Synthesis of Tr?ger's base derived ligands: PHZ-derivatized ligand with pendant donor arms

Article abstract of DOI:10.1016/j.tet.2016.07.056

A cyclic diamine ligand whose core structure was derived from Tr?ger's base, and included additional pendant arms containing ancillary donor coordination sites was prepared and coordination with transition metals attempted.

Full text of DOI:10.1016/j.tet.2016.07.056

Accepted Manuscript
Synthesis of Tröger's base derived ligands: PHZ-derivatized ligand with pendant
donor arms
Carissa S. Hampton, Michael Harmata
PII:
S0040-4020(16)30714-1
10.1016/j.tet.2016.07.056
TET 27952
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 April 2016
Revised Date: 7 July 2016
Accepted Date: 25 July 2016
Please cite this article as: Hampton CS, Harmata M, Synthesis of Tröger's base derived ligands: PHZ-
derivatized ligand with pendant donor arms, Tetrahedron (2016), doi: 10.1016/j.tet.2016.07.056.
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ACCEPTED MANUSCRIPT
Synthesis of Tröger’s Base Derived
Ligands: PHZ-Derivatized Ligand with
Pendant Donor Arms
Carissa S. Hampton and Michael Harmata

ACCEPTED MANUSCRIPT
Synthesis of Tröger’s Base Derived Ligands: PHZ-Derivatized Ligand with
Pendant Donor Arms
Carissa S. Hampton and Michael Harmata*
Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211
harmatam@missouri.edu
Abstract
A cyclic diamine ligand whose core structure was derived from Tröger’s base,
and included additional pendant arms containing ancillary donor coordination sites was
prepared and coordination with transition metals attempted.
Introduction
Cyclic polyamines and their metal complexes have been studied for several
decades, and a good deal of effort and attention has focused on the tri- and tetraamines
such as 1,5,9-triazacyclododecane ([12]aneN3) 1, and 1,4,8,11-tetraazacyclotetradecane
(cyclam) 2, among others (Figure 1).1 Mesocyclic diamines (6-8 membered rings) are
some of the smallest members of the family of cyclic polyamines and provide a link
between acyclic and macrocyclic chelating agents.2 The properties of complexes formed
with mesocyclic amines are often dictated by the constrained steric requirements and
unusual chelate bite angles.2b, 3
Figure 1. Cyclic polyamines.
(-)-Sparteine (3, Figure 2) is a naturally occurring tertiary diamine that has been
used extensively in medicinal research4 and for the asymmetric synthesis of chiral
compounds.5 (-)-Sparteine is a bidentate ligand and has been examined as a ligand by
Fujisawa’s group with zinc (II) and cadmium (II) and by Lee’s group with mercury (II)
and other metals.6 Tröger’s base (TB, 4), 2,8-dimethyl-6H,12H,-5,11-
methanodibenzo[b,f][1,5]-diazocine, has been known as a non-natural chiral amine for
more than a century.7 The fused aromatic rings and the methylene bridge result in a rigid,
twisted “V” shaped molecule, which has made Tröger’s base and its derivatives an
interesting scaffold in the field of supramolecular chemistry (Figure 2).8
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Figure 2. Structures of diamines.
Tröger’s base and similar diamines such as PHZ (5,6,11,12-tetrahydro-2,8-
dimethylphenhomazine, 5, Figure 2) in which the methylene bridge has been removed
from Tröger’s base, and DACO (1,4-diazocyclooctane, 6, Figure 2), which is a subunit of
PHZ, have been used to generate transition metal complexes.9 In 1966, Musker and
Hussain reported square planar Cu2+ and Ni2+ complexes of DACO with the ligands
adopting a chair-boat conformation (Figure 3). Hussain and Rehman stated that molecular
models indicate that metals ligated by PHZ ligands would be less sterically hindered at
the axial position because of the inability to attain a chair-boat conformation and would
be able to undergo further reactivity.2b, 3
Figure 3. Chair-boat conformation of DACO-metal complexes.
Xian-He Bu’s group has reported the syntheses of modified DACO ligands with
pendant arms,2a, 10 functionalizing the secondary amines to provide additional donor
groups on the ligand. In the early 2000s, they reported the syntheses of 8-11 from which
they determined that the pendant donor groups on DACO were a strong determining
factor on the structure and properties of metal complexes containing this ligand (Figure
4). They prepared a new series of polycoordinate ligands that could generate mono-, bi-,
and trinuclear, as well as an alternating zigzag chain complexes with Cu2+.2a These
ligands were also used to prepare Ni2+ and Cd2+ complexes.10
Figure 4. DACO derivative ligands.
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In 1995, Goldberg and Alper reported the first transition metal complexes of TB
with rhodium and iridium.11 These complexes were formed in a 1:2 TB:MCl3 ratio in
which the nitrogen atom of TB formed a donor-acceptor bond via its nonbonding sp3
orbital (Figure 5). These were then used as catalysts for hydrosilylation of alkynes.
Figure 5. Transition metal complexes of TB
Hussain and Rehman investigated several transition metal complexes of PHZ and
Tröger’s base.2b, 3, 12 They discovered that the steric requirements of Tröger’s base
prevent both nitrogen atoms from coordinating to a single metal center and it instead
forms bis-complexes with Cu2+, Hg2+, Zn2+, and Co2+. As expected, PHZ can form both
mono- and bis-complexes with transition metals such as Cu2+, Ni2+, Co2+, Pd2+, Pt2+, Pt4+.
The nature of the complex is dependent upon the stoichiometry of the ligand used.
Our group has shown that a chiral TB derivative 14 was effective in the
asymmetric addition of diethyl zinc to aromatic aldehydes (Scheme 1).13 This chemistry
presumably involved 14 serving as a ligand for Zn(II).
Scheme 1. Use of a chiral Tröger’s base ligand.
We also reported the synthesis of the alkylated PHZ derivatives shown in Figure
6.14 From these two PHZ derivatives, metal complexes were able to be isolated.
Compound 16 with only one secondary amine formed a monodentate complex with CdI2
in a ligand:metal ratio of 2:1. We believed that modifications should be made so that
steric interactions would be minimized. Thus the second ligand examined in this study,
17, contained two secondary amines. The reaction of 17 with NiCl2 afforded a product
that was characterized by, inter alia, X-ray analysis. This demonstrated the ability of
both nitrogen atoms to complex to the nickel center in a bidentate fashion giving the
complex shown in Figure 6 in which two ligand molecules each bind in a unique way
creating different size cavities around the metal center.
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Me
Me
NH
Me
a)
Me
N
Me
16
Me
H
N
b)
Me
Me
NH
Me
17
Figure 6. Alkylated PHZ derivatives and their transition metal complexes, 16 is
complexed with CdI2 and 17 is complexed with NiCl2.14
Ligand Design
We set out to prepare a ligand (18) whose structure is shown in Figure 7. It was
designed such that a metal could sit atop the eight-membered ring of the diazocine in a
boat-type conformation, coordinating to the two nitrogen atoms. The phenolic oxygens
on the pendant arms could then also ligate the metal, perhaps leaving sites open for ligand
exchange and chemical reactivity, depending on the metal. Since PHZ is less sterically
encumbered due to the inability to attain a chair-boat conformation like DACO, the
inclusion of t-butyl groups should help to guide selectivity and/or reactivity of the metal
complex formed therefrom. Further, we anticipated, ultimately incorrectly, that the t-
butyl groups would provide for solubility in organic solvents.
Figure 7. Structure of proposed ligand.
Results and Discussion
Ligand Synthesis
We envisioned the synthesis proceeding via a dialkylation of 5 with a benzylic
bromide. The core PHZ portion of the ligand was easily prepared by removal of the
methylene bridge from Tröger’s base 4 with trifluoroacetic anhydride (Scheme 2).15 In an
effort to show that a one-pot dialkylation was possible, 5 was treated first with sodium
hydride then benzyl bromide to afford 19 in 51% yield. The structure was clear from
NMR data and was corroborated by an X-ray crystal structure. This approach
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demonstrates that it is possible to achieve dialkylation of PHZ in one step and that simple
benzyl bromides are effective alkylating agents (Scheme 2).
Scheme 2. Preparation and alkylation of PHZ with benzyl bromide.
In pursuit of 18, bromide 22 was prepared as shown in Scheme 3. Reduction of
the aldehyde 20 with sodium borohydride and further conversion to the benzylic bromide
with phosphorus tribromide proceeded smoothly in almost quantitative yields in both
cases (Scheme 3).16 Attempts to directly dialkylate PHZ (5) with bromide 22 were
unsuccessful. Bases such as triethylamine or Hünig’s base were ineffective at alkylation
of the diazocine nitrogens. When 5 was treated with sodium hydride, monoalkylation
with 22 could be achieved, but dialkylation to afford the desired ligand was never
1
observed. We could see via H NMR that the monoalkylated 23 was subsequently
alkylated at the phenolic position rather than the available nitrogen atom to produce 24 as
a byproduct in this reaction (Scheme 3). This may have occurred due a proton transfer
from the more acidic phenol to the benzylic nitrogen, creating the more stable phenolate
intermediate, which served as a nucleophile for the second equivalent of 22.
Scheme 3. Alkylation of PHZ with 22.
Our first approach to the alkylation problem was to prepare an amide that would
then be reduced to the desired tertiary amine. Thus, treatment of 5 with benzoyl chloride
in the presence of Hünig’s base in dichloromethane produced 25. The yield was low, but
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no attempt was made to optimize the process. The bis-amide 25 was then reduced with
lithium aluminum hydride (LAH) to yield 19 in 89% yield as shown in Scheme 4.
Scheme 4. Synthesis of 19 via amide formation and subsequent reduction.
Attempting the same process to install the desired “arms”, salicylic acid 26 was
treated with thionyl chloride to generate an acid chloride in situ. This was then added to a
solution of 5 and DIPEA in CH2Cl2. As determined by 1H NMR, the product formed (27)
was produced by initial N-acylation followed by O-acylation, in similar fashion as 24
obtained above (Scheme 5). This method did not bode well for the ligand synthesis as the
phenolic oxygen atoms appeared more reactive for esterification than the amines were for
amidation.
Scheme 5. Attempted amide formation of 5 with salicylic acid.
As there were clearly complications arising from the free phenolic oxygen present
in these reactions, we decided that the phenol must be protected before the desired
dialkylation would occur. To this end, multiple protecting groups were examined. Ligand
structures with protecting groups such as benzyl 40, p-nitrobenzyl 41, and o-nitrobenzyl
42 were all easily prepared as outlined in Scheme 6. Aldehyde 20 could be protected with
the appropriate benzyl bromide in good yield to produce the protected aldehydes 28-30.
This was then followed by reduction with sodium borohydride to generate the benzylic
alcohols 32-34 in excellent yields. Further conversion of the benzyl alcohol to a bromide
was performed using phosphorus tribromide. Alkylation of PHZ with these derivatives
was carried out using sodium hydride in THF solvent. X-ray crystal structures of 40 and
41 confirmed their structures (Figure 8). A small amount of a monoalkylated byproduct
was sometimes isolated from these reactions as well. Attempts to deprotect the phenol’s
protecting groups included hydrogen with palladium/carbon, triethylsilane with
palladium/carbon,17 thiophenol/potassium carbonate,18 chlorosulfonyl isocyanate-sodium
hydroxide,19 TFA/thioanisole,20 magnesium/ethanol,21 indium/ammonium chloride,22 and
photochemical irradiation. Any and all deprotection attempts of the benzylic oxygen
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atoms in the presence of dibenzylic nitrogen atoms were unsuccessful and either returned
unreacted starting material, debenzylation at both oxygen and nitrogen positions, or
decomposition of the starting material.
a
Scheme 6. Preparation of protected ligands. (SEM = trimethylsilylethoxymethyl) See
discussion and experimental for results.
Figure 8. X-ray crystal structures of ligands 40 and 41.
When these protecting groups proved problematic, the next move was to change
protecting groups to something that would be more labile and able to be deprotected
without disturbing the benzylic amine structures. In this approach, we envisioned using
the trimethylsilylethoxymethyl (SEM) protecting group, which could be easily
deprotected with a fluoride source. Similar methodology as above was employed to
prepare the SEM derivative. Aldehyde 20 was protected with trimethylsilylethoxymethyl
chloride in the presence of sodium hydride to produce 31 in 85% yield. Reduction of the
aldehyde proceeded well in 90% yield to give 35 (Scheme 6). When attempting to
prepare the bromide 39, problems were encountered. The acidity of the reaction when
using PBr3 led to a transfer of the trimethylsilylethyl group to the benzylic oxygen. Other
reagents such as carbon tetrabromide,23 or methanesulfonyl chloride followed by
tetrabutylammonium bromide,24 or PBr3 with pyridine failed to generate the desired
bromide. Alternatively, N-bromosuccinimide with dimethyl sulfide,25 or N-
bromosuccinimide with triphenylphosphine26 proceeded to generate the bromide 39, but
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were not consistently reproducible. Difficulties in reproducibility led to abandonment of
the SEM protecting group for the ligand preparation.
It was at this point we came across Xian-He Bu’s work with DACO ligands
(shown in Figure 4) in which the phenols were protected with acetate groups. Initial
attempts to incorporate the acetate were pursued with protection being the first step in the
synthesis; these attempts were unsuccessful. It was later found that the acetate could be
installed after the bromination by simply heating bromophenol 22 in acetic anhydride
with catalytic acid (Scheme 7). Once the acetate was prepared, 5 was alkylated to
