Regioselectively N-methylated azacalix[8]arene octamethyl ether prepared by catalytic aryl amination reaction using a temporal N-silylation protocol

Article abstract of DOI:10.1021/ol062459p

(Chemical Equation Presented) A temporal N-silylation protocol in the catalytic aryl amination reaction has been devised to prepare nitrogen-bridged calixarene analogues. The protocol involves a smooth in situ N-silylation before aryl amination reaction, followed by spontaneous cleavage of the N-Si bond in the usual workup process, to furnish secondary aromatic amines as the cross-coupled product with no silyl group on the nitrogen atom. A successful application to the preparation of regioselectively N-methylated azacalix[8]arene is described, together with the crystallographic analysis.

Full text of DOI:10.1021/ol062459p

ORGANIC
LETTERS
2006
Vol. 8, No. 26
5991-5994
Regioselectively N-Methylated
Azacalix[8]arene Octamethyl Ether
Prepared by Catalytic Aryl Amination
Reaction Using a Temporal N-Silylation
Protocol
Koichi Ishibashi, Hirohito Tsue,* Satoshi Tokita, Kazuhiro Matsui,
Hiroki Takahashi, and Rui Tamura
Graduate School of Human and EnVironmental Studies, Kyoto UniVersity,
Sakyo-ku, Kyoto 606-8501, Japan
tsue@ger.mbox.media.kyoto-u.ac.jp
Received October 6, 2006
ABSTRACT
A temporal N-silylation protocol in the catalytic aryl amination reaction has been devised to prepare nitrogen-bridged calixarene analogues.
The protocol involves a smooth in situ N-silylation before aryl amination reaction, followed by spontaneous cleavage of the N Si bond in the
−
usual workup process, to furnish secondary aromatic amines as the cross-coupled product with no silyl group on the nitrogen atom. A
successful application to the preparation of regioselectively N-methylated azacalix[8]arene is described, together with the crystallographic
analysis.
Heteroatom-bridged calixarenes, in which methylene bridges
are replaced by heteroatoms, have attracted much interest
as a new class of calixarene scaffolds because of the
intriguing properties distinct from those of the “original”
calixarenes.1,2 For the preparation of heteroatom-bridged
calixarenes, three typical synthetic strategies have so far been
employed that are substantially identical with those estab-
lished in the methylene-bridged calixarene chemistry:3,4 that
is, (1) single-step synthesis, (2) non-convergent stepwise
synthesis, and (3) convergent fragment coupling synthesis.3
From a synthetic point of view, strategy 1 is undoubtedly
favorable, whereas the latter two alternatives may provide a
more versatile and flexible synthetic approach, by which
boron-,5 germanium-,6 nitrogen-,7 oxygen-,8 silicon-,9 phos-
phorus-,9b and sulfur-bridged10 calixarene analogues were
synthesized.
(1) Calixarenes 2001; Asfari, Z., Bo¨hhmer, V., Harrowfield, J.,
Vicens, J., Saadioui, M., Eds.; Kluwer: Dordrecht, The Netherlands,
2001.
(2) For a review on heteroatom-bridged calixarenes: Ko¨nig, B.; Fonseca,
M. H. Eur. J. Inorg. Chem. 2000, 2303.
10.1021/ol062459p CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/22/2006

In the course of our study aiming at developing a novel
host molecule, we very recently reported the preparation of
exhaustively methylated azacalix[4]arene 17k by applying
strategy 2 shown in Scheme 1, where Buchwald-Hartwig
diate linear oligomers 8, 12, and 13. As a natural conse-
quence, our efforts were directed to the establishment of a
“shortcut” by the usage of strategy 3, in which the palladium-
catalyzed aryl amination reaction was applied to the direct
coupling between trimer 9 and monomer 14.12 Benzyl groups,
easily cleavable by hydrogenolysis in due course, were
introduced onto the amino groups of 14. However, the
corresponding azacalix[4]arene 2 and other possible cyclized
products were not isolated from the reaction mixture. Instead,
debrominated trimer 10 was obtained in 56% yield, clearly
indicating that the competitive â-elimination pathway giving
10 proceeded in preference to desirable reductive elimination
yielding 2, as shown in Scheme 2.11a,13
Scheme 1. Synthesis of Azacalix[4]arene 1 by No Application
of the Temporal N-Silylation Protocol
Scheme 2. Catalytic Cycle of the Buchwald-Hartwig Aryl
Amination Reaction of Aromatic Halide with N-Benzylated
Arylamine11a
To suppress the undesirable â-elimination in the catalytic
cycle, efficient ligands such as t-Bu3P, DPEphos,14 Xant-
phos,15 and Johnphos16 were devised.17 In the present study,
a Debrominated trimer 10 was obtained in 56% yield.
