂/L

t-BuONa, dioxane

NH

Ib +

+

Ph

VIa–VIf

Ph

Hlg

Va–Vf

VII

V, Hlg = p-Cl (a), m-Cl (b), o-Cl (c), p-Br (d), m-Br (e), o-Br (f); VI, para isomer (a), meta isomer (b), ortho isomer (c).

of o-dibromobenzene with amine Ia, an appreciable

amount of m-diamino derivative VIb was formed

(6%; Table 4, run no. 2). The amination of m-di-

bromobenzene was performed in the presence of six

phosphine ligands (Table 4; run nos. 3–8). Among

them, the most efficient for the synthesis of VIb was

DavePHOS; it ensured 68% yield of the target com-

pound (Table 4, run no. 6). Reduction product VII was

formed in all the above reactions. The yield of o-di-

amino derivative VIc weakly depended on the nature

of phosphine ligand, and it ranged from 30 to 37%

(Table 4; run nos. 9, 10); the amount of reduction

product VII was comparable.

¹H NMR spectrum of the reaction mixture containing

p-diamino derivative VIa displayed fairly narrow

signals from protons in the adamantane fragments, CH

groups [δ 3.50 ppm, s (2H)], and 1,4-disubstituted ben-

zene ring [δ 6.27 ppm, s, (4H)]. Analogous pattern was

observed in the ¹³C NMR spectrum: the CH signal was

located at δ_C65.9 ppm (2C), and carbon atoms in

the 1,4-disubstituted benzene ring resonated at

δ_C114.5 ppm (4C). After chromatographic purifica-

tion, the same signals in the ¹H NMR spectrum of VIa

were very broad, while no signals were observed in the

¹³C NMR spectrum, as noted above for p-diamino

derivative IIIa.

A number of signals in the ¹H and ¹³C NMR spectra

of o- and m-diaminobenzene derivatives VIb and VIc

were doubled, indicating that these compounds are

mixtures of two couples of diastereoisomers. The

Arylation of 1-(1-adamantyl)propan-1-amine

(Ic). The reactions of 1-(1-adamantyl)propan-1-amine

(Ic) with p- and m-bromochlorobenzenes (Scheme 4)

were not so successful as analogous reactions with less

Table 3. Reaction of dihalobenzenes with (1-adamantyl)phenylmethanamine (Ib) (dihalobenzene–amine ratio 1:1)

Run no.

Dihalobenzene

Pd/L (mol %)

Product (yield, %)

Va (65)

01

p-Br,Cl

m-Br,Cl

o-Br,Cl

p-Br,Br

m-Br,Br

o-Br,Br

Pd(dba)₂/BINAP (4/4.5)

Pd(dba)₂/BINAP (8/9)

Pd(dba)₂/BINAP (4/5)

Pd(dba)₂/BINAP (4/4.5)

Pd(dba)₂/Xantphos (10/10)

Pd(dba)₂/DavePHOS (4/8)

Pd(dba)₂/BINAP (4/4.5)

Pd(dba)₂/BINAP (8/9)

Pd(dba)₂/DavePHOS (4/8)

02

03^a

Vb (75)

Vc (48, 40^b)

04

Vc (56)

05

06^c

Vd (60)

Ve (44, 37^b)

07

Ve (24)

08

09^d

Ve (11), VII (4), VIb (43)

Vf (40, 40^b)

10

11^e

Vf (44), VII (22)

Vf (9), VII (19), VIc (36)

a

b

c

d

e

Yield of 1-adamantyl phenyl ketone 18%.

After chromatographic separation.

Yield of 1-adamantyl phenyl ketone 12%.

Conversion of o-dibromobenzene 86%; yield of 1-adamantyl phenyl ketone 12%.

Conversion of o-dibromobenzene 87%.

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

AVERIN et al.

1796

Table 4. Synthesis of diaminobenzene derivatives VIa–VIc (dibromobenzene–amine ratio 1:3)

Run no.

Dibromobenzene

Pd/L (mol %)

Product (yield, %)

01

02^a

03

04

05

06

07

08

09

10^c

para

meta

ortho

Pd(dba)₂/BINAP (4/4.5)

Pd(dba)₂/DavePHOS (8/16)

Pd(dba)₂/BINAP (4/4.5)

Pd(dba)₂/PCy₂(8/16)

VIa (0), VII (48), Vd (51)

VIa (33, 17^b), VII (30, 19^b), VIb (6, 6^b)

VIb (34), VII (45)

VIb (31), VII (18)

Pd(dba)₂/P(t-Bu)₂(8/16)

Pd(dba)₂/DavePHOS (8/16)

Pd(dba)₂/P(t-Bu)₂NMe₂(8/16)

Pd(dba)₂/PPFNMe₂(8/16)

Pd(dba)₂/BINAP (4/4.5)

Pd(dba)₂/DavePHOS (8/16)

VIb (48), VII (15)

VIb (68, 63^b), VII (9, 6^b)

VIb (24), VII (15), Ve (12)

VIb (49), VII (27)

VIc (37), VII (36)

VIc (30), 26^b), VII (33, 25^b)

a

b

c

Yield of 1-adamantyl phenyl ketone 13%.

After chromatographic separation.

Yield of 1-adamantyl phenyl ketone 18%.

preciable amounts of p-chloro- and p-bromoanilines

were formed (Table 5; run nos. 1, 5). The latter could

result from arylation of intermediate Schiff base

(β-hydride elimination product; Scheme 5).

sterically hindered amines Ia and Ib, and target com-

pounds VIIIa and VIIIb were formed in 50 and

53% yield, respectively, under standard conditions (7 h

under reflux; Table 5; run nos. 1, 2). In the reaction of

o-bromochlorobenzene with amine Ic we initially ob-

tained only 35% of compound VIIIc, the conversion of

the dihalobenzene being no more than 75% (Table 5,

run no. 3). Prolonged heating (14 h) allowed us to raise

the yield of VIIIc to 50% (Table 5, run no. 4). Mod-

erate yield of the target product may be rationalized by

considerable steric hindrances in amine Ic. The reac-

tion of Ic with o-dibromobenzene was even more

difficult: the yield of compound VIIIf did not exceed

20%, and the reaction was accompanied by formation

of reduction product X (Table 5, run no. 7). In this

case, the conversion of o-dibromobenzene was also in-

complete. p- and m-Dibromobenzenes reacted appreci-

ably better, though the yields of VIIId and VIIIe did

not exceed 50% (Table 5, run nos. 5, 6). In the reac-

tions with p-bromochloro- and p-dibromobenzene ap-

The arylation of amine Ic was characterized by

formation of a considerable amount of 1-adamantyl

ethyl ketone as a result of redox process.

p-Diamino derivative IXa was detected only in the

reaction mixture obtained from 3 equiv of amine Ic; its

yield was estimated at 36%. However, attempts to

isolate compound IXa by chromatography were un-

successful; we isolated only reduction product X and

1-adamantyl ethyl ketone (Table 5, run no. 8). In the

¹H NMR spectrum of the reaction mixture p-diamino-

benzene IXa gave rise to a singlet from aromatic pro-

tons at δ 6.42 ppm (4H), and the ¹³C NMR spectrum

contained signals at δ_C114 (4C) and 142 ppm (2C).

The formation of IXa was also proved by the MALDI-

TOF mass spectrum of the reaction mixture

(m/z 460.41 [M]⁺). The synthesis of m-diaminobenzene

Scheme 4.

Me

Hlg

HN

Br

Ph

Pd(dba)₂/L

t-BuONa, dioxane

NH

Me

NH

Ic

+

Hlg

Me

VIIIa–VIIIf

IXa, IXb

X

VIII, Hlg = p-Cl (a), m-Cl (b), o-Cl (c), p-Br (d), m-Br (e), o-Br (f); IX, para isomer (a), meta isomer (b).

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

ARYLATION OF ADAMANTANAMINES: II.

1797

Scheme 5.

Hlg'

P

(1)

Hlg'

Pd

P

Hlg

(2) t-BuONa (–NaHlg)

Pd

Hlg'

N

P

Reductive elimination

P

NH

X

N

X

Ad

–

Pd

X

P

Ad

H₂N

SiO₂/H₂O

X

+

Hlg'

Ad

CHO

derivative IXb was more successful; it was obtained in

43% yield using BINAP as ligand (Table 5, run no. 9).

Though compound IXb was a mixture of two couples

Arylation of 1-(1-adamantyl)propan-2-amine

(Id). 1-(1-Adamantyl)propan-2-amine (Id) turned out

to be appreciably more reactive than isomeric amine

Ic, which may be due to lesser steric hindrances at the

nitrogen atom. Its reactions with bromochlorobenzenes

gave the corresponding N-substituted chloroanilines

XIa–XIc in 81–89% yield (Scheme 6; Table 6, run

nos. 1–3). The reaction of Id with p-dibromobenzene

was also successful, though the conversion of the latter

was 83% (Table 6, run no. 4). In the reaction with

m-dibromobenzene the yield of diamination product

XIIb was considerably lower than the yield of analo-

gous compound XIIc in the amination of o-dibromo-

benzene, and m-bromoaniline XIe was obtained in

1

of diastereoisomers, its H and ¹³C NMR spectra were

considerably simpler: only the C²atom in the benzene

ring appeared as a doubled signal (δ_C96.6, 96.7 ppm).

No desired o-diamino derivative was obtained in the

reaction of amine Ic with o-dibromobenzene. In all

cases, monoamination with subsequent reduction to

compound X was observed, and the reaction was also

accompanied by oxidation of amine Ic to 1-adamantyl

ethyl ketone (Table 5; run nos. 10, 11). Presumably, the

reason is stronger steric hindrances at the nitrogen

atom, as compared to amine Ib.

Table 5. Synthesis of N-aryl derivatives of 1-(1-adamantyl)propan-1-amine (Ic)

Run no.

01^a

Dihalobenzene Amin–dihalobenzene ratio

Pd/L (mol %)

Product (yield, %)

VIIIa (50)

p-Br,Cl

m-Br,Cl

o-Br,Cl

p-Br,Br

m-Br,Br

o-Br,Br

p-Br,Br

m-Br,Br

o-Br,Br

1:1

3:1

Pd(dba)₂/BINAP (4/4.5)

Pd(dba)₂/DavePHOS (8/16)

Pd(dba)₂/BINAP (8/9)

Pd(dba)₂/DavePHOS (8/16)

02

VIIIb (53)

03^b

04^c

05^d

06

VIIIc (35)

VIIIc (50)

VIIId (48), X (10)

VIIIe (48), X (8), IXb (3)

VIIIf (20, 13^f), X (8, 4.5^f)

IXa (36), X (42, 25^f)

IXb (43, 33^f), X (33, 24^f)

X (36)

07^e

08^g

09

10^h

11ⁱ

X (57)

a

b

c

d

e

f

Yield of p-chloroaniline 7%.

Conversion of o-bromochlorobenzene 75%; yield of 1-(1-adamantyl)propan-1-one 24%.

The reaction time was twice as long; yield of 1-(1-adamantyl)propan-1-one 20%.

Yield of p-bromoaniline 12%.

Conversion of o-dibromobenzene 82%; yield of 1-(1-adamantyl)propan-1-one 38% (21% after chromatographic separation).

After chromatographic separation.

Compound IXa was not isolated; yield of 1-(1-adamantyl)propan-1-one 40% (after chromatographic separation).

Yield of 1-(1-adamantyl)propan-1-one 28%.

Yield of 1-(1-adamantyl)propan-1-one 30%.

g

h

i

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

AVERIN et al.

1798

Scheme 6.

Me

Hlg

HN

Br

Ph

Pd(dba)₂/L

t-BuONa, dioxane

NH

Id +

+

Me

XIa–XIf

Me

XIIa–XIIc

Me

Hlg

XIII

XI, Hlg = p-Cl (a), m-Cl (b), o-Cl (c), p-Br (d), m-Br (e), o-Br (f); XII, para isomer (a), meta isomer (b), ortho isomer (c).

67% yield (Table 6, run no. 5). The reaction of amine

Id with o-dibromobenzene followed a more complex

pattern due to formation of both o-diaminobenzene

derivative XIIc and reduction product XIII; therefore,

the yield of target compound XIf was lower (Table 6;

run nos. 6, 7).

tography. As with p-diamino derivative IXa, chromato-

graphic separation gave mainly reduction product

XIII, whereas only a small amount of compound XIIa

was isolated as a mixture with other unidentified com-

pounds. The yield of reduction product XIII consider-

ably increased in the presence of excess amine Id.