produce 44 in 92% yield. The structure was confirmed by an X-ray crystal structure.
Scheme 7. Preparation of the acetate-protected ligand.
As reported in Bu’s previous work,2a deprotection of the acetate groups was
attempted with potassium hydroxide (KOH) in water; this failed to work and only starting
material was recovered. Several other reagents were also employed in an attempt to
remove the acetate protecting groups including: KOH/DMSO, Super-Hydride®, L-
Selectride®, Vitride®, lithium borohydride, lithium piperidinoborohydride, ammonium
acetate/water:methanol, sodium bicarbonate/water:methanol, hydrazine, sodium hydride,
lithium di-iso-propylamide, lithium aluminum hydride, and DIBAL-H, but most had no
effect and returned mainly unreacted starting material. The only reagents that had any
effect on the removal of the acetate were aluminum-based. Several different work-up
procedures were examined to find the best conditions to isolate the free ligand. The final
product was finally isolated by quenching a DIBAL-H reduction reaction with a saturated
Rochelle’s salt solution followed by stirring for several hours and then allowing the
mixture to stir undisturbed for 2-3 hours to precipitate the product. The free ligand 18
was filtered off and isolated as a colorless solid in 87% yield (Scheme 8). To our shock
and dismay, this material was highly insoluble in almost all solvents and only very
sparingly soluble in chlorinated solvents such as trichloroethylene or chlorobenzene. This
has hindered attempts to recrystallize the material.
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Scheme 8. Deprotection of diacetate 44.
After finally preparing the ligand with free hydroxyl groups, metal complexation
was attempted in spite of the solubility issues. Under a nitrogen atmosphere, the ligand
was suspended in THF and a diethyl zinc (in hexane) solution was added, causing the
reaction solution to become more homogeneous and clear to the eye. After 48 h, the
solution was filtered and concentrated under vacuum. The resulting colorless amorphous
1
solid was suspended in CDCl3 and evaluated by proton NMR. The H NMR spectra
(Figure 9, bottom) indicated that there is still symmetry in the complex and the proposed
1
structure of this complex is shown in Scheme 9. In the H NMR spectrum, the phenolic
oxygen peak at 8.46 ppm was gone and the shape and chemical shifts of the aromatic
proton resonances (6.9-7.4 ppm) changed as well. Also, the doublet signals for the CH2
groups adjacent to the nitrogen atoms (4.0-5.0 ppm) shifted downfield and became more
defined (Figure 9, bottom). Over time when exposed to the atmosphere this complex
partially reverted to a mixture of the free ligand (Figure 9, top) and the zinc complex as
observed by 1H NMR; peaks from the complex and the free ligand can be seen (Figure 9,
middle). If this material is exposed to additional diethyl zinc in toluene the complex is
formed once again, identical to the initial product. The very limited solubility of the
complex and the tendency to quickly decompose prevented complete characterization, as
well as recrystallization and therefore, crystal growth for X-ray diffraction.
Scheme 9. Proposed zinc complex.
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Figure 9. 1H NMR of the free ligand (top), ½ Zn complex:½ free ligand (middle), and Zn
complex (bottom).
Conclusions
Preparation of the desired ligand 18 was achieved by alkylation of PHZ with the
acetate-protected bromide 43. Deprotection of the acetate groups required a DIBAL-H
reduction with no workup procedure, allowing precipitation to yield 18 in a 69% overall
yield for the convergent synthesis. The zinc complex was isolated in 93% yield. This
ligand is simply too insoluble to explore further transition metal coordination and
reactivity. However, we anticipate that appropriate modifications to the phenolic units or
the TB structure itself will allow us to produce systems that are more user friendly. The
essential synthetic chemistry has been established; the changes that need to be studied are
straightforward.
Experimental Section
All reactions were carried out in oven-dried glassware and cooled in a desiccator prior to
use. Tetrahydrofuran (THF) was purchased and distilled from sodium-benzophenone
prior to use. All reactions were monitored by thin layer chromatography (TLC) on glass-
backed silica gel plates with fluorescent UV indicator. Flash chromatography was carried
out using 230-400 mesh silica gel with HPLC grade solvents. Unless stated otherwise, all
commercially available reagents were used as received. All compounds were
1
characterized by H and 13C Nuclear Magnetic Resonance (NMR) spectroscopy using a
Bruker DRX 300 MHz, Bruker Avance III 500 MHz, or Bruker Avance III 600 MHz
spectrometer. Proton spectra were reported in
δ units, parts per million (ppm), relative to
trimethylsilane internal standard (0.00 ppm). Carbon spectra were recorded at 75, 125,
and 150 MHz, respectively, and reported in ppm relative to deuterated chloroform (77.0
ppm). Melting points were determined with a Fisher-Johns melting point apparatus and
are uncorrected. Infrared spectra were recorded on a Perkin Elmer 1600 series FT-IR
spectrometer. High resolution mass spectra were performed by College of Science Major
Instrumentation Center, Old Dominion University, on a Bruker 12 Tesla APEX -Qe
FTICR-MS with an Apollo II ion source. X-Ray analyses were performed by Dr. Charles
L. Barnes at the University of Missouri-Columbia on a Bruker APEX II CCD
diffractometer, with graphite monochromated Mo radiation. Side products were analyzed
by NMR solely for identification purposes as they were not the target of interest, and
therefore were not fully characterized.
Procedure 1: Preparation of PHZ.
2,8-Dimethyl-5,6,11,12-tetrahydrodibenzo[b,f][1,5]diazocine (5):15 Tröger’s base
(1.0g, 3.99 mmol) was suspended in a mixture of trifluoroacetic anhydride (4.437 mL,
31.92 mmol) and dichloromethane (10 mL) and stirred at room temperature overnight for
12 h in a closed vessel. The reaction was quenched with water and basified with saturated
NaHCO3. The cloudy mixture was extracted with CH2Cl2 and the combined organic
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layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo
.
The residue was dissolved in ethanol (50 mL) with sodium hydroxide (1.0 g) and stirred
at room temperature until completion by TLC (25% EtOAc:Hexanes). The reaction
mixture was then concentrated on the rotary evaporator and the residue was dissolved in a
mixture of CH2Cl2 and H2O. The organic layer was washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo to yield
5
in 93% yield (0.4456 g). Spectra
6.82-6.78 (m, 4H), 6.47 (d, J
matches reported literature.15 1H NMR (500 MHz, CDCl3)
= 8.5 Hz), 4.44 (s, 4H), 4.06 (br s, 2H), 2.19 (s, 6H).
δ
Procedure 2: Alkylation of PHZ with benzyl bromide.
5,11-Dibenzyl-2,8-dimethyl-5,6,11,12-tetrahydrodibenzo[b,f][1,5]diazocine (19): To a
solution of n-butyl lithium (0.19 mL, 2.2 M in hexanes, 0.4616 mmol) in dry THF (7
mL) in a dry-ice/acetone bath was added a solution of
5 (0.050g, 0.2098 mmol) in dry
THF (2 mL). The mixture was stirred for 5 min then a solution of benzyl bromide (0.079
g, 0.4616 mmol) in dry THF (2 mL) was added dropwise. The mixture was stirred for 1.5
h in the cold bath then warmed to room temperature and monitored by TLC (20%
EtOAc:Hex) for 36 h. The reaction was quenched with water and extracted with CH2Cl2.
The combined organic extracts were washed with water and brine, dried over anhydrous
Na2SO4, and concentrated by rotary evaporation. The crude product was purified by
column chromatography (2.5% EtOAc:Hex) to yield 19 as a pale yellow amorphous solid
1
(mp 176
(300 MHz, CDCl3)
2H), 6.71 (s, 2H), 4.43 (br s, 4H), 4.32 (s, 4H), 2.18 (s, 6H); 13C NMR (75 MHz, CDCl3)
139.3, 132.8, 128.6, 128.3, 127.4, 127.1, 126.6, 116.2, 55.4, 55.0, 20.2; IR νmax (cm-1)
°C) (recrystallized from 2.5% EtOAc:Hex) in 51% yield (0.0446 g). H NMR
δ
7.33-7.16 (m, 10H), 6.90 (d, J = 13.5 Hz, 2H), 6.77 (d, J = 13.5 Hz,
δ
3081, 3019, 2921, 2852, 1609, 1507, 1446, 1405, 1356, 1213, 1164, 1119, 960, 742;
HRMS m/z calcd for (C30H30N2)H+ 419.2482, found 419.2479.
Procedure 3: Reduction of aldehyde 20
.
2,4-Di-tert-butyl-6-(hydroxymethyl)phenol (21):16 Sodium borohydride (0.3229 g,
8.535 mmol) was slowly added to a solution of 3,5-di- -butyl-2-hydroxybenzaldehyde 20
t
(1.00 g, 4.267 mmol) in methanol (14.2 mL). The mixture turned from yellow to
colorless during addition and stirring was continued for 10 min at room temperature. The
volatiles were removed by rotary evaporation and the resulting residue was quenched
with water. The aqueous mixture was neutralized with glacial acetic acid and extracted
with CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4 and
concentrated on the rotary evaporator to give 21 as a colorless amorphous solid (mp = 91-
1
94 °C) in 98% yield (0.987 g). Spectral data matches reported literature. H NMR (300
MHz, CDCl3)
δ
7.53 (br s, 1H), 7.28 (d,
J
= 2.4 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 4.81 (s,
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2H), 2.15 (br s, 1H), 1.43 (s, 9H), 1.28 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 153.1,
141.6, 136.5, 124.1, 124.0, 122.6, 65.8, 34.9, 34.2, 31.6, 29.7; IR νmax (cm-1) 3578, 3396,
3064, 2967, 2863, 1481, 1421, 1362, 1262, 1230, 742; HRMS m/z calcd for
(C15H24O2)Na+ 259.1669, found 259.1670.
Procedure 4: Conversion of benzylic alcohol to bromide.
2-(Bromomethyl)-4,6-di-tert-butylphenol (22):16 To a solution of 3,5-di-
t-butyl-2-
hydroxybenzyl alcohol 21 (1.12 g, 4.739 mmol) in chloroform (20 mL) was added PBr3
(0.229 mL). The mixture was stirred at room temperature for 3 h, then quenched with
cold water and stirred vigorously for 2 min. The organic layer was separated and the
aqueous residue was extracted with CHCl3. The combined organic extracts were dried
over anhydrous Na2SO4 and concentrated by rotary evaporation to isolate 22 as a
colorless amorphous solid (mp = 53-54
°C) in 98% yield (1.38 g). Spectral data matches
reported literature.16 1H NMR (300 MHz, CDCl3)
δ
7.33 (d,
J
= 2.4 Hz, 1H), 7.10 (d,
J
=
2.4 Hz, 1H), 4.58 (s, 2H), 1.43 (s, 9H), 1.29 (s, 9H);13C NMR (125 MHz, CDCl3)
δ
151.6, 143.0, 137.2, 125.6, 124.7, 123.2, 34.9, 34.3, 32.7, 31.5, 29.9; IR νmax (cm-1) 3511,
2999, 2959, 2903, 2872, 1477, 1390, 1358, 1215, 1159, 758. The sample decomposed en
route to the facility for HRMS analysis.
Procedure 5: Alkylation of PHZ with 22
.
2,4-Di-tert-butyl-6-((2,8-dimethyl-11,12-dihydrodibenzo[b,f][1,5]diazocin-5(6H)-
yl)methyl)phenol (23): Sodium hydride (0.053 g, 1.3367 mmol) was weighed into an
oven-dried round bottom flask and dry THF (16 mL) was added and the suspension
cooled in an ice bath. A solution of
5 (0.289 g, 1.2152 mmol) in dry THF (4 mL) was
then added to the reaction flask dropwise and was stirred in the ice bath for 20 min. Next,
a solution of the bromide 22 (0.400 g, 1.3367 mmol) in dry THF (4 mL) was added
dropwise and the reaction was monitored by TLC (5% and 20% EtOAx:Hex). Upon
disappearance of starting materials the reaction was quenched with water and the mixture
was extracted with CH2Cl2. The combined organic extracts were dried over anhydrous
Na2SO4 and concentrated by rotary evaporation. The crude material was purified by
column chromatography (0-5% EtOAc:Hex) to produce 23 as an amorphous colorless
1
solid in 68% yield (0.380 g). H NMR (500 MHz, CDCl3)
δ
8.82 (br s, 1H), 7.19 (d,
= 8.0 Hz, 1H), 6.99 (d, = 2.0 Hz, 1H),
= 8.0 Hz, 1H), 6.05 (s, 1H), 4.39 (s, 2H),
J =
2.0 Hz, 1H), 7.10 (d,
6.95 (s, 1H), 6.72 (d,
J
J
= 8.0 Hz, 1H), 7.04 (d,
= 8.0 Hz, 1H), 6.51 (d,
J
J
J
4.33 (s, 2H), 4.11 (s, 2H), 3.90 (br s, 1H), 2.29 (s, 3H), 1.98 (s, 3H), 1.33 (s, 9H), 1.23 (s,
9H); 13C NMR (125 MHz, CDCl3)
δ
154.0, 148.5, 146.8, 141.1, 135.8, 133.0, 132.3,
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131.7, 131.3, 129.2, 128.7, 128.5, 126.3, 123.9, 123.1, 122.2, 119.8, 118.6, 58.8, 58.4,
52.5, 34.7, 34.2, 31.8, 29.5, 20.6, 20.3.
2,4-Di-tert-butyl-6-((2,4-di-tert-butyl-6-((2,8-dimethyl-11,12-
dihydrodibenzo[b,f][1,5]diazocin-5(6H)-yl)methyl)phenoxy)methyl)phenol (24): This
1
compound was isolated as a byproduct of the synthesis of 23. H NMR (300 MHz,
CDCl3)
4H), 6.88 (d,
δ
7.55 (s, 1H), 7.28 (d,
J
= 2.4 Hz, 1H), 7.19 (d,
J
= 2.4 Hz, 1H), 7.13-6.93 (m,
= 8.1 Hz,
J
= 2.4 Hz, 1H), 6.73 (dd,
J
= 8.1 Hz, = 1.5 Hz, 1H), 6.51 (d, J
J
1H), 6.06 (s, 1H), 4.84 (s, 2H), 4.39 (s, 2H), 4.33 (s, 2H), 4.12 (s, 2H), 2.29 (s, 3H), 1.99
(s, 3H), 1.43 (s, 9H), 1.33 (s, 9H), 1.28 (s, 9H), 1.23 (s, 9H). HRMS m/z calcd for
(C46H62N2O2)H+ 675.4884, found 675.4878.
Procedure 6: Amide formation with benzoyl chloride.
(2,8-Dimethyldibenzo[b,f][1,5]diazocine-5,11(6H,12H)-diyl)bis(phenylmethanone)
(25): The diamine
5 (0.075 g, 0.3147 mmol) was dissolved in CH2Cl2 (4.3 mL) and
cooled to -40 °C under argon. Di-iso-propylethylamine (DIPEA, 0.12 mL, 0.6923 mmol)
was added dropwise to the reaction flask and stirred for 15 min. Next, a solution of
benzoyl chloride (0.093 g, 0.6608 mmol) in CH2Cl2 (2 mL) was added dropwise to the
flask and stirred for 40 min at -40 °C. The cold bath was then removed and the reaction
allowed to warm to room temperature. After completion by TLC (30% EtOAc:Hex), the
reaction was quenched with water and the layers were separated. The organic layer was
dried over anhydrous sodium sulfate and concentrated under rotary evaporation. The
crude material was purified by column chromatography (20% EtOAc:Hex) to afford 25 in
1
30% yield (0.042 g). H NMR (500 MHz, CDCl3)
δ
7.72 (s, 2H), 7.24-7.10 (m, 10H),
= 8.0 Hz, 2H), 5.67 (d, = 13.5 Hz, 2H), 4.30 (d,
13.5 Hz, 2H), 2.31 (s, 6H); 13C NMR (125 MHz, CDCl3)
169.9, 143.8, 137.4, 135.3,
6.85 (d,
J
= 8.0 Hz, 2H), 6.68 (d,
J
J
δ
J =
134.3, 133.5, 130.0, 129.4, 128.3, 128.1, 127.7, 54.7, 21.0. The slightly impure diamide
was used directly for the next step without full characterization.
Procedure 7: Reduction of diamide 25.27
The diamide 25 (0.040 g, 0.0896 mmol) was dissolved in diethyl ether (3.5 mL) and
added to a solution of lithium aluminum hydride (0.0143 g, 0.3765 mmol) in diethyl ether
(1.5 mL) at room temperature. The reaction was then heated at reflux overnight. The
14

