Hangman salen platforms containing two xanthene scaffolds

Article abstract of DOI:10.1021/jo0613075

A synthetic strategy for the construction of chiral salen ligands bearing two rigid xanthene spacers functionalized with carboxylic acid and ester groups is presented. Suzuki cross-coupling methodology is used to furnish the appropriately functionalized x

Full text of DOI:10.1021/jo0613075

Hangman Salen Platforms Containing Two Xanthene Scaffolds
Jenny Y. Yang, Julien Bachmann, and Daniel G. Nocera*
Department of Chemistry, 6-335, Massachusetts Institute of Technology, 77 Massachusetts AVenue,
Cambridge, Massachusetts 02139-4301
nocera@mit.edu
ReceiVed June 25, 2006
A synthetic strategy for the construction of chiral salen ligands bearing two rigid xanthene spacers
functionalized with carboxylic acid and ester groups is presented. Suzuki cross-coupling methodology is
used to furnish the appropriately functionalized xanthene spacers to a salicyladehyde, which is subsequently
condensed with (1R,2R)-(-)-1,2-diaminocyclohexane to produce salen ligands featuring an expandable
molecular cleft capable of multiple hydrogen-bonding interactions in addition to metallosalen oxidation
chemistry. The ability of these “Hangman” platforms to support multielectron chemistry mediated by
proton-coupled electron transfer (PCET) is established by their proclivity to promote the catalytic
disproportionation of hydrogen peroxide to oxygen and water via a high-valent metal oxo. Within this
functionalized Hangman framework, the stereochemistry of the cyclohexyl backbone of the salen platform
is revealed in the epoxidation of 1,2-dihydronaphthalene by the metal oxo.
Introduction
the hanging acid-base group to a peroxide ligated to the
metalloporphyrin.1,5-7 Our interest in generalizing the Hangman
approach led us to replace metal porphyrins with Schiff base
macrocycles.8 The synthesis of the HSX platform (pictured in
Chart 1) allows for the electronic and steric properties of the
redox platform to be more easily tuned than porphyrins. In
addition, the chiral framework that has been the centerpiece of
the development of metal salens as asymmetric oxidation
catalysts9,10 can be installed into a salen platform, though not
specifically for HSX since the acid-functionalized xanthene is
bound to a salophen ligand through the phenylenediamine
bridge.8 To rectify this design flaw, we describe the synthesis
of the HSX* and HphSX* ligands shown in Chart 1. The rigid
hydrogen bond functionalities are poised over a salen platform
that incorporates a chiral cyclohexanediimine bridge. To ac-
commodate the aliphatic bridge, we have modified the attach-
ment point of the functionalized xanthene spacer to the phenolic
arms of the ligand. The incorporation of two xanthene scaffolds
forms a convergent and symmetric molecular cleft of two
different sizes formed from a hydrogen bond group directly
attached to the xanthene and via a phenylene spacer. The PCET
Small molecule catalysis involving the making and breaking
of substrate bonds in nature is often coupled to the transport of
both protons and electrons.1-4 Our interest in catalytic processes
that are driven by proton-coupled electron transfer (PCET) has
led us to design “Hangman” ligand constructs, which position
an acid-base functionality over the face of a redox cofactor.5-8
In these systems, the acid-base functional group controls the
secondary coordination sphere for substrate assembly and
activation by the proton. In porphyrin Hangman platforms, the
high-valent metal oxo heme, evocative of the catalytic cofactor
of mono-oxygenases, is unmasked by shuttling a proton from
(1) Chang, C. J.; Chang, M. C. Y.; Damrauer, N. H.; Nocera, D. G.
Biophys. Biochim. Acta 2004, 1655, 13-28.
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2003, 103, 2167-2202.
(3) Cukier, R. I.; Nocera, D. G. Annu. ReV. Phys. Chem. 1998, 49, 337-
369.
(4) Dempsey, J. L.; Esswein, A. J.; Manke, D. R.; Rosenthal, J.; Soper,
J. D.; Nocera, D. G. Inorg. Chem. 2005, 44, 6879-6892.
(5) Yeh, C.-Y.; Chang, C. J.; Nocera, D. G. J. Am. Chem. Soc. 2001, 5,
1513-1514.
(6) Chng, L. L.; Chang, C. J.; Nocera, D. G. Org. Lett. 2003, 5, 2421-
2424.
(7) Chang, C. J.; Chng, L. L.; Nocera, D. G. J. Am. Chem. Soc. 2003,
125, 1866-1876.
(8) Liu, S.-Y.; Nocera, D. G. J. Am. Chem. Soc. 2005, 127, 5278-5279.
(9) Zhang, W.; Loebach, J. L.; Wilson, D. R.; Jacobsen, E. N. J. Am.
Chem. Soc. 1990, 112, 2081-2083.
(10) Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.; Katsuki, T. Tetrahedron
Lett. 1990, 31, 7345-7348.
10.1021/jo0613075 CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/13/2006
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J. Org. Chem. 2006, 71, 8706-8714

Hangman Salen Platforms
but only after protection of the acid with an ester.11 Methyl ester
2 was used to obtain boronic acid precursor 24, which was then
coupled to 5-bromosalicyladehyde to afford precursor 10; the
methyl ester serves as the protecting group.12,13 The two coupling
steps provided product in moderate yields, but the methyl ester
proved difficult to deprotect. Using a benzyl ester protecting
group on the acid14 to make 25, and following the same synthetic
route also resulted in a modest yield in the successive palladium-
catalyzed cross-coupling steps. As a result, although the benzyl
ester was easier to cleave, the overall yield along this synthetic
pathway was not favorable. We therefore sought an alternative
synthetic pathway to the Hangman salens.
CHART 1
Scheme 1 outlines the synthetic strategy that successfully
delivers the HSX* and HphSX* ligands in good yields. The
stepwise functionalization of the commercially available xan-
thene dibromide furnishes the benzoic acid methyl ester8 (4),
which can be deprotected to give the benzoic acid analogue
(3). With the appropriately functionalized xanthene precursors
(1-4) in hand, the construction of the salen macrocycle begins
with the catenation of 3-formyl-4-methoxyphenyl boronic acid
to the remaining bromide of 1-4. Effectively the site of boronic
acid and bromide functionalization on the xanthene and sali-
cyaldehyde has been inverted from that of Scheme S1. We found
that this modification provided a better nucleophilic site for the
Suzuki cross-coupling step than of the boronic acid function-
alized xanthene and consequently delivered 5-8 in good
yields.15 Subsequent deprotection of the methyl ether by
treatment with boron tribromide yields the appropriate xanthene-
functionalized salicyladehyde derivatives 9-12.16,17 Boron
tribromide is also known to deprotect methyl esters;18 however,
10 and 12 can be isolated by reducing the reaction time to
selectively cleave the methyl ether to achieve the desired
product. The construction of the salen ring is completed with
the condensation, in high yield, of 9-12 with 0.5 equiv of
catalysis of the HSX* and HphSX* platforms has been evaluated
by examining their catalase and epoxidation activity. We show
that the benefits of the hanging group for substrate assembly
over the redox active metal center are preserved, while this
architecture permits the additional feature of enatioselective
activity.
Results and Discussion
Initial attempts to synthesize 9, which is the precursor to
HSX*, followed established methods to functionalize the
xanthene bridge selectively with a carboxylic acid (1) from the
commercially available xanthene dibromide (see Scheme S1,
in the Supporting Information).7 The methyl ester (2) derivative
is obtained directly by protection of 1.7 We initially focused on
obtaining 9 by replacing the bromide in 1 with a boronic acid
in order to establish a site for subsequent cross-coupling with
5-bromosalicyladehyde. This was achieved using palladium-
catalyzed cross-coupling conditions with bis(pinacolato)diboron,
a
SCHEME 1
a Reagents: (a) 3-Formyl-4-methoxyphenylboronic acid, Na2CO3, Pd(PPh3)4, DMF/H2O; (b) BBr3, CH2Cl2; (c) (1R,2R)-(-)-1,2-diaminocyclohexane,
EtOH; (d) (i) Mn(OAc)2(H2O)4, EtOH, (ii) aq NaCl.
J. Org. Chem, Vol. 71, No. 23, 2006 8707

Yang et al.
FIGURE 1. Turnover number (TON) of hydrogen peroxide dismutation catalyzed by manganese compounds 23 (23* in the presence of 2 equiv
of benzoic acid), 17, 18, 19, and 20 after 1 h.
