Highly substituted Schiff base macrocycles via hexasubstituted benzene: a convenient double Duff formylation of catechol derivatives

Article abstract of DOI:10.1016/j.tet.2009.07.094

The synthesis of soluble, shape-persistent macrocycles is important for developing new materials. Double Duff formylation of 4,5-dialkylcatechol derivatives yields 3,6-diformyl-4,5-dialkylcatechols in moderate yields. These hexasubstituted aromatics are u

Full text of DOI:10.1016/j.tet.2009.07.094

Tetrahedron 65 (2009) 8113–8119
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly substituted Schiff base macrocycles via hexasubstituted benzene:
a convenient double Duff formylation of catechol derivatives
*
Kevin E. Shopsowitz, David Edwards, Amanda J. Gallant, Mark J. MacLachlan
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, Canada V6T 1Z1
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 May 2009
Received in revised form 30 July 2009
Accepted 30 July 2009
Available online 4 August 2009
The synthesis of soluble, shape-persistent macrocycles is important for developing new materials.
Double Duff formylation of 4,5-dialkylcatechol derivatives yields 3,6-diformyl-4,5-dialkylcatechols in
moderate yields. These hexasubstituted aromatics are useful precursors to highly substituted Schiff base
macrocycles. We illustrate convenient routes to these compounds as well as structural studies of two
new macrocycles with alkyl substituents.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
substituents on the phenylenediamine. The alkoxy groups on the
phenylenediamine render that subunit very electron rich and,
The development of shape-persistent macrocycles is important
for creating new materials,1 new liquid crystals,2 and for studying
the role of non-covalent interactions in supramolecular chemistry.3
Cyclic molecules based on phenyleneethynylene and phenyl-
enebutadiyne moieties, for example, have been extensively studied
and their self-assembly studied under different conditions.4 Other
macrocycles, such as cyclic d,l-peptides and bis-urea macrocycles
have also garnered interest for their abilities to organize into
tubular assemblies.5–7 In the past decade, Schiff base macrocycles
have emerged as a new class of shape-persistent molecules that can
be easily synthesized and also show interesting supramolecular
phenomena.8
Since the first Schiff base macrocycles prepared by Robson and
Pilkington,9 there has been a great deal of growth in this field.10,11
New macrocycles are being designed for complexing multiple
metal centers for studies of supramolecular chemistry,12 catalysis,13
magnetism,14 and other applications. By changing the geometry of
the diformylaromatics that are incorporated into the macrocycle,
the structure of the macrocycle can be modified.15 One of the most
studied Schiff base macrocycles is the family of conjugated [3þ3]
macrocycles (e.g., 3a) that are readily prepared by the condensation
of 3,6-diformylcatechol 1a with o-phenylenediamine derivatives
(Scheme 1).16 These shape-persistent macrocycles have proven
useful as templates for multinuclear cluster complexes and as
precursors to molecule-based nanotubes.17,18
consequently, very oxygen sensitive. The ability to incorporate
solubilizing groups on the diformyl component will avoid the
problem of oxygen sensitivity and open access to macrocycles with
new electronic and steric properties. Also, if more than six groups
are desired on the periphery of the macrocycle, then substituents
on the diformylcatechol group are necessary. Very little work has
been done to explore the functionalization of the diformylcatechol
component.19 The goal of adding alkyl groups to the diformylca-
techol group requires hexasubstituted benzenes, and we were
uncertain that the precursors could be made, or would react to
form macrocycles. Hexasubstituted benzene derivatives have been
shown to have interesting physical properties20 and are notoriously
difficult to access.
In this paper, we describe the convenient preparation of new
hexasubstituted benzene derivatives that are functionalized for the
formation of Schiff base macrocycles when reacted with phenyl-
enediamines. Two of these macrocycles have been studied by single
crystal X-ray diffraction, and preliminary evidence of metalation of
the cycles is reported.
2. Results and discussion
2.1. Synthesis of 4,5-dialkyl-3,6-diformylcatechols 1b–1d
To demonstrate the functionalization of the macrocycles with
alkyl groups on the catechol moiety, we selected three different
representative chain lengths: methyl, butyl, and hexyl substituents.
4,5-Dialkylcatechols were prepared as shown in Scheme 2.
o-Dibutylbenzene 4c and o-dihexylbenzene 4d were prepared by
Kumada coupling of o-dichlorobenzene with the corresponding
Grignard reagent.21 Bromination of 4b–4d yielded 5b–5d in good
A significant limitation of this macrocycle is that in order to
make it soluble, the macrocycle needs to be substituted with alkoxy
* Corresponding author. Tel.: þ1 604 822 3266; fax: þ1 604 822 2847.
E-mail address: mmaclach@chem.ubc.ca (M.J. MacLachlan).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.094

8114
K.E. Shopsowitz et al. / Tetrahedron 65 (2009) 8113–8119
R'
R'
R
N
N
R
O
O
R
OH HO
R
R
R
OH
OH
R'
R'
NH2
NH2
MeCN / CHCl3
+
OH
HO
N
N
HO
OH
R'
N
N
R'
1a (R = H)
2
1b (R = CH3)
1c (R = nBu)
1d (R = nHex)
R'
R'
R
R
3a (R = H, R' = alkoxy)
3b (R = CH3, R' = OEt)
3c (R = CH3, R' = OnPent)
3d (R = nBu, R' = H)
3e (R = nHex, R' = OCH3)
Scheme 1. Macrocycle synthesis.
with ethyl chloroformate gave the desired diester in good yield.
However, clean conversion of the esters to aldehydes was prob-
lematic. We found the Duff formylation was the most effective
route to 1c and 1d.