ACCEPTED MANUSCRIPT
reaction was then cooled to room temperature and quenched with 20% aqueous sodium
hydroxide. The layers were separated and the aqueous layer washed twice with diethyl
ether. The combined organic layers were dried over anhydrous sodium sulfate and
concentrated in vacuo to afford 19 in 89% yield (0.0333 g). Spectral data match that of 19
above.
Procedure 8: Attempted amide formation with salicylic acid.
2-(2,8-Dimethyl-5,6,11,12-tetrahydrodibenzo[b,f][1,5]diazocine-5-carbonyl)phenyl 2-
hydroxybenzoate (27): Salicylic acid 26 (0.500 g, 3.620 mmol) was dissolved in THF
(30 mL) and catalytic DMF (0.5 mL) was added. The solution was cooled to -10 °C and
thionyl chloride was added dropwise. The solution was stirred for 20 min then heated at
reflux for 12 h. The solution was cooled and concentrated by rotary evaporation. The
crude material was used directly. In a separate flask, the diamine
5 (0.075 g, 0.3147
mmol) was dissolved in CH2Cl2 (4 mL) and cooled to -40 °C, then DIPEA was added and
stirred for 20 min. The crude acid chloride prepared above in CH2Cl2 (2 mL) was then
added dropwise to the reaction flask. The cold bath was removed and the reaction
allowed to warm to room temperature. The reaction was quenched with water and the
layers separated. The organic layer was dried over anhydrous Na2SO4 and concentrated in
1
vacuo to give 27 in 17% yield (0.0259 g). H NMR (500 MHz, CDCl3)
δ 10.33 (s, 1H),
8.07 (dd,
7.0 Hz, 1H), 7.21 (d,
8.5 Hz, 1H), 6.99 (t,
1H), 6.52 (d, = 8.0 Hz, 1H), 5.20 (d,
(d, = 15.5 Hz, 1H), 3.99 (d, = 15.5 Hz, 1H), 3.97-3.67 (br s, 1H), 2.22 (s, 3H), 2.20 (s,
3H); 13C NMR (125 MHz, CDCl3)
168.0, 166.4, 161.9, 147.1, 146.6, 139.9, 136.9,
J
= 8.0 Hz,
J
= 1.5 Hz, 1H), 7.56 (dt,
J
= 1.5 Hz,
J
= 8.0 Hz, 1H), 7.26 (t,
J
=
J
= 7.5 Hz, 1H), 7.15 (s, 1H), 7.10 (d,
J
= 8.0 Hz, 1H), 7.06 (d,
J
=
J
= 7.5 Hz, 2H), 6.88 (s, 1H), 6.85-6.77 (m, 2H), 6.75 (d,
J = 8.0 Hz,
J
J
= 14.5 Hz, 1H), 4.60 (d, = 15.0 Hz, 1H), 4.31
J
J
J
δ
136.4, 134.3, 133.5, 130.7, 130.2, 129.9, 129.7, 129.5, 129.0, 128.6, 128.4, 128.0, 126.1,
125.4, 122.6, 119.5, 119.2, 117.7, 111.9, 53.0, 51.7, 20.8, 20.3.
Procedure 9: Protection of 20 with benzyl bromide.
2-(Benzyloxy)-3,5-di-tert-butylbenzaldehyde (28):28 Benzyl bromide (0.365 g, 2.134
mmol) and potassium carbonate (1.120 g, 8.108 mmol) were added to a stirred solution of
2-hydroxy-3,5-di-t-butylbenzaldehyde 20 (0.500 g, 2.134 mmol) in DMF (4.3 mL). The
solution was stirred at room temperature for 9 h. The reaction mixture was then filtered
over Celite and the solvent removed by rotary evaporation to produce 28 as colorless
15