A number of signals in the ¹H and ¹³C NMR spectra of

compounds XIIb and XIIc were either doubled or

broadened, indicating that they exist as mixtures of

equal amounts of two couples of diastereoisomers. By

contrast, neither doubling nor broadening of signals

was observed in the spectra of p-diamino derivative

XIIa. All amines of the adamantane series character-

istically displayed in the MALDI mass spectra a strong

peak belonging to the [M – H₂]⁺ion which is likely to

contain dehydroadamantane fragment. The highest

intensity of the [M – H₂]⁺peaks was observed in the

mass spectra of XIa–XIf and XIIa–XIIc, and the

MALDI mass spectra of XId and XIe contained only

All these reactions were performed in the presence

of standard catalytic system Pd(dba)₂/BINAP

(4/4.5 mol %). The amination of m- and o-dibromo-

benzenes with 3 equiv of amine Id in the presence of

BINAP and DavePHOS as ligands gave 51 and 46% of

compounds XIIb and XIIc, respectively (Table 6;

run nos. 9, 10). In both cases, a considerable amount of

reduction product XIII was formed. In the reaction of

p-dibromobenzene with excess amine Id p-diamino-

benzene derivative XIIa partly crystallized from the

reaction mixture on cooling (28%; Table 6, run no. 8).

However, we failed to isolate an additional amount of

compound XIIa from the reaction mixture by chroma-

Table 6. Synthesis of N-aryl derivatives of 1-(1-adamantyl)propan-2-amine (Id)

Run no. Dihalobenzene Amine–dihalobenzene ratio

Pd/L (mol %)

Product (yield, %)

XIa (89)

01

02

03

04^a

05

06

07

08^b

09

10

p-Br,Cl

m-Br,Cl

o-Br,Cl

p-Br,Br

m-Br,Br

o-Br,Br

p-Br,Br

m-Br,Br

o-Br,Br

1:1

3:1

Pd(dba)₂/BINAP (4/4.5)

Pd(dba)₂/DavePHOS (8/16)

Pd(dba)₂/BINAP (8/9)

XIb (81)

XIc (82)

XId (75)

XIe (67), XIII (6), XIIb (7)

XId (65), XIII (7), XIIc (20)

XId (50), XIII (7), XIIc (27)

XIIa (37^c, 0^d), XIII (24^c, 13^d)

XIIb (51, 50^d), XIII (27, 23^d)

XIIc (46, 35^d), XIII (33, 32^d)

Pd(dba)₂/DavePHOS (8/16)

a

b

c

d

Conversion of p-dibromobenzene 83%.

Compound XIIc crystallized from the reaction solution (yield 28%).

Isolated from the reaction mixture.

After chromatographic separation.

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

ARYLATION OF ADAMANTANAMINES: II.

1799

Scheme 7.

Ph

Pd(dba)₂/DavePHOS

t-BuONa, dioxane

Br

NH₂

HN

NH

+

Me

HN

Me

XIV (22%)

Me

Ie

XV (21%)

[M – H₂]⁺peaks, [M]⁺peaks being almost lacking.

Diamino derivatives XIIa–XIIc also displayed strong

[M – 2H₂]⁺ion peaks.

with another amine (Id) taken in excess. As a result,

we isolated 35% of unsymmetrically substituted

m-phenylenediamine XVI (Scheme 8). Likewise, the

reaction of compound Ve (generated in situ from

amine Ib and m-dibromobenzene in 52% yield) with

excess amine Id gave 49% of N,N′-disubstituted

m-phenylenediamine XVII (Scheme 9). Compound

XVII was a mixture of two couples of diastereo-

isomers in equimolar amounts, so that most signals in

its NMR spectra were doubled. In addition, com-

pounds XVI and XVII characteristically displayed in

the MALDI mass spectra very strong peaks belonging

to [M – 2H₂]⁺ions.

We tried to elucidate the reason why amine Ic (in

contrast to isomeric amine Id) does not give ortho-

diamination product in the reaction with o-dibromo-

benzene. For this purpose, the reaction of excess amine

Ie with o-dibromobenzene was examined. Like amine

Ic, molecule Ie possesses an ethyl substituent, but the

adamantane fragment therein is separated from the

amino group by two carbon atoms (as in amine Id).

This reaction afforded orto-diamino derivative XIV in

22% yield (Scheme 7), and compound XV was ob-

tained as by-product (21%). These findings indicated

that the presence of an ethyl group at the α-carbon

atom in adamantylalkylamine does not hamper forma-

tion of o-diamination products provided that the ada-

mantyl substituent is sufficiently distant from the nitro-

gen atom. Most signals in the ¹³C NMR spectrum of

compound XIV were doubled, for it was formed as

a mixture of two couples of diastereoisomers in equal

amounts.

Synthesis of unsymmetrically substituted di-

aminobenzenes and N,N′-bis(haloaryl)-substituted

diamines. Successful synthesis of a number of substi-

tuted diaminobenzenes containing two adamantylalkyl

fragments prompted us to extend the scope of this

procedure with a view to obtain derivatives containing

two different adamantylalkyl fragments. In the first

step, by reaction of equimolar amounts of aminometh-

yladamantane Ia and m-dibromobenzene we synthe-

sized compound IIe in 40% yield (in the reaction mix-

ture) and brought it (without isolation) into reaction

Effect of the AdXNH₂–ArHlg–t-BuONa ratio on

the yield of mono- and diamination products of

dihalobenzenes. While performing experiments we

found that the product yield considerably depends on

the amount of sodium tert-butoxide taken as a base.

Therefore, we specially examined how the ratio

amine–dihalobenzene–base affects the reaction direc-

tion, i.e., predominant formation of one or another

product. The use of equimolar amounts of the above

reactants in the reaction with amine Ia did not lead to

reduced yield of monoamination product IIe, as com-

pared to the reaction carried out under standard condi-

tions (1.5 equiv of t-BuONa; Table 7, run no. 1). When

the amount of the base was reduced to 0.6 equiv, the

yield decreased to 30%, the conversion of amine Ia

was 35%, and the conversion of m-dibromobenzene

was 64% (Table 7, run no. 2). A more complicated

pattern was observed in the reaction with excess amine

Ia (3 equiv). Neither mono- nor diamination product

was detected in the reaction mixture obtained from

Scheme 8.

H

Br

N

Me

Br

Pd(dba)₂/BINAP

t-BuONa, dioxane

Id, Pd(dba)₂/BINAP

t-BuONa, dioxane

Ia

+

NH

XVI

40%

35%

Br

IIe

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

AVERIN et al.

1800

Scheme 9.

H

Br

N

Me

Br

Pd(dba)₂/BINAP

t-BuONa, dioxane

Id, Pd(dba)₂/BINAP

t-BuONa, dioxane

Ib

+

NH

52%

49%

Br

Ph

Ve

Ph

XVII

m-dibromobenzene in the presence of 1.5 equiv of

sodium tert-butoxide and 4 mol % of the catalyst

[Pd(dba)₂/BINAP] despite 100% conversion of the

initial reactants (Table 7, run no. 3).

reaction was 18–26% (Table 7; run nos. 7, 8). Donor

phosphine ligand DavePHOS impaired the results

(Table 7, run no. 9). The yield of diamination product

IIIc sharply increased (66%) in the reaction with

excess amine Ia (6 equiv) in the presence of 4 equiv of

t-BuONa (Table 7, run no. 10), indicating that excess

amine over the base is critical only within a definite

range. If the amounts of these components consider-

ably exceed the amount of aryl halide, this factor is no

longer significant. In the reaction with p-dibromoben-

zene, as with m-dibromobenzene, the use of a suffi-

cient amount of DavePHOS ensures successful forma-

tion of compound IIIa in the presence of a small

amount of t-BuONa (Table 7; run nos. 11, 12). By con-

trast, another donor ligand, P(t-Bu)₃, provides a good

yield of IId (Table 7, run no. 13).

Raising the amount of the same catalyst to 8 mol %

resulted in the formation of monoamination product

IIe approximately in the same amount as under stand-

ard conditions (54%), and 7.5% of diamination product

IIIb was detected (Table 7, run no. 4). The use of

DavePHOS as more efficient diamination ligand al-

lowed us to synthesize diamination product in the pres-

ence of a smaller than equivalent amount of sodium

tert-butoxide (Table 7; run nos. 5, 6). Somewhat

different results were obtained in the amination of

o-dibromobenzene in the presence of insufficient

t-BuONa. The yield of monoamination product IIf was

57–63% with the use of 8 mol % of Pd(dba)₂/BINAP,

and the yield of diamination product IIIc in the same

The relations found for the reactions with amine Ia

were checked out in reactions with other amines, Ib

Table 7. Reaction of amine Ia with isomeric dibromobenzenes

Run

no.

Amine–dibromobenzene–

Dibromobenzene

Pd/L (mol %)

Product (yield, %)

IIe (49)

t-BuONa ratio

01

02^a

meta

ortho

para

1:1:1

Pd(dba)₂/BINAP (4/4.5)

Pd(dba)₂/BINAP (8/9)

1:1:0.6

3:1:1.5

6:1:4

IIe (30)

03

IIIb (0)

04

IIe (54), IIIb (7.5)

05^b

06^b

07

Pd(dba)₂/DavePHOS (4/5)

Pd(dba)₂/DavePHOS (10/10)

Pd(dba)₂/BINAP (8/9)

IIe (7.5), IIIb (39), IV (12)

IIIb (76), IV (24)

IIf (63), IIIc (26), IV (6)

IIf (57), IIIc (18), IV (7.5)

IIf (9), IIIc (13.5), IV (9)

IIIc (66), IV (12)

08

Pd(dba)₂/BINAP (8/9)

09

Pd(dba)₂/DavePHOS (10/10)

Pd(dba)₂/BINAP (8/9)

10

11^c

3:1:1.5

Pd(dba)₂/DavePHOS (4/5)

Pd(dba)₂/DavePHOS (10/10)

Pd(dba)₂/P(t-Bu)₂(10/10)

IId (10), IIIa (7.5), IV (15)

IId (21), IIIa (53), IV (26)

IId (54), IIIa (27)

12

13^c

a

b

c

Conversion of m-dibromobenzene 64%.

Joint chromatographic separation of the products obtained in run nos. 5 and 6 gave compound IIIb in 25% yield.

Joint chromatographic separation of the products obtained in run nos. 11 and 13 gave 9% of IV, 6% of IId, and 6% of adamantane-

1-carbaldehyde.

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

ARYLATION OF ADAMANTANAMINES: II.

Table 8. Reaction of amine Ib with isomeric dibromobenzenes

1801

Amine–dibromobenzene–

Run no.

Dibromobenzene

Pd/L (mol %)

Product (yield, %)

t-BuONa ratio

1

2

3

4

meta

ortho

para

3:1:1.5

3:1:9

Pd(dba)₂/BINAP (8/9)

VII (traces)

Pd(dba)₂/BINAP 8/9)

Vf (84)

Pd(dba)₂/DavePHOS (8/16)

VIc (36), VII (27)

VIa (55), VII (18)

3:1:9

Table 9. Reaction of amine Id with m-dibromobenzene

Yield, %

Amine–dibromobenzene–

Run no.

Pd/L (mol %)

t-BuONa ratio

XIe

XIII

XIIb

1

2

3

4

5

3:1:1.5

3:1:2.0

3:1:3.0

2:1:1.5

2:1:2.0

Pd(dba)₂/BINAP (8/9)

57

72

00

51

00

15

22

42

39

45

03.6

04.5

27.0

09.0

17.0

and Id. The reaction of Ib with m-dibromobenzene at

a Ib–dibromobenzene–t-BuONa ratio of 3:1:1.5 (cata-

lyzed by palladium complex with BINAP) gave neither

mono- nor diamination product (Table 8, run no. 1).

Quite different pattern was observed in the reaction of

Ib with o-dibromobenzene; under analogous condi-

tions, monoamination product Vf was obtained in 84%

yield which is appreciably higher than under standard

conditions (Table 8, run no. 2). Diamination experi-

ments were carried out with amine Ib in the presence

of a large excess of sodium tert-butoxide, and the

yields of both o- and p-diaminobenzene derivatives

were slightly improved (Table 8; run nos. 3, 4).

