Arylene imine macrocycles of C3h and C3 symmetry from reductive imination of nitroformylarenes

Article abstract of DOI:10.1021/ol802302x

(Chemical Equation Presented) Novel C₃-symmetric phenylene imine macrocycles have been synthesized by reductive imination of single nitroformylarenes. Pore size and geometric shape are dictated by the distance between and orientation of thei nitro and aldehyde moieties in the precursor backbone. This reaction is facile, requires no purification of the products, and is environmentally friendly.

Full text of DOI:10.1021/ol802302x

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5405-5408
Arylene Imine Macrocycles of C3h and
C3 Symmetry from Reductive Imination
of Nitroformylarenes
Andrew L. Korich and Thomas S. Hughes*
UniVersity of Vermont, Chemistry Department, Cook Physical Science Building,
82 UniVersity Place, Burlington, Vermont 05405
thomas.s.hughes@uVm.edu
Received October 4, 2008
ABSTRACT
Novel C3-symmetric phenylene imine macrocycles have been synthesized by reductive imination of single nitroformylarenes. Pore size and
geometric shape are dictated by the distance between and orientation of the nitro and aldehyde moieties in the precursor backbone. This
reaction is facile, requires no purification of the products, and is environmentally friendly.
Shape-persistent macrocycles have become an important
class of molecules in several fields, including catalysis,1
liquid crystals,2 and supramolecular chemistry.2a,b,3 By
definition these macrocycles have a very small number of
available conformations, and this structural rigidity makes
them ideal model systems and building blocks for larger
nanostructures.2d,3c,4
Imines have become an appealing moiety for shape-
persistent macrocycles in part because they are easily
synthesized, requiring only a minimal number of steps.5
Furthermore, incorporation of N heteroatoms into the back-
bone allows for metal chelation and in turn the tuning of
the physical and optical properties of the system.6
Many methods have been used to synthesize symmetric
and unsymmetric imine macrocycles. Among the most
common strategies employed is an [n + n] Schiff base
condensation between two precursors, one containing two
formyl groups and the other having two amine groups.7 Metal
templation or hydrogen bonding favors the formation of
macrocycles over linear oligomers. The orientation of the
diformyl and diamine groups (i.e., ortho, meta, para) dictates
the size and geometric shape of the resulting macrocycle.
(1) Martell, A. E.; Perutka, J.; Kong, D. Coord. Chem. ReV. 2001, 216,
55.
(5) For recient review on Schiff base macrocycles, see: (a) Borisova,
N. E.; Reshetova, M. D.; Ustynyuk, Y. A. Chem. ReV. 2007, 107, 46. (b)
MacLachlan, M. J. Pure Appl. Chem. 2006, 78, 2006.
(2) (a) Hoger, S. Chem. Eur. J. 2004, 10, 1321. (b) Lahiri, S.; Thompson,
J. L.; Moore, J. S. J. Am. Chem. Soc. 2000, 122, 11315. (c) Hoger, S.;
Spickermann, J.; Morrison, D. L.; Dziezok, P.; Rader, H. J. Macromolecules
1997, 30, 3110. (d) Shetty, A. S.; Zhang, J.; Moore, J. S. J. Am. Chem.
Soc. 1996, 118, 1019. (e) Zhang, J.; Moore, J. S. J. Am. Chem. Soc. 1994,
116, 2655. (f) Gallant, A. J.; Hui, J. K. H.; Zahariev, F. E.; Wang, Y. A.;
MacLachlan, M. J. J. Org. Chem. 2005, 70, 7936.
(6) (a) Gallant, A. J.; MacLachlan, M. J. Angew. Chem., Int. Ed. 2003,
42, 5307. (b) Ma, C.; Lo, A.; Abdolmaleki, A.; MacLachlan, M. J. Org.
Lett. 2004, 6, 3841. (c) Higuchi, M.; Shomura, R.; Ohtsuka, Y.; Hayashi,
A.; Yamamoto, K.; Kurth, D. G. Org. Lett. 2006, 8, 4723.
(7) (a) Gallant, A. J.; Yun, M.; Sauer, M.; Yeung, S.; MacLachlan, M.
J Org. Lett. 2005, 7, 4827. (b) Akine, S.; Taniguchi, T.; Nabeshima, T.
Tetrahedron Lett. 2001, 42, 8861. (c) Chadim, M.; Budeˇsˇ´ınsky´, M.;
Hodacˇova´, J.; Za´vada, J.; Junk, P. C. Tetrahedron: Asymmetry 2001, 12,
127. (d) Kuhnert, N.; Staꢀnig, C.; Lopez-Periago, A. M. Tetrahedron:
Asymmetry 2002, 13, 123. (e) Gawron´ski, J.; Kołbon, H.; Kwit, M.;
Katrusiak, A. J. Org. Chem. 2000, 65, 5768.
(3) Henze, O.; Lentz, D.; Schlu¨ter, A. D. Chem. Eur. J. 2000, 6, 2362.
(b) Grave, C.; Schlu¨ter, A. D. Eur. J. Org. Chem. 2002, 3075. (c) Shetty,
A. S.; Fischer, P. R.; Stork, K. F.; Bohn, P. W.; Moore, J. S. J. Am. Chem.
Soc. 1996, 118, 9409
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(4) Pasini, D.; Ricci, M. Curr. Org. Synth. 2007, 4, 59
.
10.1021/ol802302x CCC: $40.75
Published on Web 11/06/2008
2008 American Chemical Society

