Palladium-catalyzed synthesis of N-aryl- and N-heteroaryl-aza-crown ethers via cross-coupling reactions of aryl- and heteroaryl bromides with aza-crown ethers

Article abstract of DOI:10.1055/s-1999-2799

Palladium(0)-catalyzed cross-coupling reactions of electron deficient aryl- and heteroaryl bromides with aza-crown ethers of various ring sizes are described. The catalyst system Pd(OAc)₂/PPh₃ gave best results for cross coupling reactions of macrocyclic aza-crown ethers with electron poor aryl bromides.

Full text of DOI:10.1055/s-1999-2799

LETTER
1223
Palladium-Catalyzed Synthesis of N-Aryl- and N-Heteroaryl-aza-crown
Ethers via Cross-Coupling Reactions of Aryl- and Heteroaryl Bromides with
Aza-crown Ethers
*
Bernhard Witulski
Fachbereich Chemie, Universität Kaiserslautern, Erwin Schrödinger Straße, D-67663 Kaiserslautern, Germany
Fax +49 (0)631 205 3921; E-mail: Bernhard@chemie.uni-kl.de
Received 5 May 1999
Abstract: Palladium(0)-catalyzed cross-coupling reactions of elec-
tron deficient aryl- and heteroaryl bromides with aza-crown ethers
of various ring sizes are described. The catalyst system Pd(OAc)2/
PPh3 gave best results for cross coupling reactions of macrocyclic
aza-crown ethers with electron poor aryl bromides.
Key words: crown ether, palladium, cross-coupling reaction,
amination reaction, bipyridyl, macrocycles, supramolecular chem-
istry.
Macrocyclic ionophores based on aza-crown ether deriv-
atives have attracted much attention because of their ap-
plication as building blocks for artificial transmembrane
ion channels, carrier systems for ion and molecule trans-
port, supramolecular catalysts, and molecular elements
for supramolecular assemblies.1 Especially N-aryl-aza-
crown ethers with defined ring sizes have been combined
with photo- or redoxactive subunits and were recognized
frequently as metal cation selective sensors.2
However in terms of efficiency and flexibility most syn-
theses of N-aryl-aza-crown ethers are not satisfying: ei-
ther high dilution conditions often providing a low
yielding ring closure of the crown ether moiety,3 or high
pressure conditions (>8 kbar) for achieving a SNAr reac-
tion between the corresponding amine and an activated
aryl halide are necessary.4 Concerning strategy and syn-
thesis the direct attachment of commercially or easily
available aza-crown ethers to various aromatic compo-
nents via a cross coupling reaction promises to be the most
straightforward approach towards N-aryl- and N-heteroar-
yl-aza-crown ethers. Furthermore, such a strategy should
amines with aryl bromides and chlorides. Whereas initial-
ensure a high flexibility with respect to the ring size of the
ly a Pd(0)/P(o-tol)3 catalyst was used, more recently sec-
crown ether subunit, and the allowance for a multifold at-
ond generation catalysts based on chelating phosphine
tachment of more than one aza-crown ether component to
ligands have been proven to be superior in many cases.8
an aromatic core.5
Nevertheless, limitations towards sterically crowded
We report here a new and efficient synthesis of N-aryl-
and N-heteroaryl-crown ethers from aryl- or heteroaryl
bromides and aza-crown ethers based on a Pd(0)-mediat-
ed cross coupling reaction inducing a carbon-nitrogen
bond formation. This strategy follows our recent report on
the synthesis of N-(9-anthryl) aza-18-crown-6, a novel
chromo- and fluoroionophore.6
amines were observed, and Pd-catalyzed aryl aminations
have neither been studied with macrocyclic amines, nor
with aza-crown ethers so far.
At the outset of our studies we investigated the influence
of the steric properties of different monodentate phos-
phine ligands on the Pd(0)-catalyzed cross-coupling reac-
tion between the electronically activated 4-nitro-
bromobenzene (1, 1 equiv) and aza-[18]-crown-6 (2a, 1.2
eq.) in the presence of NaOt-Bu (1.3 equiv) in toluene as
solvent at 100 oC (Table 1). The catalyst combinations of
The intensive studies of Buchwald, Hartwig, and others
on Pd(0)-catalyzed aryl aminations7 have lead to a proto-
col that effects the coupling of primary and secondary
Synlett 1999, No. 8, 1223–1226 ISSN 0936-5214 © Thieme Stuttgart · New York

1224
B. Witulski
LETTER
Pd(dba)2, or Pd(OAc)2 with P(o-tol)3 and P(t-Bu)3 respec- the (macro)cyclic amine 2 was investigated. Cross-cou-
tively, gave only moderate to low yields of cross-coupling pling reactions of 1 with macrocyclic amines (2a and 2b),
product 3a. Whereas 3a was obtained in 84% yield with as well as with amines of medium ring sizes (2c and 2d)
the sterically small ligand PPh3 and Pd(OAc)2 (entry 1 in could be achieved with both catalysts. However the cata-
Table 1).9, 10 Omitting the Pd-catalyst did not yield any lyst based on the sterically smaller ligand PPh3 gave sig-
product under otherwise identical reaction conditions.