2 equiv of amine Id. Smaller amount of the base

favored formation of monoamination product XIe

(Table 9, run no. 4), while at an equimolar ratio of

amine Id and the base the yield of diamination product

XIIb increased (Table 9, run no. 5). However, in this

case the yield of XIIb was lower and the yield of

reduction product XIII was higher than the yields of

the same compounds obtained using 3 equiv of Id and

t-BuONa.

Thus the optimal amine–dihaloarene–sodium tert-

butoxide ratio for the monoamination of dihaloarenes

is 1:1:1.5, and for the diamination, 3:1:3 (and more).

The conversion of the initial amine in the examined

reaction remains incompletely studied. In some cases,

the amine conversion is comparable with the overall

amount of the amination products, whereas in other

cases it is appreciably higher presumably due to redox

processes with participation of that amine.

Using amine Id as the most reactive among the

examined amines, we studied the dependence of the

yields of mono- and diamination products in the reac-

tions with m-dibromobenzene upon the ratio amine–

m-dibromobenzene–sodium tert-butoxide. When the

latter was equal to 3:1:1.5, monoamination product

XIe was obtained in a good yield (Table 9, run no. 1).

Increase in the amount of the base (3:1:2) resulted in

improved yield of XIe, while the contribution of the

diamination process was insignificant (Table 9, run

no. 2). When the above reactant ratio changed to

3:1:3, no monoamination product was formed, and the

yield of diamination product XIIb increased to 27%

(Table 9, run no. 3). Simultaneously, the yield of

reduction product XIII appreciably increased in

parallel with the amount of sodium tert-butoxide.

Analogous pattern was observed in the reaction with

General relations holding in the arylation of

adamantyl-substituted amines. The data obtained in

the present and preceding studies [1] should be gen-

eralized (if possible) in order to use them in practice

and predict the results of amination reactions with

participation of other amines of the adamantane series.

The examined amines differ fairly strongly in their

reactivity which is related to steric hindrances at the

nitrogen atom. Amines in which the hydrocarbon

radical is not branched at the α-carbon atom or those in

which such branching does not give rise to consider-

able steric hindrances (e.g., amines Ia and Id) ensure

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

AVERIN et al.

1802

better yields of mono- and diamination products.

Correspondingly, amines having bulky substituents at

the α-carbon atom react with dihalobenzenes more dif-

ficultly, and in some cases ortho-diamination does not

occur at all. Simultaneously, the fraction of reduction

products increases (these products are formed with

participation of the same palladium complex).

using the solvent signals as reference (CHCl₃,

δ 7.25 ppm; CDCl₃, δ_C77.00 ppm). The mass spectra

(MALDI-TOF, positive ion detection) were obtained

on a Bruker Daltonics Ultrafex mass spectrometer with

1,8,9-trihydroxyanthracene as matrix and polyethylene

glycols as internal standards. Preparative column chro-

matography was performed on silica gel (40–60 μm,

Merck). Commercially available isomeric bromo-

chloro- and dibromobenzenes, sodium tert-butoxide,

and phosphine ligands were used without additional

purification. Amine Ia was synthesized according to

the procedure reported in [18], amines Ib–Ie were pre-

pared as described in [19], and Pd(dba)₂was prepared

as described in [20] and used without additional

recrystallization. Dioxane was distilled first over alkali

and then over metallic sodium; methylene chloride and

methanol were distilled.

Among dihalobenzenes, higher yields of mono-

amination products were obtained with bromochloro-

benzenes. This is consistent with the lower reactivity

of the chlorine atom which is involved in concurrent

side processes (such as diamination or reduction) at

a much lower rate; bromochlorobenzenes are also less

prone to undergo transformations other than amination,

as compared to dibromobenzenes. Finally, the chlorine

atom is smaller than bromine, so that N-substituted

2-chloroanilines are formed more readily than analo-

gous N-substituted 2-bromoanilines. This factor is re-

sponsible for the lower yields of monoamination prod-

ucts in the reactions of o-dibrombenzene with steri-

cally hindered amines Ib and Ic. On the other hand,

ortho-diamination in the reactions with less sterically

hindered amines such as Ia and adamantan-2-amine

[1] smoothly occurs and even competes with the

monoamination when equimolar amounts of the reac-

tants are used. On the whole, diamination of m-di-

bromobenzene with different amines involves no diffi-

culties, in contrast to para-diamination (only in a few

cases it was possible to isolate the corresponding p-di-

aminobenzene derivatives by chromatography). The

reason is that the amino group in the para position

exerts a positive mesomeric effect thus hampering re-

placement of the second bromine atom. In the case of

o-bromoanilines, mesomeric effect of the amino group

is weakened for steric reasons (see above).

N-Aryl-substituted (1-adamantyl)alkanamines

IIa–IIf, Va–Vf, VIIIa–VIIIf, and XIa–XIf (general

procedure). A two-necked flask was charged under

argon with the corresponding dihalobenzene

(0.25 mmol), Pd(dba)₂(4–10 mol %), and phosphine

ligand (4.5–16 mol %), anhydrous dioxane (2 ml),

amine Ia–Id (0.25 mmol), and sodium tert-butoxide

(0.38 mmol) were added, and the mixture was heated

for 7 h under reflux. The mixture was cooled, the

precipitate was filtered off, the filtrate was evaporated

under reduced pressure, the solid residue was dissolved

in methylene chloride, the solution was washed with

water, dried over anhydrous sodium sulfate, and evap-

orated under reduced pressure, and the residue was

subjected (if necessary) to chromatography on silica

gel using the following solvents as eluents (in succes-

sion): petroleum ether–methylene chloride (10:1 to

1:4), methylene chloride.

While studying the reactions of admantane-contain-

ing amines with dihalobenzenes, a number of various

phosphine ligands were tested. The most appropriate

ligand was BINAP; in most cases it ensured the best

yields of monoamination and meta-diamination prod-

ucts; in some cases it was also more effective for

ortho-diamination. DavePHOS turned out to be the

best ligand for the preparation of para- and ortho-di-

amination products. The yield of diamination products

depends on the amount of the catalyst: increase of the

latter from 4 to 8–10% appreciably improves the yield.

N,N′-Bis[(1-adamantyl)alkyl]benzenediamines

IIIa–IIIc, VIa–VIc, IXa, IXb, XIIa–XIIc, and XIV

(general procedure). A two-necked flask was charged

under argon with the corresponding dihalobenzene

(0.1–0.15 mmol), Pd(dba)₂(4–16 mol %), and BINAP

or DavePHOS (4.5–18 mol %), anhydrous dioxane

(1–1.5 ml), amine Ia–Ie (0.2–0.6 mmol), and sodium

tert-butoxide (0.38–0.7 mmol) were added, and the

mixture was heated for 6–8 h under reflux. The mix-

ture was cooled, the precipitate was filtered off, the

filtrate was evaporated under reduced pressure, the

solid residue was dissolved in methylene chloride, the

solution was washed with water, dried over anhydrous

sodium sulfate, and evaporated under reduced pres-

sure, and the residue was subjected (if necessary) to

chromatography on silica gel using the following

EXPERIMENTAL

1

The H and ¹³C NMR spectra were recorded from

solutions in chloroform-d on a Bruker Avance-400

spectrometer at 400 and 100.6 MHz, respectively,

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

ARYLATION OF ADAMANTANAMINES: II.

1803

solvents as eluents (in succession): petroleum ether–

methylene chloride (4:1 to 1:4), methylene chloride,

methylene chloride–methanol (100:1).

and 0.25 mmol (59 mg) of p-dibromobenzene in the

presence of 15 mg (10 mol %) of Pd(dba)₂, 15 mg

(10 mol %) of Xantphos, and 37 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

In another experiment, the reaction was carried out in

the presence of 6 mg (4 mol %) of Pd(dba)₂and 6 mg

(8 mol %) of 2-(di-tert-butylphosphino)biphenyl, other

conditions being equal. The products isolated in the

two experiments were combined and subjected to

chromatography using petroleum ether–methylene

chloride (4:1) as eluent. Yield 53 mg (33%), colorless

N-(1-Adamantylmethyl)-4-chloroaniline (IIa)

was synthesized from 0.25 mmol (41 mg) of amine Ia

and 0.25 mmol (48 mg) of p-bromochlorobenzene in

the presence of 5.5 mg (4 mol %) of Pd(dba)₂, 7 mg

(4.5 mol %) of BINAP, and 37 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

Yield 54 mg (79%), light yellow oily substance.

¹H NMR spectrum, δ, ppm: 1.57 br.s (6H) 1.63–1.78 m

(6H), 2.01 br.s (3H), 2.76 d (2H, ³J = 5.8 Hz), 3.67 br.s

1

oily substance. H NMR spectrum, δ, ppm: 1.56 br.s

3

(6H) 1.61–1.77 m (6H), 2.00 br.s (3H), 3.68 br.s (1H),

(1H), 6.53 d (2H, J = 8.7 Hz), 7.09 d (2H, J =

8.7 Hz). ¹³C NMR spectrum, δ_C, ppm: 28.3 (3C), 33.9

(1C), 37.0 (3C), 40.7 (3C), 56.3 (1C), 113.5 (2C),

125.0 (1C), 128.9 (2C), 147.8 (1C). MALDI-TOF

mass spectrum: m/z 275.1 [M]⁺.

3

6.48 d (2H, J = 8.8 Hz), 7.21 d (2H, J = 8.8 Hz).

¹³C NMR spectrum, δ_C, ppm: 28.3 (3C), 33.9 (1C),

37.0 (3C), 40.6 (3C), 56.2 (1C), 108.0 (1C), 114.0

(2C), 131.8 (2C), 148.2 (1C). MALDI-TOF mass spec-

trum: m/z 319.0975 [M]⁺. C₁₇H₂₂BrN. Calculated:

M 319.0936.

N-(1-Adamantylmethyl)-3-chloroaniline (IIb)

was synthesized from 0.25 mmol (41 mg) of amine Ia

and 0.25 mmol (48 mg) of m-bromochlorobenzene in

the presence of 5.5 mg (4 mol %) of Pd(dba)₂, 7 mg

(4.5 mol %) of BINAP, and 37 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

Yield 56 mg (81%), light yellow oily substance.

¹H NMR spectrum, δ, ppm: 1.55–1.59 m (6H), 1.64–

N-(1-Adamantylmethyl)-3-bromoaniline (IIe)

was synthesized from 0.25 mmol (41 mg) of amine Ia

and 0.25 mmol (59 mg) of m-dibromobenzene in the

presence of 5.5 mg (4 mol %) of Pd(dba)₂, 7 mg

(4.5 mol %) of BINAP, and 37 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

The product was isolated by chromatography using

petroleum ether–methylene chloride (4:1) as eluent.

Yield 31 mg (39%), colorless crystalline powder,

mp 90–92°C. ¹H NMR spectrum, δ, ppm: 1.54–1.57 m

(6H), 1.61–1.77 m (6H), 2.00 br.s (3H), 2.75 d (2H,

3

1.78 m (6H), 2.01 br.s (3H), 2.78 d (2H, J = 5.3 Hz),

3

4

3.76 br.s (1H), 6.47 d.d.d (1H, J = 8.3, J = 2.2,

4

3

0.7 Hz), 6.59 t (1H, J = 2.1 Hz), 6.61 d.d.d (1H, J =

4

3

7.9, J = 1.9, 0.7 Hz), 7.04 t (1H, J = 8.0 Hz).

¹³C NMR spectrum, δ_C, ppm: 28.3 (3C), 33.9 (1C),

37.0 (3C), 40.6 (3C), 55.9 (1C), 110.9 (1C), 112.0

(1C), 116.4 (1C), 130.0 (1C), 134.9 (1C), 150.3 (1C).

