Synthesis of 1,8-bis(cyclam) and 1,8-bis(azacrown) substituted anthracenes by palladium-catalyzed arylation of cyclam

Article abstract of DOI:10.1016/S0040-4039(01)02356-5

The Pd-catalyzed arylation of cyclam, cyclen, and azacrown ethers by aryl halides was studied. Cofacial biscyclam and bisazacrown were synthesized by direct bonding of the anthracenyl spacer to a nitrogen atom of macrocycles.

Full text of DOI:10.1016/S0040-4039(01)02356-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1193–1196
Synthesis of 1,8-bis(cyclam) and 1,8-bis(azacrown) substituted
anthracenes by palladium-catalyzed arylation of cyclam
a,
b
b
b
Irina P. Beletskaya, * Alexei D. Averin, Alla G. Bessmertnykh, Franck Denat and
b,
Roger Guilard *
a
Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, Moscow, 119899, Russia
b
LIMSAG (UMR 5633), Faculte des Sciences ‘Gabriel’, 6, Bd. Gabriel, 21100, Dijon, France
Received 20 November 2001; revised 7 December 2001; accepted 13 December 2001
Abstract—The Pd-catalyzed arylation of cyclam, cyclen, and azacrown ethers by aryl halides was studied. Cofacial biscyclam and
bisazacrown were synthesized by direct bonding of the anthracenyl spacer to a nitrogen atom of macrocycles. © 2002 Elsevier
Science Ltd. All rights reserved.
The synthesis of cofacial metallodiporphyrins has
played a significant role in the investigation of electron
transfer and of the activation of small molecules (such
as dihydrogen, dioxygen, dinitrogen, water, or ammo-
nia) and has also enabled us to understand the mecha-
Here we show that the Pd-catalyzed amination reaction
of aryl halides can be a useful tool to synthesize new
model compounds which are saturated analogues of
cofacial porphyrins containing a rigid spacer group.
Over the past 5 years the Pd-catalyzed carbonꢀnitrogen
bond formation became a remarkable method in
1,2
nism of photosynthesis. Pacman A and B porphyrins
were also used to prepare various binuclear catalysts
12
organic chemistry. However, the Pd-catalyzed aryla-
tion of polyazamacrocycles might pose several prob-
lems, given that the secondary amines are known to be
the most reluctant substrates in Pd-catalyzed arylation.
Indeed, the formation of stable palladium complexes
with polyamines and polyazamacrocycles can also be
3,4
which can be employed for dioxygen reduction. Other
types of face-to-face porphyrins have also been investi-
gated and interesting applications have been found, for
2,5,6
instance, for molecular recognition.
The distance
between the two porphyrin rings as well as the rigidity
of the spacer group play a crucial role in the chemical
1
3
observed, thus hindering the catalytic reaction. For
this reason, we have already studied the catalytic aryla-
tion of cyclam 1 and cyclen 2, which are typical repre-
sentatives of saturated tetraazamacrocycles. The
reaction of cyclam with aryl halides (chloro-, bromo-,
iodosubstituted benzenes, 1-bromonaphthalene, 4-bro-
mobiphenyl, and 9-bromoanthracene) was tested using
various combinations of a palladium source with sup-
7
properties of cofacial diporphyrins. Over the last
decade, the use of saturated bismacrocyclic ligands
instead of porphyrins has been studied because of their
8
easier synthesis. They contain two polyazamacrocycles
which are linked, either through aliphatic (or aromatic)
spacers bonded to nitrogen atoms or through two
9,10
covalently bonded carbon atoms.
Recently, the syn-
thesis of a variety of bismacrocycles bound through
11
aryl spacers has been described by our group. How-
ever, so far, only aliphatic or benzyl-type linkers have
been used to prepare these models; direct bonding of
two polyazamacrocycles to an aryl spacer can hardly be
achieved with known synthetic procedures, and this fact
strictly limits any progress in this area.
OCH3
CH3
Fe
P(C6H5)2
NH HN
NH HN
NH HN
NH
2
mol % Pd(dba)2
+
ArBr
tBuONa
N
Ar
Ar = p-C6H5C6H4 (3) : 20 %
p-NCC6H4 (4) : 22 %
1
Keywords: macrocycles; Pd catalysis; aryl halides; amines; amination.