nificantly better results with the macrocyclic amines 2a
and 2b (entry 1 and 2, Table 1). No difference in reactivity
between a catalyst based on PPh3 and P(o-tol)3 was found
in the arylamination of 1 with morpholine (2d) (entry 4,
Next, the interplay between the steric demand of the phos-
phine ligands P(o-tol)3 and PPh3,12 and the bulkiness of
Synlett 1999, No. 8, 1223–1226 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Synthesis of N-Aryl- and N-Aryl-aza-crown Ethers
1225
Table 1), indicating that the bulkiness of the aza-crown Molecule and cation binding studies and the application of
ethers contribute to the observed differences in reactivity. these new macrocyclic ligands for the synthesis of novel
chromo- and fluoroionophores are currently under inves-
tigation.
The catalyst system based on the bidentate ligand BINAP
also led to the N-aryl-aza-crown ether 3a, albeit in a di-
minished yield of 36% (Scheme 1). Surprisingly the phe-
nol ether 4 was found as major product in 40% yield,13
whereas this alkoxidation product was not observed with
the catalysts based on the ligands PPh3 and P(o-tol)3.
Since the alkoxide ion is less nucleophilic than the amine
gratefully acknowledged.
2a this result is remarkable.
Acknowledgment
We would like to thank Prof. Dr. M. Regitz for his generous sup-
port. Financial support of the ‘Fonds der Chemischen Industrie’ is
References and Notes
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Scheme 1 Catalyst and reaction conditions: i) Pd2(dba)3 (2 mol%),
Stoddart, J. F.; Bartsch, R. A.; Liotta, C. L. Crown Ethers and
BINAP (6 mol%), 1.2 eq. 2a, 1.3 eq. NaOtBu, 100 oC, 12h, toluene,
Analogs, Patai, S.; Rappoport, Z., Eds.; John Wiley, 1989.
reaction carried out in a Schlenk tube with screw cap, 4 (40%), 3a
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Scope and limitations of this new N-aryl-aza-crown ether
synthesis were further demonstrated by the results given
in Table 2, where commercially available aza-18-crown-6
(2a) was used as coupling partner.14 The protocol could be
extended to the synthesis of cyanobenzene 6, benzophe-
none 10,15 and pyridine 1416, 17 with high efficiency. In all
cases investigated, the use of the catalyst system based on
PPh3 gave consistently better results. The twofold cross-
coupling reactions of aza-crown ether 2a with the aryl
bromides 11, 15, and 17 proceeded with high yields to
give the crown ether 12,14 16,18 and 1819 in 73%, 81%, and
98%, respectively. In the cases of 11 and 15 the mono-am-
inated products 10 and 14, resulting from a b-hydride-
elimination-reduction sequence of a Pd-imido intermedi-
ate,20 could be isolated as side products respectively (entry
4 and 6, Table 2). However, the protocol is limited to elec-
tron deficient arenes and heteroarenes: a cross-coupling
reaction between bromobenzene (7) and aza-18-crown-6
(2a) could not be achieved, neither with a Pd-catalyst
based on PPh3, nor with one based on P(o-tol)3 (entry 2,
Table 2).
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(5) For a study of Pd-catalyzed multiple aryl aminations of
polybromobenzenes see: Witulski, B.; Senft, S.; Thum, A.
Synlett 1998, 504.
(6) Witulski, B.; Zimmerman, Y.; Darcos, V.; Desvergne, J.-P.;
Bassani, D. M.; Bouas-Laurent, H. Tetrahedron Lett. 1998,
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(7) Reviews and recent representative references: Hartwig, J. F.
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1998, 2046. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.;
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Inasmuch that the reductive elimination of a Pd-imido-
complex is accelerated when electron poor aryl species
are involved,20 and these electronic effects obviously sup-
port cross-coupling reaction with sterically encumbered
and therefore less reactive amines, the results obtained
here suggest furthermore, that the right interplay between
the bulkiness of the macrocyclic amine paired with the re-
duced steric demand of the phosphine ligand PPh3 is nec-
essary for an efficient and high yielding N-aryl-aza-crown
ether formation.