3

³J = 4.3 Hz), 3.73 br.s (1H), 6.51 d.d.d (1H, J = 8.3,

3

⁴J = 2.3, 0.8 Hz), 6.73–6.77 m (2H), 6.98 t (1H, J =

8.1 Hz). ¹³C NMR spectrum, δ_C, ppm: 28.3 (3C), 33.9

(1C), 37.0 (3C), 40.6 (3C), 55.9 (1C), 111.3 (1C),

114.9 (1C), 119.3 (1C), 123.3 (1C), 130.3 (1C), 150.4

(1C). MALDI-TOF mass spectrum: m/z 319.0938

[M]⁺. C₁₇H₂₂BrN. Calculated: M 319.0936. Elution

with petroleum ether–methylene chloride (2:1) gave

4 mg (7%) of reduction product IV and 5 mg (12%) of

N-(1-Adamantylmethyl)-2-chloroaniline (IIc)

was synthesized from 0.25 mmol (41 mg) of amine Ia

and 0.25 mmol (48 mg) of o-bromochlorobenzene in

the presence of 5.5 mg (4 mol %) of Pd(dba)₂, 7 mg

(4.5 mol %) of BINAP, and 37 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

Yield 64 mg (93%), light yellow oily substance.

¹H NMR spectrum, δ, ppm: 1.61–1.64 m (6H), 1.66–

1

adamantane-1-carbaldehyde. H NMR spectrum, δ,

3

ppm: 1.69–1.81 m (12H), 2.06 br.s (3H), 9.31 s (1H).

Elution with petroleum ether–methylene chloride (1:2)

gave 2 mg (4%) of diamination product IIIb.

1.81 m (6H), 2.04 br.s (3H), 2.86 d (2H, J = 5.8 Hz),

3

4

4.39 br.s (1H), 6.59 t.d (1H, J = 7.6 Hz, J = 1.3 Hz),

6.69 d (1H, ³J = 8.2 Hz), 7.12 t.d (1H, ³J = 7.8 Hz, ⁴J =

3

4

1.4 Hz), 7.25 d.d (1H, J = 7.8 Hz, J = 1.4 Hz).

¹³C NMR spectrum, δ_C, ppm: 28.3 (3C), 34.0 (1C),

37.0 (3C), 40.7 (3C), 55.8 (1C), 111.0 (1C), 116.4

(1C), 118.9 (1C), 127.6 (1C), 128.9 (1C), 144.8 (1C).

MALDI-TOF mass spectrum: m/z 275.1398 [M]⁺.

C₁₇H₂₂ClN. Calculated: M 275.1441.

N-(1-Adamantylmethyl)-2-bromoaniline (IIf)

was synthesized from 0.25 mmol (41 mg) of amine Ia

and 0.25 mmol (59 mg) of o-dibromobenzene in the

presence of 5.5 mg (4 mol %) of Pd(dba)₂, 7 mg

(4.5 mol %) of BINAP, and 37 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

After chromatographic separation using petroleum

ether–methylene chloride (4:1), yield 24 mg (30%),

N-(1-Adamantylmethyl)-4-bromoaniline (IId)

was synthesized from 0.25 mmol (41 mg) of amine Ia

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

AVERIN et al.

1804

1

colorless oily substance. H NMR spectrum, δ, ppm:

1.60 br.s (6H), 1.65–1.78 m (6H), 2.02 br.s (3H),

2.83 s (2H), 4.38 br.s (1H), 6.51 t.d (1H, ³J = 7.5, ⁴J =

(12H) 1.62–1.76 m (12H), 1.98 br.s (6H), 2.71 d (4H,

3

³J = 6.2 Hz), 3.20 t (2H, J = 6.2 Hz), 6.54 s (4H).

¹³C NMR spectrum (before chromatographic purifica-

3

1.2 Hz), 6.64 d (1H, J = 8.1 Hz), 7.14 t.d (1H, J =

tion), δ_C, ppm: 28.4 (6C), 33.7 (2C), 37.1 (6C), 40.8

4

3

4

1

7.7, J = 1.2 Hz), 7.39 d.d (1H, J = 8.0, J = 1.1 Hz).

¹³C NMR spectrum, δ_C, ppm: 28.3 (3C), 34.0 (1C),

37.0 (3C), 40.7 (3C), 56.0 (1C), 109.7 (1C), 111.2 (1C),

117.0 (1C), 128.4 (1C), 132.2 (1C), 145.7 (1C).

MALDI-TOF mass spectrum: m/z 319.2 [M]⁺. Subse-

quent elution with the same solvent system gave 17 mg

(34%) of diamino derivative IIIc and 3 mg (5%) of

reduction product IV.

(6C), 58.0 (2C), 114.5 (4C), 141.4 (2C). H NMR

spectrum (after chromatographic purification), δ, ppm:

1.58 br.s (12H) 1.62–1.76 m (12H), 1.99 br.s (6H),

2.75 br.s (4H), 6.52 br.s (4H). MALDI-TOF mass

spectrum: m/z 404.3260 [M]⁺. C₂₈H₄₀N₂. Calculated:

M 404.3191.

N,N′-Bis(1-adamantylmethyl)benzene-1,3-di-

amine (IIIb). a. Compound IIIb was synthesized from

0.75 mmol (124 mg) of amine Ia and 0.25 mmol

(59 mg) of m-dibromobenzene in the presence of

5.5 mg (4 mol %) of Pd(dba)₂, 5 mg (5 mol %) of

DavePHOS, and 37 mg (1.5 equiv) of sodium tert-

butoxide in 2.5 ml of anhydrous dioxane.

N,N′-Bis(1-adamantylmethyl)benzene-1,2-di-

amine (IIIc) [12]. H NMR spectrum, δ, ppm:

1

1.65 br.s (12H), 1.66–1.80 m (12H), 2.03 br.s (6H),

2.74 s (4H), 3.34 br.s (2H), 6.65–6.70 m (2H), 6.73–

6.78 m (2H). ¹³C NMR spectrum, δ_C, ppm: 28.5 (6C),

33.6 (2C), 37.2 (6C), 41.0 (6C), 56.9 (2C), 112.3 (2C),

119.0 (2C), 138.5 (2C). MALDI-TOF mass spectrum:

m/z 404.5 [M]⁺.

b. The reaction was carried out with the same

amounts of amine Ia and m-dibromobenzene in the

presence of 14 mg (10 mol %) of Pd(dba)₂and 10 mg

(10 mol %) of DavePHOS. The products isolated in the

two experiments were combined and subjected to chro-

matography using petroleum ether–methylene chloride

(2 :1, 1:1) as eluent. Yield 50 mg (25%), colorless

N-(1-Adamantylmethyl)aniline (IV) was synthe-

sized from 0.25 mmol (41 mg) of amine Ia and

0.25 mmol (39 mg) of bromobenzene in the presence

of 5.5 mg (4 mol %) of Pd(dba)₂, 7 mg (4.5 mol %) of

BINAP, and 37 mg (1.5 equiv) of sodium tert-butoxide

in 2.5 ml of anhydrous dioxane. Yield 49 mg (82%),

1

crystalline powder, mp 168–170°C. H NMR spec-

trum, δ, ppm: 1.58 br.s (12H) 1.62–1.76 m (12H),

1

light yellow oily substance. H NMR spectrum, δ,

ppm: 1.61 s (6H) 1.65–1.79 m (6H), 2.03 br.s (3H),

2.00 br.s (6H), 2.77 s (4H), 3.55 br.s (2H), 5.88 t (1H,

3

4

⁴J = 2.0 Hz), 5.97 d.d (2H, J = 7.9, J = 2.0 Hz),

3

6.94 t (1H, ³J = 8.0 Hz). C NMR spectrum, δ_C, ppm:

13

2.81 d (2H, J = 5.7 Hz), 3.68 br.s (1H), 6.63 d (2H,

3

³J = 8.0 Hz), 6.67 t (1H, J = 7.5 Hz), 7.17 t (2H, J =

7.9 Hz). ¹³C NMR spectrum, δ_C, ppm: 28.3 (3C), 33.8

(1C), 37.0 (3C), 40.7 (3C), 56.2 (1C), 112.5 (2C),

116.6 (1C), 129.1 (2C), 149.2 (1C). MALDI-TOF

mass spectrum: m/z 241.2 [M]⁺.

28.4 (6C), 33.8 (2C), 37.1 (6C), 40.7 (6C), 56.3 (2C),

96.7 (1C), 102.1 (2C), 129.8 (1C), 150.4 (2C).

MALDI-TOF mass spectrum: m/z 404.3174 [M]⁺.

C₂₈H₄₀N₂. Calculated: M 404.3191. Elution with petro-

leum ether–methylene chloride (4:1) gave a mixture of

monoamino derivative IIe, reduction product IV, and

adamantane-1-carbaldehyde.

N,N′-Bis(1-adamantylmethyl)benzene-1,4-di-

amine (IIIa). a. Compound IIIa was synthesized from

0.3 mmol (50 mg) of amine Ia and 0.1 mmol (24 mg)

of p-dibromobenzene in the presence of 5 mg

(9 mol %) of Pd(dba)₂, 5 mg (18 mol %) of 2-(di-tert-

butylphosphino)biphenyl, and 37 mg (4 equiv) of

sodium tert-butoxide in 1 ml of anhydrous dioxane.

N-[α-(1-Adamantyl)benzyl]-4-chloroaniline (Va)

was synthesized from 0.25 mmol (61 mg) of amine Ib

and 0.25 mmol (48 mg) of p-bromochlorobenzene in

the presence of 5.5 mg (4 mol %) of Pd(dba)₂, 7 mg

(4.5 mol %) of BINAP, and 37 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

Yield 57 mg (65%), light yellow oily substance.

¹H NMR spectrum, δ, ppm: 1.46–1.75 m (12H),

2.00 br.s (3H), 3.83 s (1H), 4.40 br.s (1H), 6.41 d (2H,

b. The reaction was carried out with the same

amounts of amine Ia and p-dibromobenzene in the

presence of 5 mg (8 mol %) of Pd(dba)₂and 6 mg

(16 mol %) of DavePHOS. The products isolated in the

two experiments were combined and subjected to

chromatography using petroleum ether–methylene

chloride (4:1) as eluent. Yield 40 mg (50%), colorless

crystalline powder, mp 230–232°C. ¹H NMR spectrum

(before chromatographic purification), δ, ppm: 1.57 br.s

3

³J = 8.8 Hz), 6.98 d (2H, J = 8.8 Hz), 7.21–7.31 m

(5H). ¹³C NMR spectrum, δ_C, ppm: 28.3 (3C), 36.4

(1C), 36.8 (3C), 39.2 (3C), 68.0 (1C), 114.1 (2C),

121.3 (1C), 126.9 (1C), 127.6 (2C), 128.5 (2C), 128.7

(2C), 139.7 (1C), 146.3 (1C). MALDI-TOF mass spec-

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

ARYLATION OF ADAMANTANAMINES: II.

1805

trum: m/z 351.1778 [M]⁺. C₂₃H₂₆ClN. Calculated:

M 351.1754.

(4.5 mol %) of BINAP, and 37 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

Yield 59 mg (60%), light yellow oily substance.

¹H NMR spectrum, δ, ppm: 1.48–1.78 m (12H),

N-[α-(1-Adamantyl)benzyl]-3-chloroaniline (Vb)

was synthesized from 0.25 mmol (61 mg) of amine Ib

and 0.25 mmol (48 mg) of m-bromochlorobenzene in

the presence of 5.5 mg (4 mol %) of Pd(dba)₂, 7 mg

(4.5 mol %) of BINAP, and 37 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

Yield 66 mg (75%), light yellow oily substance.

¹H NMR spectrum, δ, ppm: 1.46–1.74 m (12H),

2.00 br.s (3H), 3.86 s (1H), 4.47 br.s (1H), 6.36 d.d.d

3

2.00 br.s (3H), 3.83 d (1H, J = 6.4 Hz), 4.39 d (1H,

³J = 6.4 Hz), 6.37 d (2H, ³J = 8.8 Hz), 7.11 d (2H, ³J =

8.8 Hz), 7.21–7.31 m (5H). ¹³C NMR spectrum, δ_C,

ppm: 28.3 (3C), 36.4 (1C), 36.8 (3C), 39.1 (3C), 67.9

(1C), 108.3 (1C), 114.6 (2C), 126.9 (1C), 127.6 (2C),

128.5 (2C), 131.6 (2C), 139.6 (1C), 146.7 (1C).

MALDI-TOF mass spectrum: m/z 395.2 [M]⁺.