(8) (a) Sommer, N.; Staab, H. A. Tetrahedron Lett. 1966, 25, 2837. (b)
Katz, J. L.; Feldman, B.; Conry, R. R. Org. Lett. 2005, 7, 91.
(9) (a) Ko¨nig, B.; Ro¨del, M.; Bubenitschek, P.; Jones, P. G. Angew.
Chem., Int. Ed. Engl. 1995, 34, 661. (b) Ko¨nig, B.; Ro¨del, M.; Bubenitschek,
P.; Jones, P. G.; Thondorf, J. J. Org. Chem. 1995, 60, 7406.
(10) (a) Nakayama, J.; Katano, N.; Suhihara, Y.; Ishii, A. Chem. Lett.
1997, 897. (b) Sone, T.; Ohba, K.; Moriya, K.; Kumada, H.; Ito, K.
Tetrahedron 2000, 53, 10689.
(11) For reviews on the palladium-catalyzed aryl amination reaction: (a)
Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L. Acc. Chem. Res.
1998, 31, 805. (b) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (c) Hartwig,
J. F. Angew. Chem., Int. Ed. 1998, 37, 2046. (d) Muci, A. R.; Buchwald,
S. L. Top. Curr. Chem. 2002, 219, 133.
(12) As reported in ref 7k, a simpler cyclization of 7 with 8 afforded a
complicated reaction mixture.
(13) Hartwig, J. F.; Richards, S.; Baran˜ano, D.; Paul, F. J. Am. Chem.
Soc. 1996, 118, 3626.
(14) DPEphos: bis[2-(diphenylphosphino)phenyl] ether. Kranenburg, M.;
van der Burgt, Y. E. M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.;
Goubitz, K.; Fraanje, J. Organometallics 1995, 14, 3081.
(15) Xantphos: 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene. See
ref 14 for the preparation.
(16) Johnphos: 2-(di-tert-butylphosphino)biphenyl. Aranyos, A.; Old,
D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 4369.
aryl amination reaction11 was repeatedly utilized for the
synthesis of 1 starting from monomers 6 and 7 via interme-
(3) (a) Gutsche, C. D. Calixarenes; Stoddart, J. F., Ed.; Royal Society
of Chemistry: Cambridge, UK, 1989. (b) Gutsche, C. D. Calixarenes
ReVisited; Stoddart, J. F., Ed.; Royal Society of Chemistry: Cambridge,
UK, 1998.
(4) Calixarenes: A Versatile Class of Macrocyclic Compounds; Vicens,
J., Bo¨hmer, J. V., Eds.; Kluwer: Dordrecht, The Netherlands, 1991.
(5) Carre´, F. H.; Corriu, R. J.-P.; Deforth, T.; Douglas, W. E.; Siebert,
W. S.; Weinmann, W. Angew. Chem., Int. Ed. Engl. 1998, 37, 652.
(6) Ko¨nig, B.; Ro¨del, M. Chem. Ber. 1997, 130, 412.
(7) (a) Graubaum, H.; Lutze, G.; Costisella, B. J. Prakt. Chem./Chem.-
Ztg. 1997, 339, 266. (b) Graubaum, H.; Lutze, G.; Costisella, B. J. Prakt.
Chem./Chem.-Ztg. 1997, 339, 672. (c) Ito, A.; Ono, Y.; Tanaka, K. New J.
Chem. 1998, 779. (d) Ito, K.; Ono, Y.; Tanaka, K. J. Org. Chem. 1999, 64,
8236. (e) Ito, K.; Ono, Y.; Tanaka, K. Angew. Chem., Int. Ed. Engl. 2000,
39, 1072. (f) Miyazaki, Y.; Kanbara, T.; Yamamoto, T. Tetrahedron Lett.