For 1b, we developed an alternative route that gave the product
in higher yield, though requiring more steps, Scheme 4. Bromo-
methylation of 6b afforded 8 in 63% yield. Reaction with sodium
acetate gave the diacetate product 9, which was reduced in nearly
quantitative yield to 10. Oxidation with pyridinium chlorochromate
(PCC) gave compound 11 in 73% yield. Deprotection with BBr3 gave
the desired compound 1b. Our attempts to extend this route to the
preparation of 1c and 1d were not successful as the bromomethy-
lated compounds analogous to 8 could not be isolated in good yield.
R
R
R
R
Br
R
OMe
OMe
R
R
OH
OH
BBr3
DCM
Br2, I2
CuBr
Br NaOMe/ R
MeOH
4b (R = Me)
5b (R = Me)
6b (R = Me)
6c (R = nBu)
7b (R = Me)
7c (R = nBu)
7d (R = nHex)
4c (R = nBu)
5c (R = nBu)
4d (R = nHex)
5d (R = nHex)
6d (R = nHex)
Scheme 2. Synthesis of 4,5-dialkylcatechol derivatives 7b–7d.
yield.22 Ullman-type coupling of NaOMe with the brominated
aromatics 5b–5d afforded 4,5-dialkylveratrole derivatives 6b–6d.
Mu¨llen and co-workers recently reported an alternative route to
related compounds 7 that may be more amenable to scale-up.23
Duff formylation with hexamethylenetetraamine (HMTA) in
trifluoroacetic acid (TFA) is a well-known route to salicylaldehyde
derivatives, although it usually proceeds in low yield.24,25 Duff
formylation of catechol directly gives mostly unidentified products
(possibly oligomers), with compound 1a isolated in very low yield
(<1%). In fact, there are no reports of formylation of any un-
protected catechol derivative. To our surprise, Duff formylation of
compounds 7b–7d (obtained from the demethylation of 6b–d with
BBr3 and used directly) gave the dialkyldiformylcatechol com-
pounds 1b–1d, Scheme 3. The yields for the preparation of 1c and
1d were w30%, but the yield of 1b was considerably lower (w10%).
We do not have an explanation for the difference, but perhaps the
longer alkyl chains shield the products or intermediates from side
reactions.
OAc
OMe
Br
(CH2O)n,
TFA,
NaOAc/
AcOH
HBr / AcOH
OMe
OMe
6b
OMe
OAc
Br
O
8
9
LAH,
THF
OH
OMe
OMe
BBr3, DCM
PCC, DCM
OMe
1b
OMe
OH
10
O
O
1) HMTA / TFA
2) HCl / H2O
R
R
OH
OH
R
R
OH
OH
11
Scheme 4. Synthesis of 1b via bromomethylation.
O
2.2. Properties of the hexasubstituted molecules
7b
7c
7d
1b
1c
1d
(R = Me)
(R = nBu)
(R = nHex)
(R = CH3)
(R = nBu)
(R = nHex)
Hexasubstituted molecules 1b–1d were fully characterized. The
1H NMR spectra of these molecules contain a downfield hydroxyl
peak at w12 ppm; the large downfield shift is characteristic of
strong intramolecular hydrogen-bonding. This hydrogen bond was
also evident in the red-shifted C–O stretch (ca. 1650 cmꢀ1) in the IR
spectra. The structure of compound 1c was determined by single
crystal X-ray diffraction and is shown in Figure 1. Notably, the
asymmetric unit contains two different molecules (A and B) of
compound 1c. In one conformation (A), both carbonyl groups are
positioned for hydrogen-bonding with the two hydroxyl groups. In
Scheme 3. Synthesis of 1b–1d via Duff formylation.
We tried other routes to 1c and 1d with limited success. For
example, dilithiation of 6c and 6d followed by quenching with
DMF gave mixtures of starting material, monoformylated com-
pound, and diformylated compound. The desired diformylated
compound was the minor product and was difficult to separate
from the other components. Quenching the dilithiated compound

K.E. Shopsowitz et al. / Tetrahedron 65 (2009) 8113–8119
8115
phenylenediamines to give macrocyclic products with longer alk-
oxy groups, but in this case the products were isolated as oils and
we have not been able to fully purify them. Nevertheless, 1H NMR
data and mass spectrometry confirmed that they are the major
products formed, and can be isolated in ca. 95% purity. We are
hopeful that more dodecasubstituted macrocycles can be isolated,
enabling access to liquid crystalline trimetallic complexes.
2.4. Macrocycle structures
To further investigate the influence of the alkyl groups on the
sterics of the macrocycles, we undertook structural studies of
macrocycles 3b and 3d. Single crystals of 3b and 3d suitable for
X-ray diffraction were grown from DMF and CH3CN/CH2Cl2,
respectively. Figure 2 shows the solid-state structure of macrocycle
3b, and Figure 3 shows the solid-state structure of macrocycle 3d.
Figure 1. ORTEP depiction of molecules A and B in the solid-state structure of 1c.
Thermal ellipsoids are shown at 50% probability.
the second conformation (B), one of the carbonyl groups is involved
in hydrogen-bonding while the other is rotated 180ꢁ. The hydroxyl
group not involved in intramolecular hydrogen-bonding in B is
hydrogen-bonded to the oxygen atoms of A in the solid state.
Moreover, molecule A is arranged into dimers in the solid state,
with p-stacking present.
As expected, the solid-state structure of 1c shows considerable
distortion. The C–C–C angle between the formyl group (not in-
volved in hydrogen-bonding) and the benzene ring is 114ꢁ, sub-
stantially less than the expected 120ꢁ angle. Other bond angles
around the ring show small, but significant distortions.
2.3. Macrocycle synthesis
With diols 1b–d in hand, we set out to explore their reactivity.