(1R,2R)-(-)-1,2-diaminocyclohexane to produce the desired
Hangman salen ligands 13-16. Mass spectral evidence shows
no evidence of any singly condensed diamine product, and the
1H NMR integrations are consistent with two functionalized
xanthenes to one cyclohexyldiamine bridge. Analogous por-
phyrins ligands bearing two xanthene bridges possess two
different atropisomers (xanthenes facing each other across the
macrocycle as opposed to the xanthenes being one-up and one-
down) that can be independently identified by 1H NMR
spectroscopy. For these porphyrin ligands, no exchange is
observed between the two atropisomers in solution at room
1
temperature.15,19 In contrast, the H NMR for the HSX* and
HphSX* ligands at room temperature show only one set of well-
resolved ligand peaks, suggesting there is either one atropisomer
in solution or exchange between the two is extremely rapid.
Manganese ion may be inserted into the salen core by refluxing
the ligand with an excess of manganese acetate in air, followed
by workup with a saturated aqueous sodium chloride solution.
FIGURE 2. Oxygen release from hydrogen peroxide dismutation
catalyzed by manganese compounds 23 (0), 23* (*in the presence of
2 equiv of benzoic acid) (]), 17 (b), 18 (×), 19 ([), and 20 (O) over
Products 17-20 are obtained with chloride ion occupying an
axial coordination position of the Mn(III) ion.
1 h.
Complexes 17 and 19 comprise a structurally homologous
series of doubly bridged Hangman constructs in which the acid-
base group can be differentially extended over the face of the
salen. Since the metal ion defines the site for substrate binding
and activation, the positioning of the acid-base group proximal
to the metal, a priori, would appear to be important to the PCET
activity of these doubly bridged Hangman salens. To probe this
issue, the PCET activation of O-O bonds by 17 and 19 was
examined by studying the disproportionation of H2O2, an
important PCET process that is catalyzed by a variety of
enzymes.20 Figure 1 shows the turnover numbers (TONs) for
oxygen production by 17 and 19 and control systems in which
(i) a proton is absent from the hanging group (18 and 20) and
(ii) the salen platform is unmodified [Mn(5-phsalen)Cl] (23).
The presence of the acid-base hanging group results in a
dramatic increase in catalase-type reactivity. Whereas high
TONs can be achieved with 17 and 19, relatively low TONs
are observed when the carboxylic acid functionality is replaced
by an ester (18 and 20). Similarly, control experiments with
the redox-only manganese salen complex 23 show low activity
for disproportionation. The addition of an external H+ source
(11) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508-7510.
(12) Deng, Y.; Chang, C. K.; Nocera, D. G. Angew. Chem., Int. Ed. 2000,
39, 1066-1068.
(13) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(14) Neises, B.; Andries, T.; Steglich, W. J. Chem. Soc., Chem. Commun.
1982, 1132-1133.
(15) Chang, C. J.; Yeh, C.-Y.; Nocera, D. G. J. Org. Chem. 2002, 67,
1403-1406.
(16) Kende, A. S.; Rizzi, J. P. Tetrahedron Lett. 1981, 22, 1779-1982.
(17) Brooks, P. R.; Wirtz, M. C.; Vetelino, M. G.; Rescek, D. M.;
Woodworth, G. F.; Morgan, B. P.; Coe, J. W. J. Org. Chem. 1999, 64,
9719-9712.
(18) Felix, A. M. J. Org. Chem. 1974, 39, 1427-1429.
(19) Ships, G., Jr.; Rebek, J., Jr. Tetrahedron Lett. 1994, 35, 6823-
6825.
(20) Nicholls, P.; Fita, I.; Loewen, P. C. AdV. Inorg. Chem. 2001, 51,
51-106.
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Hangman Salen Platforms
SCHEME 2
(benzoic acid) enhances the TON of the parent salen complex,
but the activity remains far inferior to that of Mn(HSX*)Cl (17)
and Mn(HphSX*)Cl (19), which manage the proton by intramo-
lecular transfer from the hanging functional group. The superior
activity of 17 and 19 is reflected in the activity profiles shown
in Figure 2. Both 17 and 19 exhibit similar reactivity profiles.
Initial turnover frequencies are similar for both catalysts, but
17 appears to be more robust over time and hence exhibits higher
overall activity.
strates the ligand can access a range of metal-to-acid distances
depending on the rotation of the xanthene bridge around the
macrocycle (Figure 3a). Whereas one carboxylic acid can
hydrogen bond with the unbound oxygen on the hydroperoxide
at an acid-to-metal distance of ∼5 Å, the other forms an
unconstructive intramolecular hydrogen bond with the oxygen
on the xanthene. To form this intramolecular hydrogen bond,
the xanthene tilts appreciably toward the plane of the macrocycle
ring presumably driven by the stabilization incurred from the
formation of the six-membered ring. This intramolecular bond
has been observed in porphyrin xanthene complexes in the
absence of substrate.24 Hence, only one hanging group need be
involved for substrate assembly, even when two are available.
The hydrogen bond network is structurally different for the
phenyl-spaced system. Two analogous energy-minimized cal-
culation of the hydroperoxide-bound Mn(HphSX*-COOH) (19)
were performed. The first revealed that the addition of the
phenylene spacer permits the two acids to comfortably span
the distance above the salen platform to form an intramolecular
carboxylic acid dimer (Figure 3b). An alternative structure was
explored by tilting the xanthene scaffolds away from each other
so that, while both carboxylic acids can still form productive
hydrogen bonds with the bound hydroperoxide, they are not
facing each other and thus cannot form a -(COOH)2- dimer
(Figure S3.1). The structure is destabilized by 44 kJ/mol relative
to that of the -(COOH)2- dimer (Table S3.2) showing that
formation of the dimer confers significant stabilization to 19.
The formation of this stabilizing intramolecular hydrogen bond
is likely accompanied by a decrease in the acidity of the proton
over the reactive cleft. Accordingly, substrate assembly will be
diminished due to the reduced ability to form additional
hydrogen bonds, thus accounting for the lower catalase activity
of 19 as compared to that of 17 (see Figure 1) where the two
acids are too far apart to form an intramolecular dimer.
The role of the acid-to-metal distance in promoting catalase
activity may be understood in the context of recent experimental
and theoretical investigations of Mn-salen catalysts. The
replacement of H2O2 by aryl peroxide permits the catalase cycle
at a Hangman salophen platform to be arrested, and accordingly,
intermediates can be detected by stopped-flow spectroscopy.21
Proton transfer to the aryl peroxide coordinated to the Mn(III)
center furnishes a high-valent Mn(V) oxo intermediate. The
stopped-flow studies reveal that this step, however, is not rate-
determining, and for this reason the acid-to-metal distance is
less crucial for the first step in the catalase cycle in the Hangman
systems. Instead, subsequent oxidation of peroxide by the Mn-
(V) oxo appears to be rate-determining, a contention that is
supported by recent theoretical investigations of Mn salen
catalase activity.22,23 The catalase cycle deduced from compu-
tational studies is shown in Scheme 2. The highest energy
intermediate in the cycle (presumably giving rise to the rate-
determining step) is found to be the Mn(V) oxo associated with
H2O2 in an end-on fashion; this intermediate is depicted by A
in Scheme 2 for the system reported here. The hanging acid-
base group would be beneficial to promoting the formation of
the end-on intermediate via a hydrogen-bonding network.
Therefore, the {Mn(V) oxo-H2O2} assembly is expected to be
sensitive to the positioning of the acid-base group over the
face of the salen platform. An energy-minimized calculation of
the geometry of hydroperoxide-bound Mn(HSX*-COOH) (with
an ethylenediamine bridge instead of the cyclohexyl) demon-
The modified chiral salen macrocycle transfers stereochemical
information in an oxygen atom transfer reaction when H2O2 is
replaced by prochiral substrates. With the use of sodium
hypochlorite as the oxygen atom transfer source, epoxidation
of the prochiral olefin 1,2-dihydronaphthalene by Mn(HSX*-
(21) Liu, S.-Y.; Soper, J. D.; Yang, J. Y.; Rybak-Akimova, E. V.; Nocera,
D. G. Inorg. Chem., 2006, 45, 7572-7574.
(22) Abashkin, Y. G.; Burt, S. K. Inorg. Chem. 2005, 44, 1425-1432.
(23) Abashkin, Y. G.; Burt, S. K. J. Phys. Chem. B 2004, 108, 2708-
2711.
(24) Chang, C. K.; Bag, N.; Guo, B.; Peng, S.-M. Inorg. Chim. Acta
2003, 351, 261-268.
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Yang et al.