In conclusion, we have developed a protocol for the syn-
thesis of N-aryl- and N-heteroaryl-aza crown ethers based
on Pd-catalyzed cross coupling reactions of electron defi-
cient aryl bromides with aza-crown ethers of various ring
sizes. However, the working catalyst system Pd(OAc)2/
PPh3 is limited to its use with electron poor aryl bromides.
Synlett 1999, No. 8, 1223–1226 ISSN 0936-5214 © Thieme Stuttgart · New York

1226
B. Witulski
LETTER
Hartwig, J. F. Synlett 1997, 329. Guari, Y.; van Es, D. S.;
Reek, J. N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.
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0.06 mmol), PPh3 (32 mg, 0.12 mmol), and toluene (10 ml).
The sealed tube was kept at 100 oC for 2 days. The reaction
mixture was diluted with CH2Cl2 and filtered through a plug
of celite. After evaporation of the solvent the organic residue
was chromatographed. Column chromatography (Al2O3,
AcOEt with 0.5% MeOH) gave 10 (115 mg, 0.26 mmol)
[25%] as minor product and 12 (516 mg, 0.73 mmol) [73%] as
major product.
12: colorless oil, Rf: 0.3 (Al2O3-TLC, AcOEt/MeOH =
95.5:0.5 (v/v)); 1H NMR (400 MHz, CDCl3) d = 7.73 (d, J =
8.8 Hz, 4 H), 6.69 (d, J = 8.8 Hz, 4 H), 3.69 (m, 32 H), 3.72
(m, 16 H); 13C NMR (200 MHz, CDCl3/TMS) d = 193.5 (s),
150.6 (s), 132.3 (d), 126.1 (s), 110.3 (d), 70.8 (t), 70.7 (t),
70.75 (t), 68.4 (t), 51.3 (t); MS (EI, 70 eV) m/z (%): 704 (100,
M+), 486 (15), 372 (10), 232 (45); C37H56N2O11 (704.86) calc.:
704.3884; found: 704.3884.
(15) 10: colorless oil, Rf: 0.3 (Al2O3-TLC, hexanes/AcOEt = 4:6
(v/v)); 1H NMR (400 MHz, CDCl3) d = 7.77 (d, J = 8.8 Hz, 2
H), 7.71 (d, J = 7.6 Hz, 2 H), 7.52 (“t“, J ≈ 7.6 Hz, 2 H), 6.69
(d, J = 8.8 Hz, 2H), 3.5-3.7 (m, 24 H); 13C NMR (200 MHz,
CDCl3/TMS) d = 194.9 (s), 151.4 (s), 139.2 (s), 132.9 (d),
131.1 (d), 129.4 (d), 127.0 (d), 124.7 (s), 110.4 (d), 70.8 (t),
70.76 (t), 70.74 (t), 70.61 (t), 68.4 (t); C25H33NO6 (443.54)
calc.: C 67.70, H 7.50, N 3.16; found: C 67.29, H 7.51, N 3.10.
(16) 14: colorless oil, Rf: 0.5 (Al2O3-TLC, hexanes/AcOEt = 1:1
(v/v)); 1H NMR (400 MHz, CDCl3) d = 8.10 (ddd, J = 5.0 Hz,
J = 2.0 Hz, J = 0.8 Hz, 1 H), 7.40 (ddd, J = 8.7 Hz, J = 7.0 Hz,
J = 2.0 Hz, 1 H), 6.56 (d, J = 8.7 Hz, 1 H), 6.50 (ddd, J = 7.0
Hz, J = 5.0 Hz, J = 0.8 Hz, 1 H), 3.64-3.79 (m, 24 H); 13C NMR
(200 MHz, CDCl3/TMS) d = 157.8 (s), 147.8 (d), 137.0 (d),
111.3 (d), 105.7 (d), 70.8 (t), 70.7 (t), 70.65 (t), 70.6 (t), 69.2
(t); C17H28N2O5 (340.42) calc.: C 59.98, H 8.29, N 8.23;
found: C 59.63, H 8.16, N 8.02.
(17) For cross coupling reactions of 13 with morpholine (2d) and
allyl amines see: Wagaw, S.; Buchwald, S. L. J. Org. Chem.
1996, 61, 7240. Jaime-Figueroa, S.; Liu, Y.; Muchowski, J.
M.; Putman, D. G. Tetrahedron Lett. 1998, 39, 1313.