As these are hexasubstituted aromatics, we expected them to be
much less reactive than 1a, and perhaps unlikely to form a macro-
cycle. Reaction of 1b with phenylenediamine 2 (R0¼OEt) gave
macrocycle 3b in 87% yield, Scheme 1. A second macrocycle (3c)
with R0¼OC5H11 was prepared by an analogous route (77%). The
macrocycles were identified by NMR spectroscopy, mass spec-
trometry, and both gave satisfactory analysis. Notably, mass spec-
trometry confirmed that the products were the [3þ3] macrocycles
and not larger cycles. Each macrocycle showed a single imine C]N
stretch in the IR spectrum at ca. 1600–1620 cmꢀ1. 1H NMR spectra
showed a single OH resonance near 14 ppm, and a single imine
resonance at 9.0 ppm for both macrocycles. These data are con-
sistent with the threefold symmetry of the macrocycles in solution.
Macrocycles 3d and 3e, with n-butyl and n-hexyl substituents,
respectively, were readily prepared by condensation of 1c and 1d
with phenylenediamines 2 (R0¼H or R0¼OMe), Scheme 1. The
macrocycles were also characterized by NMR spectroscopy, mass
spectrometry, and elemental analysis.
Figure 2. ORTEP depiction of the solid-state structure of macrocycle 3b. Thermal
ellipsoids are drawn at 50% probability level. (Black¼C, Red¼O, Blue¼N).
Figure 3. ORTEP depiction of the solid-state structure of macrocycle 3d. Thermal el-
As expected, changing the substituents has a large effect on the
optical properties of the macrocycles. Macrocycle 3a with only
alkoxy substituents displays an absorption peak around 400 nm
lipsoids are drawn at 50% probability level.
In the solid state, macrocycle 3b is mostly planar, with one
catechol unit rotated out of the plane, having a dihedral C–C–N]C
angle of 46ꢁ, Figure 2. The hydrogen atoms on the hydroxyl groups
were not located, but the imine groups are oriented for strong
hydrogen-bonding with these groups as expected from the 1H NMR
solution data. We were surprised that the incorporation of alkyl
groups did not lead to considerable torsion about the Ar–imine
bond. The macrocycles pack in staggered planes to accommodate
the twisted phenyl ring. A slight overlap of the macrocycles in
different planes and an interplanar distance of 3.43 Å suggest that
that is associated with a
p
–
p transition of the ring. Macrocycles 3b,
*
3c, and 3e, which have alkoxy substitutents on the diamine units
and alkyl substituents on the diol units, all display absorption
maxima near 410–415 nm in solution. On the other hand, macro-
cycle 3d, which has no peripheral alkoxy chains has no strong
absorption peaks in the visible region, and only lmax at 370 nm. The
alkoxy groups have a strong role in shifting the absorption spectra
of the macrocycles, likely as a consequence of donating
density to the cycle.
p-electron
We were surprised that the macrocycles were easily formed,
particularly considering the steric hindrance around the formyl
groups. Compounds 1c and 1d also react with 4,5-dialkoxy-1,2-
p
–
p
interactions are occurring in the solid state.
The solid-state structure of macrocycle 3d, as shown in Figure 3,
is quite different from that of 3b. Although the phenyl rings

8116
K.E. Shopsowitz et al. / Tetrahedron 65 (2009) 8113–8119
associated with the diimine groups are nearly coplanar, the cate-
chol groups are all rotated in one direction relative to the plane
derived from the phenylenediimine rings. The interior hydroxyl
groups are hydrogen-bonded to imine groups and to a water
molecule at the center of the ring. This conformation produces
a shallow bowl shape, analogous to that observed when macro-
cycles 3a are metalated.17 The macrocycles pack in staggered rows
of alternating orientation, allowing for each pair of macrocycles to
spectrometer. MALDI-TOF mass spectrometry was performed on
a Bruker Biflex IV instrument with a dithranol matrix. Electrospray
ionization (ESI) mass spectra were obtained on a Bruker Esquire LC
instrument in MeOH (ca. 1ꢂ10ꢀ4 mol Lꢀ1). Elemental analyses
(CHN) were performed at the UBC Microanalytical Services Labo-
ratory. Melting points were obtained on a Fisher-John’s melting
point apparatus.
X-ray crystal structures were obtained on a Bruker X8 APEX II
have strong
of 3.56 Å.
p
–
p
interactions between six phenyl rings at a distance
diffractometer with graphite monochromated Mo Ka radiation. The
structures were solved by direct methods29 and refined using
SHELXL-97.30 Thermal ellipsoid plots of the molecular structures
were prepared using ORTEP.
We have been unable to freeze-out conformations of macro-
cycles 3a, and DFTcalculations indicate that the catechol groups can
rotate within the macrocycle with
a barrier of less than
w5 kcal molꢀ1. Low temperature 1H NMR studies of macrocycle 3c
also failed to freeze-out any conformations down to ꢀ60 ꢁC, in spite
of the bulky alkyl groups in the molecule.
4.2. 1,2-Dimethoxy-4,5-dibutylbenzene (6c)
To 3.042 g (8.74 mmol) 1,2-dibromo-4,5-dibutylbenzene 5c
were added 100 mL of 25 wt % NaOMe in MeOH, three drops of
ethyl acetate, and 27 mg CuBr (0.19 mmol, 2 mol %). This produced
a dark blue suspension that was heated to reflux overnight under
nitrogen. After confirming that the reaction had proceeded to
completion by 1H NMR spectroscopy, the mixture was poured into
100 mL of ice water. The resulting pale blue suspension was
extracted with 3ꢂ60 mL diethylether. The organic layer was
washed with 50 mL dilute (w0.1 M) NH4OH(aq) then 2ꢂ50 mL
water, dried over MgSO4, and filtered. After solvent was removed
under vacuum, compound 6c (1.948 g, 7.78 mmol, 89% yield) was
Macrocycles 3a have been shown to react with 7 equiv of zinc
acetate in ethanol to form metallocavitands containing seven zinc
ions, six bridging acetates, and one m
-oxo ligand.17 The analogous
reaction with macrocycle 3b was carried out and MALDI-TOF mass
spectrometry indicated that the expected heptazinc cluster was
formed (spectrum in Supplementary data). Interestingly, the solu-
bility properties of this new metallomacrocycle are quite unusual:
the metallomacrocycle formed from 3b is very soluble in ethanol
and even ethanol/water mixtures while the metallomacrocycle
formed from 3a with ethoxy chains is insoluble in ethanol. This has
so far frustrated crystallization of the zinc complex of 3b. Further
studies are underway to investigate the multimetallic complexes
formed from these macrocycles.