FIGURE 3. Energy-minimized structures obtained from DFT of the hydroperoxide complexes of (a) Mn(HSX*-COOH) showing one of the
carboxylic acids is hydrogen bonded to the oxygen on the xanthene scaffold, while the other is hydrogen bonded to the hydroperoxide and (b)
Mn(HphSX*-COOH) showing the two carboxylic acids span the face of the salen macrocycle to make a -(COOH)2- dimer that interacts with the
hydroperoxide via a hydrogen bond.
COOH)Cl (17) was examined. The epoxide product was
resolved with 23% enantiomeric excess (ee), demonstrating
communication with the chiral backbone and substrate despite
the bulky xanthene functionalizations situated at the 5 and 5′
position of the macrocycle. Whereas this ee is inferior to the
best salen epoxidation catalysts, it is on par with the “intro-
ductory” ee’s observed for first generation catalysts. More
specifically, the ee is consistent with salen macrocycles un-
functionalized in the 3 and 3′ positions.9,25,26 The addition of
bulky functional groups in the 3 and 3′ positions is believed to
enhance the selectivity in epoxidation reactions by directing
olefin approach over the chiral-inducing cyclohexyl bridge by
sterically blocking alternative substrate orientations.10,25 With
this in mind, we intend to modify the substituents about the
macrocycle to optimize the enantiomeric selectivity of electron-
rich substrates within this Hangman framework.
with pendant acid and methyl ester groups establishes the
importance of the hydrogen-bonding group in facilitating
catalysis. Computational studies suggest that only one carboxylic
acid is needed to promote the favored end-on hydrogen peroxide
assembly with the metal oxo catalytic intermediate. When the
functional group is extended with a phenylene spacer, the two
carboxylic acids are sufficiently close to form a -(COOH)2-
dimer, which reduces the propensity of the hanging group to
promote substrate assembly; accordingly, lower catalytic activity
is observed. When the H2O2 substrate is replaced by prochiral
substrates such as 1,2-dihydronaphthalene, asymmetric epoxi-
dation is observed with introductory ee’s of 23%. Increases in
ee will be sought by introducing steric substituents at crucial
positions on the salen macrocycle so as to promote substrate
interaction with the chiral cyclohexyldiamine backbone of the
salen macrocycle.
In conclusion, we have developed an easy and versatile
methodology to install Hangman scaffolds on salen macrocycles
while maintaining the ligand’s chiral framework. Two func-
tionalized xanthene scaffolds form a symmetric molecular cleft,
which can be structurally tuned with spacers appended to the
xanthene scaffold. Comparison of the reactivity profiles and
overall TON for H2O2 dismutation between Hangman salens
Experimental Section
General Information. Details are given in the Supporting
Information.
4-(5-Bromo-2,7-di-tert-butyl-9,9-dimethyl-9H-xanthen-4-yl)-
benzoic Acid (3). A solution of 4-(5-bromo-2,7-di-tert-butyl-9,9-
dimethyl-9H-xanthen-4-yl)-benzoic acid methyl ester (4) (0.414 g,
0.773 mmol) in 10 mL of THF was refluxed with 5 mL of saturated
sodium hydroxide in water for 2 h. The mixture was neutralized
with aqueous HCl and extracted with 3 × 25 mL of dichlo-
romethane. The combined organic layers were dried with MgSO4,
and the solvent was removed by rotary evaporation to yield the
colorless product (0.334 g, 83.1% yield). 1H NMR (500 MHz,
(25) Jacobsen, E. N.; Wu, M. H. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York,
1999; pp 649-677.
(26) Lin, G.-Q.; Li, Y.-M.; Chan, A. S. C. In Principles and Applications
of Asymmetric Synthesis; Wiley-Interscience: New York, 2001; pp 237-
241.
8710 J. Org. Chem., Vol. 71, No. 23, 2006

Hangman Salen Platforms
CDCl3, δ): 8.07 (d, J ) 6.0 Hz, 2H), 7.65 (d, J ) 6.0 Hz, 2H),
7.48 (s, 1H), 7.36 (s, 1H), 7.30 (s, 1H), 7.22 (s, 1H), 1.63 (s, 6H),
1.28 (m, 18H). 13C NMR (500 MHz, CDCl3, δ): 172.6, 147.1,
146.3, 145.5, 145.4, 144.0, 131.4, 130.6, 130.2, 130.1, 128.6, 128.3,
128.0, 126.3, 122.9, 121.8, 110.4, 35.6, 34.83, 34.79, 35.4, 31.7,
31.6. HRESI-MS ([M + H]+) C30H33O3Br m/z, Calcd 521.1686,
found 521.1679.
δ): 189.9, 171.9, 161.1, 146.0, 145.94, 145.88, 145.5, 137.4, 135.3,
130.9, 130.5, 130.0, 129.8, 129.7, 128.3, 128.2, 128.1, 127.0,
125.73, 125.70, 124.4, 122.7, 121.9, 111.0, 55.8, 35.4, 34.8, 31.83,
31.79, 31.77, 29.9, 27.5. HRESI-MS ([M + Na]+) C38H40O5Na m/z,
Calcd 599.2768, found 599.2757.
4-[2,7-Di-tert-butyl-5-(3-formyl-4-methoxy-phenyl)-9,9-dimethyl-
9H-xanthen-4-yl]-benzoic Acid Methyl Ester (8). Under nitrogen,
a mixture of 4-(5-bromo-2,7-di-tert-butyl-9,9-dimethyl-9H-xanthen-
4-yl)-benzoic acid methyl ester (4) (0.200 g, 0.374 mmol), 3-formyl-
4-methoxyphenylboronic acid (0.074 g, 0.411 mmol), sodium
carbonate (0.058 g, 0.563 mmol), tetrakis(triphenylphosphine)-
palladium (0.016 g, 0.022 mmol), DMF (9 mL), and deionized water
(1 mL) was heated to 90 °C for 36 h. Upon cooling, the mixture
was extracted with 3 × 100 mL of dichloromethane. The organic
portions were combined and dried over MgSO4, and the solvent
was removed by rotary evaporation. The crude solid was purified
by column chromatography (silica gel, dichloromethane) to elute
the colorless product (0.219 g, 99.1% yield). 1H NMR (500 MHz,
CDCl3, δ): 10.39 (s, 1H), 7.77 (d, J ) 8.5 Hz, 2H), 7.74 (d, J )
2.5 Hz, 1H), 7.47 (d, J ) 2.5 Hz, 1H), 7.44 (d, J ) 2.5 Hz, 1H),
7.38 (dd, J ) 8.5 Hz, 2.5 Hz, 1H), 7.31 (d, J ) 8.5 Hz, 2H), 7.16
(m, 2H), 6.57 (2, J ) 8.5 Hz, 1H), 3.97 (s, 3H), 3.89 (s, 3H), 1.74
(s, 6H), 1.36 (s, 9H), 1.35 (s, 9H). 13C NMR (500 MHz, CDCl3,
δ): 190.3, 167.8, 161.5, 146.5, 146.42, 146.40, 146.3, 144.0, 138.1,
131.4, 131.3, 131.1, 130.4, 130.0, 129.7, 128.9, 128.5, 128.4,
126.23, 126.17, 124.9, 123.0, 122.4, 111.5, 56.2, 52.7, 35.9, 35.3,
32.3, 32.2. HRESI-MS ([M + Na]+) C39H42O5Na m/z, Calcd
613.2924, found 613.2920.
2,7-Di-tert-butyl-5-(3-formyl-4-methoxy-phenyl)-9,9-dimethyl-
9H-xanthene-4-carboxylic Acid (5). Under nitrogen, a mixture of
4-hydroxycarbonyl-5-bromo-2,7-di-tert-butyl-9,9-dimethylxan-
thene (1) (0.150 g, 0.338 mmol), 3-formyl-4-methoxyphenylboronic
acid (0.067 g, 0.371 mmol), sodium carbonate (0.052 g, 0.507
mmol), tetrakis(triphenylphosphine)palladium (0.015 g, 0.020 mmol),
DMF (9 mL), and deionized water (1 mL) was heated to 90 °C for
36 h. Upon cooling, 10 mL of water was added, and the mixture
was extracted with 3 × 25 mL of dichloromethane. The organic
portions were combined and dried over MgSO4, and the solvent
was removed by rotary evaporation. The crude solid was purified
by column chromatography (silica gel, 8:2 pentane/ethyl acetate)
to elute the colorless product (0.108 g, 64% yield). 1H NMR (500
MHz, CDCl3, δ): 10.55 (s, 1H), 8.03 (d, J ) 2.5 Hz, 1H), 7.98 (d,
J ) 2.5 Hz, 1H), 7.70 (dd, J ) 8.5 Hz, 2 Hz, 1 H), 7.68 (d, J )
2.5 Hz, 1H), 7.49 (d, J ) 2.5 Hz, 1H), 7.21 (d, J ) 2 Hz, 1H),
7.15 (d, J ) 8.5 Hz, 1H), 4.02 (s, 3H), 1.73 (s, 6H), 1.37 (s, 9H),
1.34 (s, 9H). 13C NMR (500 MHz, CDCl3, δ): 190.1, 167.8, 161.7,
148.3, 147.1, 146.3, 144.7, 137.6, 134.2, 131.3, 130.1, 130.0, 129.3,
128.21, 128.16, 126.4, 124.8, 122.1, 116.9, 112.2, 56.0, 35.1, 34.83,
34.80, 32.0, 31.7, 31.5. HRESI-MS ([M - H]-) C32H35O5 m/z,
Calcd 499.2490, found 499.2482.