2002, 43, 7945. (g) Wang, M.-X.; Zhang, X.-H.; Zheng, Q.-Y. Angew.
Chem., Int. Ed. 2004, 43, 838. (h) Wang, M.-X.; Yang, H.-B. J. Am. Chem.
Soc. 2004, 126, 15412. (i) Suzuki, Y.; Yanagi, T.; Kanbara, T.; Yamamoto,
T. Synlett 2005, 263. (j) Fukushima, W.; Kanbara, T.; Yamamoto, T. Synlett
2005, 2931. (k) Tsue, H.; Ishibashi, K.; Takahashi, H.; Tamura, R. Org.
Lett. 2005, 7, 2165. (l) Yan, X. Z.; Pawlas, J.; Goodson, T., III; Hartwig,
J. F. J. Am. Chem. Soc. 2005, 127, 9105.
(17) For a review on phosphine ligands: Mauger, C. C.; Mihnani, G. A.
Aldrichim. Acta 2006, 39, 17.
5992
Org. Lett., Vol. 8, No. 26, 2006

we examined an additional procedure in which the silyl group
without any hydrogen on the silicon atom was attached onto
an amino group in place of methyl and benzyl groups hitherto
used in our synthetic pathways. As an eventual outcome,
we found this method highly efficient for the palladium-
catalyzed aryl amination reaction in terms of the following
three points. First, N-silylation of the amino group smoothly
proceeds in situ. Second, the resultant silylamine is subjected
in one pot to the cross-coupling reaction with aromatic halide.
Third and finally, the N-silylation of the amino group is
temporal because the N-Si bond is labile to hydrolysis,18
thereby furnishing the final cross-coupling product with no
silyl group on the nitrogen atom after the usual workup
process. In this paper, we report a temporal N-silylation
protocol in the catalytic aryl amination reaction and a
successful application of it to the preparation of regioselec-
tively N-methylated azacalix[8]arene octamethyl ether 3.
As a model reaction, the aryl amination reaction of aniline
with bromobenzene was examined to establish the general
procedure of the temporal N-silylation protocol. Essentially
the same reaction conditions as those employed in the cross-
coupling reaction 6 + 7 f 87k were applied to this model
reaction. A control experiment was conducted with N-
benzylaniline, which was transformed to the corresponding
cross-coupling product in 38% yield (entry 1 in Table 1). In
for tert-butyldiphenylsilyl chloride (TBDPSCl), whereas tert-
butyldimethylsilyl chloride (TBDMSCl) and triphenylsilyl
chloride (TPSCl) failed to give good yields. The exact reason
for the observed variation in the reaction yields by the use
of different silylating agents remains unclear at this moment.
Nevertheless, the DMPS group was demonstrated to be the
best among the silylating agents examined herein, and thus
a general procedure for the temporal N-silylation protocol
in the catalytic aryl amination reaction was established.19,20
As described above, the convergent fragment coupling
between trimer 9 and monomer 14 did not furnish any
cyclized product. Thus, we next examined the reaction of
trimer 9 with monomer 7 as an application of the temporal
N-silylation protocol. Essentially the same reaction conditions
as those employed in the final ring-closing reaction 13 f
17k in Scheme 1 were applied, and DMPSCl was used as a
silylating agent. As a result, regioselectively N-methylated
azacalix[8]arene octamethyl ether 3 was isolated in 23% yield
after flash column chromatography on silica gel. However,
smaller azacalix[4]arene 4 was not obtained from the reaction
mixture, probably due to the highly steric demand of the
DMPS group. From a thermodynamic point of view, transi-
tion state energy of the final cyclization step yielding
azacalix[8]arene 3 must be lower than that of azacalix[4]-
arene 4 because the former must be more flexible than the
latter with smaller ring size. Hence, it is reasonable to
presume that kinetically favorable azacalix[8]arene 3 forms
in preference to azacalix[4]arene 4 by using the temporal
N-silylation protocol. The isolated yield of 3 (23%) was less
satisfactory as a reaction but acceptable to us when consider-
ing that no cyclized products were produced in the reaction
of 9 with 14. It is worth noting that, because palladium-
catalyzed cross-coupling reactions must occur four times in
succession in the reaction of 9 with 7 to give 3, the average
yield of ca. 70% per one cross-coupling reaction is compa-
rable to that observed in the model reaction mentioned above.