ACCEPTED MANUSCRIPT
crystalline plates (mp = 94-95
10.34 (s, 1H), 7.76 (d, = 2.5 Hz, 1H), 7.66 (d,
2H), 7.43 (t, = 7.5 Hz, 2H), 7.37 (t,
9H);13C NMR (125 MHz, CDCl3)
°
C) in 100% yield (0.745 g). 1H NMR (500 MHz, CDCl3)
= 3.0 Hz, 1H), 7.50 (d, = 8.0 Hz,
δ
J
J
J
J
J
= 7.5 Hz, 1H), 5.04 (s, 2H), 1.46 (s, 9H), 1.34 (s,
δ
190.8, 159.7, 146.6, 143.1, 136.6, 130.9, 129.3,
128.6, 128.1, 127.0, 124.0, 80.4, 35.4, 34.7, 31.3, 30.9; IR νmax (cm-1) 3201, 3015, 2963,
2907, 2868, 2740, 1680, 1588, 1461, 1370, 1211, 1159, 1116, 1000, 889, 754; HRMS
m/z calcd for (C22H28O2)Na+ 347.1982, found 347.1981.
Procedure 10: Reduction of aldehyde 28
.
(2-(Benzyloxy)-3,5-di-tert-butylphenyl)methanol (32):28 To a solution of aldehyde 28
(0.662 g, 2.1338 mmol) in ethanol (15 mL) was added sodium borohydride (0.113 g,
2.987 mmol) portionwise. The reaction was stirred at room temperature for 2.5 h before
being quenched with 1 M NaOH. The ethanol was removed in vacuo and the aqueous
solution was extracted with EtOAc. The combined organic extracts were washed with 1
M NaOH, water, brine, dried over anhydrous Na2SO4, and concentrated under rotary
1
evaporation to give 32 as an amorphous white solid in 95% yield (0.633 g). H NMR
(300 MHz, CDCl3)
δ
7.50 (d,
J
= 7.2 Hz, 2H), 7.43-7.29 (m, 5H), 5.25 (s, 1H), 4.98 (s,
153.9, 146.3,
2H), 4.75 (s, 2H), 1.43 (s, 9H), 1.33 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ
142.1, 137.7, 133.7, 128.5, 127.7, 126.9, 124.8, 124.2, 75.9, 61.7, 35.4, 34.5, 31.5, 31.3.
IR νmax (cm-1) 3606, 3426, 2959, 2899, 2863, 1473, 1358, 1219, 1199, 1127, 1024, 913,
742, 650; HRMS m/z calcd for (C22H30O2)Na+ 349.2138, found 349.2134.
Procedure 11: Conversion of benzylic alcohol 32 to bromide.
2-(Benzyloxy)-1-(bromomethyl)-3,5-di-tert-butylbenzene
(36):28
Phosphorus
tribromide (0.23 mL, 2.347 mmol) was added dropwise to a stirred solution of alcohol 32
(0.667 g, 2.133 mmol) in Et2O (21.3 mL) over 10 min. After stirring 15 min more, the
solution was cooled in an ice bath and quenched with saturated NH4Cl. The layers were
separated and the aqueous layer extracted with Et2O. The combined organic layers were
dried over anhydrous Na2SO4 and concentrated under rotary evaporation to give 36 as a
white solid (mp = 86-87
° δ 7.58-
C) in 92% yield (0.738 g). 1H NMR (300 MHz, CDCl3)
7.28 (m, 7H), 5.12 (s, 2H), 4.58 (s, 2H), 1.43 (s, 9H), 1.33 (s, 9H); 13C NMR (125 MHz,
CDCl3)
δ 154.2, 146.6, 142.5, 137.6, 130.9, 128.5, 127.7, 127.3, 126.8, 125.3, 75.2, 35.6,
34.6, 31.4, 31.2, 30.1; IR νmax (cm-1) 3015, 2967, 2904, 2872, 1469, 1358, 1211, 1163,
1008, 762; HRMS m/z calcd for (C22H29BrO)Na+ 411.1294, found 411.1294.
Procedure 12: Alkylation of PHZ.
16