2,7-Di-tert-butyl-5-(3-formyl-4-methoxy-phenyl)-9,9-dimethyl-
9H-xanthene-4-carboxylic Acid Methyl Ester (6). Under nitrogen,
a mixture of 4-methoxycarbonyl-5-bromo-2,7-di-tert-butyl-9,9-
dimethylxanthene (2) (0.300 g, 0.653 mmol), 3-formyl-4-methoxy-
phenyl-boronic acid (0.130 g, 0.722 mmol), sodium carbonate
(0.101 g, 0.981 mmol), tetrakis(triphenylphosphine)palladium (0.029
g, 0.040 mmol), DMF (9 mL), and deionized water (1 mL) was
heated to 90 °C for 36 h. Upon cooling, the mixture was extracted
with 3 × 75 mL of dichloromethane. The organic portions were
combined and dried over MgSO4, and the solvent was removed by
rotary evaporation. The crude solid was purified by column
chromatography (silica gel, 3:7 hexane/dichloromethane) to elute
the colorless product (0.333 g, 99.1% yield). 1H NMR (500 MHz,
CDCl3, δ): 10.54 (s, 1H), 8.01 (d, J ) 2.5 Hz, 1H), 7.85 (dd, J )
8.5 Hz, 2.5 Hz, 1H), 7.57 (s, 2H), 7.43 (d, J ) 2.5 Hz, 1H), 7.21
(d, J ) 2.5 Hz, 1H), 7.10 (d, J ) 8.5 Hz, 1H), 4.01 (s, 3H), 3.50
(s, 3H), 1.70 (s, 6H), 1.36 (s, 9H), 1.33 (s, 9H). 13C NMR (500
MHz, CDCl3, δ): 190.0, 167.7, 160.9, 147.4, 146.1, 145.3, 145.2,
138.2, 131.4, 131.1, 130.2, 130.0, 127.9, 126.3, 126.2, 125.9, 124.5,
121.9, 119.7, 111.2, 56.0, 52.0, 35.0, 34.7, 34.6, 32.1, 31.7, 31.5.
HRESI-MS ([M + Na]+) NaC33H38O5 m/z, Calcd 537.2611, found
537.2601.
4-[2,7-Di-tert-butyl-5-(3-formyl-4-methoxy-phenyl)-9,9-dimethyl-
9H-xanthen-4-yl]-benzoic Acid (7). Under nitrogen, a mixture of
4-(5-bromo-2,7-di-tert-butyl-9,9-dimethyl-9H-xanthen-4-yl)-ben-
zoic acid (3) (0.300 g, 0.575 mmol), 3-formyl-4-methoxyphenyl-
boronic acid (0.114 g, 0.633 mmol), sodium carbonate (0.089 g,
0.864 mmol), tetrakis(triphenylphosphine)palladium (0.025 g, 0.034
mmol), DMF (9 mL), and deionized water (1 mL) was heated to
90 °C for 36 h. Upon cooling, the mixture was extracted with 3 ×
100 mL of dichloromethane. The organic portions were combined
and dried over MgSO4, and the solvent was removed by rotary
evaporation. The crude solid was purified by column chromatog-
raphy (silica gel, 98:2 dichloromethane/methanol) to elute the
colorless product (0.323 g, 97.3% yield). 1H NMR (500 MHz,
CDCl3, δ): 10.41 (s, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7.74 (d, J )
1.25 Hz, 1H), 7.49 (d, J ) 2.5 Hz, 1 H), 7.45 (d, J ) 2.5 Hz, 1 H),
7.43 (dd, J ) 6 Hz, 2.5 Hz, 1H), 7.36 (d, J ) 8 Hz, 2H), 7.18 (dd,
J ) 8 Hz, 2 Hz, 2H), 6.68 (d, J ) 8.5 Hz, 1H), 3.96 (s, 3H), 1.75
(s, 6H), 1.37 (s, 9H), 1.36 (s, 9H). 13C NMR (500 MHz, CDCl3,
2,7-Di-tert-butyl-5-(3-formyl-4-hydroxy-phenyl)-9,9-dimethyl-
9H-xanthene-4-carboxylic Acid (9). 2,7-Di-tert-butyl-5-(3-formyl-
4-methoxy-phenyl)-9,9-dimethyl-9H-xanthene-4-carboxylic acid (5)
(0.545 g, 1.11 mmol) was added to 20 mL of dry dichloromethane,
and the mixture was cooled to 0 °C. A solution of boron tribromide
(3 mL, 1.0 M in dichloromethane) was added, and upon stirring
for 3 h, 20 mL of water was added. The organic layer was separated,
washed with 10 mL of water, and dried over MgSO4. The solvent
was evaporated, and the residue was purified by column chroma-
tography (silica gel, 98:2 dichloromethane/methanol) to elute the
product (0.330 g, 62% yield). X-ray quality crystals were grown
1
by slow evaporation of a saturated dichloromethane solution. H
NMR (500 MHz, CDCl3, δ): 11.13 (s, 1H), 9.97 (s, 1H), 8.02 (d,
J ) 2.5 Hz, 1H), 7.79 (d, J ) 2.5 Hz, 1H), 7.71 (d, J ) 2.5 Hz,
1H), 7.69 (d, J ) 2.5 Hz, 1H), 7.50 (d, J ) 2.5 Hz, 1H), 7.23 (d,
J ) 2.5 Hz, 1H), 7.13 (d, J ) 8.5, 1H), 1.74 (s, 6H), 1.39 (s, 9H),
1.38 (s, 9H). 13C NMR (500 MHz, CDCl3, δ): 198.0, 169.8, 160.8,
147.0, 146.4, 145.7, 145.3, 138.7, 136.0, 130.6, 130.4, 130.1, 127.5,
126.4, 125.9, 125.8, 122.2, 121.5, 120.5, 117.5, 44.9, 35.1, 34.8,
34.7, 32.2, 31.7, 31.6. HRESI-MS ([M - H]-) C31H33O5 m/z, Calcd
485.2323, found 485.2234.
2,7-Di-tert-butyl-5-(3-formyl-4-hydroxy-phenyl)-9,9-dimethyl-
9H-xanthene-4-carboxylic Acid Methyl Ester (10). 2,7-Di-tert-
butyl-5-(3-formyl-4-methoxy-phenyl)-9,9-dimethyl-9H-xanthene-4-
carboxylic acid methyl ester (6) (0.200 g, 0.389 mmol) was added
to 8 mL of dichloromethane, and the mixture was cooled to 0 °C.
A solution of boron tribromide (1.2 mL, 1.0 M in dichloromethane)
was added, and upon stirring for 1 h, 4 mL of water was added.
The organic layer was separated, washed with 10 mL of water,
and dried over MgSO4. The solvent was evaporated, and the residue
was purified by column chromatography (silica gel, 99:1 dichlo-
romethane/methanol) to elute the product (0.054 g, 28% yield). 1H
NMR (500 MHz, CDCl3, δ): 11.12 (s, 1H), 10.07 (s, 1H), 7.96 (d,
J ) 2 Hz, 1H), 7.76 (dd, J ) 8.5 Hz, 2 Hz, 1H), 7.58 (d, J ) 2.5
Hz, 1H), 7.56 (d, J ) 2 Hz, 1H), 7.45 (d, J ) 2.5 Hz, 1H), 7.25 (d,
J ) 2 Hz, 1H), 7.09 (d, J ) 8.5 Hz, 1H), 3.55 (s, 3H), 1.71 (s,
6H), 1.38 (s, 9H), 1.34 (s, 9H). 13C NMR (500 MHz, CDCl3, δ):
197.8, 167.5, 160.8, 147.3, 146.3, 145.4, 145.3, 138.9, 135.9, 131.0,
130.3, 130.2, 127.6, 126.4, 126.0, 125.8, 122.2, 120.3, 119.8, 117.2,
52.3, 35.1, 34.8, 34.7, 32.3, 31.8, 31.6. HRESI-MS ([M + H]+)
C32H37O5 m/z, Calcd 501.2636, found 501.2625.