The molecular structure of this new azacalix[8]arene 3 was
Table 1. Palladium-Catalyzed Aryl Amination Reaction of
Aniline with Bromobenzene by Using the Temporal N-Silylation
Protocola
entry
R
silylating agent
yield (%)b
1
2
3
4
5
Bn
H
H
H
H
none
38
79
70
36
35
1
fully characterized by FD MS, IR, H NMR, 13C NMR,
DMPSCl
TBDPSCl
TBDMSCl
TPSCl
elemental analysis, and X-ray crystallographic analysis.
A single crystal of azacalix[8]arene 3 suitable for X-ray
crystallographic analysis was obtained by slow crystallization
from benzene involving a few drops of acetone.22 The
compound crystallized with two molecules of benzene and
half a molecule of acetone (see Figure S4 in the Supporting
Information) into a monoclinic form, space group C2/c (Z
a Reaction conditions of step 1: 1 mmol of aniline, 1 mmol of
bromobenzene, 1 mmol of silylating agent, 3 mmol of t-BuONa, 2 mL of
anhydrous toluene; heated at 80 °C for 30 min under an Ar atmosphere.
Step 2: 5 mol % of Pd(OAc)2, 7.5 mol % of DPEphos; heated at 80 °C for
18 h. b Yields were determined by means of normal phase HPLC analyses.
(19) General procedure (entry 2): a Schlenk tube was charged with a
suspension of aniline (93.1 mg, 1.00 mmol), bromobenzene (158.4 mg, 1.01
mmol), DMPSCl (171.4 mg, 1.00 mmol), and t-BuONa (288.9 mg, 3.01
mmol) in anhydrous toluene (2 mL). After stirring at 80 °C for 30 min
under an Ar atmosphere, Pd(OAc)2 (11.9 mg, 53.0 µmol) and DPEphos
(42.5 mg, 78.9 µmol) were added to the tube, and the reaction mixture was
stirred at 80 °C for an additional 18 h. After cooling to room temperature,
EtOAc was added. The organic layer was washed with saturated NaHCO3,
dried over anhydrous K2CO3, filtered, and evaporated. The resulting residue
was subjected to normal phase HPLC analysis, using hexane/isopropanol
(99:1, v/v) as eluent. The experimental procedure for the synthesis of
azacalix[8]arene 3 is described in the Supporting Information.
contrast, the reaction yield was drastically improved to 79%
in entry 2, where an equimolar amount of dimethylphenylsilyl
chloride (DMPSCl) was employed. Unlike entry 1, the
DMPS group introduced in situ onto the nitrogen atom was
deprotected after the usual workup because of the high
instability of N-Si bond to water18 used in the extraction
process, thus allowing the temporal protection of the amino
group only during the reaction. A similar result was obtained
(20) Applications of the temporal N-silylation protocol to the aromatic
C-N coupling reaction are limited to the described examples at the present
moment. Further studies are necessary to fully understand the scope and
limitation of this newly devised protocol.
(18) (a) ProtectiVe Groups in Organic Synthesis, 3rd ed.; Green, T. W.,
Wuts, P. G., Eds.; Wiley & Sons: New York, 1999; p 600. (b) Fessenden,
R.; Fessenden, J. S. Chem. ReV. 1961, 61, 361.
(21) Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
Org. Lett., Vol. 8, No. 26, 2006
5993

) 4). As shown in Figures 1 and S3, azacalix[8]arene 3
possesses a roughly ellipsoidal shape, and the conformation
with C2-symmetry is less symmetrical than that reported for
the carbocyclic analogue 5, which adopts a conformation with
C4V-symmetry in the solid state.23 The asymmetric unit of 3
involves half a molecule, and the structure is described with
four different types of the aromatic units designated as A,
B, C, and D (Figure 1). Of them, three aromatic rings B, C,
compared with that of diphenylamine at δ 5.0 ppm, strongly
suggesting that the intramolecular bifurcated NH‚‚‚OMe
hydrogen bonds are sustainable even in solution.