ACCEPTED MANUSCRIPT
5,11-Bis(2-(benzyloxy)-3,5-di-tert-butylbenzyl)-2,8-dimethyl-5,6,11,12-tetrahydro
dibenzo[b,f][1,5]diazocine (40): To a suspension of sodium hydride (0.011 g, 0.4616
mmol) in dry THF (10 mL) in an ice bath was added the diamine
5 (0.050 g, 0.2098
mmol) in THF (1 mL). The solution was stirred for 15 min then the bromide 36 (0.173 g,
0.4616 mmol) in THF (1 mL) was added dropwise to the reaction flask. The reaction was
stirred at 0 °C for 2 h then allowed to warm to room temperature and stir overnight. After
disappearance of
5 by TLC (20% EtOAc:Hex), the reaction was quenched with water and
extracted with CH2Cl2. The combined organic layers were washed with water and brine,
dried over anhydrous Na2SO4, and concentrated on the rotary evaporator. The crude
product was purified by column chromatography (2.5% EtOAc:Hex) to give 40 as
colorless crystals (mp = 191-193
1H NMR (300 MHz, CDCl3)
7.30-7.26 (m, 4H), 7.23-7.10 (m, 10H), 6.90-6.79 (m, 4H),
6.62-6.25 (br s, 2H), 4.69 (s, 4H), 4.50-3.70 (m, 8H), 2.10 (s, 6H), 1.44 (s, 18H), 1.21 (s,
°C, recrystallized from EtOH) in 63% yield (0.113 g).
δ
18H); 13C NMR (75 MHz, CDCl3)
δ 154.5, 145.7, 141.7, 137.7, 132.5, 131.8, 128.6,
128.2, 127.3, 126.7, 122.8, 117.3, 75.2, 51.1, 35.4, 34.4, 31.5, 31.3, 20.2; IR νmax (cm-1)
3003, 2958, 2901, 2864, 1609, 1507, 1454, 1360, 1213, 1164, 1115, 1017, 756; HRMS
m/z calcd for (C60H74N2O2)Na+ 877.5643, found 877.5626.
5-(2-(Benzyloxy)-3,5-di-tert-butylbenzyl)-2,8-dimethyl-5,6,11,12-tetrahydrodibenzo
[b,f][1,5]diazocine (S1): In another preparation of 40 this compound was isolated as a
byproduct in the synthesis as a colorless powder (mp = 157-158
°
C) in 43% yield (0.4978
7.38-7.29 (m, 7H), 6.95-6.85 (m, 4H), 6.64 (s, 1H),
= 8.0 Hz, 1H), 4.84 (s, 2H), 4.74 (s, 2H), 4.43 (s, 2H), 4.34 (s, 2H), 4.20-4.00
(br s, 1H), 2.27 (s, 3H), 2.17 (s, 3H), 1.48 (s, 9H), 1.29 (s, 9H); 13C NMR (125 MHz,
CDCl3) 154.4, 148.2, 145.72, 145.70, 141.7, 137.8, 132.6, 131.7, 131.3, 129.7, 128.56,
1
g). H NMR (500 MHz, CDCl3)
6.55 (d,
δ
J
δ
128.55, 128.3, 128.2, 127.6, 127.3, 126.7, 125.0, 124.4, 122.9, 118.2, 117.2, 75.1, 55.0,
51.7, 51.2, 35.4, 34.5, 31.5, 31.3, 20.3, 20.2; IR νmax (cm-1) 3408, 3007, 2959, 2907,
2864, 1608, 1505, 1481, 1358, 1211, 1163, 1124, 1012, 881, 814, 758, 663; HRMS m/z
calcd for (C38H46N2O)H+ 547.3682, found 547.3686.
17

ACCEPTED MANUSCRIPT
3,5-Di-tert-butyl-2-((4-nitrobenzyl)oxy)benzaldehyde (29): p-Nitrobenzyl bromide
(0.461 g, 2.134 mmol) and potassium carbonate (1.120 g, 8.108 mmol) were added to a
stirred solution of 2-hydroxy-3,5-di-t-butylbenzaldehyde 20 (0.500 g, 2.134 mmol) in
DMF (4.3 mL). The solution was stirred at room temperature for 9 h. The reaction
mixture was then filtered over Celite and the solvent removed by rotary evaporation to
produce 29 as a yellow solid (mp = 136-138
MHz, CDCl3) 10.25 (s, 1H), 8.30 (d,
= 8.5 Hz, 2H), 7.68 (d,
NMR (125 MHz, CDCl3)
°
C) in 100% yield (0.788 g). 1H NMR (500
δ
J = 8.5 Hz, 2H), 7.74 (d, J = 3.0 Hz, 1H), 7.69 (d,
J
J
δ
= 3.0 Hz, 1H), 5.13 (s, 2H), 1.44 (s, 9H), 1.35 (s, 9H); 13C
190.4, 158.4, 147.6, 147.2, 144.0, 143.1, 131.1, 129.1, 127.2,
125.7, 123.9, 77.9, 35.4, 34.8, 31.3, 30.9; IR νmax (cm-1) 3015, 2963, 2864, 2744, 1688,
1600, 1521, 1473, 1346, 1215, 1159, 1112, 1012, 853, 758; HRMS m/z calcd for
(C22H27NO4)Na+ 392.1832, found 392.1831.
(3,5-Di-tert-butyl-2-((4-nitrobenzyl)oxy)phenyl)methanol (33): To a solution of
aldehyde 29 (0.800 g, 2.1653 mmol) in ethanol (30 mL) was added sodium borohydride
(0.15 g, 3.0315 mmol) portionwise. The reaction was stirred at room temperature for 2.5
h before being quenched with 1 M NaOH. The ethanol was removed in vacuo and the
aqueous solution was extracted with EtOAc. The combined organic extracts were washed
with 1 M NaOH, water, brine, dried over anhydrous Na2SO4, and concentrated under
rotary evaporation to give 33 as a yellow solid (mp = 118-119
1H NMR (300 MHz, CDCl3)
8.28 (d, = 8.7 Hz, 2H), 7.67 (d,
= 2.4 Hz, 1H), 7.32 (d, = 2.7 Hz, 1H), 5.14 (s, 2H), 4.71 (s, 2H), 1.41 (s, 9H), 1.33 (s,
9H); 13C NMR (75 MHz, CDCl3)
°C) in 95% yield (0.760 g).
δ
J
J
= 8.4 Hz, 2H), 7.37 (d,
J
J
δ
153.5, 147.4, 146.9, 145.3, 142.1, 133.3, 126.9,
125.3, 124.6, 123.8, 74.7, 61.5, 35.5, 34.6, 31.5, 31.2; IR νmax (cm-1) 3424, 3011, 2959,
2899, 2868, 1604, 1517, 1473, 1342, 1219, 1159, 1120, 1012, 885, 838, 758; HRMS m/z
calcd for (C22H29NO4)Na+ 394.1989, found 394.1988.
1-(Bromomethyl)-3,5-di-tert-butyl-2-((4-nitrobenzyl)oxy)benzene (37): Phosphorus
tribromide (0.14 mL, 1.480 mmol) was added dropwise to a stirred solution of alcohol 33
(0.500 g, 1.346 mmol) in Et2O (15 mL) over 10 min. After stirring 15 min more, the
solution was cooled in an ice bath and quenched with saturated NH4Cl. The layers were
separated and the aqueous layer extracted with Et2O. The combined organic layers were
dried over anhydrous Na2SO4 and concentrated under rotary evaporation to give 37 as an
18