J. Org. Chem, Vol. 71, No. 23, 2006 8711

Yang et al.
4-[2,7-Di-tert-butyl-5-(3-formyl-4-hydroxy-phenyl)-9,9-dimethyl-
9H-xanthen-4-yl]-benzoic Acid (11). 4-[2,7-Di-tert-butyl-5-(3-
formyl-4-methoxy-phenyl)-9,9-dimethyl-9H-xanthen-4-yl ]-benzoic
acid (7) (0.300 mg, 0.520 mmol) was added to 10 mL of
dichloromethane, and the mixture was cooled to 0 °C. A solution
of boron tribromide (1.6 mL, 1.0 M in dichloromethane) was added,
and upon stirring for 2 h, 6 mL of water was added. The organic
layer was separated, washed with 10 mL of water, and dried over
MgSO4. The solvent was evaporated, and the residue was purified
by column chromatography (silica gel, 98:2 dichloromethane/
methanol) to elute the product (0.181 g, 62% yield). 1H NMR (500
MHz, C4D8O, δ): 9.45 (s, 1H), 7.74 (d, J ) 8 Hz, 1H), 7.68 (d, J
) 8 Hz, 1H), 7.54 (d, J ) 2 Hz, 2H), 7.45 (m, 4H), 7.31 (d, J )
8 Hz, 1H), 7.23 (dd, J ) 10.5, 1.5 Hz, 1H), 6.73 (d, J ) 8.5 Hz,
1H), 1.36 (s, 18H). 13C NMR (500 MHz, C4D8O, δ): 196.9, 167.5,
161.7, 146.74, 146.66, 143.6, 138.6, 135.5, 133.0, 132.9, 132.5,
131.6, 131.5, 130.7, 130.6, 130.3, 130.1, 129.4, 129.3, 129.0, 126.7,
126.5, 123.3, 122.8, 121.8, 117.7, 36.1, 35.4, 32.0, 25.8, 25.6, 25.3,
25.2. HRESI-MS ([M - H]-) C37H37O5 m/z, Calcd 561.2646, found
561.2646.
9H), 1.33 (s, 9H). 13C NMR (500 MHz, CDCl3, δ): 168.2, 165.3,
160.3, 147.4, 146.0, 145.4, 145.2, 134.0, 133.2, 131.2, 130.1, 129.1,
128.6, 126.2, 126.1, 125.7, 121.4, 120.1, 118.3, 116.5, 72.9, 52.1,
35.1, 34.73, 34.70, 33.5, 32.1, 31.9, 31.7, 31.6, 24.4. HRESI-MS
([M + H]+) C70H83N2O8 m/z, Calcd 1079.6144, found 1079.6167.
H2(HphSX*-COOH) (15). 4-[2,7-Di-tert-butyl-5-(3-formyl-4-
hydroxy-phenyl)-9,9-dimethyl-9H-xanthen-4-yl]-benzoic acid (11)
(0.025 g, 0.044 mmol) was combined with (1R,2R)-(-)-1,2-
diaminocyclohexane (0.003 g, 0.022 mmol) in 5 mL of absolute
ethanol, and the mixture was refluxed for 15 h. Upon cooling, the
solvent was removed by rotary evaporation, and the resulting yellow
solid was washed with 0.5 mL of cold methanol and dried under
vacuum to yield the product as a dull yellow solid (0.026 g, 97%
yield). 1H NMR (500 MHz, CDCl3, 25 °C, δ): 7.91 (m, 4H), 7.47
(d, J ) 7 Hz, 2H), 7.68 (m, 4H), 7.55 (d, J ) 7 Hz, 2H), 7.39 (m,
4H), 7.19 (m, 2H), 7.11 (s, 2H), 7.10 (s, 2H), 3.54 (bs, 2H), 2.33
(bs, 4H), 2.05 (bs, 4H), 1.72 (s, 12H), 1.35 (s, 18H), 1.30 (s, 18H).
HRESI-MS ([M - H]-) C80H85N2O8 m/z, Calcd 1201.6311, found
1201.6329.
H2(HphSX*-COOMe) (16). 4-[2,7-Di-tert-butyl-5-(3-formyl-
4-hydroxy-phenyl)-9,9-dimethyl-9H-xanthen-4-yl]-benzoic acid meth-
yl ester (12) (0.018 g, 0.031 mmol) was combined with (1R,2R)-
(-)-1,2-diaminocyclohexane (0.002 g, 0.016 mmol) in 5 mL of
absolute ethanol, and the mixture was refluxed for 8 h. Upon
cooling, the solvent was removed by rotary evaporation, and the
resulting yellow solid was washed with 0.5 mL of cold methanol
4-[2,7-Di-tert-butyl-5-(3-formyl-4-hydroxy-phenyl)-9,9-dimethyl-
9H-xanthen-4-yl]-benzoic Acid Methyl Ester (12). 4-[2,7-Di-tert-
butyl-5-(3-formyl-4-methoxy-phenyl)-9,9-dimethyl-9H-xanthen-4-
yl ]-benzoic acid methyl ester (8) (0.100 g, 0.169 mmol) was added
to 8 mL of dichloromethane, and the mixture was cooled to 0 °C.
A solution of boron tribromide (0.51 mL, 1.0 M in dichloromethane)
was added, and upon stirring for 1 h, 4 mL of water of was added.
The organic layer was separated, washed with 10 mL of water,
and dried over MgSO4. The solvent was evaporated, and the residue
was purified by column chromatography (silica gel, dichlo-
1
and dried under vacuum (0.019 mg, 98% yield). H NMR (500
MHz, CDCl3, δ): 13.09 (bs, 2H), 8.05 (s, 2H), 7.65 (d, J ) 8 Hz,
2H), 7.61 (d, J ) 8 Hz, 2H), 7.43 (d, J ) 1.5 Hz, 2H), 7.35 (d, J
) 2 Hz, 2H), 7.20 (m, 4H), 7.13 (d, J ) 2 Hz, 2H), 7.09 (d, J )
1.5 Hz, 2H), 7.02 (m, 4H), 6.50 (d, J ) 8 Hz, 2H), 4.37 (t, J )
11.5 Hz, 2H), 3.25 (bs, 2H), 2.97 (m, 4H), 1.72 (s, 6H), 1.67 (s,
6H), 1.53 (bs, 2H), 1.34 (s, 18H), 1.38 (s, 18H). 13C NMR (500
MHz, CDCl3, δ): 167.1, 164.8, 160.3, 146.1, 145.9, 145.6, 142.9,
138.1, 135.3, 133.5, 132.8, 130.9, 130.43, 130.37, 129.6, 129.0,
128.8, 128.5, 128.1, 125.8, 125.6, 122.2, 121.2, 118.2, 116.3, 72.8,
52.1, 35.4, 34.8, 34.74, 34.68, 33.0, 32.14, 32.11, 31.7, 31.2, 29.91,
29.87, 29.6, 24.4. HRESI-MS ([M + H]+) C82H91N2O8 m/z, Calcd
1231.6770, found 1231.6799.
Mn(HSX*-COOH)Cl (17). H2(HSX*-COOH) (13) (0.100 g,
0.095 mmol) and manganese(II) acetate tetrahydrate (0.035 g, 0.143
mmol) were added to 8 mL of ethanol, and the mixture was refluxed
for 3 h in air. Upon cooling, 1 mL of an aqueous saturated sodium
chloride solution was added, and after stirring for 5 min, an
additional 10 mL of water was added. The mixture was then
extracted with 2 × 6 mL of dichloromethane. The combined organic
portions were then washed with 5 mL of water and dried over
MgSO4. The solvent was removed by rotary evaporation to yield
the brown product (0.101 g, 93% yield). HRESI-MS ([M - Cl]-)
C68H76MnN2O8 m/z, Calcd 1103.4977, found 1103.4931. Anal.
Calcd for C68H76ClMnN2O8‚2H2O: C, 69.46; H, 6.86; N, 2.38.
Found: C, 69.65; H, 6.67; N, 2.21.
Mn(HSX*-COOMe)Cl (18). H2(HSX*-COOMe) (14) (0.020
g, 0.019 mmol) and manganese(II) acetate tetrahydrate (0.007 g,
0.029 mmol) were added to 4 mL of ethanol, and the mixture was
refluxed for 2 h in air. Upon cooling, 0.5 mL of an aqueous
saturated sodium chloride solution was added, and the mixture was
extracted with 2 × 15 mL of dichloromethane. The combined
organic portions were then washed with 15 mL of water and dried
over MgSO4. The solvent was removed by rotary evaporation to
yield the brown product (0.021 g, 98% yield). HRESI-MS ([M -
Cl]-) C70H80MnN2O8 m/z, Calcd 1131.5290, found 1131.5318.