isolated as a colorless oil. 1H NMR (400 MHz, CDCl3)
d (ppm): 6.62
(s, 2H, Ar–H), 3.84 (s, 6H, OCH3), 2.53 (t, 3JHH¼7.6 Hz, 4H, Ar–CH2),
1.53 (m, 4H, Ar–CH2CH2), 1.39 (m, 4H, Ar–CH2CH2CH2), 0.94 (t,
3JHH¼7.2 Hz, 6H, CH2CH3). 13C NMR (100 MHz, CDCl3)
d (ppm):
3. Conclusion
146.8, 132.6, 112.6, 55.9, 33.9, 32.1, 22.8, 14.0. IR (neat)
n
(cmꢀ1)¼2957, 2930, 2860, 1609, 1598, 1578, 1495, 1460, 1394,
We have demonstrated the first Duff formylation of catechol
derivatives to yield dialkyldiformyldihydroxybenzenes, one of
which was characterized in the solid state. These hexasubstituted
aromatics undergo condensation with phenylenediamines to afford
[3þ3] Schiff base macrocycles in good yield. Structural studies of
two new macrocycles, including the first dodecasubstituted tri-
angular Schiff base macrocycle, indicate that these cycles are nearly
flat, and that the steric hindrance of the additional alkyl groups
does not substantially interfere with the chemistry of the formyl or
imine groups. These macrocycles react with transition metals to
form multinuclear metal complexes. We are now exploring the use
of these macrocycles as templates for monodisperse cluster com-
plexes, and as precursors to trimetallic discotic liquid crystals.
1260, 1200, 1051, 875, 750. UV–vis (CH2Cl2) lmax (nm) (3): 284 nm
(430 L molꢀ1 cmꢀ1). EIMS: m/z¼250 [M]þ. Anal. Calcd for C16H26O2:
C 76.75, H 10.47. Found: C 76.59, H 10.44.
4.3. 1,2-Dimethoxy-4,5-dihexylbenzene (6d)
Conditions analogous to those for the preparation of 1,2-dime-
thoxy-4,5-dibutylbenzene (6c) were employed. Compound 6d was
obtained as a colorless oil (91% yield). 1H NMR (400 MHz, CDCl3)
d
(ppm): 6.64 (s, 2H, Ar–H), 3.84 (s, 6H, OCH3), 2.52 (t, 3JHH¼7.6 Hz,
4H, Ar–CH2), 1.3–1.6 (m, 16H, Ar–CH2CH2CH2CH2CH2), 0.89
(t, JHH¼7.2 Hz, 6H, CH2CH3). 13C NMR (100 MHz, CDCl3)
d (ppm):
3
146.8, 132.5, 112.6, 55.9, 33.9, 32.1, 31.6, 29.8, 22.8, 14.0. IR (neat)
n
(cmꢀ1): 2956, 2928, 2856, 1610, 1519, 1465, 1266, 1224, 1115, 1036,
4. Experimental
4.1. General
1006, 859, 742. UV–vis (CH2Cl2) lmax (nm) (3
): 282 (380 L molꢀ1 cmꢀ1).
EIMS: m/z¼306 [M]þ. Anal. Calcd for C20H34O2: C 78.38, H 11.18.
Found: C 78.03, H 11.00.
Compounds 2b–d,26 4c–d,27 5b–d,21,22 6b,28 and 8 were pre-
pared by literature methods. Deuterated solvents were purchased
from Cambridge Isotope Laboratories, and other reagents were
obtained from Aldrich. All reactions were carried out under air
unless otherwise noted. 1H and 13C NMR spectra were recorded on
either a Bruker AV-300 or AV-400 spectrometer. 13C NMR spectra
4.4. 2,3-Dibutyl-5,6-dihydroxybenzene-1,4-dialdehyde (1c)
via catechol 7c
To 2.332 g (9.31 mmol) 1,2-dimethoxy-4,5-dibutylbenzene 6c
was added 100 mL dicholoromethane and the resulting solution
chilled to 0 ꢁC under nitrogen. To this solution was added 3.8 mL
(w40 mmol, w2 equiv) boron tribromide by syringe. The solution
was stirred under nitrogen overnight warming to room tempera-
ture then quenched by addition of 150 mL distilled water followed
by three drops of concentrated HCl. The aqueous layer was
extracted with 3ꢂ50 mL dichloromethane (DCM) and the organic
fractions dried over Na2SO4, filtered, and the solvent removed in
vacuo affording 7c as a tan solid; this material was found to slowly
degrade on standing in air and was used without additional puri-
were recorded using a proton decoupled pulse sequence. 1H and 13
NMR spectra were calibrated to the residual protonated solvent at
7.27 and 77.23, respectively, in CDCl3 or at 5.32 and 54.00,
C
d
d
respectively, in CD2Cl2. UV–vis spectra were obtained in DCM (ca.