ACCEPTED MANUSCRIPT
1
orange solid (mp = 108-110 °C) in 91% yield (0.530 g). H NMR (500 MHz, CDCl3)
δ
8.30 (d,
J
= 9.0 Hz, 2H), 7.71 (d,
J
= 9.0 Hz, 2H), 7.37 (d,
J
= 2.5 Hz, 1H), 7.34 (d,
J
=
13
2.5 Hz, 1H), 5.24 (s, 2H), 4.51 (s, 2H), 1.41 (s, 9H), 1.33 (s, 9H); C NMR (125 MHz,
CDCl3)
δ 153.7, 147.5, 147.2, 145.0, 142.5, 130.7, 127.5, 126.9, 125.6, 123.8, 73.8, 35.6,
34.6, 31.4, 31.2, 29.7. IR νmax (cm-1) 2965, 1649, 1607, 1518, 1437, 1344, 1229, 1182,
1121, 901, 746, 650; The sample decomposed en route to the facility for HRMS analysis.
5,11-Bis(3,5-di-tert-butyl-2-((4-nitrobenzyl)oxy)benzyl)-2,8-dimethyl-5,6,11,12-
tetrahydrodibenzo[b,f][1,5]diazocine (41): To a suspension of sodium hydride (0.011 g,
0.4616 mmol) in dry THF (5 mL) in an ice bath was added the diamine
5 (0.050 g,
0.2098 mmol) in THF (1 mL). The solution was stirred for 30 min then the bromide 37
(0.191 g, 0.4406 mmol) in THF (1 mL) was added dropwise to the reaction flask. The
reaction was stirred at 0 °C for 1 h then allowed to warm to room temperature and stir
overnight (14 h). After disappearance of
5 by TLC (20% EtOAc:Hex), the reaction was
quenched with water and extracted with CH2Cl2. The combined organic layers were
washed with water and brine, dried over anhydrous Na2SO4, and concentrated on the
rotary evaporator. The crude product was purified by column chromatography (2.5%
EtOAc:Hex) to give 41 as yellow crystals (recrystallized from EtOH, mp = 216-218
°
C)
= 8.0 Hz, 4H), 7.30 (s,
= 8.0 Hz, 2H), 6.75-6.30 (br
s, 2H), 4.80-4.60 (br s, 4H), 4.55-3.70 (m, 8H), 2.14 (s, 6H), 1.40 (s, 18H), 1.26 (s, 18H);
13C NMR (125 MHz, CDCl3)
154.1, 147.0, 146.4, 145.2, 141.8, 132.7, 131.2, 128.7,
1
in 73% yield (0.075 g). H NMR (500 MHz, CDCl3)
δ 8.01 (d, J
4H), 7.25-7.12 (br s, 4H), 6.94 (d, = 8.0 Hz, 2H), 6.82 (d,
J
J
δ
127.9, 126.8, 124.7, 123.4, 123.2, 117.1, 73.8, 67.4, 58.5, 35.4, 34.5, 31.5, 31.3, 20.3; IR
νmax (cm-1) 3006, 2959, 2904, 2864, 1604, 1517, 1457, 1342, 1295, 1215, 1159, 1112,
1032, 877, 842, 814, 754; HRMS m/z calcd for (C60H72N4O6)H+ 945.5525, found
945.5510.
5-(3,5-Di-tert-butyl-2-((4-nitrobenzyl)oxy)benzyl)-2,8-dimethyl-5,6,11,12-tetrahydro
dibenzo[b,f][1,5]diazocine (S2): This compound was isolated as a byproduct in the
19

ACCEPTED MANUSCRIPT
synthesis of 41 and was isolated as a yellow foam (mp = 87-89
°
C). 1H NMR (500 MHz,
= 8.5 Hz, 2H), 7.30
= 8.0 Hz, 1H), 4.82 (s,
2H), 4.39 (s, 2H), 4.30 (s, 2H), 4.28 (s, 2H), 2.23 (s, 3H), 2.14 (s, 3H), 1.39 (s, 9H), 1.29
CDCl3)
δ 8.12 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 2.5 Hz, 1H), 7.34 (d, J
(d, = 2.5 Hz, 1H), 6.93-6.83 (m, 4H), 6.54 (s, 1H), 6.51 (d,
J
J
13
(s, 9H); C NMR (125 MHz, CDCl3)
δ 154.0, 148.2, 147.1, 146.3, 145.6, 145.4, 141.7,
132.7, 131.4, 131.3, 129.8, 128.62, 128.59, 128.53, 127.5, 126.8, 125.3, 123.8, 123.5,
123.1, 118.4, 117.0, 73.7, 53.9, 51.6, 50.9, 35.4, 34.6, 31.5, 31.3, 20.3, 20.2; IR νmax (cm-
1) 3408, 3003, 2959, 2915, 2860, 1604, 1517, 1473, 1342, 1215, 1159, 1116, 1028, 877,
814, 754; HRMS m/z calcd for (C38H45N3O3)H+ 592.3534, found 592.3536.
3,5-Di-tert-butyl-2-((2-nitrobenzyl)oxy)benzaldehyde (30): o-Nitrobenzyl bromide
(0.700 g, 3.240 mmol) and potassium carbonate (1.701 g, 12.312 mmol) were added to a
stirred solution of 2-hydroxy-3,5-di-t-butylbenzaldehyde 20 (0.759 g, 3.240 mmol) in
DMF (10 mL). The solution was stirred at room temperature for 9 h. The reaction
mixture was then filtered over Celite and the solvent removed by rotary evaporation to
produce 30 as a colorless solid (139-140
CDCl3) 10.18 (s, 1H), 8.23 (t, = 8.0 Hz, 2H), 7.81 (t,
Hz, 1H), 7.70 (d, = 3.0 Hz, 1H), 7.54 (t, = 7.5 Hz, 1H), 5.47 (s, 2H), 1.43 (s, 9H), 1.36
°
C) in 77% yield (0.877 g). 1H NMR (500 MHz,
δ
J
J = 7.5 Hz, 1H), 7.77 (d, J = 3.0
J
J
13
(s, 9H); C NMR (125 MHz, CDCl3)
δ 190.2, 158.5, 147.1, 145.9, 143.0, 134.4, 133.9,
131.0, 129.1, 128.3, 127.7, 125.2, 125.0, 76.3, 35.4, 34.7, 31.3, 30.9; IR νmax (cm-1) 2963,
2864, 2756, 1688, 1573, 1521, 1461, 1366, 1338, 1215, 1116, 1008, 750; HRMS m/z
calcd for (C22H27NO4)Na+ 392.1832, found 392.1833.
(3,5-Di-tert-butyl-2-((2-nitrobenzyl)oxy)phenyl)methanol (34): To a solution of
aldehyde 30 (0.750 g, 2.030 mmol) in ethanol (20 mL) was added sodium borohydride
(0.153 g, 4.060 mmol) portionwise. The reaction was stirred at room temperature for 15
min before being quenched with 1 M NaOH. The ethanol was removed in vacuo and the
aqueous solution was extracted with EtOAc. The combined organic extracts were washed
with 1 M NaOH, water, brine, dried over anhydrous Na2SO4, and concentrated under
rotary evaporation to give 34 as an off-white solid (mp = 148-149
(0.730 g). 1H NMR (500 MHz, CDCl3)
8.19 (dd, = 8.0 Hz, = 1.0 Hz, 1H), 8.18 (dd,
= 8.0 Hz, = 1.0 Hz, 1H), 7.77 (t, = 8.0 Hz, 1H), 7.51 (t, = 8.0 Hz, 1H), 7.37 (d,
2.5 Hz, 1H), 7.34 (d, = 2.5 Hz, 1H), 5.41 (s, 2H), 4.65 (s, 2H), 1.40 (s, 9H), 1.34 (s,
9H); 13C NMR (125 MHz, CDCl3)
°C) in 97% yield
δ
J
J
J
J
J
J
J =
J
δ
153.4, 146.8, 146.2, 142.1, 134.9, 134.2, 133.5,
127.9, 127.8, 125.0, 124.9, 124.4, 72.7, 61.4, 35.4, 24.6, 31.5, 31.2; IR νmax (cm-1) 3424,
3019, 2963, 2907, 2868, 1612, 1525, 1473, 1441, 1338, 1302, 1215, 1159, 1120, 1020,
885, 858, 762, 663; HRMS m/z calcd for (C22H29NO4)Na+ 394.1989, found 394.1990.
20