*
Corresponding authors. Fax: 33.3.80.39.61.17; e-mail: rguilard@
u-bourgogne.fr
Scheme 1.
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02356-5

1
194
I. P. Beletskaya et al. / Tetrahedron Letters 43 (2002) 1193–1196
porting ligands: Pd(dba) , Pd(OAc) , PdCl , dppf,
Besides, the use of the very promising tri-tert-
2
2
2
BINAP, tBu P, P(o-Tol) , P(Cy) but none of them
butylphosphine as a supporting ligand in this reaction
3
3
3
17
proved to be suitable for our purpose. We have only
noted the full or partial reduction of aryl halides into
the corresponding hydrocarbons. Yet, the reaction of
cyclam with 4-bromobiphenyl and 4-bromobenzonitrile
also failed.
In order to avoid an undesirable reduction of the
dichloride derivative, N,N%,N¦-trisubstituted derivatives
of cyclam should be used: indeed, they seem more
suitable than the free cyclam which contains four sec-
ondary amino groups capable of participating in the
reduction of dichloroanthracene. The reactions of
N,N%,N¦-trimethylcyclam 7 promoted by the Pd com-
plex (Pd(dba) , 16 mol%) with tBu P generated a
1
4
using PPF-OMe, afforded N-arylated cyclams 3 and 4
in 20–22% yields (Scheme 1). It is remarkable to note
15
that among numerous derivatives of cyclam, only the
N-arylated molecules containing electron-withdrawing
groups on the aromatic substituents were obtained by
aromatic nucleophilic substitution. Thus, the Pd-cata-
lyzed arylation of cyclam leads to a wider range of
tetraazamacrocycles possessing aromatic substituents
directly bonded to the nitrogen atom.
2
3
monocyclam derivative of anthracene 8 in 45% yield.
Only traces of the aimed biscyclam product 9 were
detected in the mass spectrum. Further attempts to use
Pd(dba) /BINAP as a catalytic system (16 mol%),
2
The possible Pd-catalyzed arylation of cyclam led us to
study the synthesis of saturated analogues of cofacial
diporphyrins. The 1,8-disubstituted anthracene was
chosen as a spacer since we had carried out the amina-
tion of 1,8-dichloroanthracene with primary and sec-
resulted in the formation of the target compound 9 in
10% yield together with the monosubstituted anthra-
cene 8 (35%) (Scheme 2).
This preparation of the aimed cofacial biscyclam led us
to demonstrate the applicability of such a methodology
regarding the synthesis of biscrown substituted anthra-
cene. Previously, only a few aryl substituted azacrown
1
6
ondary amines. During the first experiments, we used
the catalytic system Pd(dba) /BINAP instead of the
2
expensive PPF-OMe. The reaction of 1,8-dichloroan-
thracene with cyclam in the presence of 4–8 mol% of
18
ethers were known. The reaction of 1-aza-4,7,10,13-
Pd(dba) /BINAP and tBuONa only led to the forma-
tetraoxacyclopentadecane 10 with 1,8-dichloroan-
2
tion of anthracene, which is the reduction product of
the starting dichloride. The same reaction starting from
the less basic cyclen 2 in the presence of 5 mol%
thracene in the presence of Pd(dba) /BINAP gave the
2
target face-to-face bisazacrown 11 in 11% yield (Scheme
3).
Pd(dba) /BINAP has been more successful, yielding a
2
mixture of monocyclen substituted anthracenes 5, 6
together with the free anthracene (Scheme 2). Neverthe-
less, a prolonged heating of the reaction mixture and
the use of a greater amount of the catalyst precursor
did not produce biscyclen substituted anthracene.