Anal. Calcd for C70H80ClMnN2O8: C, 72.00; H, 6.90; N, 2.40.
Found: C, 71.82; H, 6.72; N, 2.48.
Mn(HphSX*-COOH)Cl (19). H2(HphSX*-COOH) (15) (0.010
g, 0.008 mmol) and manganese(II) acetate tetrahydrate (0.003 g,
0.012 mmol) were added to 3 mL of ethanol, and the mixture was
refluxed for 4 h in air. Upon cooling, 0.5 mL of an aqueous
saturated sodium chloride solution was added, and the mixture was
1
romethane) to elute the product (0.076 g, 78% yield). H NMR
(500 MHz, CDCl3, δ): 10.87 (s, 1H), 9.29 (s, 1H), 7.26 (d, J )
8.5 Hz, 2H), 7.49 (d, J ) 2.5 Hz, 1H), 7.46 (m, 2H), 7.33 (m, 2H),
7.31 (s, 1H), 7.20 (d, J ) 2 Hz, 1H), 7.17 (d, J ) 2 Hz, 1H), 6.85
(d, J ) 8.5 Hz, 1H), 4.00 (s, 3H), 1.76 (s, 6H), 1.37 (s, 18H). 13C
NMR (500 MHz, CDCl3, δ): 197.0, 167.4, 161.1, 146.5, 146.4,
146.1, 146.0, 143.6, 138.6, 135.8, 130.93, 130.91, 130.4, 130.3,
129.6, 129.1, 128.9, 128.1, 126.3, 126.0, 123.2, 122.7, 120.8, 117.8,
52.8, 35.8, 35.3, 32.7, 32.3. HRESI-MS ([M + Na]+) C38H40O5Na
m/z, Calcd 599.2768, found 599.2756.
H2(HSX*-COOH) (13). 2,7-Di-tert-butyl-5-(3-formyl-4-hy-
droxy-phenyl)-9,9-dimethyl-9H-xanthene-4-carboxylic acid (9) (0.100
g, 0.206 mmol) was combined with (1R,2R)-(-)-1,2-diaminocy-
clohexane (0.012 g, 0.103 mmol) in 4 mL of absolute ethanol, and
the mixture was refluxed for 12 h. Upon cooling, the solvent was
removed by rotary evaporation, and the resulting yellow solid was
washed with 1 mL of cold methanol and dried under vacuum to
yield 0.100 g of product (92% yield). 1H NMR (500 MHz, CDCl3,
δ): 8.63 (s, 2H), 7.90 (d, J ) 2 Hz, 2H), 7.76 (d, J ) 2.5 Hz, 2H),
7.58 (d, J ) 2.5 Hz, 2H), 7.38 (m, 4H), 7.23 (d, J ) 2 Hz, 2H),
6.95 (d, J ) 8.5 Hz, 2H), 3.60 (d, J ) 9.5 Hz, 2H), 2.07 (d, J )
11.5 Hz, 2H), 1.95 (d, J ) 9.5 Hz), 1.76 (s, 6H), 1.73 (m, 2H),
1.68 (s, 2H), 1.61 (s, 6H), 1.36 (s, 18H), 1.35 (s, 18H). HRESI-
MS ([M - H]-) C68H77N2O8 m/z, Calcd 1049.5676, found
1049.5676.
H2(HSX*-COOMe) (14). 2,7-Di-tert-butyl-5-(3-formyl-4-hy-
droxy-phenyl)-9,9-dimethyl-9H-xanthene-4-carboxylic acid methyl
ester (10) (0.050 g, 0.100 mmol) was combined with (1R,2R)-(-
)-1,2-diaminocyclohexane (0.006 mg, 0.050 mmol) in 5 mL of
absolute ethanol, and the mixture was refluxed for 8 h. Upon
cooling, the solvent was removed by rotary evaporation, and the
resulting solid was washed with 1 mL of cold methanol and dried
under vacuum to yield the product as a yellow solid (0.053 g, 98%).
1H NMR (500 MHz, CDCl3, δ): 13.42 (bs, 2H), 8.46 (s, 2H), 7.55
(d, J ) 2.5 Hz, 2H), 7.52 (d, J ) 2.5 Hz, 2H), 7.56 (s, 2H), 7.45
(d, J ) 2.5 Hz, 2H), 7.38 (d, J ) 2.5 Hz, 2H), 7.16 (d, J ) 2.5 Hz,
2H), 6.96 (d, J ) 9 Hz, 2H), 3.45 (d, J ) 9 Hz, 2H), 3.32 (s, 6H),
1.99 (d, J ) 9 Hz, 2H), 1.92 (d, J ) 9 Hz, 2H), 1.78 (d, J ) 9 Hz,
2H), 1.69 (s, 6H), 1.67 (s, 6H), 1.53 (t, J ) 9 Hz, 2H), 1.43 (s,
8712 J. Org. Chem., Vol. 71, No. 23, 2006

Hangman Salen Platforms
extracted with 2 × 15 mL of dichloromethane. The combined
organic portions were then washed with 15 mL of water and dried
over MgSO4. The solvent was removed by rotary evaporation to
yield the brown product (0.010 g, 93% yield). HRESI-MS ([M -
Cl]-) C80H84MnN2O8 m/z, Calcd 1255.5603, found 1255.5605.
Anal. Calcd for C80H84ClMnN2O8: C, 74.37; H, 6.55; N, 2.17.
Found: C, 74.21; H, 6.72; N, 2.10.
Mn(HphSX*-COOMe)Cl (20). H2(HphSX*-COOMe) (16)
(0.010 g, 0.008 mmol) and manganese(II) acetate tetrahydrate (0.003
g, 0.012 mmol) were added to 3 mL of ethanol, and the mixture
was refluxed for 4 h in air. Upon cooling, 0.5 mL of an aqueous
saturated sodium chloride solution was added, and the mixture was
extracted with 2 × 15 mL of dichloromethane. The combined
organic portions were then washed with 15 mL of water and dried
over MgSO4. The solvent was removed by rotary evaporation to
yield the brown product (0.010 g, 93% yield). HRESI-MS ([M -
Cl]-) C82H88MnN2O8 m/z, Calcd 1283.5926, found 1283.5857.
Anal. Calcd for C82H88ClMnN2O8: C, 74.61; H, 6.72; N, 2.12.
Found: C, 74.53; H, 6.60; N, 2.10.
(R,R)-N,N′-Bis(5-phenylsalicylidene)-1,2-cyclohexanedia-
mine (22). 4-Hydroxy-biphenyl-3-carbaldehyde (21) (0.300 g, 1.51
mmol) was refluxed with (1R,2R)-(-)-1,2-diaminocyclohexane
(0.086 g, 0.757 mmol) in 5 mL of absolute ethanol for 12 h, and
the mixture was then cooled to 0 °C and filtered. The precipitate
was collected by vacuum filtration and washed with 2 × 5 mL of
cold ethanol and dried in vacuo to yield 0.241 g of the bright yellow
product in 67% yield. 1H NMR (500 MHz, CDCl3, δ): 13.39 (bs,
2H), 8.35 (s, 2H), 7.50 (d, J ) 2 Hz, 2H), 7.47 (m, 2H), 7.46 (s,
2H), 7.40 (s, 2H), 7.38 (m, 4H), 7.30 (s, 2H), 7.29 (s, 2H), 6.97 (d,
J ) 9 Hz, 2H), 3.38 (d, J ) 9 Hz, 2H), 1.99 (m, 2H), 1.92 (d, J )
9 Hz, 2H), 1.78 (d, J ) 9 Hz, 2H), 1.51 (t, J ) 9 Hz, 2H). 13C
NMR (500 MHz, CDCl3, δ): 165.0, 160.7, 140.4, 132.1, 131.2,
130.1, 128.9, 126.9, 126.7, 118.9, 117.5, 72.9, 33.3, 24.3. HRESI-
MS ([M + H]+) C32H31N2O2 m/z, Calcd 475.2380, found 475.2371.