In summary, we have devised a temporal N-silylation
protocol, of which the efficiency in palladium-catalyzed aryl
amination reaction has been demonstrated by the successful
application to the preparation of regioselectively N-methy-
lated azacalix[8]arene octamethyl ether 3. X-ray crystal-
lographic analysis and NMR measurement clearly revealed
that intramolecular bifurcated MeO‚‚‚NH‚‚‚OMe hydrogen
bonds between each bridging NH group and two methoxy
groups located on the neighboring aromatic rings played a
decisive role in the control of the conformation of 3 in the
solid state and in solution. We should emphasize that the
preparation of azacalix[8]arene 3 has been realized by a
strategic management of stability and instability of the N-Si
bond under anhydrous and moist conditions, respectively.
From the present experimental results, we anticipate that the
temporal N-silylation protocol is general and applicable to a
wide variety of molecular systems. To assess our prospect,
further work on the preparation of azacalix[n]arenes without
any substituent on the bridging nitrogen atoms is currently
underway in our laboratory.
Supporting Information Available: Experimental pro-
cedures and characterization data for all the new compounds
(including NMR spectra, crystal structure, and crystal-
lographic data in CIF format for azacalix[8]arene 3). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 1. ORTEP21 drawing of azacalix[8]arene 3. The displace-
ment ellipsoids are drawn at the 50% probability level. Solvent
molecules and all hydrogen atoms but for the bridging NH groups
are omitted for clarity. The tert-butyl group located on ring B is
disordered over two positions and refined isotropically. Numbers
indicate O‚‚‚H distances (Å) of intramolecular MeO‚‚‚NH hydrogen
bonds.
OL062459P
(22) The X-ray data were collected on a Rigaku RAXIS RAPID imaging
plate area detector. The crystal structure was solved by direct methods and
refined by full-matrix least squares. All non-hydrogen atoms were refined
anisotropically, except for one molecule of benzene, acetone, and disordered
tert-butyl group that were refined isotropically. Hydrogen atoms were refined
by using the riding model. All calculations were performed with a
crystallographic software package, CrystalStructure version 3.7.0.24 Crystal
data for 3‚0.5 acetone‚2 benzene: Mr ) 1659.34, monoclinic, space group
C2/c, a ) 24.468(2) Å, b ) 24.214(3) Å, c ) 19.304(2) Å, â )
102.267(7)°, V ) 11176(2) Å3, Z ) 4, Fcalc ) 0.986 g cm-3, 2θmax ) 55.0°,
Mo KR (λ ) 0.71075 Å), µ ) 0.621 cm-1, θ-ω scans, T ) 173 K, 12738
independent reflections, 11618 observed reflections, 578 refined parameters,
and D nearly lie on one plane, whereas ring A is considerably
tilted toward the perpendicular with respect to it. Two sets
of intramolecular bifurcated MeO‚‚‚NH‚‚‚OMe hydrogen
bonds formed between rings B and C and between rings C
and D are responsible for the almost flat arrangement of these
three aromatic rings. In other words, aromatic ring A with
NMe groups on both sides lacks such hydrogen bonding
interactions, thereby giving rise to inclination of the ring, as
observed in the 1,3-alternate conformation of our previously
R1 ) 0.1226 (I > 2σ(I)), wR2 ) 0.3856, ∆Fmax ) 0.89 eÅ-3, ∆Fmin
)
-0.31 eÅ-3. CCDC 622392. See the Supporting Information for crystal-
lographic data in CIF format.
1
reported azacalix[4]arene 1.7k Of further interest is the H
(23) Bolte, M.; Brusko, V.; Bo¨hmer, V. J. Supramol. Chem. 2002, 2,
57.
(24) CrystalStructure, version 3.7.0; Rigaku and Rigaku/MSC: The
Woodlands, TX, 2000-2005.
NMR spectrum of 3 (Figure S1), the NH hydrogens of which
experience a strong downfield shift at δ 6.49 ppm as
5994
Org. Lett., Vol. 8, No. 26, 2006