1ꢂ10ꢀ6 mol Lꢀ1) on a Varian Cary 5000 UV–vis–near-IR spectro-
photometer using a 1 cm quartz cuvette. IR spectra were collected
neat in the solid state on a Thermo Nicolet 6700 FT-IR spectrometer
or in a KBr pellet on a Nicolet 4700 FT-IR spectrometer. All mass
spectrometry experiments were conducted at the UBC Microana-
lytical Services Laboratory. EIMS was conducted on a Kratos MS-50
fication (1H NMR (400 MHz, CDCl3):
2H, ArOH), 2.46 (t, 4H, Ar–CH2), 1.48–1.52 (m, 4H, Ar–CH2CH2),
d 6.65 (s, 2H, Ar–H), 5.27 (br s,

K.E. Shopsowitz et al. / Tetrahedron 65 (2009) 8113–8119
8117
1.25–1.35 (m, 4H, Ar–CH2CH2CH2), 0.88 (t, 6H, CH2CH3)). The solid
was dissolved in 75 mL trifluoroacetic acid under nitrogen. To the
resulting pink solution was added 5.430 g HMTA (38.7 mmol,
w2 equiv relative to 1,2-dimethoxy-4,5-dibutylbenzene), and the
solution heated to reflux under nitrogen. On heating, the solution
changed from pink to orange to dark red. After 3 h at reflux, the
solution was cooled to room temperature and 100 mL w4 M HCl(aq)
was added. This solution was then heated to reflux overnight under
nitrogen. The resulting orange/red solution was cooled to room
temperature, transferred to a separatory funnel, and diluted with
100 mL distilled water. A suspension formed and was extracted
with DCM (4ꢂ60 mL). The pooled organic extracts were rinsed with
60 mL distilled water, 80 mL 1% NaHCO3(aq), and another 60 mL
distilled water then dried over Na2SO4, filtered, and the solvent
removed by rotary evaporation. The crude material was obtained as
a viscous orange/red tar and was purified by chromatography on
silica using 0.5% acetone in DCM as the eluent. The desired product
eluted first, with subsequent fractions containing a sizeable pro-
portion of the product along with impurities. Later fractions were
retained and resubjected to the column conditions. The product
2,3-dibutyl-5,6-dihydroxybenzene-1,4-dialdehyde was obtained as
a waxy, bright orange solid (0.899 g, 3.23 mmol, 35% yield after
chromatography). Crystals suitable for X-ray diffraction were
grown by slow evaporation of a hexanes solution. 1H NMR
crystals formed that were isolated by filtration and dried under
vacuum. Compound 9 was obtained as white needles. Yield:
325 mg (0.98 mmol, 58%). 1H NMR (400 MHz, CDCl3)
d
(ppm): 5.22
(s, 4H, Ar–CH2), 3.83 (s, 6H, OCH3), 2.21 (s, 6H, CH3), 2.05 (s, 6H,
CH3). 13C NMR (100 MHz, CDCl3)
(ppm): 171.0, 150.0, 133.8, 128.8,
61.3, 51.8, 20.8, 15.7. IR (neat)
(cmꢀ1): 2983, 2939, 2830, 1732,
d
n
1587, 1457, 1380, 1221, 1101, 1015, 965, 710, 621, 582, 438. UV–vis
(CH2Cl2) lmax (nm)
(
3
): 288 (3.06ꢂ103 L molꢀ1 cmꢀ1), 226
(1.59ꢂ104 L molꢀ1 cmꢀ1). ESI-MS: m/z¼333.1 [MþNa]þ. Anal. Calcd
for C16H22O6: C 61.92, H 7.15. Found: C 62.20, H 7.21. Mp: 78–80 ꢁC.
4.8. 3,6-Di(hydroxymethyl)-1,2-dimethoxy-4,5-
dimethylbenzene (10)
Under N2, a solution of 9 (300 mg, 0.90 mmol) in 40 mL of dry
THF was added slowly with a syringe to a suspension of LiAlH4
(137 mg, 3.6 mmol) in 50 mL dry THF. After heating the mixture to
reflux for 20 h, the excess LiAlH4 was slowly quenched with water
(10 mL), then the reaction mixture was filtered through Celite.
Rotary evaporation gave an off-white solid that was pure by 1H
NMR spectroscopy. Yield: 188 mg (0.83 mmol, 92%). 1H NMR
(300 MHz, CDCl3)
2.31 (s, 6H, Ar–CH3), 1.87 (s, 2H, OH). 13C NMR (100 MHz, CDCl3)
(ppm): 149.0, 132.8, 99.9, 60.8, 57.5, 15.8. IR (neat)
(cmꢀ1): 3202,
2992, 2938, 2895, 2831, 2719, 1489, 1459, 1419, 1383, 1322, 1260,
d (ppm): 4.78 (s, 4H, Ar–CH2), 3.89 (s, 6H, OCH3),
d
n
(400 MHz, CDCl3)
d (ppm): 11.95 (s, 2H, Ar–OH), 10.35 (s, 2H, Ar–
3
CHO), 2.86 (t, JHH¼7.6 Hz, 4H, Ar–CH2), 1.44–1.56 (m, 8H,
1095, 999, 859, 674, 430. UV–vis (CH2Cl2) lmax (nm) (3): 286 nm
Ar–CH2CH2CH2), 0.98 (t, JHH¼7.2 Hz, 6H, CH2CH3). 13C NMR
(1.07ꢂ103 L molꢀ1 cmꢀ1), 225 nm (6.55ꢂ103 L molꢀ1 cmꢀ1). HRMS
calcd for C12H8O4 [M]þ: 226.12051. Found: 226.12085. Mp:
136–140 ꢁC.
3
(100 MHz, CDCl3) d (ppm): 196.6, 151.2, 132.4, 120.9, 35.5, 26.2, 22.9,
13.8. IR (thin film)
n
(cmꢀ1): 3388, 3085, 2959, 2929, 1646, 1554,
1439, 1397, 1294, 1247, 1195, 929, 758. UV–vis (CH2Cl2) lmax (nm)
(
3
): 304 (1.5ꢂ104 L molꢀ1 cmꢀ1), 441 (3.5ꢂ103 L molꢀ1 cmꢀ1). EIMS:
4.9. 3,6-Diformyl-1,2-dimethoxy-4,5-dimethylbenzene (11)
m/z¼278 [M]þ. Anal. Calcd for C16H22O4: C 69.04, H 7.97. Found:
C 69.07, H 7.99. Mp: 52–55 ꢁC.