Several groups have made triangular,7a-d rhombodial,6c,8 and
hexagonal9 imine macrocycles via the [n + n] synthetic
strategy; an example of a triangular macrocycle is shown in
Scheme 1.
of 2-bromobenzaldehyde with (triisopropylsilyl)acetylene in
90% yield followed by removal of the TIPS silyl protecting
group with TBAF to afford 7 in 90% yield. Subsequent
coupling with 1-iodo-4-nitrobenzene yielded 6 in 81% yield,
while coupling with 5 gave 8 in 23% yield. The purification
of 8 required sublimation because it coeluted with the Hay
coupled dimer of 7 during chromatography.
Scheme 1.
[3 + 3] Schiff base Strategy6a
Scheme 2. Synthesis of Nitroformylarene Precursors
Few imine macrocycles can be traced back to a single
fragment that contains both the amine and the carbonyl
moieties.10 This is most likely due to spontaneous condensa-
tion of the amine and carbonyl under a wide variety of
conditions that would lead to difficulties in the purification
of such a fragment. Difficulties also arise if the single
fragment is produced in situ. For example, many of the
methods used to reduce nitroarenes to the respective anilines
are also used to reduce aldehydes to the primary alcohol.11
To circumvent this issue we have developed a simple and
environmentally friendly one-pot procedure for imine forma-
tion from nitroarenes and arylaldehydes. Powdered Fe(0) in
an acidic ethanol/water mixture acts as a reducing agent for
the nitroarene.12 The resulting aniline undergoes imine
condensation with the desired aldehyde in situ to give the
Schiff base. We report the synthesis and structural charac-
terization of novel C3-symmetric arylene imine macrocycles
via this methodology starting from nitroaldehyde precursors.
Suzuki-Miyaura coupling of 2-formylphenylboronic acid
and 1-iodo-4-nitrobenzene or 3-formylphenylboronic acid
and 1-iodo-3-nitrobenzene gave the corresponding nitro-
formylarene 113 or 2 in 86% and 84% yields, respectively
(Scheme 2). Compound 314 was prepared in 74% yield by
cross-coupling 1-iodo-4-nitrobenzene with 3-formylphenyl-
boronic acid. Nitroformylnaphthalene 4 was prepared by
triflation of 4-nitro-1-naphthol to afford 5 in 62% yield,
followed by coupling of 5 with 2-formylphenylboronic acid
under similar condition as before to give 4 in 74% yield.
Alkyne precursor 615 was prepared via Sonogashira coupling
Because of the difficulty in isolating 8, it was also
synthesized by cross-coupling of 5 with (triisopropylsilyl)-
acetylene to afford 9 in modest 65% yield. Silyl deprotection
of 9 in the presence of AcOH occurred smoothly (95% yield),
and coupling the terminal ethynylene with 2-bromobenz-
aldehyde afforded 8 in 56% yield after purification by flash
chromatography.
(8) Gawron´ski, J.; Brzostowska, M.; Kwit, M.; Plutecka, A.; Rychlewska,
U. J. Org. Chem. 2005, 70, 10147. Tian, Y.; Tong, J.; Frenzen, G.; Sun, J.
J. Org. Chem. 1999, 64, 1442
.
(9) (a) Zhao, D.; Moore, J. S. J. Org. Chem. 2002, 67, 3548. (b) Hui,
J. K.; MacLachlan, M. J. Chem. Commun. 2006, 2480.
(10) Melson, G. A.; Busch, D. H. J. Am. Chem. Soc. 1965, 87, 1706.
(11) (a) Mendenhall, D.; Smith, P. A. S. Organic Synthesis; Wiley: New
York, 1973; Collect. Vol. V, p 829.
Various nitroarene reduction methods to afford the cor-
responding imine macrocycles were explored. Hydrogenation
of 1 at 65 psi as well as at atmospheric pressure gives a
complex mixture of products, presumably because of reduc-
tion of both the nitro and aldehyde moieties as well as
reduction of the resulting imines. Reduction by first row
(12) Korich, A. L.; Hughes, T. S. Synlett 2007, 2602.
(13) Zhao, J.; Yue, D.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc.
2007, 129, 5288.
(14) Kabalka, G. W.; Namboodiri, V.; Wang, L. Chem. Commun. 2001,
775.
(15) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M.
J. Am. Chem. Soc. 2003, 125, 9028.
5406
Org. Lett., Vol. 10, No. 23, 2008