3

4

(1H, J = 8.4, J = 2.2, 0.7 Hz), 6.50 t (1H, J =

N-[α-(1-Adamantyl)benzyl]-3-bromoaniline (Ve)

was synthesized from 0.25 mmol (61 mg) of amine Ib

and 0.25 mmol (59 mg) of m-dibromobenzene in the

presence of 5.5 mg (4 mol %) of Pd(dba)₂, 7 mg

(4.5 mol %) of BINAP, and 37 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

Yield 37 mg (37%) (after chromatography; petroleum

ether–methylene chloride, 4:1), colorless oily sub-

3

4

2.0 Hz), 6.55 d.d.d (1H, J = 7.9, J = 1.9, 0.8 Hz),

6.95 t (1H, J = 8.0 Hz), 7.22–7.32 m (5H). ¹³C NMR

3

spectrum, δ_C, ppm: 28.3 (3C), 36.4 (1C), 36.8 (3C),

39.2 (3C), 67.7 (1C), 111.2 (1C), 112.9 (1C), 116.6

(1C), 126.9 (1C), 127.7 (2C), 128.5 (2C), 129.9 (1C),

134.7 (1C), 139.5 (1C), 148.9 (1C). MALDI-TOF

mass spectrum: m/z 351.1805 [M]⁺. C₂₃H₂₆ClN. Calcu-

lated: M 351.1754.

1

stance. H NMR spectrum, δ, ppm: 1.45–1.80 m

(12H), 1.99 br.s (3H), 3.84 d (1H, ³J = 5.8 Hz), 4.41 d

(1H, ³J = 5.7 Hz), 6.37 d.d (1H, ³J = 8.4, ⁴J = 1.7 Hz),

N-[α-(1-Adamantyl)benzyl]-2-chloroaniline (Vc)

was synthesized from 0.25 mmol (61 mg) of amine Ib

and 0.25 mmol (48 mg) of o-bromochlorobenzene in

the presence of 5.5 mg (4 mol %) of Pd(dba)₂, 7 mg

(4.5 mol %) of BINAP, and 37 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

Yield 35 mg (40%) (after chromatography, petroleum

ether–methylene chloride, 4:1). Colorless crystalline

3

6.65–6.70 m (2H), 6.86 t (1H, J = 8.0 Hz), 7.20–

7.30 m (5H). ¹³C NMR spectrum, δ_C, ppm: 28.4 (3C),

36.6 (1C), 36.9 (3C), 39.2 (3C), 67.7 (1C), 111.5 (1C),

115.9 (1C), 119.6 (1C), 123.0 (1C), 127.0 (1C), 127.7

(2C), 128.5 (2C), 130.3 (1C), 139.5 (1C), 149.1 (1C).

MALDI-TOF mass spectrum: m/z 395.1271 [M]⁺.

C₂₃H₂₆BrN. Calculated: M 395.1249. Elution with the

same solvent system gave 7 mg (12%) of 1-adamantyl

phenyl ketone.

1

powder, mp 176–178°C. H NMR spectrum, δ, ppm:

3

1.50–1.82 m (12H), 2.01 br.s (3H), 3.91 d (1H, J =

6.4), 5.13 d (1H, ³J = 6.3 Hz), 6.33 d (1H, ³J = 8.2 Hz),

3

4

3

6.50 t.d (1H, J = 7.6, J = 1.4 Hz), 6.89 t (1H, J =

N-[α-(1-Adamantyl)benzyl]-2-bromoaniline (Vf)

was synthesized from 0.25 mmol (61 mg) of amine Ib

and 0.25 mmol (59 mg) of o-dibromobenzene in the

presence of 5.5 mg (4 mol %) of Pd(dba)₂, 7 mg

(4.5 mol %) of BINAP, and 37 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

Yield 40 mg (40%) (after chromatography; petroleum

ether–methylene chloride, 4:1), colorless oily sub-

3

4

7.8 Hz), 7.20 d.d (1H, J = 7.8, J = 1.4 Hz), 7.21–

7.31 m (5H). ¹³C NMR spectrum, δ_C, ppm: 28.4 (3C),

36.6 (1C), 36.9 (3C), 39.3 (3C), 67.8 (1C), 112.0 (1C),

116.5 (1C), 119.2 (1C), 126.9 (1C), 127.5 (1C), 127.6

(2C), 128.6 (2C), 128.7 (1C), 139.5 (1C), 143.4 (1C).

MALDI-TOF mass spectrum: m/z 351.1772 [M]⁺.

C₂₃H₂₆ClN. Calculated: M 351.1754. Elution with

petroleum ether–methylene chloride (2:1) gave 11 mg

1

stance. H NMR spectrum, δ, ppm: 1.47–1.80 m

1

(12H), 2.01 br.s (3H), 3.91 d (1H, ³J = 6.4 Hz), 5.16 d

(1H, ³J = 6.4 Hz), 6.30 d.d (1H, ³J = 8.1, ⁴J = 1.0 Hz),

(18%) of 1-adamantyl phenyl ketone. H NMR spec-

trum, δ, ppm: 1.68–1.78 m (6H), 2.00 br.s (6H),

3

4

3

2.06 br.s (3H), 7.35–7.45 m (3H), 7.53 d.d (2H, J =

6.43 t.d (1H, J = 7.6, J = 1.4 Hz), 6.92 t.d (1H, J =

7.8, ⁴J = 1.0 Hz), 7.21–7.31 m (5H), 7.36 d.d (1H, ³J =

4

8.2, J = 1.3 Hz). ¹³C NMR spectrum, δ_C, ppm: 28.1

8.0, J = 1.4 Hz). ¹³C NMR spectrum, δ_C, ppm: 28.4

4

(3C), 36.5 (3C), 39.1 (3C), 46.9 (1C), 127.1 (2C),

127.9 (2C), 130.1 (1C), 139.6 (1C), 210.2 (1C).

(3C), 36.7 (1C), 36.9 (3C), 39.3 (3C), 68.0 (1C), 110.1

(1C), 112.1 (1C), 117.1 (1C), 126.9 (1C), 127.7 (2C),

128.2 (1C), 128.6 (2C), 132.0 (1C), 139.4 (1C), 144.3

(1C). MALDI-TOF mass spectrum: m/z 395.1261

[M]⁺. C₂₃H₂₆BrN. Calculated: M 395.1249. Elution

N-[α-(1-Adamantyl)benzyl]-4-bromoaniline (Vd)

was synthesized from 0.25 mmol (61 mg) of amine Ib

and 0.25 mmol (59 mg) of p-dibromobenzene in the

presence of 5.5 mg (4 mol %) of Pd(dba)₂, 7 mg

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

AVERIN et al.

1806

with the same solvent system gave 7 mg (12%) of

1-adamantyl phenyl ketone.

of Pd(dba)₂, 16 mg (16 mol %) of DavePHOS, and

72 mg (3 equiv) of sodium tert-butoxide in 2.5 ml of

anhydrous dioxane. Yield 36 mg (26%) (after chroma-

tography; petroleum ether–methylene chloride, 4:1),

N,N′-Bis[α-(1-adamantyl)benzyl]benzene-

1,4-diamine (VIa) was synthesized from 0.75 mmol

(182 mg) of amine Ib and 0.25 mmol (59 mg) of

p-dibromobenzene in the presence of 12 mg (8 mol %)

of Pd(dba)₂, 16 mg (16 mol %) of DavePHOS, and

72 mg (3 equiv) of sodium tert-butoxide in 2.5 ml of

anhydrous dioxane. Yield 23 mg (17%) (after chroma-

tography; petroleum ether–methylene chloride, 2:1),

1

colorless oily substance. H NMR spectrum, δ, ppm

(mixture of two diastereoisomers): 1.48–1.80 m (48H),

2.05 br.s (12H), 3.93 s (2H), 3.94 s (2H), 4.23 br.s

(4H), 6.28-6.36 m (4H), 6.41–6.47 m (4H), 7.20–

7.25 m (4H), 7.28–7.35 m (16H). ¹³C NMR spectrum,

δ_C, ppm (mixture of two diastereoisomers): 28.6 (12C),

36.5 (4C), 37.1 (12C), 39.6 (12C), 68.0 (4C), 112.8

(2C), 113.1 (2C), 118.5 (4C), 126.7 (4C), 127.6 (8C),

128.5 (4C), 128.6 (4C), 137.0 (2C), 137.1 (2C), 140.1

(2C), 140.2 (2C). MALDI-TOF mass spectrum: m/z

556.3 [M]⁺. Elution with the same solvent system gave

1

colorless oily substance. H NMR spectrum (after

chromatography), δ, ppm: 1.50–1.76 m (24H), 1.93 br.s

(6H), 3.70 br.s (4H), 6.25 br.s (4H), 7.18 br.s (10H).

¹³C NMR spectrum (after chromatography), δ_C, ppm:

28.5 (6C), 37.0 (6C), 39.3 (6C), 126.5 (2C), 127.4 br.s

(4C), 128.7 (4C) (signals from 12 carbon atoms were

not observed). MALDI-TOF mass spectrum: m/z 556.2

[M]⁺. Elution with petroleum ether–methylene chloride

(4:1) gave 15 mg (19%) of N-[α-(1-adamantyl)benzyl]-

aniline (VII), 8 mg (13%) of 1-adamantyl phenyl

ketone, and 8 mg (6%) of diamination product VIb.

1

20 mg (25%) of reduction product VII [14]. H NMR

spectrum, δ, ppm: 1.48–1.80 m (12H), 2.02 br.s (3H),

3

3.91 s (1H), 4.34 br.s (1H), 6.52 d (2H, J = 7.7 Hz),

6.60 t (1H, ³J = 7.3 Hz), 7.06 t (2H, ³J = 7.9 Hz), 7.20–

7.34 m (5H). ¹³C NMR spectrum, δ_C, ppm: 28.4 (3C),

36.5 (1C), 36.9 (3C), 39.2 (3C), 67.9 (1C), 113.1 (2C),

116.7 (1C), 126.7 (1C), 127.6 (2C), 128.7 (2C), 129.0

(2C), 140.0 (1C), 147.9 (1C). MALDI-TOF mass spec-

trum: m/z 317.2100 [M]⁺. C₂₃H₂₇N. Calculated:

M 317.2143. Elution with petroleum ether–methylene

chloride (2:1) gave 11 mg (18%) of 1-adamantyl

phenyl ketone.

N,N′-Bis[α-(1-adamantyl)benzyl]benzene-

1,3-diamine (VIb) was synthesized from 0.75 mmol

(182 mg) of amine Ib and 0.25 mmol (59 mg) of

m-dibromobenzene in the presence of 12 mg (8 mol %)

of Pd(dba)₂, 16 mg (16 mol %) of DavePHOS, and

72 mg (3 equiv) of sodium tert-butoxide in 2.5 ml of

anhydrous dioxane. Yield 88 mg (63%) (after chroma-

tography; petroleum ether–methylene chloride, 4:1,

N-[1-(1-Adamantyl)propyl]-4-chloroaniline

(VIIIa) was synthesized from 0.25 mmol (48 mg) of

amine Ic and 0.25 mmol (48 mg) of p-bromochloro-

benzene in the presence of 5.5 mg (4 mol %) of

Pd(dba)₂, 7 mg (4.5 mol %) of BINAP, and 37 mg

(1.5 equiv) of sodium tert-butoxide in 2.5 ml of anhy-

drous dioxane. Yield 38 mg (50%), light yellow oily

substance. ¹H NMR spectrum, δ, ppm: 0.86 t (3H, ³J =

7.3 Hz), 1.08–1.20 m (1H), 1.50–1.82 m (13H),

1.95 br.s (3H), 2.75 t (1H, ³J = 10.2 Hz), 3.35 d (1H,

³J = 9.8 Hz), 6.48 d (2H, ³J = 8.8 Hz), 7.02 d (2H, ³J =

8.8 Hz). ¹³C NMR spectrum, δ_C, ppm: 11.9 (1C), 23.0

(1C), 28.4 (3C), 37.1 (3C), 37.8 (1C), 39.0 (3C), 64.6

(1C), 113.2 (2C), 119.8 (1C), 128.2 (2C), 149.0 (1C).

MALDI-TOF mass spectrum: m/z 303.1694 [M]⁺.

C₁₉H₂₆ClN. Calculated: M 303.1754.