Mn[(R,R)-N,N′-Bis(5-phenylsalicylidene)-1,2-cyclohexanedi-
aminato]Cl (23). (R,R)-N,N′-Bis(5-phenylsalicylidene)-1,2-cyclo-
hexanediamine (22) (0.050 g, 0.105 mmol) and manganese(II)
acetate tetrahydrate (0.039 g, 0.158 mmol) were added to 4 mL of
ethanol, and the mixture was refluxed for 4 h in air. Upon cooling,
1 mL of an aqueous saturated sodium chloride solution was added,
and the mixture was extracted with 2 × 15 mL of dichloromethane.
The combined organic portions were then washed with 15 of mL
of water and dried over MgSO4. The solvent was removed by rotary
evaporation to yield a brown product (0.050 g, 84% yield). HRESI-
MS ([M - Cl]-) C32H28MnN2O2 m/z, Calcd 527.1526, found
527.1518. Anal. Calcd for C32H28ClMnN2O2: C, 68.27; H, 5.01;
N, 4.98. Found: C, 68.20; H, 5.21.; N, 5.08.
34.5, 33.0, 32.9, 31.7, 31.5, 24.9. HRESI-MS ([M + H]+)
C25H34O5B m/z, Calcd 425.2495, found 425.2494.
5-Bromo-2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene-4-car-
boxylic Acid Benzyl Ester (25). 4-Hydroxycarbonyl-5-bromo-2,7-
di-tert-butyl-9,9-dimethylxanthene (1) (0.500 g, 1.12 mmol), 4-(di-
methylamino)pyridine (0.013 g, 0.107 mmol), and benzyl alcohol
(0.12 mL, 1.12 mmol) were added to 50 mL of dry dichloromethane,
and the solution was cooled to 0 °C in an ice water bath. To this,
1.22 mL of a 1.0 M solution of 3-dicyclohexylcarbodiimide in
dichloromethane (1.22 mmol) was added, and the reaction mixture
was stirred at 0 °C for 10 min, then warmed to room temperature.
Upon stirring for an addition 6 h at room temperature, the solution
was again cooled to 0 °C, filtered, and washed with a minimal
amount of cold dichloromethane (about 6 mL). The filtrate was
reduced by rotary evaporation; the crude product was purified by
column chromatography (silica gel, 9:1 hexane/ethyl acetate) to
elute the product as a pale yellow oil that solidified under vacuum
1
overnight (0.599 g, 99% yield). H NMR (500 MHz, CDCl3, δ):
7.71 (d, J ) 2.5 Hz, 1H), 7.54 (m, 3H), 7.45 (d, J ) 2.4 Hz, 1H),
7.38 (m, 2H), 7.33 (m, 2H), 5.50 (s, 2H), 1.65 (s, 6H), 1.34 (s,
9H), 1.33 (s, 9H). 13C NMR (500 MHz, CDCl3, δ): 167.1, 147.4,
147.3, 145.7, 145.3, 136.5, 131.1, 130.7, 128.74, 128.72, 128.68,
128.3, 126.7, 126.6, 121.7, 119.7, 110.5, 67.3, 35.4, 34.79, 34.76,
32.2, 31.6, 20.8. HRESI-MS ([M + Na]+) C31H35O3BrNa m/z, Calcd
557.16406, found 557.1641.
2,7-Di-tert-butyl-5-(3-formyl-4-hydroxy-phenyl)-9,9-dimethyl-
9H-xanthene-4-carboxylic Acid Benzyl Ester (26). Under nitro-
gen, 5-bromo-2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene-4-car-
boxylic acid benzyl ester (25) (0.500 g, 0.93 mmol), potassium
acetate (0.321 g, 3.27 mmol), bis(pinacolato)diboron (0.355 g, 1.40
mmol), and dichloro[1,1′-bis(diphenyl-phosphino)ferrocene]palla-
dium (II) dichloromethane adduct (0.068 g, 0.093 mmol) were
added to 5 mL of anhydrous dimethyl sulfoxide, and the mixture
was heated to 90 °C for 24 h. Upon cooling, 25 mL of benzene
was added, and the solution was washed with 3 × 50 mL of water
and dried with MgSO4. The solvent was removed by rotary
evaporation, and the resulting crude black oil was put under vacuum
overnight to give a crude black solid. The solid was stirred in 100
mL of hexane and filtered; this procedure was repeated three times.
The combined filtrate was rotary evaporated to reveal a semicrys-
talline colorless solid which was used without further purification.
1
(The H NMR showed this to be the desired intermediate 2,7-di-
tert-butyl-9,9-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-
2-yl)-9H-xanthene-4-carboxylic acid benzyl ester along with some
2,3-dimethyl-butane-2,3-diol impurities from hydrolysis of the bis-
(pinacolato)diboron.) Under nitrogen, this was added to 5-bromo-
salicyladehyde (0.187 g, 0.93 mmol), sodium carbonate (0.144 g,
1.39 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium-
(II) dichloromethane adduct (0.041 g, 0.056 mmol), 14 mL of 1,2-
dimethoxyethane, and 6 mL of deionized water, and the mixture
was heated to 90 °C for 48 h. Upon cooling, 50 mL of dichlo-
romethane was added, and the solution was washed with 2 × 50
mL of deionized water. The combined aqueous layers were
extracted with 20 mL of dichloromethane, and the combined organic
5-(Boronic Acid)-2,7-di-tert-butyl-9,9-dimethyl-9H-xanthene-
4-carboxylic Acid Methyl Ester (24). Under nitrogen, 4-meth-
oxycarbonyl-5-bromo-2,7-di-tert-butyl-9,9-dimethylxanthene (2)
(1.00 g, 2.18 mmol), bis(pinacolato)diboron (0.830 g, 3.27 mmol),
potassium acetate (0.747 g, 7.63 mmol), and dichloro[1,1′-bis-
(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct
(0.159 g, 0.218 mmol) were added to 10 mL of anhydrous dimethyl
sulfoxide, and the mixture was heated to 90 °C for 36 h. Upon
cooling, 60 mL of benzene was added, and the solution was washed
with 3 × 100 mL of deionized water. The organic layer was dried
over MgSO4 and reduced by rotary evaporation to obtain a black
crude product which was taken up in 200 mL of hexane and filtered;
this was repeated three times. The combined filtrates were reduced
by rotary evaporation, and the resulting solid was recrystallized in
hot isopropyl alcohol to yield the product as a white crystalline
solid upon cooling (0.398 g, 43% yield). X-ray quality crystals were
layers were dried with MgSO4. Upon solvent removal by rotary
evaporation the crude solid was purified by column chromatography
(silica gel, 8:2 hexane/ethyl acetate) to elute the desired product as
1
a colorless solid (0.100 g, 19%). H NMR (500 MHz, CDCl3, δ):
11.03 (s, 1H), 9.96 (s, 1H), 7.91 (d, J ) 2.5 Hz, 1H), 7.72 (dd, J
) 8.5 Hz, 2 Hz, 1H), 7.58 (m, 2H), 7.46 (d, J ) 2 Hz, 1H), 7.24
(m, 4H), 7.15 (m, 2H), 7.00 (2, J ) 8.5 Hz, 1H), 5.06 (s, 2H), 1.71
(s, 6H), 1.37 (s, 9H), 1.33 (s, 9H). HRESI-MS ([M + Na]+)
C38H40O5Na m/z, Calcd 599.2768, found 599.2781.
2,7-Di-tert-butyl-5-(3-formyl-4-hydroxy-phenyl)-9,9-dimethyl-
9H-xanthene-4-carboxylic Acid Methyl Ester (10) via (24). Under
nitrogen, 2,7-di-tert-butyl-5-(3-formyl-4-hydroxy-phenyl)-9,9-di-
methyl-9H-xanthene-4-carboxylic acid methyl ester (10) (0.250 g,
0.590 mmol), 5-bromosalicyladehyde (0.119 g, 0.590 mmol),
sodium carbonate (0.092 g, 0.884 mmol), dichloro[1,1′-bis(diphe-
1
grown from isopropyl alcohol. H NMR (500 MHz, CDCl3, δ):
7.56 (d, J ) 2.5 Hz, 1H), 7.51 (d, J ) 2.5 Hz, 1H), 7.48 (m, 2H),
3.95 (s, 3H), 1.62 (s, 6H), 1.41 (bs, 2H), 1.34 (s, 9H), 1.33 (s, 9H).
13C NMR (500 MHz, CDCl3, δ): 166.7, 152.6, 149.1, 145.8, 145.0,
135.5, 131.4, 128.6, 128.0, 127.4, 126.2, 125.5, 116.2, 64.3, 52.8,
J. Org. Chem, Vol. 71, No. 23, 2006 8713

Yang et al.
nylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.026
g, 0.035 mmol), 14 mL of dimethoxyethane, and 6 mL of deionized
water were heated to 90 °C for 48 h. Upon cooling, 25 mL of
dichloromethane was added, and the solution was washed with 2
× 25 mL of deionized water. The aqueous portions were extracted
with 10 mL of dichloromethane. The combined organic portions
were dried under MgSO4, and the solvent was removed by rotary
evaporation; the resulting residue was purified by column chro-
matography (silica gel, 99:1 dichloromethane/methanol) to elute
the product as a colorless solid (0.118 g, 40% yield).