(18) 16: colorless oil; Rf: 0.25 (Al2O3-TLC, hexanes/AcOEt = 3:7
(v/v)); 1H NMR (400 MHz, CDCl3) d = 7.22 (t, J = 8.0 Hz,
1H), 5.79 (d, J = 8.0 Hz, 2H), 3.62-3.70 (m, 48 H); 13C NMR
(200 MHz, CDCl3/TMS) d = 156.6 (s), 138.5 (d), 92.5 (d),
70.8 (t), 70.75 (t), 70.7 (t), 70.6 (t), 69.5 (t), 49.5 (t);
C29H51N3O10 (601.74) calc.: C 57.89, H 8.54, N 6.98; found:
C 57.85, H 8.55, N 6.81.
Tetrahedron Lett. 1998, 39, 5731. Kamikawa, K.; Sugimoto,
S.; Uemura, M. J. Org. Chem. 1998, 63, 8407. Guram, S.;
Rennels, R. A.; Buchwald, S. L. Angew. Chem. 1995, 107,
1456; Angew. Chem. Int. Ed. Engl. 1995, 34, 1348.
(8) Some representative references include the following:
Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120,
7369. Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996,
118, 7217. Wolfe, J. P. Wagaw, S.; Buchwald, S. L. 1996,
118, 7215.
(9) The catalyst system Pd(0)/PPh3 was used for intramolecular
aryl amination reactions. However, it was described as less
effective for intermolecular aminations with primary and
secondary amines: Peat, A. J.; Buchwald, S. L. J. Am. Chem.
Soc. 1996, 118, 1028. Wolfe, J. P.; Rennels, R. A.; Buchwald,
S. L. Tetrahedron 1996, 52, 7525.
(10) It is assumed that Pd(OAc)2 is reduced to a Pd(0) species
under the reaction conditions.
(11) All new compounds were characterized by IR, MS, 1H- and
13C-NMR, elemental analysis and/or HRMS. 3a and 3b have
been synthesized previously by other means: Dix, J. P.;
Vögtle, F. Angew. Chem. 1978, 90, 893; Angew. Chem. Int.
Ed. Engl. 1978, 11, 857.
(12) Cone angle q [0]: P(o-tol)3 [194]; P(t-Bu)3 [182]; PPh3 [145].
Tolman, C. A. Chem. Rev. 1977, 77, 313.
(19) 18: colorless needles (CHCl3/pentane); m.p. 86-87 oC; Rf:
0.25 (Al2O3-TLC, hexanes/AcOEt = 1:9 (v/v)); 1H NMR (400
MHz, CDCl3) d = 7.58 (“d“, J ≈ 7 Hz, 2 H), 7.50 (“t“, J ≈ 8 Hz,
2 H); 6.55 (d, J = 8.3 Hz, 2 H, 3.67-3.86 (m, 48 H); 13C NMR
(200 MHz, CDCl3/TMS) d = 156.9 (s), 154.7 (s), 137.7 (d),
108.5 (d), 105.4 (d), 70.8 (t), 70.75 (t), 70.70 (t), 70.6 (t), 69.2
(t), 49.6 (t); C34H54N4O10 (678.82) calc.: C 60.16, H 8.02, N
8.25; found: C 60.11, H 7.89, N 8.14.
(20) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120,
3694. Hartwig, J. F.; Richards, S.; Barañano, D.; Frédéric, P.
J. Am. Chem. Soc. 1996, 118, 3629, and references therein.
(21) Kishii, N.; Araki, K.; Shiraishi, S. Bull. Chem. Soc. Jpn. 1984,
57, 2121.
(13) The same catalyst yielded 4 in 95% in the absence of an
amine, whereas omitting the catalyst did not yield any 4.
Mixtures of aryl amines and aryl ethers were also found with
other electron poor aryl bromides and BINAP as ligand
indicating that reductive eliminations of Pd-alkoxide
intermediates can compete with reductive eliminations of Pd-
imido intermediates when electron poor aryl bromides are
involved. (B. Witulski, S. Senft, A. Thum, unpublished
results). For Pd-catalyzed cross-coupling reactions of aryl
bromides with alkoxides see: Mann, G.; Incarvito, C.;
Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121,
3224. Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem.
Soc. 1996, 118, 10333.
(14) Typical procedure: In a Schlenk tube with screw cap were
introduced under argon 4,4´-dibromobenzophenone (11) (340
mg, 1 mmol), carefully dried aza-18-crown-6 (2a) (640 mg,
2.4 mmol), NaOtBu (250 mg, 2.6 mmol), Pd(OAc)2 (14 mg,
Article Identifier:
1437-2096,E;1999,0,08,1223,1226,ftx,en;G13499ST.pdf
Synlett 1999, No. 8, 1223–1226 ISSN 0936-5214 © Thieme Stuttgart · New York