In conclusion, we have shown that the Pd-catalyzed
amination reaction is a convenient tool for the prepara-
tion of aryl substituted tetraazamacrocycles and aza-
crown ethers including saturated analogues of
face-to-face porphyrins. Despite the fact that up to now
R
N
R
R
N
N
n
R
n
R
n
R
R
N
N
N
N
Cl
Cl
NH
N
N
N
R
N
N
N
n
n
n
R
R
R
+
R
4
-16 mol %, Pd(dba)2
N
n
L, tBuONa
X
N
n
L=BINAP: R = H, n=0 5 X=Cl (26%) 6 X=H (13%)
L=t Bu P: R=Me, n=1 8 X=H (45%)
9 (10%)
3
L=BINAP: R=Me, n=1
8
X=H (35%)
Scheme 2.
O
NH
O
O
O
O
O
Cl
Cl
O
N
N
O
O
N
O
O
O
O
O
O
10
+
8
mol %, Pd(dba) ,BINAP
2
tBuONa
O
11 (11 %)
12 (44%)
Scheme 3.

I. P. Beletskaya et al. / Tetrahedron Letters 43 (2002) 1193–1196
1195
yields have been low, this is a unique methodology
References
for the one-pot synthesis of such demanded molecules
which uses commercially available materials as start-
ing compounds. Moreover, these compounds are
important ligands for the complexation of a great
variety of metal ions and for the study of their reac-
tivity towards oxygen and other small molecules. This
work is in progress in our group.
1. (a) Wasielewski, M. R. Chem. Rev. 1992, 92, 435; (b)
Osuka, A.; Kobayashi, F.; Nakajima, S.; Maruyama, K.;
Yamazaki, I.; Nishimura, Y. Chem. Lett. 1993, 161; (c)
Arnold, D. P.; Nitschinsk, L. J. Tetrahedron Lett. 1993,
3
4, 693; (d) Lin, V. S. Y.; DiMango, S. G.; Therein, M.
J. Science 1994, 264, 1105; (e) Senge, M. O.; Vicente, M.
G. H.; Gerzevske, K. R.; Forsyth, T. P.; Smith, K. M.
Inorg. Chem. 1994, 33, 5625.
. Collman, J. P.; Wagenknecht, P. S.; Hutchison, J. E.
Angew. Chem., Int. Ed. Engl. 1994, 33, 1537.
Synthesis of 1,8-N,N%-bis(4,8,11-trimethyl-1,4,8,11-tetra-
2
3
azacyclotetradecyl-1) anthracene 9:
A
two-necked
flask filled with argon was charged with 1,8-
dichloroanthracene (247 mg, mmol), N,N%,N¦-
trimethylcyclam (484 mg, 2 mmol), Pd(dba) (92 mg,
. (a) Chang, C. K.; Abdalmuhdi, I. J. Org. Chem. 1983, 48,
1
5
388; (b) Guilard, R.; Lopez, M. A.; Tabard, A.;
2
Richard, P.; Lecomte, C.; Brand e` s, S.; Hutchison, J. E.;
Collman, J. P. J. Am. Chem. Soc. 1992, 114, 9877; (c)
Chang, C. K.; Abdalmuhdi, I. Angew. Chem., Int. Ed.
Engl. 1984, 23, 164; (d) Collman, J. P.; Hutchison, J. E.;
Lopez, M. A.; Tabard, A.; Guilard, R.; Seok, W. K.;
Ibers, J. A.; L’Her, M. J. Am. Chem. Soc. 1992, 114,
9869.
0
.16 mmol), BINAP (110 mg, 0.178 mmol), tBuONa
(
400 mg, 4 mmol) and 10 ml of dioxane. The reaction
mixture was refluxed for ca. 100 h, then dioxane was
evaporated in vacuum, and the solid residue was
taken in dichloromethane (30 ml), washed three times
with 10 ml of water, dried over Na SO , evaporated
2
4
in vacuum and chromatographed on silica (CH Cl /
4. (a) Guilard, R.; Brand e` s, S.; Tardieux, C.; Tabard, A.;
L’Her, M.; Miry, C.; Gouerec, P.; Knop, Y.; Collman, J.