Compound 10 (50 mg, 0.221 mmol) was dissolved in ca. 50 mL
of DCM at room temperature. Pyridinium chlorochromate (PCC)
(229 mg, 1.06 mmol) was added slowly turning the reaction mix-
ture orange-brown in color. The reaction mixture was left stirring
for ca. 14 h at room temperature. Most of the solvent was removed
under vacuum leaving w3 mL of a dark brown oil. This was
flushed through a silica plug with w300 mL of DCM and the
solvent was then removed under vacuum leaving behind a pale
yellow solid (36 mg) that was pure by 1H NMR spectroscopy.
4.5. 2,3-Dihexyl-5,6-dihydroxybenzene-1,4-dialdehyde (1d)
via catechol 7d31
Conditions analogous to those for the preparation of 2,3-dibu-
tyl-5,6-dihydroxybenzene-1,4-dialdehyde (1c) were employed.
Analytically pure 1d was obtained as a waxy, bright orange solid
(31% yield after chromatography). 1H NMR (400 MHz, CDCl3)
d
(ppm): 11.96 (s, 2H, Ar–OH), 10.34 (s, 2H, Ar–CHO), 2.85
Yield: 36 mg (0.16 mmol, 73%). 1H NMR (300 MHz, CDCl3)
10.56 (s, 2H, CHO), 3.96 (s, 6H, OCH3), 2.43 (s, 6H, Ar–CH3). 13C
NMR (100 MHz, CDCl3) (ppm): 193.1, 134.9, 133.1, 99.9, 62.1, 15.3.
IR (neat)
(cmꢀ1): 3365, 2978, 2944, 2865, 2759, 2560, 2359,
d (ppm):
(t, 3JHH¼7.6 Hz, 4H, Ar–CH2), 1.50 (m, 4H, Ar–CH2CH2), 1.30 (m, 12H,
Ar–CH2CH2CH2CH2CH2), 0.98 (t, 3JHH¼7.2 Hz, 6H, CH2CH3). 13C NMR
d
(100 MHz, CDCl3)
d
(ppm): 196.6, 151.2, 132.4, 120.9, 35.5, 32.6, 29.6,
n
26.2, 22.9, 13.8. IR (neat)
1555, 1440, 1397, 1296, 1236, 1117, 1094, 936, 764. UV–vis
n
(cmꢀ1): 3387, 3085, 2956, 2856, 1645,
2341, 1915, 1690, 1557, 1453, 1396, 1259, 1047, 956, 789, 575. HRMS
calcd for C12H14O4 [M]þ: 222.08921. Found: 222.08938. Mp: 47–
49 ꢁC.
(CH2Cl2) lmax (nm) (
3
): 299 nm (1.4ꢂ104 L molꢀ1 cmꢀ1), 436 nm
(3.1ꢂ103 L molꢀ1 cmꢀ1). EIMS: m/z¼334 [M]þ. Anal. Calcd for
C20H30O4: C 71.82, H 9.04. Found: C 72.02, H 9.11. Mp: 39–41 ꢁC.
4.10. 3,6-Diformyl-1,2-dihydroxy-4,5-dimethylbenzene (1b)
4.6. 2,3-Dimethyl-5,6-dihydroxybenzene-1,4-dialdehyde (1b)
via catechol 7b32
Under
a
nitrogen atmosphere, compound 11 (482 mg,
2.2 mmol) was dissolved in w50 mL of dry DCM cooled in an ice/
water bath. BBr3 (0.9 mL, 9.8 mmol) was added turning the re-
action mixture red in color. After stirring for 14 h at room tem-
perature, the reaction was quenched with water and the product
extracted with DCM. The combined organic fractions were dried
over MgSO4, filtered, and dried under vacuum to leave an orange
solid (431 mg, >100%) that was nearly pure by 1H NMR spec-
troscopy. Recrystallization from a mixture of DCM/hexanes yielded
1b as orange needles. Yield: 342 mg (1.76 mmol, 80%). 1H NMR
Conditions analogous to those for the preparation of 2,3-dibu-
tyl-5,6-dihydroxybenzene-1,4-dialdehyde (1c) were employed.
Analytically pure 1b was obtained as a waxy, bright orange solid
(11% yield after chromatography). Spectroscopic data are provided
in Section 4.10.
4.7. 3,6-Diacetylmethyl-1,2-dimethoxy-4,5-dimethylbenzene (9)
(400 MHz, CDCl3)
2.48 (s, 6H, Ar–CH3). 13C NMR (100 MHz, CDCl3)
150.8, 127.8, 121.2, 13.3. IR
(cmꢀ1): 3040, 2920, 2799, 1641, 1610,
d
(ppm): 11.89 (s, 2H, OH), 10.45 (s, 2H, CHO),
A mixture of compound 8 (595 mg, 1.69 mmol), sodium acetate
(1.54 g, 18.8 mmol), acetic anhydride (1.5 mL, 15 mmol), and acetic
acid (45 mL) was heated to reflux under N2 for 23 h. The solution
was poured into w300 mL of water. Upon cooling overnight, white
d
(ppm): 195.6,
n
1552, 1416, 1379, 1274, 1243, 1098, 922, 739, 595, 491. UV–vis
(CH2Cl2) lmax (nm)
(3
): 443 (2.45ꢂ103 L molꢀ1 cmꢀ1), 302

8118
K.E. Shopsowitz et al. / Tetrahedron 65 (2009) 8113–8119
(1.31ꢂ104 L molꢀ1 cmꢀ1), 226 (9.96ꢂ103 L molꢀ1 cmꢀ1). EIMS:
m/z¼194 [M]þ. Anal. Calcd for C10H10O4: C 61.85, H 5.19. Found:
C 62.00, H 5.55. Mp: 172–175 ꢁC.