ACCEPTED MANUSCRIPT
1-(Bromomethyl)-3,5-di-tert-butyl-2-((2-nitrobenzyl)oxy)benzene (38): Phosphorus
tribromide (0.17 mL, 1.777 mmol) was added dropwise to a stirred solution of alcohol 34
(0.600 g, 1.615 mmol) in CHCl3 (16 mL) over 10 min. After stirring 15 min more, the
solution was quenched with saturated NH4Cl. The layers were separated and the aqueous
layer extracted with CH2Cl2. The combined organic layers were dried over anhydrous
Na2SO4 and concentrated under rotary evaporation to give 38 as a sticky yellow oil in
45% yield (0.315 g). 1H NMR (500 MHz, CDCl3)
δ
J
8.224 (d,
= 8.0 Hz, 1H), 7.37 (d,
J = 2.5 Hz, 1H), 5.53 (s, 2H), 4.44 (s, 2H), 1.40 (s, 9H), 1.33 (s, 9H); C
J
= 8.0 Hz, 1H), 8.218 (d,
J
= 8.0 Hz, 1H), 7.79 (t,
J
= 8.0 Hz, 1H), 7.53 (t,
J
= 2.5 Hz,
13
1H), 7.33 (d,
NMR (125 MHz, CDCl3)
δ 153.7, 147.0, 146.2, 142.5, 134.8, 134.2, 130.7, 128.0, 127.8,
127.4, 125.5, 125.0, 72.4, 35.5, 34.6, 31.4, 31.3, 29.5; IR νmax (cm-1) 2959, 2868, 1612,
1525, 1469, 1362, 1342, 1267, 1223, 1167, 1096, 1008, 909, 881, 790, 758, 722, 670,
579; HRMS m/z calcd for (C22H28NO3)Na+ 456.1145, found 456.1147.
5,11-Bis(3,5-di-tert-butyl-2-((2-nitrobenzyl)oxy)benzyl)-2,8-dimethyl-5,6,11,12-tetra
hydrodibenzo[b,f][1,5]diazocine (42): To a suspension of sodium hydride (0.0066 g,
0.2767 mmol) in dry THF (4 mL) in an ice bath was added the diamine
5 (0.030 g,
0.1258 mmol) in THF (1 mL). The solution was stirred for 30 min then the bromide 38
(0.115 g, 0.2643 mmol) in THF (1 mL) was added dropwise to the reaction flask. The
reaction was stirred at 0 °C for 1 h then allowed to warm to room temperature and stir
overnight. After disappearance of
5 by TLC (20% EtOAc:Hex), the reaction was
quenched with water and extracted with CH2Cl2. The combined organic layers were
washed with water and brine, dried over anhydrous Na2SO4, and concentrated on the
rotary evaporator. The crude product was purified by column chromatography (2.5%
1
EtOAc:Hex) to give 42 as a yellow oil in 36% yield (0.043 g). H NMR (500 MHz,
CDCl3)
= 8.0 Hz, 2H), 7.28 (d,
6.60-6.35 (br s, 2H), 5.06 (s, 4H), 4.45-3.75 (m, 8H), 2.15 (s, 6H), 1.39 (s, 18H), 1.23 (s,
18H); 13C NMR (125 MHz, CDCl3)
154.0, 146.2, 145.7, 141.6, 134.6, 133.9, 132.4,
δ
8.07 (d,
J
= 8.0 Hz, 2H), 7.77-7.60 (br s, 2H), 7.52 (t,
J
= 7.0 Hz, 2H), 7.38 (t,
J
J
= 5.0 Hz, 4H), 6.91 (d, = 8.0 Hz, 2H), 6.80 (d,
J
J
= 8.0 Hz, 2H),
δ
131.3, 128.5, 128.0, 127.8, 127.6, 124.6, 122.9, 117.4, 72.0, 50.6, 35.3, 34.4, 31.4, 31.3,
21

ACCEPTED MANUSCRIPT
20.2; IR νmax (cm-1) 2959, 2864, 1525, 1473, 1338, 1211, 1116, 1016, 953, 758; HRMS
m/z calcd for (C60H72N4O6)Na+ 967.5344, found 967.5344.
Procedure 13: Protection of 20 with SEMCl.
3,5-Di-tert-butyl-2-((2-(trimethylsilyl)ethoxy)methoxy)benzaldehyde (31): To
a
suspension of sodium hydride (0.113 g, 4.694 mmol) in dry THF (25 mL) at 0 °C was
added a solution of aldehyde 20 in THF (10 mL) dropwise. The solution was stirred for
15 min then a solution of trimethylsilylethoxymethyl chloride (SEMCl, 0.783 g, 4.695
mmol) in THF (10 mL) was added dropwise to the reaction flask. The reaction was
stirred at 0 °C and monitored by TLC (5% EtOAC:Hexanes). The reaction was quenched
with saturated NH4Cl and extracted with CH2Cl2. The combined organic layers were
washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo
The crude product was purified by column chromatography (2% EtOAc:Hex) to yield 31
as a colorless oil in 80% yield (1.24 g). 1H NMR (300 MHz, CDCl3)
10.24 (s, 1H), 7.72
(d, = 2.7 Hz, 1H), 7.63 (d, = 2.7 Hz, 1H), 5.07 (s, 2H), 3.92-3.84 (m, 2H), 1.44 (s,
9H), 1.32 (s, 9H), 1.07-1.00 (m, 2H), 0.04 (s, 9H); C NMR (75 MHz, CDCl3)
.
δ
J
J
13
δ
191.7,
158.0, 146.5, 142.8, 130.5, 130.1, 123.5, 100.7, 67.8, 35.2, 34.7, 31.3, 30.9, 18.0, -1.5; IR
νmax (cm-1) 2951, 2899, 2868, 1684, 1473, 1385, 1247, 1147, 1084, 957, 937, 858, 834;
HRMS m/z calcd for (C21H36O3Si)Na+ 387.2326, found 387.2321.
(3,5-Di-tert-butyl-2-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)methanol (35): To a
solution of aldehyde 31 (1.24 g, 3.420 mmol) in ethanol (17 mL) was added sodium
borohydride (0.258 g, 6.840 mmol) portionwise. The reaction was stirred at room
temperature for 1 h before being quenched with 1 M NaOH. The ethanol was removed in
vacuo and the aqueous solution was extracted with EtOAc. The combined organic
extracts were washed with 1 M NaOH, water, brine, dried over anhydrous Na2SO4, and
1
concentrated under rotary evaporation to give 35 as a pale yellow oil in 86% yield. H
NMR (300 MHz, CDCl3)
δ
7.34 (d,
J
= 3.0 Hz, 1H), 7.27 (d,
= 7.2 Hz, 1H), 1.40 (s, 9H),
154.1, 146.6,
J = 3.0 Hz, 1H), 5.03 (s,
2H), 4.58 (d, = 7.2 Hz, 2H), 4.00-3.91 (m, 2H), 3.71 (t,
J
J
1.31 (s, 9H), 1.14-1.07 (m, 2H), 0.07 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ
142.1, 134.4, 126.4, 124.4, 98.7, 67.5, 62.0, 35.1, 34.5, 31.5, 31.3, 18.0, -1.5; IR νmax (cm-
1) 3444, 2955, 2899, 1469, 1358, 1247, 1219, 1195, 1064, 973, 858, 834, 647; HRMS
m/z calcd for (C21H38O3Si)Na+ 389.2482, found 389.2477.
Procedure 14/15: Conversion of benzylic alcohol 35 to bromide.
22

ACCEPTED MANUSCRIPT
(2-((2-(Bromomethyl)-4,6-di-tert-butylphenoxy)methoxy)ethyl)trimethylsilane (39):
Preparation with NBS/Me2S: To a solution of
N-bromosuccinimide (0.144 g, 0.8064
mmol) in dry CH2Cl2 (4 mL) was added dimethylsulfide (0.07 mL) at 0 °C under argon.
The mixture turned a bright yellow cloudy color and was stirred 15 min. Next, a solution
of alcohol 35 (0.200 g, 0.5486 mmol) in dry CH2Cl2 (1.4 mL) was added dropwise to the
reaction flask and was stirred in the ice bath, monitoring by TLC (10% EtOAc:Hex). The
reaction was quenched by adding it to ice-cold water. The mixture was extracted with
CH2Cl2 and the combined organic layers were washed with saturated NaHCO3, water and
brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was
purified by column chromatography to yield 39 in 55% yield (0.130 g).
Preparation with NBS/PPh3: A solution of alcohol 35 (0.150 g, 0.4114 mmol) and
triphenylphosphine (0.162 g, 0.6171 mmol) in CH2Cl2 (4.1 mL) under argon was stirred
in an ice bath for 25 min. Then N-bromosuccinimide (0.119 g, 0.6171 mmol) was added
and the reaction monitored by TLC (5% EtOAC:Hex). The reaction was quenched with
water and extracted with CH2Cl2. The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified
by column chromatography (1% EtOAc:Hex) to yield 39 as a pale orange oil in 74%
1
yield (0.129 g). H NMR (300 MHz, CDCl3)
δ 7.34 (d, J = 2.4 Hz, 1H), 7.32 (d, J = 2.4
Hz, 1H), 5.19 (s, 2H), 4.76 (s, 2H), 4.02-3.94 (m, 2H), 1.43 (s, 9H), 1.33 (s, 9H), 1.15-
1.07 (m, 2H), 0.10 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 153.0, 146.3, 142.6, 130.8,
127.1, 125.1, 98.4, 67.3, 35.3, 34.5, 31.4, 31.3, 31.1, 18.2, -1.4; IR νmax (cm-1) 3015,
2955, 2900, 2872, 1473, 1362, 1211, 1148, 1080, 961, 858, 830, 750, 663; HRMS m/z
calcd for (C21H37BrO2Si)Na+ 451.1638, found 451.1638.
Procedure 16: Protection of 22 with an acetate group.
2-(Bromomethyl)-4,6-di-tert-butylphenyl acetate (43): The bromide 22 (0.340 g, 1.136
mmol) in acetic anhydride (11 mL) with catalytic concentrated sulfuric acid (3 drops)
was heated at 65 °C for 2 h. Upon reaction completion, the solution was cooled and
diluted with water and CH2Cl2. The mixture was extracted with CH2Cl2 and the combined
organic layers were dried over anhydrous Na2SO4, and concentrated in vacuo. The crude
product was purified by column chromatography (5% EtOAC:Hex) to give 43 as a
colorless powder (mp = 87-89
°
C) in 90% yield (0.352 g). 1H NMR (300 MHz, CDCl3)
δ
7.40 (d, = 2.4 Hz, 1H), 7.29 (d,
J
J
= 2.4 Hz, 1H), 4.32 (s, 2H), 2.40 (s, 3H), 1.35 (s, 9H),
1.31 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ
169.6, 148.6, 145.4, 141.3, 129.9, 126.3,
125.5, 35.0, 34.7, 31.4, 30.6, 29.6, 21.5; IR νmax (cm-1) 2959, 2900, 2864, 1759, 1473,
1370, 1223, 1159, 1100, 1004, 897, 754; HRMS m/z calcd for (C17H25BrO2)Na+
363.0930, found 363.0930.
Procedure 17: Alkylation of PHZ with 43
.
23