1

2:1). Light brown crystals, mp 100–102°C. H NMR

spectrum, δ, ppm (mixture of two diastereoisomers):

1.40–1.72 m (48H), 1.98 br.s (12H), 3.69 br.s (2H),

3.77 s (2H), 4.13 br.s (4H), 5.61 br.s (1H), 5.73 br.s

(1H), 5.80 d.d (2H, ³J = 8.0, ⁴J = 0.9 Hz), 5.82 d.d (2H,

4

3

³J = 8.0, J = 0.8 Hz), 6.73 t (1H, J = 8.0 Hz), 6.75 t

(1H, ³J = 8.0 Hz), 7.15–7.32 m (20H). ¹³C NMR spec-

trum, δ_C, ppm (mixture of two diastereoisomers): 28.4

(12C), 36.5 (4C), 36.9 (12C), 39.1 (6C), 39.2 (6C),

67.6 (2C), 68.0 (2C), 97.6 (1C), 98.2 (1C), 102.8 (2C),

103.1 (2C), 126.4 (2C), 126.5 (2C), 127.4 (8C), 128.5

(4C), 128.7 (4C), 129.3 (1C), 129.4 (1C), 140.6 (2C),

140.7 (2C), 148.9 (2C), 149.0 (2C). MALDI-TOF

mass spectrum: m/z 556.3880 [M]⁺. C₄₀H₄₈N₂. Cal-

culated: M 556.3817. Elution with petroleum ether–

methylene chloride (4:1) gave 5 mg (6%) of reduction

product VII.

N-[1-(1-Adamantyl)propyl]-3-chloroaniline

(VIIIb) was synthesized from 0.25 mmol (48 mg) of

amine Ic and 0.25 mmol (48 mg) of m-bromochloro-

benzene in the presence of 5.5 mg (4 mol %) of

Pd(dba)₂, 7 mg (4.5 mol %) of BINAP, and 37 mg

(1.5 equiv) of sodium tert-butoxide in 2.5 ml of anhy-

drous dioxane; the mixture was heated for 7 h under

N,N′-Bis[α-(1-adamantyl)benzyl]benzene-

1,2-diamine (VIc) was synthesized from 0.75 mmol

(182 mg) of amine Ib and 0.25 mmol (59 mg) of

o-dibromobenzene in the presence of 12 mg (8 mol %)

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

ARYLATION OF ADAMANTANAMINES: II.

1807

reflux. Yield 40 mg (53%), light yellow oily substance.

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

3

¹H NMR spectrum, δ, ppm: 0.88 t (3H, J = 7.3 Hz),

Yield 41 mg (48%), light yellow oily substance.

3

¹H NMR spectrum, δ, ppm: 0.89 t (3H, J = 7.3 Hz),

1.07–1.19 m (1H), 1.50–1.74 m (12H), 1.75–1.84 m

3

1.08–1.19 m (1H), 1.50–1.74 m (12H), 1.75–1.83 m

(1H), 1.96 br.s (3H), 2.78 t (1H, J = 10.3 Hz), 3.43 d

3

4

(1H, ³J = 9.8 Hz), 6.44 d.d (1H, ³J = 8.2 , ⁴J = 2.2 Hz),

(1H), 1.97 br.s (3H), 2.79 t.d (1H, J = 10.3, J =

3

1.2 Hz), 3.41 d (1H, J = 10.0 Hz), 6.48 d.d (1H, J =

6.52 d (1H, J = 7.8 Hz), 6.55 t (1H, J = 1.9 Hz),

4

3

6.98 t (1H, ³J = 8.0 Hz). C NMR spectrum, δ_C, ppm:

13

8.0, J = 2.0 Hz), 6.67 d (1H, J = 7.9 Hz), 6.72 br.s

(1H), 6.94 t (1H, ³J = 8.0 Hz). ¹³C NMR spectrum, δ_C,

ppm: 11.9 (1C), 22.9 (1C), 28.4 (3C), 37.1 (3C), 37.8

(1C), 39.0 (3C), 64.3 (1C), 110.9 (1C), 114.7 (1C),

118.5 (1C), 123.2 (1C), 130.4 (1C), 151.6 (1C).

MALDI-TOF mass spectrum: m/z 347.3 [M]⁺.

11.8 (1C), 22.9 (1C), 28.4 (3C), 37.1 (3C), 37.8 (1C),

39.0 (3C), 64.3 (1C), 110.5 (1C), 111.7 (1C), 115.5

(1C), 130.0 (1C), 134.8 (1C), 151.5 (1C). MALDI-

TOF mass spectrum: m/z 303.1778 [M]⁺. C₁₉H₂₆ClN.

Calculated: M 303.1754.

N-[1-(1-Adamantyl)propyl]-2-bromoaniline

(VIIIf) was synthesized from 0.25 mmol (48 mg) of

amine Ic and 0.25 mmol (59 mg) of o-dibromobenzene

in the presence of 5.5 mg (4 mol %) of Pd(dba)₂, 7 mg

(4.5 mol %) of BINAP, and 37 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane;

the mixture was heated for 14 h under reflux. Yield

11 mg (13%) (after chromatography; petroleum ether–

methylene chloride, 10:1), colorless oily substance.

N-[1-(1-Adamantyl)propyl]-2-chloroaniline

(VIIIc) was synthesized from 0.25 mmol (48 mg) of

amine Ic and 0.25 mmol (48 mg) of o-bromochloro-

benzene in the presence of 5.5 mg (4 mol %) of

Pd(dba)₂, 7 mg (4.5 mol %) of BINAP, and 37 mg

(1.5 equiv) of sodium tert-butoxide in 2.5 ml of anhy-

drous dioxane. Yield 38 mg (50%), light yellow oily

substance. ¹H NMR spectrum, δ, ppm: 0.89 t (3H, ³J =

7.0 Hz), 1.15–1.25 m (1H), 1.51–1.80 m (13H),

3

¹H NMR spectrum, δ, ppm: 0.89 t (3H, J = 7.2 Hz),

3

4

1.96 br.s (3H), 2.88 t.d (1H, J = 10.3, J = 1.3 Hz),

3

4

1.10–1.20 m (1H), 1.50–1.74 m (12H), 1.75–1.85 m

(1H), 1.97 br.s (3H), 2.88 t.d (1H, ³J = 10.3 Hz), 4.11 d

(1H, ³J = 9.5 Hz), 6.44 t (1H, ³J = 7.5 Hz), 6.67 d (1H,

³J = 8.3 Hz), 7.09 t (1H, ³J = 7.5 Hz), 7.38 d (1H, ³J =

7.8 Hz). ¹³C NMR spectrum, δ_C, ppm: 11.8 (1C), 22.9

(1C), 28.5 (3C), 37.2 (3C), 37.9 (1C), 39.0 (3C), 64.9

(1C), 109.2 (1C), 111.6 (1C), 116.2 (1C), 128.2 (1C),

132.4 (1C), 146.8 (1C). MALDI-TOF mass spectrum:

m/z 347.1302 [M]⁺. C₁₉H₂₆BrN. Calculated:

M 347.1249. Elution with the same solvent system

gave 3 mg (4.5%) of reduction product X. Elution with

petroleum ether–methylene chloride (2:1) gave 10 mg

(21%) of 1-(1-adamantyl)propan-1-one. ¹H NMR spec-

4.07 d (1H, J = 9.6 Hz), 6.49 t.d (1H, J = 7.9, J =

3

1.3 Hz), 6.69 d (1H, J = 8.1 Hz), 7.04 t (1H, J =

7.8 Hz), 7.20 t.d (1H, ³J = 7.8, ⁴J = 1.3 Hz). ¹³C NMR

spectrum, δ_C, ppm: 11.7 (1C), 22.8 (1C), 28.4 (3C),

37.1 (3C), 37.8 (1C), 38.9 (3C), 64.6 (1C), 111.4 (1C),

115.6 (1C), 123.1 (1C), 127.5 (1C), 129.0 (1C), 145.8

(1C). MALDI-TOF mass spectrum: m/z 303.16 [M]⁺.

N-[1-(1-Adamantyl)propyl]-4-bromoaniline

(VIIId) was synthesized from 0.25 mmol (48 mg) of

amine Ic and 0.25 mmol (59 mg) of p-dibromobenzene

in the presence of 5.5 mg (4 mol %) of Pd(dba)₂, 7 mg

(4.5 mol %) of BINAP, 37 mg (1.5 equiv) of sodium

tert-butoxide in 2.5 ml of anhydrous dioxane; the mix-

ture was heated for 7 h under reflux. Yield 41 mg

(48%), light yellow oily substance. ¹H NMR spectrum,

3

trum, δ, ppm: 0.99 t (3H, J = 7.5 Hz), 1.63–1.76 m

(6H), 1.79 br.s (6H), 2.02 br.s (3H), 2.45 q (3H,

³J = 7.5 Hz).

3

δ, ppm: 0.88 t (3H, J = 7.2 Hz), 1.07–1.19 m (1H),

N,N′-Bis[1-(1-adamantyl)propyl]benzene-

1,4-diamine (IXa) was synthesized from 0.75 mmol

(144 mg) of amine Ic and 0.25 mmol (59 mg) of

p-dibromobenzene in the presence of 12 mg (8 mol %)

of Pd(dba)₂, 14 mg (9 mol %) of BINAP, and 72 mg

(3 equiv) of sodium tert-butoxide in 2.5 ml of anhy-

drous dioxane. The diamination product was detected

1.50–1.73 m (12H), 1.74–1.82 m (1H), 1.96 br.s (3H),

3

2.76 t (1H, J = 9.5 Hz), 3.37 d (1H, J = 9.9 Hz),

3

6.46 d (2H, J = 8.6 Hz), 7.17 d (2H, J = 8.6 Hz).

¹³C NMR spectrum, δ_C, ppm: 11.9 (1C), 23.0 (1C),

28.4 (3C), 37.1 (3C), 37.8 (1C), 39.0 (3C), 64.5 (1C),

106.8 (1C), 113.7 (2C), 131.7 (2C), 149.4 (1C).

MALDI-TOF mass spectrum: m/z 347.3 [M]⁺.

1

only in the reaction mixture. H NMR spectrum:

N-[1-(1-Adamantyl)propyl]-3-bromoaniline

(VIIIe) was synthesized from 0.25 mmol (48 mg) of

amine Ic and 0.25 mmol (59 mg) of m-dibromoben-

zene in the presence of 5.5 mg (4 mol %) of Pd(dba)₂,

7 mg (4.5 mol %) of BINAP, and 37 mg (1.5 equiv) of

δ 6.42 ppm (C₆H₄). ¹³C NMR spectrum, δ_C, ppm: 114.0

(4C) and 142.0 (2C) (C₆H₄). MALDI-TOF mass spec-

trum: m/z 460.41 [M]⁺. Chromatographic separation

using petroleum ether–methylene chloride (5:1) as

eluent gave 17 mg (25%) of reduction product X, and

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

AVERIN et al.

1808

elution with petroleum ether–methylene chloride (2:1)

gave 19 mg (40%) of 1-(1-adamantyl)propan-1-one.

of amine Id and 0.25 mmol (48 mg) of m-bromo-

chlorobenzene in the presence of 5.5 mg (4 mol %) of

Pd(dba)₂, 7 mg (4.5 mol %) of BINAP, and 37 mg

(1.5 equiv) of sodium tert-butoxide in 2.5 ml of anhy-

drous dioxane. Yield 61 mg (81%), light yellow oily

substance. ¹H NMR spectrum, δ, ppm: 1.14 d (3H, ³J =

5.2 Hz), 1.22–1.31 m (2H), 1.54 br.s (6H), 1.58–

N,N′-Bis[1-(1-adamantyl)propyl]benzene-

1,3-diamine (IXb) was synthesized from 0.75 mmol

(144 mg) of amine Ic and 0.25 mmol (59 mg) of

m-dibromobenzene in the presence of 12 mg (8 mol %)

of Pd(dba)₂, 14 mg (9 mol %) of BINAP, and 72 mg

(3 equiv) of sodium tert-butoxide in 2.5 ml of anhy-

drous dioxane. Yield 38 mg (33%) (after chromatog-

raphy; petroleum ether–methylene chloride, 5:1), color-

3

1.72 m (6H), 1.94 br.s (3H), 3.44 d (1H, J = 7.7 Hz),

3

3.52–3.62 m (1H), 6.40 d (1H, J = 8.1 Hz), 6.53 br.s

3

(1H), 6.60 d (1H, J = 7.8 Hz), 7.04 t.d (1H, J = 8.0,

⁴J = 1.0 Hz). ¹³C NMR spectrum, δ_C, ppm: 23.1 (1C),

28.6 (3C), 32.5 (1C), 36.9 (3C), 43.0 (3C), 44.0 (1C),

52.8 (1C), 111.1 (1C), 112.2 (1C), 116.2 (1C), 130.2

(1C), 135.0 (1C), 148.3 (1C). MALDI-TOF mass

spectrum: m/z 303.1778 [M]⁺. C₁₉H₂₆ClN. Calculated:

M 303.1754.