P. J. Am. Chem. Soc. 1995, 117, 11721; (b) Lachkar, M.;
Tabard, A.; Brand e` s, S.; Guilard, R.; Atmani, A.; De
Cian, A.; Fischer, J.; Weiss, R. Inorg. Chem. 1997, 36,
2
2
MeOH/NH (aq)=10:3:1). Yield of 9 after chromato-
3
1
graphy 67 mg (10%). H NMR (200 MHz, CDCl )
3
lH ppm (JHH, Hz): 1.71 q (4H, 6.4), 1.75 q (4H, 6.4),
2
.17 s (6H), 2.20 s (6H), 2.30 s (6H), 2.34–2.68 m
4141.
(
24H), 3.38 t (4H, 6.6), 3.48 t (4H, 6.8), 7.11 d (2H,
5
6
7
. Risch, N.; Gauler, R.; Keuper, R. Tetrahedron Lett.
1999, 40, 2925.
. Hayashi, T.; Nonoguchi, M.; Aya, T.; Ogoshi, H. Tetra-
hedron Lett. 1997, 38, 1603.
. Kadish, K. M.; Smith, K. M.; Guilard, R. The Porphyrin
7
9
2
5
5
.0), 7.35 t (2H, 7.7), 7.65 d (2H, 8.3), 8.33 s (1H),
13
.26 s (1H). C NMR (50 MHz, CDCl ) l , ppm:
3
C
4.0 (4C), 43.6 (4C), 43.8 (2C), 50.5 (2C), 51.9 (2C),
3.3 (2C), 53.4 (2C), 53.7 (2C), 54.8 (2C), 55.0 (2C),
5.5 (2C), 116.5 (2C), 119.4 (1C), 123.1 (2C), 125.2
Handbook; Academic Press: New York, 2000; Vol. 3, p.
(
2C), 126.6 (1C), 128.1 (2C), 133.0 (2C), 149.6 (2C).
M ] 658.7.
235.
+
[
8
. (a) Bradshaw, J. S.; Krakowiak, K. E.; Izatt, R. M.
Aza-Crown Macrocycles; Wiley: New York, 1993; 51; (b)
Lindoy, L. F. The Chemistry of Macrocyclic Ligand Com-
plexes; Cambridge University Press: Cambridge, 1989;
Synthesis of 1,8-N,N%-bis(1-aza-4,7,10,13-tetraoxacyclo-
pentadecyl-1)anthracene 11: 1,8-Dichloroanthracene
(
123
mg,
0.5
mmol),
1-aza-4,7,10,13-tetra-
122.
oxapentadecane 10 (264 mg, 1.0 mmol), tBuONa (200
mg, 2.1 mmol), Pd(dba)2 (23 mg, 0.04 mmol) and
BINAP (62 mg, 0.1 mmol) were dissolved in dioxane
9. (a) Schneider, R.; Riesen, A.; Kaden, T. A. Helv. Chim.
Acta 1985, 68, 53; (b) Ciampolini, M.; Fabbrizzi, L.;
Perotti, A.; Poggi, A.; Seghi, B.; Zanobini, F. Inorg.
Chem. 1987, 26, 3527; (c) Urfer, A.; Kaden, T. A. Helv.
Chim. Acta 1994, 77, 23; (d) Bridger, G. J.; Skerlj, R. T.;
Thornton, D.; Padmanabhan, S.; Martellucci, S. A.; Hen-
son, G. W.; Abrams, M. J.; Yamamoto, N.; De Vreese,
K.; Pauwels, R.; De Clercq, E. J. Med. Chem. 1995, 38,
(
40 ml) in a Schlenk flask under argon. The reaction
mixture was refluxed for 48 h. The reaction mixture
was cooled down to room temperature and concen-
trated in vacuum. The residue was taken in
dichloromethane (30 ml), washed with water, dried
over Na SO and evaporated in vacuum. The residue
366.
2
4
1
0. (a) Buttafava, A.; Fabbrizzi, L.; Perotti, A.; Seghi, B. J.
Chem. Soc., Chem. Commun. 1982, 1166; (b) Fabbrizzi,
L.; Montagna, L.; Poggi, A.; Kaden, T. A.; Siegfried, L.