ACCEPTED MANUSCRIPT
((2,8-Dimethyldibenzo[b,f][1,5]diazocine-5,11(6H,12H)-diyl)bis(methylene))bis(2,4-
di-tert-butyl-6,1-phenylene) diacetate (44): To a suspension of sodium hydride (0.060
g, 2.5176 mmol) in dry THF (11 mL) in an ice bath was added the diamine
5 (0.200 g,
0.8392 mmol) in THF (3 mL). The solution was stirred for 15 min then the bromide 43
(0.601 g, 1.7623 mmol) in THF (3 mL) was added dropwise to the reaction flask. The
reaction was stirred at 0 °C for 2 h then allowed to warm to room temperature and stir for
2 d. After disappearance of
5 by TLC (10% EtOAc:Hex), the reaction was quenched with
water and stirred for 1 hour. The resulting precipitate was collected by filtration and
purified by column chromatography (5% EtOAc:Hex) to give 44 as a pale yellow solid
(mp = 257-259
Hz, 2H), 7.23 (s, 2H), 6.87 (d,
4.80-3.80 (m, 8H), 2.15 (s, 12H), 1.35 (s, 18H), 1.24 (s, 18H); 13C NMR (125 MHz,
°
C) in 92% yield (0.586 g). 1H NMR (300 MHz, CDCl3)
δ
7.32 (d,
J = 2.1
J
= 8.1 Hz, 2H), 6.73 (d, J = 8.1 Hz, 2H), 6.55 (br s, 2H),
CDCl3)
δ 169.5, 147.9, 145.5, 140.5, 132.7, 131.0, 128.6, 127.5, 125.9, 124.2, 122.9,
122.3, 116.4, 55.5, 51.5, 34.8, 34.6, 31.5, 30.6, 21.3, 20.2; IR νmax (cm-1) 3019, 2962,
2868, 1753, 1593, 1503, 1475, 1360, 1213, 1160, 1111, 1046, 1009, 923, 878, 821, 751;
HRMS m/z calcd for (C50H66N2O4)Na+ 781.4915, found 781. 4909.
2,4-Di-tert-butyl-6-((2,8-dimethyl-11,12-dihydrodibenzo[b,f][1,5]diazocin-5(6H)-
yl)methyl)phenyl acetate (S3): In another preparation of 44 this compound was isolated
1
as a byproduct in the synthesis as a colorless powder (0.026 g). H NMR (300 MHz,
CDCl3)
Hz, 1H), 6.53 (d,
3H), 1.35 (s, 9H), 1.23 (s, 9H); 13C NMR (125 MHz, CDCl3)
δ
7.30-7.27 (m, 2H), 6.90-6.80 (m, 3H), 6.73 (d,
= 7.8 Hz, 1H), 4.55-4.05 (m, 7H), 2.22 (s, 3H), 2.18 (s, 3H), 2.16 (s,
169.5, 148.0, 147.4,
J = 7.8 Hz, 1H), 6.66 (d, J = 1.5
J
δ
145.4, 140.5, 132.3, 131.1, 130.8, 130.6, 129.0, 128.9, 128.7, 124.5, 123.1, 118.4, 77.2,
34.8, 34.6, 31.4, 30.6, 29.7, 21.3, 20.4, 20.3; IR νmax (cm-1) 3337, 3003, 2959, 2919,
2868, 1751, 1608, 1509, 1362, 1207, 1148, 1104, 813, 754, 663; HRMS m/z calcd for
(C33H42N2O2)Na+ 521.3139, found 521.3142.
Procedure 18: Deprotection of 44
.
24

ACCEPTED MANUSCRIPT
6,6'-((2,8-dimethyldibenzo[b,f][1,5]diazocine-5,11(6H,12H)-
diyl)bis(methylene))bis(2,4-di-tert-butylphenol) (18): To a suspension of 44 (0.470 g,
0.6185 mmol) in toluene (12.3 mL) under an argon atmosphere was added di-iso
-
butylaluminum hydride (DIBAL-H, 20 equiv., 2.20 mL, 12.370 mmol) via syringe. The
solution was stirred at room temperature for 24-36 h until all starting material was
consumed by TLC (5% EtOAc:Hex). The reaction was then quenched with saturated
aqueous Rochelle’s salt (sodium potassium tartrate), diluted with CH2Cl2, and stirred for
4-6 h at room temperature until two clearly separable layers were attained. The stirring
was stopped and the solution allowed to stand for 4 h until a precipitate collected between
the two layers. The mixture was filtered over filter paper and the solid material collected
and dried to isolate 18 in 87% yield (0.364 g) as an amorphous colorless powder (mp =
251-253 °C). 1H NMR (500 MHz, CDCl3)
δ
8.46 (s, 2H), 7.32 (s, 2H), 7.20-7.15 (m, 2H),
= 8.0 Hz, 2H), 5.48 (s, 2H), 4.46 (d, = 12.0 Hz, 2H),
= 14.0 Hz, 2H), 3.87 (d, = 14.0 Hz, 2H), 2.96 (s,
154.2, 151.6, 141.6,
7.02 (d,
4.24 (d,
J
J
= 8.0 Hz, 2H), 6.92 (d,
J
J
= 12.0 Hz, 2H), 4.14 (d,
J
J
6H), 1.41 (s, 18H), 1.13 (s, 18H); 13C NMR (125 MHz, CDCl3)
δ
136.0, 132.9, 132.5, 132.0, 128.5, 124.2, 123.5, 122.5, 117.3, 62.1, 58.6, 34.5, 34.3, 31.9,
29.2, 20.6; IR νmax (cm-1) 2943, 2900, 2848, 1469, 1410, 1227, 1195, 1084, 881, 810,
762, 544; HRMS m/z calcd for (C46H62N2O2)H+ 675.4884, found 675.4885.
Procedure 19. Complexation of ligand 44
.
Zinc complex of ligand 18 (45): To a scintillation vial under an argon atmosphere was
added a magnetic stirrer and ligand 44 (0.125 g, 0.185 mmol). To this was added
THF:toluene (1:1, 20 mL) followed by 0.12 mL of 1.6 M diethylzinc in hexane solution
(0.12 mL, 1.6 M, 0.192 mmol). The reaction was allowed to stir at room temperature for
24 h. The solvents were removed under vacuum to yield 45 as a white powder in 93%
1
yield (0.127 g). H NMR (600 MHz, CDCl3)
δ
7.13 (d,
J
= 2.4 Hz, 2H), 7.09 (d,
J
= 8.4
= 10.8
= 16.8 Hz, 2H), 4.02 (d, J = 10.8 Hz, 2H),
Hz, 2H), 7.01 (d,
Hz, 2H), 4.43 (d,
J
J
= 2.4 Hz, 2H), 6.99 (d,
= 16.8 Hz, 2H), 4.32 (d,
J
= 7.8 Hz, 2H), 5.95 (s, 2H), 4.86 (d, J
J
2.04 (s, 6H), 1.38 (s, 18H), 1.03 (s, 18H).
25

ACCEPTED MANUSCRIPT
Acknowledgements
This work was supported by the Department of Chemistry at the University of Missouri-
Columbia. We thank Dr. Justin R. Walensky (University of Missouri-Columbia) for his
interest in this project and Dr. Charles L. Barnes (University of Missouri-Columbia) for
acquisition of X-ray data.
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