1

less oily substance. H NMR spectrum, δ, ppm: 0.90 t

3

(6H, J = 7.2 Hz), 1.07–1.17 m (2H), 1.53–1.71 m

(24H), 1.77 d.q.d (2H, ³J = 13.2, 6.8, 1.9 Hz), 1.95 br.s

3

(6H), 2.75 t (2H, J = 8.7 Hz), 3.17 d (2H, J =

3

6.8 Hz), 5.83 s (1H), 5.87 d (2H, J = 8.0 Hz), 6.85 t

(1H, J = 7.9 Hz). ¹³C NMR spectrum, δ_C, ppm: 12.2

3

(2C), 23.3 (2C), 28.6 (6C), 37.3 (6C), 37.8 (2C), 39.2

(6C), 64.3 (2C), 96.6 and 96.7 (1C), 101.4 (2C), 129.6

(1C), 151.5 (2C). MALDI-TOF mass spectrum: m/z

460.3738 [M]⁺. C₃₂H₄₈N₂. Calculated: M 460.3817.

Elution with petroleum ether–methylene chloride,

(10:1) gave 16 mg (24%) of reduction product X.

N-[2-(1-Adamantyl)-1-methylethyl]-2-chloroani-

line (XIc) was synthesized from 0.25 mmol (48 mg) of

amine Id and 0.25 mmol (48 mg) of o-bromochloro-

benzene in the presence of 5.5 mg (4 mol %) of

Pd(dba)₂, 7 mg (4.5 mol %) of BINAP, and 37 mg

(1.5 equiv) of sodium tert-butoxide in 2.5 ml of anhy-

drous dioxane. Yield 62 mg (82%), light yellow oily

substance. ¹H NMR spectrum, δ, ppm: 1.18 d (3H, ³J =

6.1 Hz), 1.30 d.d (1H, ²J = 14.6, ³J = 3.7 Hz), 1.40 d.d

(1H, J = 14.6, J = 7.5 Hz), 1.57 br.s (6H), 1.58–

1.72 m (6H), 1.94 br.s (3H), 3.59–3.68 m (1H), 4.10 d

(1H, ³J = 7.4 Hz), 6.57 t (1H, ³J = 7.6 Hz), 6.67 d (1H,

³J = 8.1 Hz), 7.13 t (1H, ³J = 7.3 Hz), 7.24 d (1H, ³J =

8.2 Hz). ¹³C NMR spectrum, δ_C, ppm: 23.1 (1C), 28.6

(3C), 32.5 (1C), 36.9 (3C), 43.0 (3C), 43.8 (1C), 52.7

(1C), 111.1 (1C), 116.1 (1C), 118.8 (1C), 127.7 (1C),

129.2 (1C), 143.0 (1C). MALDI-TOF mass spectrum:

m/z 303.12 [M]⁺.

3

¹H NMR spectrum, δ, ppm: 0.91 t (3H, J = 7.0 Hz),

1.12–1.18 m (1H), 1.55–1.74 m (12H), 1.77–1.84 d.q.d

3

(1H, J = 14.2 Hz, J = 7.4, 2.5 Hz), 1.97 br.s (3H),

3

2

3

2.83 t (1H, J = 9.5 Hz), 3.32 d (1H, J = 9.0 Hz),

6.57 t (1H, ³J = 7.4 Hz), 6.59 d (2H, J = 7.8 Hz),

3

13

7.11 t (2H, J = 7.9 Hz). C NMR spectrum, δ_C, ppm:

12.0 (1C), 23.2 (1C), 28.5 (3C), 37.3 (3C), 37.9 (1C),

39.2 (3C), 64.3 (1C), 112.3 (2C), 115.8 (1C), 129.2

(2C), 150.4 (1C). MALDI-TOF mass spectrum:

m/z 269.2208 [M]⁺. C₁₉H₂₇N. Calculated: M 269.2143.

N-[2-(1-Adamantyl)-1-methylethyl]-4-chloroani-

line (XIa) was synthesized from 0.25 mmol (48 mg) of

amine Id and 0.25 mmol (48 mg) of p-bromochloro-

benzene in the presence of 5.5 mg (4 mol %) of

Pd(dba)₂, 7 mg (4.5 mol %) of BINAP, and 37 mg

(1.5 equiv) of sodium tert-butoxide in 2.5 ml of anhy-

drous dioxane. Yield 67 mg (89%), light yellow oily

substance. ¹H NMR spectrum, δ, ppm: 1.14 d (3H, ³J =

5.4 Hz), 1.23 d.d (1H, ²J = 14.5, ³J = 4.0 Hz), 1.30 d.d

N-[2-(1-Adamantyl)-1-methylethyl]-4-bromoani-

line (XId) was synthesized from 0.25 mmol (48 mg)

of amine Id and 0.25 mmol (59 mg) of p-dibromoben-

zene in the presence of 5.5 mg (4 mol %) of Pd(dba)₂,

7 mg (4.5 mol %) of BINAP, and 37 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

Yield 65 mg (75%), light yellow oily substance.

2

3

¹H NMR spectrum, δ, ppm: 1.10 t (3H, J = 6.1 Hz),

(1H, J = 14.5, J = 7.2 Hz), 1.54 br.s (6H), 1.57–

3

1.18 d.d (1H, ²J = 14.5, ³J = 4.0 Hz), 1.25 d.d (1H, ²J =

1.72 m (6H), 1.93 br.s (3H), 3.36 d (1H, J = 7.7 Hz),

3.50–3.59 m (1H), 6.47 d (2H, ³J = 8.6 Hz), 7.13 d (2H,

³J = 8.6 Hz). ¹³C NMR spectrum, δ_C, ppm: 23.1 (1C),

28.6 (3C), 32.5 (1C), 36.9 (3C), 43.0 (3C), 44.2 (1C),

52.7 (1C), 113.8 (2C), 120.9 (1C), 129.0 (2C), 145.8

(1C). MALDI-TOF mass spectrum: m/z 303.18 [M]⁺.

3

14.5, J = 7.0 Hz), 1.50 br.s (6H), 1.53–1.69 m (6H),

3

1.89 br.s (3H), 3.42 d (1H, J = 7.6 Hz), 3.45–3.55 m

3

(1H), 6.39 d (2H, J = 8.9 Hz), 7.18 d (2H, J =

8.9 Hz). ¹³C NMR spectrum, δ_C, ppm: 23.0 (1C), 28.5

(3C), 32.4 (1C), 36.8 (3C), 42.9 (3C), 44.0 (1C), 52.6

(1C), 107.6 (1C), 114.2 (2C), 131.8 (2C), 146.1 (1C).

MALDI-TOF mass spectrum: m/z 345.0 [M – H₂]⁺.

N-[2-(1-Adamantyl)-1-methylethyl]-3-chloroani-

line (XIb) was synthesized from 0.25 mmol (48 mg)

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

ARYLATION OF ADAMANTANAMINES: II.

1809

(petroleum ether–methylene chloride, 5:1 to 2:1) we

isolated 9 mg (13%) of reduction product XIII.

N-[2-(1-Adamantyl)-1-methylethyl]-3-bromoani-

line (XIe) was synthesized from 0.25 mmol (48 mg) of

amine Id and 0.25 mmol (59 mg) of m-dibromoben-

zene in the presence of 5.5 mg (4 mol %) of Pd(dba)₂,

7 mg (4.5 mol %) of BINAP, and 37 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

Yield 58 mg (67%), light yellow oily substance.

N,N′-Bis[2-(1-adamantyl)-1-methylethyl]benzene-

1,3-diamine (XIIb) was synthesized from 0.75 mmol

(144 mg) of amine Id and 0.25 mmol (59 mg) of

m-dibromobenzene in the presence of 12 mg (8 mol %)

of Pd(dba)₂, 14 mg (9 mol %) of BINAP, and 72 mg

(3 equiv) of sodium tert-butoxide in 2.5 ml of anhy-

drous dioxane. Yield 58 mg (50%) (after chromatog-

raphy; petroleum ether–methylene chloride, 1:1), color-

less oily substance. ¹H NMR spectrum, δ, ppm: 1.17 d

(6H, ³J = 6.2 Hz), 1.21 d.d (2H, ²J = 14.4, ³J = 3.9 Hz),

3

¹H NMR spectrum, δ, ppm: 1.14 d (3H, J = 6.1 Hz),

1.21–1.32 m (2H), 1.55 br.s (6H), 1.57–1.74 m (6H),

3

1.94 br.s (3H), 3.44 d (1H, J = 7.5 Hz), 3.52–3.62 m

3

(1H), 6.45 d (1H, J = 8.1 Hz), 6.68 br.s (1H), 6.75 d

3

(1H, J = 7.6 Hz), 6.98 t (1H, J = 8.0 Hz). ¹³C NMR

spectrum, δ_C, ppm: 23.0 (1C), 28.6 (3C), 32.5 (1C),

36.9 (3C), 43.0 (3C), 44.0 (1C), 52.8 (1C), 111.5

(1C), 115.1 (1C), 119.1 (1C), 123.3 (1C), 130.5 (1C),

148.5 (1C). MALDI-TOF mass spectrum: m/z 345.0

[M – H₂]⁺.

2

3

1.34 d.d (2H, J = 14.4, J = 6.8 Hz), 1.58 br.s (12H),

1.59–1.71 m (12H), 1.94 br.s (6H), 3.26 br.s (2H),

3

3.54–3.64 m (2H), 5.79 br.s (1H), 5.92 d (2H, J =

3

7.9), 6.95 t (two very closely located triplets, 1H, J =

8.0 Hz). ¹³C NMR spectrum, δ_C, ppm: 23.5 (1C), 23.6

(1C), 28.7 (6C), 32.5 (2C), 37.0 (6C), 43.1 (6C), 44.0

(2C), 53.0 (2C), 97.1 and 97.3 (1C), 102.3 (1C), 102.4

(1C), 129.9 (1C), 148.4 (2C). MALDI-TOF mass spec-

trum: m/z 460.3790 [M]⁺. C₃₂H₄₈N₂. Calculated:

M 460.3817. Elution with petroleum ether–methylene

chloride (5:1) gave 16 mg (23%) of compound XIII.

N-[2-(1-Adamantyl)-1-methylethyl]-2-bromoani-

line (XIf) was synthesized from 0.25 mmol (48 mg) of

amine Id and 0.25 mmol (59 mg) of o-dibromoben-

zene in the presence of 5.5 mg (4 mol %) of Pd(dba)₂,

7 mg (4.5 mol %) of BINAP, and 37 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

Yield 56 mg (65%), light yellow oily substance.

N,N′-Bis[2-(1-adamantyl)-1-methylethyl]benzene-

1,2-diamine (XIIc) was synthesized from 0.75 mmol

(144 mg) of amine Id and 0.25 mmol (59 mg) of

o-dibromobenzene in the presence of 12 mg (8 mol %)

of Pd(dba)₂, 16 mg (16 mol %) of DavePHOS, and

72 mg (3 equiv) of sodium tert-butoxide in 2.5 ml of

anhydrous dioxane. Yield 41 mg (35%) (after chroma-

tography; petroleum ether–methylene chloride, 2:1),

3

¹H NMR spectrum, δ, ppm: 1.18 d (3H, J = 6.3 Hz),

1.31 d.d (1H, ²J = 14.5 Hz, ³J = 3.2 Hz), 1.40 d.d (1H,

²J = 14.5 Hz, ³J = 7.8 Hz), 1.57 br.s (6H), 1.58–1.71 m

(6H), 1.94 br.s (3H), 3.57–3.68 m (1H), 4.12 d (1H,

³J = 7.1 Hz), 6.50 t (1H, ³J = 7.6 Hz), 6.63 d (1H, ³J =

3

8.1 Hz), 7.17 t (1H, J = 7.7 Hz), 7.40 d (1H, J =

7.8 Hz). ¹³C NMR spectrum, δ_C, ppm: 23.1 (1C), 28.6

(3C), 32.5 (1C), 37.0 (3C), 43.0 (3C), 44.1 (1C), 52.8

(1C), 109.7 (1C), 111.2 (1C), 116.7 (1C), 128.4 (1C),

132.5 (1C), 143.9 (1C). MALDI-TOF mass spectrum:

m/z 347.3 [M]⁺.