transition metals or main group metals, however, gave the
desired imine macrocycle 10 in good yields (Table 1, entries
3-8).
Table 2. Reductive Imination of Nitroformylarenes
Table 1. Reducing Conditions for Macrocycle 10 Formation
entry
reducing agent
product(s) (yield, %)
ref
1a
2b
3c
4d
5
6
7
8
H2, Pd-C
H2, Pd-C
Fe, HCl
Fe, HCl
Al, NiCl2·6H2O
Sn, HCl
complex mixture
complex mixture
10 (56)
10 (26)
10 (41)
10 (47)
starting material
10 (23)
11
11
12
12
16
17
18
19
Zn, NaOH
Zn, HCl
a At 65 psi. b At atmospheric pressure. c 0.003 M in 1. d 0.3 M in 1.
Fe(0) reduction in acidic aqueous ethanol proceeded
smoothly, yielding the macrocycle 10 in 56% yield. Upon
treatment of 1 with either Sn and HCl or Al and NiCl2·H2O,
10 was formed in 47% and 41% yields, respectively.
Although the yields are comparable to that of the Fe(0)
reaction, isolation and purification of 10 was more difficult
with these two methods. Zn reduction of aryl nitro groups
has been reported to occur under both basic and acidic
conditions.15,16 However, reduction of 1 under basic condi-
tions returned only starting material, whereas acidic condi-
tions gave the desired macrocycle in 23% after purification.
Macrocycle 10 is formed at both high and low concentra-
tions of nitroformylarene, although the yield of the reaction
at 0.3 M is lower than at 0.003 M (entries 3 and 4, Table 1).
The mere halving of the yield of a macrocyclic product upon
a hundredfold concentration suggests that the imine macro-
cycle may be formed under thermodynamic conditions, as
might be expected of imines in an aqueous medium.
Varying the orientations of the functional groups about
the precursor framework (i.e., ortho-para in 1 to meta-meta
in 2) does not have a drastic affect on reaction yield (Table
2). Macrocycles 10, 11, and 14 all possess C3 symmetry,20
a Reaction conditions: 1 equiv; 0.003 M; Fe(0) (10 equiv); HCl (6 equiv);
EtOH/H2O (2:1 v/v). b Insoluble solid not characterized.
1
which is evident by the simplicity of the H NMR spectra.
However, attempts to synthesize the larger C6 hexamer
12 from precursor 3 produced an insoluble solid that did
not show any MALDI mass peaks corresponding to a
macrocycle but did exhibit an IR band at 1596 cm-1 and
UV bands at 271 and 332 nm, consistent with imine
formation. The formation of a macrocycle from 8 was also
unsuccessful, perhaps because the poor solubilities of the
larger hexamer expected from 3 and the more hydrophobic
backbone of 8.
These macrocycles are stable in the solid state for months
and exhibit only approximately 15% hydrolysis in acidic
CH2Cl2 at room temperature after 24 h.
(16) Sarmah, P.; Barua, N. C. Tetrahedron Lett. 1990, 31, 4065.
(17) Doxsee, K. M.; Feigel, M.; Stewart, K. D.; Canary, J. W.; Knobler,
C. B.; Cram, D. J. J. Am. Chem. Soc. 1987, 109, 3098.
(18) Martin, E. L. Organic Synthesis; Wiley: New York, 1943; Collect.
Vol. II, p 501
(19) Compound 1 (1 equiv; 0.003 M); Zn(0) (10 equiv); HCl (6 equiv);
EtOH/H2O (2:1 v/v) (see Supporting Information).
Each macrocycle can exist in several different conforma-
tions in which the imine nitrogen is either endo or exo in
(20) For other routes to C3-symmetric imine macrocycles, see ref 10
and Hartley, C. S.; Moore, J. S. J. Am. Chem. Soc. 2007, 129, 11682.
Org. Lett., Vol. 10, No. 23, 2008
5407