4.14. Macrocycle 3e (R[nC6H13, R0[OCH3)
Macrocycle 3e was prepared using a procedure analogous to
that used to prepare macrocycle 3d, but with compound 1d in the
place of 1c and dialkoxyphenylenediamine 2b in place of phenyl-
enediamine. Compound 3e was obtained as a black powder (28%
yield, >95% pure by NMR integration). 1H NMR (400 MHz, CDCl3)
4.11. Macrocycle 3b (R[CH3, R0[OC2H5)
Under a nitrogen atmosphere, 51 mg (0.26 mmol) of 1,2-dieth-
oxy-4,5-diaminobenzene was dissolved in 10 mL of 1:1 degassed
CHCl3/MeCN. Diformyldiol 1b (50 mg, 0.26 mmol) was added
turning the solution from colorless to deep red. After heating at
reflux (90 ꢁC) for 4 h, the solution was cooled to room temperature,
yielding a red microcrystalline solid of 3b. Macrocycle 3b was iso-
lated on a Bu¨chner funnel, washed with cold MeCN, and dried
under vacuum. Yield: 81 mg, 87%. 1H NMR (400 MHz, CDCl3)
d
(ppm): 14.65 (s, 6H, OH), 8.97 (s, 6H, CH]N), 6.86 (s, 6H, Ar–H),
4.02 (s, 18H, O–CH3), 2.84 (br m, 12H, Ar–CH2), 1.58 (br m, 12H, Ar–
CH2CH2), 1.49 (br m, 12H, Ar–CH2CH2CH2), 1.35 (br m, 24H,
CH2CH2CH3), 0.91 (br t, 18H, CH2CH3). 13C NMR (100 MHz, CDCl3)
d
(ppm): 160.8, 152.5,150.8,136.1,131.0,119.2,103.3, 46.2, 33.9, 32.7,
30.7, 28.8, 23.7, 15.1. IR (neat)
y
(cmꢀ1): 2952, 2920, 2851, 1604,
1510, 1455, 1435, 1317, 1259, 1193, 1005, 842, 627, 554. UV–vis
d
(ppm): 13.93 (s, 6H, OH), 8.98 (s, 6H, CH]N), 6.80 (s, 6H, Ar–H),
(CH2Cl2) lmax (nm)
(
3
): 413 (4.35ꢂ104 L molꢀ1 cmꢀ1), 347
4.15 (q, 12H, OCH2), 2.36 (s, 18H, Ar–CH3), 1.48 (t, 3JHH¼6.8 Hz, 18H,
(3.05ꢂ104 L molꢀ1 cmꢀ1), 229 (5.27ꢂ104 L molꢀ1 cmꢀ1). HRMS calcd for
CH2CH3). IR n
(cmꢀ1): 3543, 2977, 2929,1604,1505,1473,1377,1309,
C84H114N6O12 [MþH]þ: 1399.8567. Found: 1399.8519. Mp: 145–147 ꢁC.
1180, 1098, 1031, 978, 798, 619, 571. UV–vis (CH2Cl2) lmax (nm) (3):
412 (4.27ꢂ104 L molꢀ1 cmꢀ1), 349 (2.03ꢂ104 L molꢀ1 cmꢀ1), 229
(3.56ꢂ104 L molꢀ1 cmꢀ1). ESI-MS: m/z¼1064 [MþH]þ, 1102
[MþK]þ. Anal. Calcd for 3b$2H2O (C60H70N6O14): C 65.56, H 6.42,
N 7.65. Found: C 65.31, H 6.23, N 7.63. Single crystals were obtained
from DMF. Mp: >260 ꢁC.
4.15. X-ray crystallography
Crystals of 1c were obtained from hexanes. X-ray crystal data for
1c: C16H22O4, Mw¼278.34 g molꢀ1, orange plate (1.4ꢂ1.2ꢂ0.05 mm),
monoclinic, space group P21/a (#14), a¼18.1497(6), b¼7.2908(7),
c¼24.030(2) Å,
a
¼90.00ꢁ,
b
¼109.146(5)ꢁ,
g
¼90.00ꢁ,
4.12. Macrocycle 3c (R[CH3, R0[OnC5H11
)
V¼3003.8(5) Å3, Z¼8, rcalcd¼1.231 g/cm3, F000¼1200, Mo K
a radia-
tion,
l
¼0.71073 Å, T¼173(2) K, 2qmax¼27.23ꢁ, 56,005 reflections
Macrocycle 3c was prepared by a procedure analogous to that
used to prepare macrocycle 3b, but with 1,2-dipentyloxy-4,5-dia-
were collected, 6689 were unique (Rint¼0.0528). Final GoF¼0.991,
R1¼0.0632, R2¼0.1605, R indices based on 4348 reflections with
minobenzene. Yield: 77%. 1H NMR (400 MHz, CDCl3)
d
(ppm): 13.83
I>2s(I). All non-hydrogen atoms were refined anisotropically. Hy-
(br s, 6H, OH), 8.97 (s, 6H, CH]N), 6.81 (s, 6H, Ar–H), 4.03 (br t, 12H,
OCH2), 2.35 (s, 18H, Ar–CH3), 1.84 (m, 12H, OCH2CH2), 1.42 (m, 24H,
drogen atoms were located through difference mapping or calcu-
lated positions and were refined isotropically.