2,7-Di-tert-butyl-5-(3-formyl-4-hydroxy-phenyl)-9,9-dimethyl-
9H-xanthene-4-carboxylic Acid (9) via Deprotection of (10). 2,7-
Di-tert-butyl-5-(3-formyl-4-hydroxy-phenyl)-9,9-dimethyl-9H-xan-
thene-4-carboxylic acid methyl ester (10) (0.050 g, 0.10 mmol) was
added to 8 mL of dichloromethane, and the mixture was cooled to
0 °C. A solution of boron tribromide (1.2 mL, 1.0 M in dichlo-
romethane) was added, and the reaction mixture was warmed to
room temperature and stirred for 4 h, after which 4 mL of water
was added. The organic layer was separated, washed with 10 mL
of water, and dried over MgSO4. The solvent was evaporated, and
the residue was purified by column chromatography (silica gel, 99:5
dichloromethane/methanol) to elute the product (0.014 g, 28%
yield).
2,7-Di-tert-butyl-5-(3-formyl-4-hydroxy-phenyl)-9,9-dimethyl-
9H-xanthene-4-carboxylic Acid (9) via Deprotection of (26).
Under nitrogen, 2,7-di-tert-butyl-5-(3-formyl-4-hydroxy-phenyl)-
9,9-dimethyl-9H-xanthene-4-carboxylic acid benzyl ester (26)
(0.100 g, 0.174 mmol) was added to 20 mL of ethyl acetate and
palladium (5% on activated carbon, 0.015 g), and the mixture was
placed under a hydrogen balloon overnight at room temperature.
The mixture was then filtered over Celite, the filtrate was reduced
by rotary evaporation, and the residue was purified by column
chromatography (silica gel, 95:5 dichloromethane/methanol) to elute
the desired product 26 (0.061 g, 72%) yield.
Hydrogen Peroxide Disproportionation Reactions. Dismuta-
tion reactions were performed at room temperature in a sealed
(PTFE septum) 20 mL reaction vial equipped with a magnetic
stirbar and a capillary gas delivery tube linked to an inverted
graduated buret filled with water. The reaction vial was charged
with a stock solution of the corresponding catalyst in CH2Cl2 (1.0
mL). Methanol (0.5 mL) was added, followed by H2O2 (790 µL,
8.22 mmol; 10.4 M (30%) aq solution), and the reaction mixture
was stirred vigorously. The time was set to zero immediately after
addition of H2O2. The conversion was monitored volumetrically,
and the amount of produced O2 (n) was calculated through the
perfect gas equation pV ) nRT, assuming that p ) 1 atm. As a
check on our experimental setup, MnO2 was employed to dismutate
the hydrogen peroxide completely. Calibration runs show that the
amount of oxygen collected matches the amount expected, given
the concentration of the hydrogen peroxide solution.
Epoxidation of 1,2-Dihydronaphthalene. The epoxidation
method and conditions are modified from previous epoxidation
studies using manganese salen complexes.27 A volume of 1 mL of
a 0.05 M solution of Na2HPO4 was added to 2.5 mL of commercial
bleach. The pH of this solution (∼55 M in NaOCl) was adjusted
to pH 11 by the dropwise addition of 1.0 M NaOH solution, and
the mixture was cooled to 0 °C. This was added to a precooled 0
°C solution of 1,2-dihydronaphthalene (100 mg, 0.77 mmol) and
Mn(HSX*-COOH) (17) (85 mg, 0.077 mmol, 10% catalyst
loading) in 2 mL of dichloromethane. Upon stirring for 12 h, the
layers were separated, and the aqueous layer was extracted with 2
× 6 mL of dichloromethane. The combined organic layers were
washed with 10 mL of water and 10 mL of a saturated sodium
chloride solution and dried over MgSO4. After solvent removal by
rotary evaporation the crude product was purified to by column
chromatography (silica gel, 98:2 petane/ethyl acetate) to yield the
epoxide product (0.090 g, 83% yield).
DFT Calculations. Gas-phase density functional theoretical
(DFT) calculations of Mn(HSX*-COOH) and Mn(HphSX*-
COOH) were performed using the Amsterdam Density Functional
(ADF2002.02)28,29 package on a home-built Linux cluster of 60
Intel processors running in parallel groups of 12. To simplify the
calculation, the tert-butyl and methyl groups were removed from
the xanthenes, as well as replacing the cyclohexyl backbone to
ethylenediamine. The generalized gradient approximation (GGA)
was implemented by use of Becke’s 1988 exchange functional30
and Perdew et al.’s 1991 correlation functional.31 The basis set was
of triple-ú quality for manganese, oxygen, and nitrogen, with a
double set of polarization functions for Mn and a single polarization
set for O and N, and of double-ú quality with a single polarization
set for C and H; the frozen core approximation was used for the 1s
shell of C, N, and O and for the 1s, 2s, and 2p shells of Mn. Full
geometry optimizations of the entire complexes were run at 0 K.
All computations were carried out in the quintet spin state, and the
spin restriction was lifted. The molecular geometries and the spatial
components of the resulting Kohn-Sham single-electron wave
functions were visualized and analyzed using the software Mole-
kel.32,33
Acknowledgment. We thank Professor Timothy Jamison for
the use of his chiral gas chromatograph, Chudi Ndubaku and
Ryan Moslin for instrument assistance, David R. Manke for
assistance in obtaining and solving the X-ray crystal structures,
the MIT Department of Chemistry Instrumentation Facility for
performing high-resolution mass spectroscopy, and Shih-Yuan
Liu, Steve Reece, Leng Leng Chng, and Christopher J. Chang
for fruitful discussions. This work was supported by funding
from the DOE DE-FG02-05ER15745.
Supporting Information Available: Initial synthetic scheme,
1
X-ray crystal structures and related tables, H NMR spectra of
selected compounds, selected bond distances from the DFT
calculations of the Hangman compounds, as well as general
experimental methods. This material is available free of charge via
the Internet at http://pubs.acs.org.
The amount of catalyst used to obtain the results of Figures 1
and 2 was as follows: Mn(5-phsalen)Cl (23) (1.0 mL from a
solution of 5.3 mg in 10 mL of CH2Cl2 or 0.00095 mmol) to give
an average of 1.01 mL of O2 in 1 h. Mn(5-phsalen)Cl (23) with 1
equiv of benzoic acid (1.0 mL from a solution of 2.7 mg of Mn-
(5-phsalen)Cl and 0.6 mg of benzoic acid in 5 mL of CH2Cl2 or
0.00095 mmol of each) to give 3.21 mL of O2 in 1 h. Mn(HSX*-
COOH)Cl (17) (1.0 mL from a solution of 5.6 mg in 5 mL of CH2-
Cl2 or 0.00095 mmol) to give 35.91 mL of O2 in 1 h. Mn(HSX*-
COOMe)Cl (18) (1.0 mL from a solution of 5.54 mg in 5 mL of
CH2Cl2 or 0.00095 mmol) to give 1.61 mL of O2 in 1 h. Mn(Hph-
SX*-COOH)Cl (19) (1.0 mL from a solution of 2.5 mg in 2 mL
of CH2Cl2 or 0.00095 mmol) to give 18.01 mL of O2 in 1 h. Mn(Hph-
SX*-COOMe)Cl (20) (1.0 mL from a solution of 2.5 mg in 2 mL
of CH2Cl2 or 0.00095 mmol) to give 2.01 mL of O2 in 1 h. The
standard deviations on the TON measurements over 1 h are derived
from at least three data points.
JO0613075
(27) Zheng, W.; Jacobsen, E. N. J. Org. Chem. 1991, 56, 2296-2298.
(28) te Velde, G.; Bickelhaupt, F. M.; van Gisbergen, A. J. A.; Fonseca
Guerra, C.; Baerends, E. J.; Snijders, J. G.; Ziegler, T. J. Comput. Chem.
2001, 22, 931-967.
(29) Fonseca Guerra, C.; Snijders, J. G.; te Velde, G.; Baerends, E. J.
Theor. Chem. Acc. 1998, 99, 391-403.
(30) Becke, A. D. Phys. ReV. A 1998, 38, 3098-3100.
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8714 J. Org. Chem., Vol. 71, No. 23, 2006