relation to the macrocyclic backbone, and in the case of 10,
13, and 14, a simple crankshaft motion allows the intercon-
version of the N-exo and N-endo conformations for each
imine. The sharpness of the NMR peaks suggests a rapid
interconversion of the various conformers at room temper-
ature.
Reduction of 4 gives macrocycle 13, which is isolated as
an inseparable mixture of diastereomers syn-13 and anti-13
(Figure 1). The restricted rotation of the biaryl moieties in
13 prevents interconversion between these diastereomers,
which is not observed on the NMR time scale in CDCl3 or
C6D6 up to 75 °C. HPLC indicates a 1:1 mixture of syn-
and anti-13, while MM2, AM1, and HF/6-31(G) calculations
indicate anti-13 should be 1.6, 1.2, and 2.4 kcal/mol more
stable than syn-13, respectively.21
Figure 2. Absorption spectra for macrocycles 10 (pink), 11 (red),
13 (diastereomeric mixture, yellow), 14 (green), and bistolylimine
16 (blue). Spectra were obtained in CHCl3 at concentrations between
0.05 and 0.15 µM.
Table 3. UV-vis Spectroscopy of Macrocycles
compound
λmax (nm) (molar absorptivity, M-1 cm-1
)
16
10
11
13
14
268 (10200) 323 (7600)
246 (9100) 275 (3100) 317 (5100)
246 (15000) 268 (8700) 300 (7400)
Figure 1. HF/6-31G(d) minimized structures of syn-(PPP)-13 and
anti-(PPM)-13.
250 (20200)
297 (6500) 346 (8100)
276 (4000) 301 (1200) 342 (5100)
Extending the backbone with an alkyne linker affords
macrocycle 14 in a modest 52% yield. Interestingly, a
significant downfield shift of 0.80 ppm is observed in the
1H NMR for the azomethine proton in 14 when compared
to 10. These protons are different distances from the nearest
aromatic ring within their respective macrocycles, but the
downfield shift could also be attributed to a weak aromatic
ring current arising from the [4n + 2] π-electron circuit
present and is consistent with observed NMRs other conju-
gated shape persistent macrocycles, namely, dehydrobenzo-
[n]annulenes.18
In summary, we have developed an efficient methodology
for the synthesis of C3-symmetric imine macrocycles by
reductive imination of nitroformylarenes. This method is
simple, inexpensive and environmentally friendly. Solution
aggregation and the use of 10, 11, 13, and 14 in dynamic
combinatorial chemistry are currently being explored in our
laboratory.
Acknowledgment. The authors gratefully acknowledge the
University of Vermont, Vermont EPSCoR (EPS 0236976),
and the NSF (CHE 0719231) for support of this work. The
authors would also like to thank Bruce Deker of the
University of Vermont for his assistance with NMR analyses.
Mass spectrometry was provided by the Washington Uni-
versity Mass Spectrometry Resource with support from the
NIH National Center for Research Resources (Grant
P41RR0954).
Macrocycles 10 and 11 show absorption spectra similar
to that of bistolylimine 16, having two λmax at ∼270 and
315 nm (Figure 2, Table 3) along with an additional λmax at
246 nm. Macrocycle 11 exhibits a greater molar absorptivity
than 10 or 16, which could be the result of the greater
planarity of the biphenyl moiety in 11. The mixture of syn-
13 and anti-13 shows two λmax at 297 and 346 nm as well
as a short wavelength shoulder at 250 nm. Not surprisingly,
13 and 14 display longer wavelength absorptions compared
to 10, which can be attributed to the extended conjugation
of the naphthyl moiety or ethynyl backbone, respectively.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds,
optimized Cartesian coordinates for syn-(PPP)-13 and anti-
(PPM)-13, and full ref 18. This material is available free of
charge via the Internet at http://pubs.acs.org.
(21) Frisch, M. J. et al. Gaussian 03; Gaussian Inc.: Wallingford, CT,
2004.
(22) (a) Haley, M. M.; Grand, S. C.; Pak, J. J. Angew. Chem., Int. Ed.
1997, 36, 836. (b) Wan, W. B.; Haley, M. M. J. Org. Chem. 2001, 66,
3893. (c) Marsden, J. A.; Miller, J. J.; Shirtcliff, L. D.; Haley, M. M. J. Am.
Chem. Soc. 2005, 127, 2464.
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