3
OCH2CH2CH2CH2), 0.95 (t, JHH¼7.0 Hz, 18H, CH2CH3). 13C NMR
Crystals of macrocycle 3b suitable for X-ray diffraction were
d
(ppm): 161.1, 150.8, 149.1, 135.9, 124.7, 119.0, 105.8, 70.0, 29.1, 28.2,
obtained from hot DMF. X-ray crystal data for 3b: C75H101N11O18,
22.5, 14.5, 14.1. IR
n
(cmꢀ1): 2953, 2931, 2869, 1604, 1507, 1467, 1377,
):
Mw¼1444.67 g molꢀ1, red prism (0.70ꢂ0.15ꢂ0.10 mm), triclinic,
space group P-1 (#2), a¼12.3499(14), b¼17.709(3), c¼19.450(3) Å,
1312, 1258, 1181, 984, 826, 624, 504. UV–vis (CH2Cl2) lmax (nm) (
3
415 (2.76ꢂ104 L molꢀ1 cmꢀ1), 350 (1.85ꢂ104 L molꢀ1 cmꢀ1), 228
(1.52ꢂ104 L molꢀ1 cmꢀ1). ESI-MS: m/z¼1315.7 [MþH]þ, 1337.6
[MþNa]þ. Anal. Calcd for 3c$H2O (C78H102N6O13): C 70.24, H 7.86,
N 6.30. Found: C 70.45, H 7.60, N 6.70. Mp: >260 ꢁC.
a
¼64.827(5)ꢁ,
b
¼84.172(6)ꢁ,
g
¼80.874(6)ꢁ, V¼3798.3(9) Å3, Z¼2,
rcalcd¼1.263 g cmꢀ3, F000¼1544, Mo K
a
radiation,
l
¼0.71073 Å,
T¼173(2) K, 2qmax¼22.72ꢁ, 45,369 reflections were collected, 9757
were unique (Rint¼0.1080). Final GoF¼1.020, R1¼0.0692,
wR2¼0.1686, R indices based on 4641 reflections with I>2
s(I). All
4.13. Macrocycle 3d (R[nC4H9, R0[H)
non-hydrogen atoms were refined anisotropically. Hydrogen atoms
were located through difference mapping or calculated positions
and were refined isotropically. An isolated oxygen atom is present
in the structure that is believed to be a solvent water molecule. The
long O–H bond (O4–H4) is likely due to strong hydrogen-bonding
between H4 and the adjacent imine nitrogen.
In a 100 mL round bottom flask, 2,3-dibutyl-5,6-dihydroxy-
benzene-1,4-dialdehyde (1c; 0.359 g, 1.29 mmol) was dissolved in
50 mL acetonitrile and 10 mL chloroform. o-Phenylenediamine
(0.142 g, 1.35 mmol) was added and the resulting yellow solution
stirred briefly under nitrogen for 5 min. A drop of piperidine was
added immediately turning the solution dark red. This solution
was heated at reflux overnight under nitrogen, then cooled to
room temperature, at which point a fine precipitate formed. The
solid was isolated by filtration on a Buchner funnel and washed
with a small volume of ice-cold acetonitrile. After air drying, the
product 3d was obtained as an orange/brown powder (0.108 g,
0.103 mmol, 24% yield, >95% pure by NMR integration). Slow dif-
fusion of acetonitrile into a concentrated dichloromethane solu-
tion afforded single crystals suitable for X-ray diffraction. 1H NMR
Crystals of macrocycle 3d suitable for X-ray diffraction were
obtained by slow diffusion of acetonitrile into a concentrated DCM
solution of 3d. X-ray crystal data for 3d: C68H83N7O7,
Mw¼1110.41 g molꢀ1, red blade (0.50ꢂ0.10ꢂ0.05 mm), triclinic,
space group P-1 (#2), a¼13.2837(6), b¼16.4922(7), c¼16.7747(7) Å,
a
¼61.505(2)ꢁ,
b
¼68.968(2)ꢁ,
g
¼80.205(3)ꢁ, V¼3014.6(3) Å3, Z¼2,
rcalcd¼1.223 g cmꢀ3, F000¼1192, Mo K
a
radiation,
l
¼0.71073 Å,
T¼173(2) K, 2qmax¼21.81ꢁ, 34,184 reflections were collected, 7172
were unique (Rint¼0.0292). Final GoF¼1.036, R1¼0.0788,
wR2¼0.2109, R indices based on 5467 reflections with I>2
s(I). All
(400 MHz, CDCl3)
d
(ppm): 14.00 (s, 6H, OH), 8.92 (s, 6H, CH]N),
non-hydrogen atoms were refined anisotropically. Hydrogen atoms
were located through difference mapping or calculated positions
and were refined isotropically. The somewhat aberrant Ueq values
for C49 and C56 are likely attributable to disorder in the alkyl side
chains where they reside.
7.36 (br d, 6H, Ar–H), 7.16 (br d, 6H, Ar–H), 2.79 (m, 12H, Ar–CH2),
1.49 (br m, 24H, Ar–CH2CH2CH2), 0.97 (br t, 18H, CH2CH3). 13C NMR
(100 MHz, CDCl3)
118.5, 35.0, 27.6, 23.0, 13.9. IR (thin film)
2955, 2924, 2856, 1618, 1556, 1493, 1465, 1383, 1327, 1215, 1140,
d
(ppm): 162.0, 151.9, 143.6, 129.4, 127.6, 119.6,
n
(cmꢀ1): 3339, 3198,
1101, 827, 748 cmꢀ1
.
UV–vis (CH2Cl2) lmax (nm)
(
3
): 370
Acknowledgements
(1.58ꢂ105 L molꢀ1 cmꢀ1). MALDI-TOF: m/z¼1051.3 [MþH]þ. Anal.
Calcd for C66H78N6O6: C 75.40, H 7.48, N 7.99. Found: C 75.09, H
8.19, N 7.17. Mp: 199–202 ꢁC.
We thank the Natural Sciences and Engineering Research
Council (NSERC) of Canada for funding (Discovery Grant). K.E.S. and

K.E. Shopsowitz et al. / Tetrahedron 65 (2009) 8113–8119
8119
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A.J.G. thank NSERC for graduate scholarships. We are also grateful
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Supplementary data
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Supporting spectra are available for this article. CCDC 742116–
742118 contain the crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB21EZ, UK (fax: þ44 1223 336
033; or email: deposit@ccdc.cam.ac.uk)). Supplementary data as-
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