1

colorless oily substance. H NMR spectrum, δ, ppm:

3

1.18 d (6H, J = 5.6 Hz), 1.24–1.33 m (2H), 1.37–

1.46 m (2H), 1.58 br.s (12H), 1.60–1.72 m (12H),

1.94 br.s (6H), 3.04 br.s (2H), 3.52–3.62 m (2H),

6.71 br.s (2H), 6.76 br.s (2H). ¹³C NMR spectrum, δ_C,

ppm: 23.1 (1C), 23.5 (1C), 28.7 (6C), 32.5 (1C), 32.6

(1C), 37.0 (6C), 43.1 (6C), 43.8 (1C), 44.2 (1C), 53.0

(1C), 53.1 (1C), 112.0 (1C), 113.1 (1C), 118.2 (1C),

118.6 (1C), 136.4 (1C), 136.7 (1C). MALDI-TOF

mass spectrum: m/z 460.34 [M]⁺. Elution with petro-

leum ether–methylene chloride (5:1) gave 22 mg

N,N′-Bis[2-(1-adamantyl)-1-methylethyl]benzene-

1,4-diamine (XIIa) was synthesized from 0.75 mmol

(144 mg) of amine Id and 0.25 mmol (59 mg) of

p-dibromobenzene in the presence of 12 mg (8 mol %)

of Pd(dba)₂, 16 mg (16 mol %) of DavePHOS, and

72 mg (3 equiv) of sodium tert-butoxide in 2.5 ml of

anhydrous dioxane. Compound XIIa separated from

the reaction mixture as colorless crystals. Yield 32 mg

1

(32%) of reduction product XIII. H NMR spectrum,

3

2

1

3

δ, ppm: 1.15 d (3H, J = 7.0 Hz), 1.22 d.d (1H, J =

(28%). H NMR spectrum, δ, ppm: 1.12 t (6H, J =

3

2

3

6.0 Hz), 1.17 d.d (2H, ²J = 14.1, ³J = 4.1 Hz), 1.31 d.d

14.4, J = 4.2 Hz), 1.31 d.d (1H, J = 14.4, J =

7.2 Hz), 1.55 br.s (6H), 1.57–1.70 m (6H), 1.92 br.s

(3H), 3.33 br.s (1H), 3.55–3.65 m (1H), 6.55 d (2H,

2

3

(2H, J = 14.1, J = 6.3 Hz), 1.55 br.s (12H), 1.57–

1.71 m (12H), 1.92 br.s (6H), 2.87 br.s (2H), 3.47 br.s

(2H), 6.49 s (4H). ¹³C NMR spectrum, δ_C, ppm: 23.6

(2C), 28.7 (6C), 32.5 (2C), 37.0 (6C), 43.1 (6C), 45.3

(2C), 52.9 (2C), 115.3 (4C), 139.4 (2C). MALDI-TOF

mass spectrum: m/z 460.35 [M]⁺. By chromatography

³J = 8.5 Hz), 6.64 t (1H, J = 7.0 Hz), 7.15 t (2H, J =

7.5 Hz). ¹³C NMR spectrum, δ_C, ppm: 23.3 (1C), 28.7

(3C), 32.6 (1C), 37.0 (3C), 43.1 (3C), 44.1 (1C), 53.0

(1C), 112.9 (2C), 116.5 (1C), 129.3 (2C) (signal from

3

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

AVERIN et al.

(2H), 3.40 br.s (2H), 3.54–3.63 m (1H), 5.83 br.s (1H),

1810

one quaternary carbon atom was not observed).

MALDI-TOF mass spectrum: m/z 269.2140 [M]⁺.

C₁₉H₂₇N. Calculated: M 269.2143.

3

4

5.92 d (1H, J = 8.0 Hz), 5.96 d.d (1H, J = 7.4, J =

3

1.2 Hz), 6.93 t (1H, J = 7.9 Hz). ¹³C NMR spectrum,

δ_C, ppm: 23.5 (1C), 28.4 (3C), 28.7 (3C), 32.5 (1C),

33.7 (1C), 37.0 (3C), 37.1 (3C), 40.7 (3C), 43.1 (3C),

44.0 (1C), 53.0 (1C), 56.3 (1C), 97.0 (1C), 102.0

(1C), 102.5 (1C), 129.9 (1C), 148.4 (1C), 150.4 (1C).

MALDI-TOF mass spectrum, m/z: 432.3464 [M]⁺,

428.36 (base peak) [M – 2H₂]⁺. C₃₀H₄₄N₂. Calculated:

M 432.3504.

N,N′-Bis[1-(1-adamantylmethyl)propyl]benzene-

1,2-diamine (XIV) was synthesized from 0.3 mmol

(62 mg) of amine Ie and 0.1 mmol (24 mg) of o-di-

bromobenzene in the presence of 5 mg (9 mol %) of

Pd(dba)₂, 4.5 mg (11 mol %) of DavePHOS, and

37 mg (4 equiv) of sodium tert-butoxide in 1 ml of

anhydrous dioxane. Yield 11 mg (22%) (after chroma-

tography; petroleum ether–methylene chloride, 4:1),

N¹-[α-(1-Adamantyl)benzyl]-N³-[2-(1-adaman-

tyl)-1-methylethyl]benzene-1,3-diamine (XVII) was

synthesized from 0.3 mmol (72 mg) of amine Ib and

0.3 mmol (71 mg) of m-dibromobenzene in the

presence of 7 mg (4 mol %) of Pd(dba)₂, 8.5 mg

(4.5 mol %) of BINAP, and 50 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

Yield of compound Ve 52% (in the reaction mixture).

Compound Ve was then brought (without isolation)

into reaction with 0.25 mmol (48 mg) of amine Ib in

the presence of 5.5 mg (4 mol %) of Pd(dba)₂, 7 mg

(4.5 mol %) of BINAP, and 40 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

Chromatographic separation using petroleum ether–

methylene chloride (1:1) as eluent gave 39 mg (49%)

of compound XVII as a colorless oily substance.

¹H NMR spectrum, δ, ppm (two diastereoisomers):

1

colorless oily substance. H NMR spectrum, δ, ppm

(two diastereoisomers): 0.88 t (6H, ³J = 7.5 Hz), 1.12–

1.70 m (32H), 1.91 br.s (6H), 3.08 br.s (2H), 3.28–

3.40 m (2H), 6.60–6.67 m (2H), 6.71–6.76 m (2H).

¹³C NMR spectrum, δ_C, ppm (two diastereoisomers):

9.7 (1C), 9.8 (1C), 28.2 (1C), 28.7 (6C), 29.0 (1C),

32.5 (2C), 37.0 (6C), 43.1 (6C), 49.2 (1C), 49.4 (1C),

50.0 (1C), 50.2 (1C), 111.7 (1C), 112.6 (1C), 118.0

(1C), 118.3 (1C), 136.3 (1C), 136.6 (1C). MALDI-

TOF mass spectrum: m/z 488.4117 [M]⁺. C₃₄H₅₂N₂.

Calculated: M 488.4130_.Elution with the same solvent

system gave 6 mg (21%) of reduction product XV.

¹H NMR spectrum, δ, ppm: 0.90 t (3H, ³J = 7.2), 1.12–

1.70 m (16H), 1.91 br.s (3H), 3.08 br.s (1H), 3.30–

3.40 m (1H), 6.53 d (2H, ³J = 8.5 Hz), 6.61 t (1H, ³J =

3

7.2 Hz) 7.15 t (2H, J = 7.9 Hz). ¹³C NMR spectrum,

3

0.96 d (3H, J = 6.7 Hz), 1.08 d (3H, J = 6.2 Hz),

0.94–1.21 m (4H), 1.46 br.s (12H), 1.51 br.s (12H),

1.55–1.72 m (24H), 1.91 br.s (6H), 1.97 br.s (6H),

3.32–3.45 m (2H), 3.84 s (1H), 3.86 s (1H), 5.65 br.s

δ_C, ppm: 9.9 (1C), 28.7 (3C), 29.7 (1C), 32.5 (1C),

37.0 (3C), 43.1 (1C), 49.3 (1C), 50.0 (1C), 112.7 (2C),

116.2 (1C), 129.2 (2C), 147.5 (1C). MALDI-TOF

mass spectrum: m/z 283.26 [M]⁺.

3

N¹-(1-Adamantylmethyl)-N³-[2-(1-adamantyl)-1-

methylethyl]benzene-1,3-diamine (XVI) was synthe-

sized from 0.3 mmol (50 mg) of amine Ia and

0.3 mmol (71 mg) of m-dibromobenzene in the

presence of 7 mg (4 mol %) of Pd(dba)₂, 8.5 mg

(4.5 mol %) of BINAP, and 50 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

Yield of compound IIe 40% (in the reaction mixture).

Compound IIe was then brought (without isolation)

into reaction with 0.25 mmol (48 mg) of amine Id in

the presence of 5.5 mg (4 mol %) of Pd(dba)₂, 7 mg

(4.5 mol %) of BINAP, and 40 mg (1.5 equiv) of

sodium tert-butoxide in 2.5 ml of anhydrous dioxane.

Chromatographic separation using petroleum ether–

methylene chloride (1:1) as eluent gave 18 mg (35%)

of compound XVI as a colorless oily substance.

(1H), 5.67 br.s (1H), 5.82 d (2H, J = 7.7 Hz), 5.85 d

(1H, ³J = 7.5 Hz), 5.87 d (1H, ³J = 7.5 Hz), 6.81 t (2H,

3

³J = 7.9 Hz), 7.17 t (1H, J = 8.4 Hz), 7.18 t (1H, J =

8.4 Hz), 7.23–7.27 m (8H) (signals from the NH pro-

tons were not assigned unambiguously). ¹³C NMR

spectrum, δ_C, ppm: 23.3 (1C), 23.5 (1C), 28.4 (6C),

28.7 (6C), 34.7 (2C), 36.5 (2C), 36.9 (6C), 37.0 (6C),

39.3 (6C), 42.9 (3C), 43.0 (3C), 43.9 (1C), 44.0 (1C),

52.9 (1C), 53.0 (1C), 68.0 (1C), 68.1 (1C), 97.4 (1C),

97.6 (1C), 102.6 (1C), 102.7 (3C), 126.6 (2C), 127.5

(4C), 128.7 (4C), 129.6 (2C), 140.7 (1C), 140.8 (1C),

148.2 (2C), 149.1 (1C), 149.2 (1C). MALDI-TOF

mass spectrum, m/z: 508.3894 [M]⁺, 504.34 (base

peak) [M – 2H₂]⁺. C₃₆H₄₈N₂. Calculated: M 508.3817.

This study was performed under financial support

by the Russian Academy of Sciences (program P-8,

“Development of Methodology of Organic Synthesis

and Design of Compounds with Practically Important

Properties”) and by the Russian Foundation for Basic

Research (project no. 10-03-01108).

3

¹H NMR spectrum, δ, ppm: 1.15 d (3H, J = 6.2 Hz),

1.20 d.d (1H, ²J = 14.4, ³J = 4.2 Hz), 3.01 d.d (1H, ²J =

3

14.4, J = 7.2 Hz), 1.56 s (6H), 1.57 s (6H), 1.58–

1.76 m (12H), 1.92 br.s (3H), 1.99 br.s (3H), 2.76 s

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

ARYLATION OF ADAMANTANAMINES: II.

1811

8. Fleck, R.W., Guo, X., Lo, H.Y., and Man, C.C., PCT

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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 12 2010

Article Doi

Arylation of adamantanamines: II.* Palladium-catalyzed amination of dihalobenzenes with adamantylalkanamines

DOI: 10.1134/S1070428010120055

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Article abstract of DOI:10.1134/S1070428010120055

Full text of DOI:10.1134/S1070428010120055

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