C. Inorg. Chem. 1986, 25, 2672; (c) Buttafava, A.; Fab-
brizzi, L.; Perotti, A.; Poggi, A.; Seghi, B. Inorg. Chem.
was chromatographed on silica using CH Cl /MeOH
2
2
1
(
100:3). Yield of 11 36 mg (11%). H NMR (200
MHz, CDCl ) l , ppm (JHH, Hz): 3.60–3.80 m (40H),
3
H
7
8
.23 d (2H, 7.2), 7.35 t (2H, 4.2), 7.67 d (2H, 8.6),
13
.33 s (1H), 9.15 s (1H). C NMR (50 MHz, CDCl3)
1
984, 23, 3917; (d) Kajiwara, T.; Yamaguchi, T.; Kido,
H.; Kawabata, S.; Kuroda, R.; Ito, T. Inorg. Chem. 1993,
2, 4990.
lC, ppm: 54.3 (4C), 70.3 (4C), 70.6 (4C), 70.8 (4C),
1.0 (4C), 117.0 (2C), 119.6 (1C), 123.4 (2C), 125.4
7
3
(
2C), 126.9 (1C), 128.4 (2C), 133.2 (2C), 148.7 (2C).
11. Brand e` s, S.; Gros, C.; Denat, F.; Pullumbi, P.; Guilard,
R. Bull. Soc. Chim. Fr. 1996, 133, 65.
1
2. (a) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem.
Acknowledgements
1999, 576, 125; (b) Hartwig, J. F. Angew. Chem., Int. Ed.
Engl. 1998, 37, 2047; (c) Wolfe, J. P.; Buchwald, S. L. J.
Org. Chem. 2000, 65, 1144; (d) Wolfe, J. P.; Tomori, H.;
Sadighi, J. P.; Yin, J. J.; Buchwald, S. L. J. Org. Chem.
2000, 65, 1158.
The authors are grateful to INTAS (grant 97-0791)
for financial support of the research.

1
196
I. P. Beletskaya et al. / Tetrahedron Letters 43 (2002) 1193–1196
13. (a) Zhang, D.; Busch, D. H. Inorg. Chem. 1994, 33,
Lett. 1998, 39, 617.
5
138; (b) Bazzicalupi, C.; Bencini, A.; Cohen, H.; Giorgi,
18. (a) Matsumoto, K.; Hashimoto, M.; Toda, M.; Tsukube,
H. J. Chem. Soc., Perkin Trans. 1 1995, 2497; (b)
Tsukube, H.; Minatogawa, H.; Munakata, M.; Toda, M.;
Matsumoto, K. J. Org. Chem. 1992, 57, 542; Pd-catalyzed
approach; (c) Witulski, B. Synlett 1999, 1223; (d) Witul-
ski, B.; Zimmermann, Y.; Darcos, V.; Desvergne, J.-P.;
Bassani, D. M.; Bouas-Laurent, H. Tetrahedron Lett.
1998, 39, 4807 when this manuscript was in preparation a
study of azacrown arylation was published by Buchwald
and Witulski; (e) Zhang, X. X.; Buchwald, S. L. J. Org.
Chem. 2000, 65, 8027; (f) Witulski, B.; Weber, M.;
Bergstraesser, U.; Desvergne, J.-P.; Bassani, D. M.;
Bouas-Laurent, H. Org. Lett. 2001, 3, 1467.
C.; Golub, G.; Meyerstein, D.; Navon, N.; Paoletti,
P.; Valtancoli, B. J. Chem. Soc., Dalton Trans. 1998,
1
625.
1
1
1
4. Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem.
Soc. 1998, 120, 9722.
5. Beletskaya, I. P.; Artamkina, G. A.; Ivushkin, V. A.;
Guilard, R. Tetrahedron Lett. 2000, 41, 313.
6. (a) Beletskaya, I. P.; Averin, A. D.; Bessmertnykh, A. G.;
Guilard, R. Tetrahedron Lett. 2001, 42, 4983; (b) Belet-
skaya, I. P.; Averin, A. D.; Bessmertnykh, A. G.;
Guilard, R. Tetrahedron Lett. 2001, 42, 4987.
1
7. Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron