Synthesis of 1,8-diazaanthracenes as building blocks for internally functionalized aromatic oligoamide foldamers

Article abstract of DOI:10.1021/jo402852m

The synthesis of a variety of 9-functionalized 1,8-diazaanthracene diesters and amino acids is described. Derivatization at the 9-position relies on facile reactions performed on the 9-chloro and 9-bromomethyl precursors. This has allowed the incorporation of nucleophilic or sensitive functional groups that otherwise cannot be incorporated under standard methods for synthesizing these compounds. Additionally, the synthesis of the protected amino acids via a high-yielding monosaponification and subsequent Curtius rearrangement has been accomplished on a multigram scale. These units, together with the functionalized derivatives, should prove to be useful monomers in the synthesis of aromatic oligoamide foldamers.

Full text of DOI:10.1021/jo402852m

Article
pubs.acs.org/joc
Synthesis of 1,8-Diazaanthracenes as Building Blocks for Internally
Functionalized Aromatic Oligoamide Foldamers
Michael L. Singleton,†,‡ Nicola Castellucci,†,‡,§ Stephane Massip,∥,⊥,# Brice Kauffmann,∥,⊥,#
́
Yann Ferrand,†,‡ and Ivan Huc*,†,‡
†University of Bordeaux, CBMN (UMR 5248), Institut Europee
́
n de Chimie Biologie, 2 rue Robert Escarpit, 33600 Pessac, France
‡CNRS, CBMN (UMR 5248), 2 rue Robert Escarpit, 33600 Pessac, France
§Dipartimento di Chimica “G. Ciamician” Alma Mater Studiorum Universita
̀
di Bologna via Selmi 2, 40126 Bologna, Italy
∥University of Bordeaux, Institut Europee
́
n de Chimie Biologie (UMS 3033/US 001), 2 rue Robert Escarpit, 33600 Pessac, France
n de Chimie Biologie (UMS 3033), 2 rue Robert Escarpit, 33600 Pessac, France
#INSERM, Institut Europee
n de Chimie Biologie (US 001), 2 rue Robert Escarpit, 33600 Pessac, France
* Supporting Information
⊥CNRS, Institut Europee
́
́
S
ABSTRACT: The synthesis of a variety of 9-functionalized 1,8-diazaanthracene diesters and amino acids is described.
Derivatization at the 9-position relies on facile reactions performed on the 9-chloro and 9-bromomethyl precursors. This has
allowed the incorporation of nucleophilic or sensitive functional groups that otherwise cannot be incorporated under standard
methods for synthesizing these compounds. Additionally, the synthesis of the protected amino acids via a high-yielding
monosaponification and subsequent Curtius rearrangement has been accomplished on a multigram scale. These units, together
with the functionalized derivatives, should prove to be useful monomers in the synthesis of aromatic oligoamide foldamers.
blocks afforded to chemists has given rise to folded systems
more distinctly removed from their natural counterparts. These
include, but are not limited to, oligomers comprised of m-
phenylene ethynylenes,13,14 pyridine-pyridazines,15,16 ureas,17,18
and aromatic amides.19,20 This last group, aromatic oligoamide
foldamers, has shown particular promise in the development of
complex architectures as a result of their high predictability,
stability, and tunability.
The connection of aromatic rings via an amide linkage gives a
planar or close to planar system as a result of conjugation.
Thus, with a functionalized aromatic ring, one of two
conformations can be expected, with the preference for syn
versus anti dictated by the local attractive and repulsive
electrostatic interactions between the amide and any endo- or
exocyclic heteroatoms on the ring (Figure 1a).19,20 Extension of
these principles to subsequent monomers consequently results
INTRODUCTION
■
The past decade has seen a significant advancement in the
synthesis of molecules designed to mimic both structural and
functional aspects of biopolymers.1,2 Chemists can now readily
synthesize oligomeric or even polymeric systems that, through
the same principles that direct folding in biological molecules,
adopt complex secondary structural features including helices,
linear strands, and, more rarely, sheets.3−8 These artificial
folded molecular architectures, termed foldamers,9 are typically
comprised of small distinct units that, when connected
together, self-organize into specifically shaped macromolecules,
the properties of which are dependent on the composition of
the monomers used. In this respect, the development of new
foldamers can be said to be monomer driven. Thus, the
synthesis of novel monomer units is an important endeavor for
expanding the diversity of this class of molecules.
While the majority of synthetic foldamers make use of
aliphatic units derived from α-amino acids or the homologous
β- and γ-amino acids,10−12 the myriad of chemical building
Received: December 23, 2013
Published: February 7, 2014
© 2014 American Chemical Society
2115
dx.doi.org/10.1021/jo402852m | J. Org. Chem. 2014, 79, 2115−2122

The Journal of Organic Chemistry
Article
have been studied for both their photophysical and
pharmaceutical applications.27−30 Despite this, the variety of
such compounds is not extensive, and while units of this type
have been used in the development of helical aromatic
oligoamides,24−26,31−34 their diversity has been limited to the
two units shown in Figure 1c.
The typical synthetic route to make these molecules likely
contributes to this limited diversity (Scheme 1). The synthesis
a
Scheme 1. Typical Synthesis of 1,8-Diazaanthracenes
a
Reaction conditions: (a) dimethyl acetylenedicarboxylate, MeOH;
(b) Ph2O, Δ; (c) diisopropyl azodicarboxylate, PPh3, ROH, THF.
is accomplished via an initial Michael addition of 2 equiv of
dimethyl acetylenedicarboxylate to the appropriate 1-function-
alized 2,6-diaminobenzene.27 Thermal cyclization in refluxing
diphenyl ether at 260 °C and then alkylation of the resulting
4,5-dihydroxy-1,8-diazaanthracenes under Mitsunobu condi-
tions give the final monomers.23,26,33 Through this protocol,
variation of the 9-position substituent is limited to the range of
functional groups that can be incorporated into the starting
diaminobenzene moiety and that are capable of withstanding
the harsh conditions of the cyclization step: i.e., either high
temperature27 or strongly acidic conditions.35 In addition, this
route requires a substituent on the diaminobenzene precursor
and does not allow one to directly reach the 9-H 1,8-
diazaanthracene. Without this substituent, a 1,7-phenanthroline
is obtained instead of a 1,8-diazaanthracene.27,36
For modification of the 9-position, it would be ideal to have
monomers that could be readily modified after their initial
synthesis. The current work provides methods for easily
introducing a number of aromatic and alkyl functional groups at
the 9-position of the diazaanthracene monomers. Furthermore,
because functionalization takes place after the cyclization step,
previously unobtainable monomers, such as the 9-hydro
derivative, are now accessible.27,36
Additionally, the synthetic route affords symmetrical units
having ester functional groups both in the 2- and 7-positions.
This has until now hampered the production of multimeric
segments of 1,8-diazaanthracene units, their development being
limited to the use of less stable connections such as
anhydrides.33 In order to increase the applicability of these
units in the synthesis of aromatic oligoamides, two methods for
the desymmetrization of the monomers and formation of the
amino acids are reported here. Through these synthetic routes,
a novel class of large aromatic amino acids with a variety of side
chains has been obtained.
Figure 1. (a) Conformational exchange between syn and anti forms of
an aromatic amide. (b, c) Examples of aromatic building blocks for
aromatic oligoamides, including 1,8-diazaanthracenes (c) that have
been used for foldamer synthesis. (d) Potential ways for using 1,8-
diazaanthracenes for arranging convergent functional groups in a
helical foldamer scaffolds.
in an overall structure that is defined by the collection of local
conformational preferences. In the case of helical structures,
where these preferences bring the additional monomers around
in a full turn, steric interactions result in the strand being
twisted out of planarity and the secondary structure that begins
to form being further stabilized by aromatic π−π stacking
interactions.
Monomers for these designs (Figure 1b,c), as long as they
fulfill the structural requirements described above, can be
readily modified to tune many of the properties of the
foldamers, including solubility, curvature, and aggregative
tendencies. Specifically, by tuning the width of the monomers
in a sequence and the angle between their amino and carboxy
groups, large cavities capable of encapsulating guest molecules
can be developed. Several such systems based on aromatic
oligoamides have now been reported.21−26 However, current
limitations on these systems involve both limited cavity sizes
and limited functional group diversity on the interior surfaces.
Pyrido[3,2-g]quinolines, hereafter referred to as 1,8-diazaan-
thracenes in this paper (Figure 1c), represent an attractive
candidate for expanding both the size and the interior
complexity of such helical receptors. These units offer a long
distance (∼9 Å) and wide angle (∼120°) between connection
sites at positions 2 and 7, which can allow interior cavities of
exceptionally large size to be synthesized. Additionally, because
only the outer two aromatic rings are used for structural
stability by means of their endocyclic nitrogen atom, the central
ring, i.e. position 9, can be modified in order to potentially
provide enhanced interactions between the host and guest
molecules or even provide catalytic sites through the use of
functional groups that converge toward the interior of a helical
cavity (Figure 1d). As a class of molecules, 1,8-diazaanthracenes
RESULTS AND DISCUSSION
■
Derivatization of the 9-Position of the Diazaanthra-
cenes. As shown in Scheme 2, the starting materials for
diversification of the diazaanthracene series are the 9-methyl34
2116
dx.doi.org/10.1021/jo402852m | J. Org. Chem. 2014, 79, 2115−2122

The Journal of Organic Chemistry
Article
a
1-N3 in good yield. However, attempted reduction of the azide
to the amine did not give good conversion either by standard
reduction with Pd/C and H2 or by a Staudinger reduction using
PPh3. Instead, a Gabriel-type synthesis of the amine was used
by initially substituting 1-Br with di-tert-butylimidocarbonate to
give the bis(tert-butoxycarbonyl)-protected benzylic amine.37
Selective mono-Boc deprotection using Mg(ClO4)2 in refluxing
MeCN gave the derivative 1-NHBoc in 80% yield across the
two steps.
Scheme 2. Derivatization of Diazaanthracene Units
Cationic nitrogen centers could also be generated quite
readily. The reaction of N-methylimidazole with 1-Br gave the
imidazolium salt 1-imid in 83% yield after precipitation in
diethyl ether. In addition to the positive charge that it can
provide, this derivative could also provide carbene-based
reactivity inside of a foldamer capsule.
2-Cl could similarly be derivatized through nucleophilic
displacement of the chloride. Sulfur-based nucleophiles readily
add to the diazaanthracene. Even at room temperature, the
reaction of benzyl mercaptan with 2-Cl in the presence of
Cs2CO3 proceeds to give 2-SBn as a bright red solid in 86%
yield.
In order to obtain the 9-amino derivative 2-NH2, it was
envisaged that reaction of 2-Cl with NaN3 in DMF would give
an intermediate azide bearing diazaanthracene that could be
reduced to give the amine. However, at the temperatures
required for substitution to occur, the resulting azide
decomposed, presumably to the nitrene, and gave a mixture
of species, including the amine, in low yield (<30%) as well as
an unstable species assigned to the 9-azido complex on the
basis of a strong IR signal at 2116 cm−1 (KBr pellet), and
several unidentified species attributed to decomposition
products resulting from side reactions with the nitrene
intermediate. By combining the displacement and reductive
steps through the addition of PPh3 to the reaction mixture, as
described by Kandakar et al.,38 the yield could be greatly
increased (61%) and the amine obtained as a bright red
crystalline solid after workup.
a
Reaction conditions: (a) NBS, BPO, C6H6, 60 °C, 89%; (b) Ag2CO3,
dioxane/H2O, Δ, 80%; (c) AgOAc, dioxane, 91%; (d) AgONO2,
dioxane, 81%; (e) (1) AgOAc, dioxane, (2) MeOH, H2SO4 cat. 80%;
(f) AgONO2, dioxane, then Et3N, dioxane, Δ, 41%; (g) NaN3, 15-
crown-5, dioxane, 71%; (h) (1) KNBoc2, DMF, 50 °C, (2)
Mg(ClO4)2, MeCN, Δ, 80%; (i) methylimidazole, Δ, 83%; (j)
NaN3, PPh3, DMF, Δ, 61%; (k) NaN3, PPh3, DMF, Δ, then Boc2O,
DMAP, dioxane, Δ, 80%; (l) HSBn, Cs2CO3, toluene 86%; (m) Pd/C,
H2, K2CO3, DMF, 79%; (n) C/O2, toluene, 100 °C, 83%.
Protection of 2-NH2 by reaction with Boc2O proceeds only
at high temperatures and with the addition of DMAP. Under
these conditions, the reaction cannot be stopped at the mono-
Boc complex. Rather, even when the reaction is stopped before
completion, only starting material and the di-Boc complex 2-
NBoc2 are observed.
Most importantly for complex 2-Cl, it provides a method for
the synthesis of the 9-hydro compound 2, an ideal unit for
designing large foldamer capsules because of its lack of space-
filling functional groups. Hydrodehalogenation of 2-Cl occurs
readily in DMF with K2CO3 as a base. The use of a weaker base
such as Et3N or less polar solvent does not give the desired
hydrodehalogenation; rather, the major product is a 1,2,3,4-
tetrahydropyrido[3,2-g]quinoline species, 2-Clred (Figure 2c),
resulting from reduction of one of the pyridine rings. Even
under the ideal conditions the initial product from the
hydrodehalogenation, the 9-hydro compound 2, is further
reduced to the 9,10-dihydro compound 2-H2. Despite our best
efforts to stop the reaction before the second reduction occurs,
a mixture of both products was always obtained. Compound 2-
H2 can, however, be reoxidized back to the fully aromatic 2.
While several conditions for the reoxidation were tested,
including MnO2, DDQ, and Pd/C under N2, the best results
(compound 1) and 9-chloro (compound 2-Cl) derivatives,
both readily obtained from reaction of the corresponding
pyrido-quinolinone with isobutyl alcohol under Mitsunobu
conditions. 1 can be brominated in the benzylic position using
N-bromosuccinimide and benzoyl peroxide to give 1-Br in
good yield (89%). Subsequent substitution of the bromide by
reaction of Ag2CO3, AgOAc, or AgONO2 gave the derivatives
1-OH, 1-OAc, and 1-ONO2, respectively. Interestingly, while
both the acetate and nitrate ester groups were initially planned
as methods for getting to the alcohol, the nitrate ester proved
resistant to hydrolysis by water and attempted transester-
ification of the acetate derivative by methanol in the presence of
catalytic sulfuric acid instead resulted in the formation of the
methyl ether derivative 1-OMe. The nitrate ester, however,
appears to be a reasonable precursor for synthesis of the
aldehyde derivative 1=O, by reaction with multiple equivalents
of Et3N in refluxing dimethoxyethane.
39
Nitrogen-containing side chains are similarly incorporated.
The reaction of 5 equiv of sodium azide with 1-Br in the
presence of 15-crown-5 proceeds at room temperature to give
were obtained from activated C and O2 in refluxing toluene.
The reaction progress was monitored by 1H NMR through loss
of the triplet signals at 4.53 and 4.07 ppm and the appearance
2117
dx.doi.org/10.1021/jo402852m | J. Org. Chem. 2014, 79, 2115−2122

The Journal of Organic Chemistry
Article
a
Scheme 3. Synthesis of Protected Amino Acids 4 and 4-Me
Figure 2. Top (left) and side (right) views of ball and stick
representations of the X-ray crystal structures of (a) 2, (b) 2-H2, and
(c) the tetrahydropyrido[3,2-g]quinoline byproduct 2-Clred from failed
hydrodehalogenation attempts. Protons and included solvent mole-
cules have been removed, and in the top view, isobutoxy side chains
have been shortened for clarity.
a
Reaction conditions: (a) NaOH, THF/MeOH, 89%; (b) (1) oxalyl
chloride, CHCl3, (2) TMSN3, CHCl3, (3) tBuOH, Δ, 77%; (c) KOH,
MeOH, 60−30 °C, 90%; (d) dppa, toluene, room temperature, then
toluene, tBuOH, Δ, 62%.
of two singlets at 9.29 and 9.20 ppm consistent with the
oxidation of the central ring. The combined yield for both the
reduction and reoxidation steps is close to 66%, and compound
2 can be obtained in multigram quantities. The lack of a
functional group in the 9-position now allows other derivatives
to be synthesized through electrophilic aromatic reactions. As
one example, 2 was converted into the 9-bromo compound 2-
Br through reaction with NBS at elevated temperature.
Compounds 2, 2-H2, and the byproduct with the reduced
pyridine ring were all characterized by X-ray crystallography
(Figure 2). While the byproduct (Figure 2c) shows significant
differences from both 2 and 2-H2, the latter compounds are
very similar in structure with the central ring of 2-H2, showing
only minor distortion into a chair conformation. The change in
C−C bond lengths between the 9- or 10-position carbons and
the adjacent pyridine rings, 1.49 Å in 2-H2 to 1.40 Å in 2, is
nevertheless consistent with the different degrees of saturation
in the central ring.
isolated in a pure form by filtration. For 3-Me, the compound
was left as the sodium salt and used this way for subsequent
steps, while for 3, the product was washed with a citric acid
solution to obtain the acid. Compound 3-Me was converted
into the Boc-protected amino acid through initial reaction with
oxalyl chloride followed by acyl azide formation with
trimethylsilyl azide. The Curtius rearrangement was performed
in refluxing tert-butyl alcohol to give the Boc-protected amine
4-Me. As a side product of this reaction, a dimeric species, 4-
dimer, was observed where the nitrene that formed during the
rearrangement underwent an intermolecular C−H insertion at
the position ortho to the methyl ester in a second molecule of
diazaanthracene (Figure 3). While the formation of this side
product could be limited by further dilution of the reaction, it
was never fully eliminated under the conditions used.
Desymmetrization and Amino Acid Synthesis. As
stated earlier, for the facile synthesis of diazaanthracene
oligoamide segments, it would be ideal to develop amino acid
derivatives. This involves two important steps: the first is the
desymmetrization by monosaponification of the equivalent
diesters, and the second is the conversion of the resulting acid
into the protected amine functionality. As shown in Scheme 3,
the synthetic approach is different depending on the starting
compound.
For both 1 and 2, high yields in the monosaponification step
rely on the limited solubility of the monocarboxylate salt. With
1, it was found that a 75/25 THF/MeOH solvent mixture and
NaOH as the base gave 3-Me in the best yields, while for 2,
initial solvation in hot methanol followed by the addition of
KOH afforded 3 in 90% yield after a short reaction time at 60
°C followed by reaction overnight at 35 °C. For both
compounds the carboxylate salt precipitates out and can be
Figure 3. Ball and stick representation of the X-ray crystal structure of
the dimeric byproduct 4-dimer. Protons and included solvent
molecules have been removed and isobutoxy side chains shortened
for clarity.
2118
dx.doi.org/10.1021/jo402852m | J. Org. Chem. 2014, 79, 2115−2122

The Journal of Organic Chemistry
Article
mmol, 0.1 equiv) was added. The reaction was carefully monitored by
TLC and stopped when the intermediate product was no longer visible
(∼30 min). The reaction mixture was diluted with 100 mL of EtOAc
and washed with first water and then brine solution. The organic layer
was dried over MgSO4 and filtered, and then the solvent was removed
by rotary evaporation. The crude yellow solid was recrystallized with
Use of a similar scheme for 3 resulted in low yields as a result
of instability during the acid chloride formation. Unlike 3-Me,
which stays yellow after reaction with the oxalyl chloride, a
solution of 3 turns black and little or no product is obtained.
Similar results were obtained with thionyl chloride and 1-
chloro-N,N,2-trimethylpropenylamine. As an alternative, diphe-
nylphosphoryl azide was used, but it required first an initial
reaction in toluene overnight at room temperature, followed by
further dilution with toluene and tBuOH before heating to
reflux for several hours. This dilution step is again required to
limit the formation of byproducts that occur during the Curtius
rearrangement.
1
DCM/MeOH to give 1-NHBoc as a yellow solid (4.31 g, 81%). H
NMR (CDCl3, 300 MHz): δ 9.23 (s, 1H), 7.52 (s, 2H), 6.4 (bs, 1H),
5.79 (d, 2H, 3JHH = 5.6 Hz), 4.15 (d, 3JHH = 6.4 Hz, 4H), 4.09 (s, 6H),
3
2.37 (m, 2H), 1.42 (s, 9H), 1.20 (d, JHH = 6.6 Hz, 12H). 13C NMR
(CDCl3, 75 MHz): δ 166.4, 163.7, 156.4, 150.4, 145.6, 145.6, 121.8,
116.0, 98.9, 78.8, 75.4, 53.3, 38.2, 28.7, 28.4, 19.3. Mp: 215−218 °C.
HRMS (ESI): m/z calcd for C30H40N3O8 [M + H]+ 570.2815, found
570.2817.
Dimethyl 1,8-Diaza-4,5-diisobutoxy-9-[azidomethyl]-2,7-anthra-
cenedicarboxylate (1-N3). In a dry 50 mL round-bottomed flask 1-Br
(1.00 g, 1.9 mmol) and sodium azide (0.52 g, 9.4 mmol, 5.0 equiv)
were slurried in 15 mL of dioxane. 15-crown-5 (0.5 mL) was added,
and the reaction mixture was stirred at room temperature for 72 h.
Solvent was removed, and the crude yellow solid was redissolved in
100 mL of dichloromethane. The solution was then filtered through
Celite to remove the residual salts. Solvent was removed on a rotary
evaporator, and the crude product was recrystallized from DCM/
MeOH to give 1-N3 as a yellow solid (0.90 g, 97%). 1H NMR (CDCl3,
CONCLUSION
■
All compounds described above represent derivatives that are
difficult to obtain in good yield through the standard synthetic
routes described for the precursors 1 and 2-Cl. Additionally, the
methods for desymmetrization and conversion to the protected
amino acids have provided large, rigid aromatic units that
should serve as important building blocks in the development
of supramolecular architectures. The synthetic routes described
for these compounds offer a complementary method for
incorporating functional groups into aromatic oligoamide
foldamers for the purposes of molecular recognition or
reactivity. Studies looking at incorporating these units into
longer sequences are under way and will be reported in due
course.
300 MHz): δ 9.29 (s, 1H), 7.52 (s, 2H), 5.87 (s, 2H), 4.15 (d, 3JHH
=
6.2 Hz, 4H), 4.08 (s, 6H), 2.37 (m, 2H), 1.20 (d, 3JHH = 6.6 Hz, 12H).
13C NMR (CDCl3, 75 MHz): δ 166.4, 163.6, 151.2, 146.1, 134.3,
121.8, 117.3, 99.3, 75.5, 53.3, 45.0, 28.5, 19.3. Mp: 231−235 °C.
HRMS (ESI): m/z calcd for C25H30N5O6 [M + H]+ 496.2191, found
496.2194. X-ray structure: see the Supporting Information.
Dimethyl 1,8-Diaza-4,5-diisobutoxy-9-[(acetyloxy)methyl]-2,7-
anthracenedicarboxylate (1-OAc). In a dry 50 mL round-bottomed
flask 1-Br (1.00 g, 1.9 mmol) and silver acetate (0.47 g, 2.8 mmol, 1.5
equiv) were slurried in 30 mL of dioxane. The reaction mixture was
heated to 60 °C and stirred overnight. The solution was poured into
dichloromethane (100 mL) and then filtered through Celite to remove
the residual silver salts. Solvent was removed on a rotary evaporator,
and the crude product was recrystallized from DCM/MeOH to give 1-
OAc as a yellow solid (0.80 g, 91%). 1H NMR (CDCl3, 300 MHz): δ
EXPERIMENTAL SECTION
■
General Procedures. Unless otherwise stated, all solvents and
reagents were used without further purification. When required, dry
solvents and bases were obtained directly prior to use by either
distilling from CaH2 (CHCl3, triethylamine, and diisopropylethyl
amine) or drying over alumina (THF, toluene, and DCM). All solvent
mixtures for chromatography are reported as v/v. Compound 1 and
dimethyl 10-chloro-4,6-dioxo-1,4,6,9-tetrahydropyrido[3,2-g]-
quinoline-2,8-dicarboxylate were synthesized as previously re-
ported.27,34 1H and 13C NMR chemical shifts are reported in ppm
and are calibrated against residual 1H and 13C solvent signals of CDCl3
(δ 7.26, 77.2) and DMSO-d6 (δ 2.50, 39.4). The following notation is
3
9.36 (s, 1H), 7.54 (s, 2H), 6.68 (s, 2H), 4.18 (d, JHH = 6.4 Hz, 4H),
4.11 (s, 6H), 2.40 (m, 2H), 2.11 (s, 3H), 1.23 (d, 3JHH = 6.7 Hz, 12H).
13C NMR (CDCl3, 75 MHz): δ 171.2, 166.5, 163.5, 151.1, 146.3,
133.5, 121.6, 117.7, 99.0, 75.4, 58.0, 53.2, 28.4, 21.3, 19.3. Mp: 211−
213 °C. HRMS (ESI): m/z calcd for C27H33N2O8 [M + H]+ 513.2237,
found 513.2235. X-ray structure: see the Supporting Information.
Dimethyl 1,8-Diaza-4,5-diisobutoxy-9-(hydroxymethyl)-2,7-an-
thracenedicarboxylate (1-OH). In a dry 25 mL round-bottomed
flask 1-Br (0.60 g, 1.1 mmol) and silver carbonate (0.62 g, 2.3 mmol,
2.0 equiv) were slurried in 10 mL of a 10% H2O/dioxane solution
under an inert gas atmosphere. The reaction mixture was then stirred
for 12 h at 90 °C. DCM (30 mL) was added, and the solution was
passed through Celite to remove the precipitated silver salts. Solvent
was removed on a rotary evaporator, and the crude yellow solid was
recrystallized with DCM/MeOH to give 1-OH as a yellow solid (0.43
1
used for the H NMR spectral splitting patterns: singlet (s), broad
singlet (bs), doublet (d), triplet (t), multiplet (m). High-resolution
electrospray ionization oribitrap (ESI-orbitrap) mass spectra were
measured in the positive ion mode.
Synthesis. Dimethyl 1,8-Diaza-4,5-diisobutoxy-9-(bromometh-
yl)-2,7-anthracenedicarboxylate (1-Br). In a 100 mL round-
bottomed flask, 1 (5.00 g, 11.0 mmol), freshly recrystallized NBS
(2.15 g, 12.1 mmol, 1.1 equiv), and benzoyl peroxide (1.33 g, 5.5
mmol, 0.5 equiv) were slurried in benzene (30 mL). The mixture was
then heated to 65 °C and stirred overnight. Solvent was removed by
rotary evaporation, and the yellow residue was recrystallized from
1
g, 80%). H NMR (CDCl3, 300 MHz): δ 9.22 (s, 1H), 7.50 (s, 2H),
6.36 (t, 3JHH = 6.6 Hz, 1H), 6.15 (d, 3JHH = 6.4 Hz, 2H), 4.14 (d, 3JHH
1
DCM/MeOH to yield 1-Br as yellow crystals (5.2 g, 89%). H NMR
3
(CDCl3, 300 MHz): δ 9.27 (s, 1H), 7.51 (s, 2H), 6.16 (s, 2H), 4.14 (d,
= 6.4 Hz, 4H), 4.08 (s, 6H), 2.37 (m, 2H), 1.20 (d, JHH = 6.8 Hz,
12H). 13C NMR (CDCl3, 75 MHz): δ 166.1, 163.8, 150.0, 145.3,
137.9, 121.6, 115.9, 98.9, 75.4, 59.9, 53.4, 28.4, 19.3. Mp: 235−237 °C.
HRMS (ESI): m/z calcd for C25H31N2O7 [M + H]+ 471.2131, found
471.2126.
3JHH = 6.4 Hz, 4H), 4.10 (s, 6H), 2.36 (m, 2H), 1.19 (d, 3JHH = 6.8 Hz,
12H). 13C NMR (CDCl3, 75 MHz): δ 166.4, 163.5, 151.0, 145.1,
135.9, 121.9, 117.2, 99.4, 75.4, 53.4, 28.4, 25.3, 19.3. Mp: 253−255 °C.
HRMS (ESI): m/z calcd for C25H30BrN2O6 [M + H]+ 533.1287,
found 533.1287. X-ray structure: see the Supporting Information.
Dimethyl 1,8-Diaza-4,5-diisobutoxy-9-{[(tert-butoxycarbonyl)-
amino]methyl}-2,7-anthracenedicarboxylate (1-NHBoc). In a dry
50 mL round-bottomed flask 1-Br (5.00 g, 9.4 mmol) and potassium
di-tert-butyliminodicarbonate37,40 (2.89 g, 11.3 mmol, 1.2 equiv) were
slurried in 20 mL of anhydrous DMF under an inert gas atmosphere.
The flask was then heated to 50 °C for 12 h. Solvent was removed on
the vacuum line, and then the crude residue was dissolved in 10 mL of
MeCN. The mixture was heated to reflux, and Mg(ClO4)2 (0.21 g, 0.9
Dimethyl 1,8-Diaza-4,5-diisobutoxy-9-(nitrooxymethyl)-2,7-an-
thracenedicarboxylate (1-ONO2). In a dry 50 mL round-bottomed
flask 1-Br (0.50 g, 0.9 mmol) and silver nitrate (0.24 g, 1.4 mmol, 1.5
equiv) were slurried in 20 mL of dioxane under an inert gas
atmosphere. The reaction mixture was then stirred for 12 h at room
temperature. DCM (30 mL) was added, and the solution was passed
through Celite to remove the precipitated silver salts. Solvent was
removed on a rotary evaporator, and the crude yellow solid was
recrystallized with DCM/MeOH to give 1-ONO2 as a yellow solid
2119
dx.doi.org/10.1021/jo402852m | J. Org. Chem. 2014, 79, 2115−2122

The Journal of Organic Chemistry
Article
1
(0.39 g, 81%). H NMR (CDCl3, 300 MHz): δ 9.36 (s, 1H), 7.51 (s,
(d, 3JHH = 6.4 Hz, 4H), 4.11 (s, 6H), 2.37 (m, 2H), 1.21 (d, 3JHH = 6.8
Hz, 12H). 13C NMR (CDCl3, 75 MHz): δ 166.2, 163.8, 152.0, 144.4,
134.6, 122.5, 115.1, 99.8, 75.7, 53.7, 28.4, 19.3. Mp: 261−263 °C.
HRMS (ESI): m/z calcd for C24H27ClN2O6 [M + H]+ 475.1636,
found 475.1634. X-ray structure: see the Supporting Information.
Dimethyl 1,8-Diaza-4,5-diisobutoxy-9-amino-2,7-anthracenedi-
carboxylate (2-NH2). In a dry 25 mL round-bottomed flask 1-Cl
(0.50 g, 1.1 mmol) and triphenylphosphine (0.55 g, 2.2 mmol, 2.0
equiv) were slurried in 8.5 mL of DMF. Sodium azide (0.14 g, 2.2
mmol, 2.0 equiv) was added, and the solution was heated to 120 °C.
The reaction was then monitored by TLC (50/50 Hex/EtOAc). When
the starting material was no longer visible, 1 N HCl (1.69 mL) was
added and the reaction mixture was stirred for an additional 3 h.
Solvent was removed by azeotropic distillation with toluene on a
rotary evaporator. The crude orange-red solid was purified by
recrystallization from DCM/MeOH to give 1-NH2 as a bright red
solid (0.30 g, 63%). 1H NMR (CDCl3, 300 MHz): δ 8.19 (s, 1H), 7.44
(s, 2H), 6.68 (bs, 2H), 4.09 (d, 3JHH = 6.4 Hz, 4H), 4.06 (s, 6H), 2.36
(m, 2H), 1.18 (d, 3JHH = 6.8 Hz, 12H). 13C NMR (CDCl3, 75 MHz):
δ 166.4, 163.0, 146.1, 145.1, 133.4, 122.7, 99.8, 98.3, 75.1, 53.1, 26.5,
19.4. Mp: 200−202 °C. HRMS (ESI): m/z calcd for C24H30N3O6 [M
+ H]+ 456.2135, found 456.2134. X-ray structure: see the Supporting
Information.
3
2H), 7.07 (s, 2H), 4.15 (d, JHH = 6.4, 4H), 4.08 (s, 6H), 2.37 (m,
3
2H), 1.20 (d, JHH = 6.8 Hz, 2H). 13C NMR (CDCl3, 75 MHz): δ
166.1, 163.5, 151.6, 146.5, 128.8, 121.5, 119.0, 99.3, 75.5, 66.6, 53.3,
28.4, 19.3. Mp: 224−227 °C. HRMS (ESI): m/z calcd for C25H30N3O9
[M + H]+ 516.1982, found 516.1978. X-ray structure: see the
Supporting Information.
Dimethyl 1,8-Diaza-4,5-diisobutoxy-9-[(methyloxy)methyl]-2,7-
anthracenedicarboxylate (1-OMe). In a dry 25 mL round-bottomed
flask 1-OAc (0.10 g, 0.2 mmol) was slurried in 20 mL of MeOH.
Concentrated sulfuric acid (0.01 mL, 0.2 mmol, 1.0 equiv) was added,
and the reaction mixture was stirred at reflux for 3 h. The mixture was
then neutralized with a saturated solution of NaHCO3, and the
product was extracted with DCM. Solvent was removed on a rotary
evaporator, and the crude yellow solid was recrystallized with DCM/
1
MeOH to give 1-OMe as a yellow solid (0.08 g, 80%). H NMR
(CDCl3, 300 MHz): δ 9.29 (s, 1H), 7.50 (s, 2H), 5.97 (s, 2H), 4.14 (d,
3JHH = 6.4, 4H), 4.08 (s, 6H), 3.64 (s, 3H), 2.36 (m, 2H), 1.20 (d, 3JHH
= 6.6 Hz, 12H). 13C NMR (CDCl3, 75 MHz): δ 166.5, 163.4, 151.0,
146.5, 135.8, 121.7, 117.1, 99.0, 75.3, 64.6, 59.4, 53.2, 28.4, 19.3. Mp:
211−214 °C. HRMS (ESI): m/z calcd for C26H33N2O7 [M + H]+
485.2282, found 485.2285.
Dimethyl 1,8-Diaza-4,5-diisobutoxy-9-(formyl)-2,7-anthracene-
dicarboxylate (1=O). In a dry 50 mL round-bottomed flask 1-
ONO2 (0.40 g, 0.8 mmol) was slurried in 30 mL of dry dioxane.
Triethylamine (0.97 mL, 8.0 mmol, 10.0 equiv) was added, and the
reaction mixture was heated to 85 °C for 16 h. The reaction mixture
was poured into ice−water, and the product was extracted into DCM.
Solvent was removed on a rotary evaporator, and the crude yellow
solid was purified by column chromatography with cyclohexane/
Dimethyl 1,8-Diaza-4,5-diisobutoxy-9-[bis(tert-butoxycarbonyl)-
amino]-2,7-anthracenedicarboxylate (2-NBoc2). In a dry 25 mL
round-bottomed flask 2-NH2 (0.25 g, 0.5 mmol) was slurried in 4 mL
of dioxane. Di-tert-butyldicarbonate (1.20 g, 5.0 mmol, 10.0 equiv),
diisopropylethylamine (0.28 mL, 5.0 mmol, 10.0 equiv), and
dimethylaminopyridine (0.07 g, 0.5 mmol, 1.0 equiv) were added,
and the solution was stirred overnight at 70 °C. Solvent was removed,
and the crude yellow solid was purified by column chromatography
with cyclohexane/EtOAc (50/50). Solvent was removed on a rotary
evaporator, and the product was recrystallized from DCM/MeOH to
1
acetone to give 1=O as a light yellow solid (0.15 g, 41%). H NMR
(CDCl3, 300 MHz): δ 11.86 (s, 1H), 9.51 (s, 1H), 7.58 (s, 2H), 4.17
(d, 3JHH = 6.4, 4H), 4.09 (s, 6H), 2.38 (m, 2H), 1.21 (d, 3JHH = 6.8 Hz,
12H). 13C NMR (CDCl3, 75 MHz): δ 194.5, 166.1, 163.6, 152.9,
146.8, 129.4, 122.5, 121.7, 99.70, 75.6, 53.61, 28.4, 19.3. Mp: 252−255
°C. HRMS (ESI): m/z calcd for C25H29N2O7 [M + H]+ 469.1975,
found 469.1970.
Dimethyl 1,8-Diaza-4,5-diisobutoxy-9-[N-(N′-methylimida-
zolium)methyl]-2,7-anthracenedicarboxylate (1-imid). In a dry 50
mL round-bottomed flask 1-Br (0.50 g, 0.9 mmol) was slurried in 20
mL of methylimidazole. The reaction mixture was then stirred
overnight at 60 °C. The solution was cooled to room temperature, and
diethyl ether (100 mL) was added. The powdery yellow product was
collected by filtration and dried on the filter to give 1-imid as a yellow
solid (0.48 g, 83%). 1H NMR (CDCl3, 300 MHz): δ 9.55 (s, 1H), 9.34
(s, 1H), 7.88 (s, 1H), 7.70 (s, 1H), 7.53 (s, 2H), 6.71 (s, 2H), 4.18 (s,
6H), 4.17 (d, 3JHH = 6.8 Hz, 4H), 4.15 (s, 3H), 2.38 (m, 2H), 1.19 (d,
3JHH = 6.6 Hz, 12H). 13C NMR (CDCl3, 75 MHz): δ 165.7, 164.1,
1
give 2-Boc2 as a light yellow solid (0.29 g, 81%). H NMR (CDCl3,
300 MHz): δ 9.22 (s, 1H), 7.48 (s, 2H), 4.13 (d, 3JHH = 6.42 Hz, 4H),
3
4.01 (s, 6H), 2.32 (m, 2H), 1.34 (s, 18H), 1.19 (d, JHH = 6.8 Hz,
12H). 13C NMR (CDCl3, 75 MHz): δ 166.7, 163.3, 152.4, 151.3,
143.4, 135.8, 122.0, 116.0, 99.3, 82.1, 75.4, 52.9, 28.4, 28.0, 19.3. Mp:
207−212 °C. HRMS (ESI): m/z calcd for C34H46N3O10 [M + H]+
656.3183, found 656.3196.
Dimethyl 1,8-Diaza-4,5-diisobutoxy-9-[benzylmercapto]-2,7-an-
thracenedicarboxylate (2-SBn). In a dry 25 mL round-bottomed flask
2-Cl (1.00 g, 2.1 mmol), and Cs2CO3 (0.89 g, 2.7 mmol, 1.3 equiv)
were slurried in 5 mL of toluene. Benzyl mercaptan (0.32 mL, 2.7
mmol, 1.3 equiv) was added, and the solution was stirred at room
temperature overnight. Solvent was removed on a rotary evaporator,
and the crude orange-red solid was purified by column chromatog-
raphy with toluene/EtOAc (80/20). Solvent was removed on the
rotary evaporator, and the product was recrystallized from DCM/
151.8, 145.4, 137.4, 129.7, 124.2, 123.0, 121.7, 119.4, 99.6, 75.7, 53.8,
43.9, 37.3, 28.3, 19.2. Mp: 192−195 °C. HRMS (ESI): m/z calcd for
C29H35N4O6 [M + H]+ 535.2551, found 535.2552.
1
MeOH to give 2-SBn as a bright red solid (1.02 g, 86%). H NMR
(CDCl3, 300 MHz): δ 9.08 (s, 1H), 7.53 (dd, Jortho = 6.5, Jmeta = 1.5 Hz,
3
2H), 7.49 (s, 2H), 7.23−7.16 (m, 3H), 5.22 (s, 2H), 4.12 (d, JHH
=
C
Dimethyl 1,8-Diaza-4,5-diisobutoxy-9-chloro-2,7-anthracenedi-
carboxylate (2-Cl). In a dry 1 L round-bottomed flask, a mixture of
dimethyl 10-chloro-4,6-dioxo-1,4,6,9-tetrahydropyrido[3,2-g]-
quinoline-2,8-dicarboxylate (26.0 g, 71.8 mmol), freshly distilled 2-
methylpropanol (15.2 mL, 158.0 mmol, 2.2 equiv), and triphenyl-
phosphine (41.4 g, 158.0 mmol, 2.2 equiv) was suspended in 500 mL
of anhydrous THF (freshly distilled). The flask was then hermetically
closed and remained under protecting gas during the reaction time.
(The reagents are not soluble in THF before the addition of
diisopropyl azodicarboxylate). The reaction mixture was cooled to 0
°C in an ice bath. DIAD (31.1 mL, 158.0 mmol, 2.2 equiv) was then
added slowly to this mixture, and the resulting solution was stirred at 0
°C for 30 min and then overnight at room temperature. Solvents were
removed by a rotary evaporator, and the residue was recrystallized
from MeOH/DCM (1/1) by slow removal of the dichloromethane on
the rotary evaporator. Crystals were filtered using a fine sintered-glass
funnel and washed with cold methanol (−18 °C). The product was
dried under reduced pressure to yield 2-Cl as a yellow solid (24.1 g,
71%). 1H NMR (CDCl3, 300 MHz): δ 9.22 (s, 1H), 7.57 (s, 2H), 4.16
6.2, 4H), 4.07 (s, 6H), 2.35 (m, 2H), 1.19 (d, 3JHH = 6.8 Hz, 12H). 13
NMR (CDCl3, 75 MHz): δ 166.5, 163.7, 149.8, 147.0, 139.6, 136.8,
129.8, 128.3, 127.0, 122.1, 114.2, 99.2, 75.4, 53.3, 40.9, 28.5, 19.3. Mp:
217−219 °C. HRMS (ESI): m/z calcd for C31H35N2O6S [M + H]+
563.2216, found 563.2221. X-ray structure: see the Supporting
Information.
Dimethyl 1,8-Diaza-4,5-diisobutoxy-9,10-dihydro-2,7-anthrace-
nedicarboxylate (2-H2). In a dry 250 mL round-bottomed flask, 2-
Cl (10.0 g, 21.1 mmol), K2CO3 (20.4 g, 147.7 mmol, 7.0 equiv), and
10% Pd/C (2.2 g) were slurried in 100 mL of dry DMF. Nitrogen was
then bubbled through the solution for 15 min to remove oxygen. The
solution was then saturated with H2 by passing a stream of H2 through
the solution for 15 min. The reaction mixture was then kept under an
atmosphere of H2 (provided by a balloon) for several hours (5−6 h
was usually sufficient) while carefully being monitored by TLC (1%
MeOH in DCM). When the starting material was no longer visible,
the reaction mixture was diluted with DCM and passed through Celite.
After removal of solvent on a rotary evaporator, the crude product was
2120
dx.doi.org/10.1021/jo402852m | J. Org. Chem. 2014, 79, 2115−2122

The Journal of Organic Chemistry
Article
triturated with MeOH and collected by filtration. After drying on the
characterization, 100 mg of 3-Me was washed with a 5% citric acid
solution and then extracted into CHCl3. After it was washed with
water and brine, the solution was dried over Na2SO4. Solvent was
removed on a rotary evaporator and the residue then dried under
1
vacuum line 2-H2 was obtained as an off-white solid (7.3 g, 79%). H
NMR (CDCl3, 300 MHz): δ 7.56 (s, 2H), 4.50 (t, 3JHH = 3.0 Hz, 2H),
4.05 (t, 3JHH = 3.0 Hz, 2H), 4.01 (s, 6H), 3.94 (d, 3JHH = 6.4 Hz, 4H),
3
1
2.21 (m, 2H), 1.11 (d, JHH = 6.8 Hz, 12H). 13C NMR (CDCl3, 75
vacuum to give the carboxylic acid. H NMR (CDCl3, 300 MHz): δ
3
9.19 (s, 1H), 7.58 (s, 1H), 7.52 (s, 1H), 4.18 (d, JHH = 6.4 Hz, 2H),
MHz): δ 166.2, 163.1, 155.7, 147.9, 120.9, 106.3, 74.8, 53.1, 40.2, 28.3,
22.1, 19.1. Mp: 213−216 °C. HRMS (ESI): m/z calcd for C24H31N2O6
[M + H − H2]+ 441.2026, found 441.2024. The loss of hydrogen from
protonated 9,10-dihydroanthracenes, to give the [M − H]+ cation, is
an established phenomenon in 9,10-dihydroanthracenes.41 X-ray
structure: see the Supporting Information.
4.15 (d, 3JHH = 6.4 Hz, 2H), 4.11 (s, 3H), 3.43 (s, 3H) 2.38 (m, 2H),
3
3
1.21 (d, JHH = 6.8 Hz, 6H), 1.20 (d, JHH = 6.8 Hz, 6H). 13C NMR
(CDCl3, 75 MHz): δ 166.2, 164.9, 164.3, 163.3, 150.3, 147.9, 145.7,
143.3, 137.1, 121.6, 121.1, 114.0, 99.2, 96.4, 75.7, 75.3, 53.3, 28.5, 28.4,
19.3, 19.2, 12.7. HRMS (ESI): m/z calcd for C24H29N2O6 [M + H]+
441.2020, found 441.2018.
Dimethyl 1,8-Diaza-4,5-diisobutoxy-2,7-anthracenedicarboxy-
late (2). 2-H2 (5.0 g, 11.3 mmol) and dry carbon (2.5 g) were
slurried in 50 mL of dry toluene in a 250 mL round-bottomed flask.
The solution was placed under an O2 atmosphere and heated to 100
°C for 16 h. The reaction mixture was then diluted with 200 mL of
DCM and poured onto a pad of silica. The product was then eluted
with 2% MeOH in DCM. Solvent was removed on a rotary evaporator,
and the product was recrystallized from DCM/MeOH to give 2 as a
bright yellow solid (4.2 g, 84%). 1H NMR (CDCl3, 300 MHz): δ 9.27
Methyl 1,8-Diaza-4,5-diisobutoxy-7-[(tert-butoxycarbonyl)-
amino]-2-anthracenecarboxylate (4). In a dry 100 mL round-
bottomed flask equipped with a stir bar, 3 (3.46 g, 8.1 mmol) was
slurried in 25 mL of dry toluene under a nitrogen atmosphere. DIPEA
(2.83 mL, 16.2 mmol, 2 equiv) and DPPA (3.49 mL, 16.2 mmol, 2
equiv) were added, and the reaction mixture was stirred at room
temperature overnight. The reaction mixture was then diluted with an
additional 20 mL of dry toluene, and anhydrous tBuOH (40 mL) was
added. The flask was then transferred to a 100 °C oil bath and the
mixture stirred for 6 h. Solvent was removed on a rotary evaporator,
and the crude material was redissolved in 1/1 DCM/MeOH. After
slow evaporation of DCM on the rotary evaporator, the solid product
was collected by filtration and dried under vacuum to yield 4 as a light
3
(s, 1H), 9.18 (s, 1H), 7.51 (s, 2H), 4.15 (d, JHH = 6.4 Hz, 4H), 4.11
3
(s, 6H), 2.37 (m, 2H), 1.20 (d, JHH = 6.8 Hz, 12H). 13C NMR
(CDCl3, 75 MHz): δ 166.2, 163.3, 151.6, 147.7, 131.0, 122.0, 116.9,
99.1, 75.3, 53.5, 28.3, 19.2. Mp: 244−246 °C. HRMS (ESI): m/z calcd
for C24H29N2O6 [M + H]+ 441.2026, found 441.2022. X-ray structure:
see the Supporting Information.
1
yellow solid (2.49 g, 62%). H NMR (CDCl3, 300 MHz): δ 9.11 (s,
1H), 8.60 (s, 1H), 7.68 (s, 1H), 7.66 (s, 1H), 7.44 (s, 1H), 4.12 (d,
Dimethyl 1,8-Diaza-4,5-diisobutoxy-9-bromo-2,7-anthracenedi-
carboxylate (2-Br). In a dry 25 mL round-bottomed flask, compound
2 (0.50 g, 1.1 mmol) and freshly recrystallized NBS (0.24 g, 1.3 mmol,
1.2 equiv) were slurried in 10 mL of a 1/1 mixture of CHCl3 and
DMF. The solution was heated to 60 °C and stirred overnight. Solvent
was then removed, and the crude product was purified by column
chromatography using 10% EtOAc/90% toluene to obtain 2-Br (0.41
3JHH = 6.4 Hz, 2H), 4.11 (d, 3JHH = 6.4 Hz, 2H), 4.10 (s, 3H), 2.35 (m,
2H), 1.55 (s, 9H), 1.19 (d, 3JHH = 6.8 Hz, 6H), 1.18 (d, 3JHH = 6.8 Hz,
6H). 13C NMR (CDCl3, 75 MHz): δ 166.6, 163.6, 163.4, 154.7, 152.7,
151.0, 148.2, 147.4, 126.1, 120.8, 119.4, 116.8, 98.3, 92.4, 81.6, 75.2,
75.0, 53.5, 28.4, 19.4, 19.3. Mp: 258−263 °C. HRMS (ESI): m/z calcd
for C27H36N3O6 [M + H]+ 498.2604, found 498.2605.
1
g, 70%). H NMR (CDCl3, 300 MHz): δ 9.29 (s, 1H), 7.57 (s, 2H),
Methyl 1,8-Diaza-4,5-diisobutoxy-7-[(tert-butoxycarbonyl)-
amino]-9-methyl-2-anthracenecarboxylate (4-Me). The sodium
salt of 3-Me (10.0 g, 21.7 mmol), in a nitrogen-flushed 250 mL
round-bottomed flask equipped with a septum and stir bar, was
slurried in dry DCM (50 mL). A needle was inserted into the septum
to act as a gas vent while oxalyl chloride (12.9 mL, 151.6 mmol, 7
equiv) was added slowly to the mixture via a syringe. The reaction
mixture was stirred for 2−4 h at room temperature, after which time
the solution turned orange and appeared slightly cloudy. Solvent was
removed under vacuum, and the yellow-orange solid was further dried
on a vacuum line for 4 h. The solid was then redissolved in dry DCM
(50 mL), and trimethylsilyl azide (8.5 mL, 65.0 mmol, 3 equiv) was
added. The mixture was then stirred overnight (12 h) at room
temperature. Solvent was removed under vacuum. Anhydrous tBuOH
(50 mL) was then added via syringe and the resulting yellow slurry
refluxed for 12 h. Solvent was removed with a rotary evaporator. The
crude solid was then dissolved in DCM and filtered through Celite.
After removal of solvent, the mixture was recrystallized by slow
evaporation of DCM from a 2/1 mixture of DCM and MeOH to give
4.17 (d, 3JHH = 6.2 Hz, 2H), 4.11 (s, 6H), 2.37 (m, 2H), 1.21 (d, 3JHH
= 6.6 Hz, 12H). 13C NMR (CDCl3, 75 MHz): δ 166.2, 163.9, 152.3,
145.7, 122.9, 116.3, 99.7, 75.7, 53.7, 28.5, 27.1, 19.3. Mp: 253−259 °C.
HRMS (ESI): m/z calcd for C24H28BrN2O6 [M + H]+ 519.1131,
found 519.1132. X-ray structure: see the Supporting Information.
1,8-Diaza-4,5-diisobutoxy-7-(methoxycarbonyl)-2-anthracene-
carboxylic Acid (3). 2 (4.00 g, 9.1 mmol) was slurried in boiling
MeOH (200 mL) and heated to 65 °C with stirring until all of the
solid dissolved. To this solution was added dropwise KOH (0.76 g,
13.6 mmol, 1.5 equiv) dissolved in 20 mL of MeOH. The reaction
mixture was stirred at 65 °C until a precipitate was observed. The
reaction mixture was then cooled to 35 °C and stirred overnight. The
solid was collected by filtration and washed with cold MeOH, 5% citric
acid solution, and then water. After it was dried on the filter for 1 h,
the solid was redissolved in DCM and further dried over Na2SO4. The
solution was then filtered and solvent removed on a rotary evaporator.
After drying on the vacuum line, 3 was obtained as a yellow solid (3.50
1
g, 90%). H NMR (CDCl3, 300 MHz): δ 9.31 (s, 1H), 9.04 (s, 1H),
7.58 (s, 1H), 7.55 (s, 1H), 4.19 (d, 3JHH = 6.4 Hz, 2H), 4.17 (d, 3JHH
=
1
4-Me as a bright yellow solid (8.5 g, 77%). H NMR (CDCl3, 300
6.4 Hz, 2H), 4.13 (s, 3H), 2.39 (m, 2H), 1.21 (d, 3JHH = 6.8 Hz, 6H),
MHz): δ 9.01 (s, 1H), 7.67 (s, 1H), 7.56 (s, 1H), 7.42 (s, 1H), 4.11 (d,
3
1.20 (d, JHH = 6.8 Hz, 6H). 13C NMR (CDCl3, 75 MHz): δ 166.1,
3JHH = 6.4 Hz, 4H), 4.08 (s, 3H), 3.23 (m, 3H), 2.34 (m, 2H), 1.57 (s,
3
3
9H), 1.19 (d, JHH = 6.8 Hz, 6H), 1.18 (d, JHH = 6.4 Hz, 6H). 13C
NMR (CDCl3, 75 MHz): δ 166.7, 163.6, 163.5, 152.9, 152.6, 149.3,
146.2, 145.2, 133.6, 119.9, 119.0, 113.4, 97.7, 91.9, 81.3, 74.9, 53.2,
28.4, 19.3, 12.6. Mp: 233−235 °C. HRMS (ESI): m/z calcd for
C28H38N3O6 [M + H]+ 512.2761, found 512.2760.
165.0, 164.3, 163.6, 152.2, 150.3, 147.9, 145.5, 129.3, 122.4, 122.1,
117.8, 99.6, 97.2, 76.0, 75.6, 53.7, 28.4, 28.4, 19.3, 19.3. HRMS (ESI):
m/z calcd for C23H27N2O6 [M + H]+ 427.1864, found 427.1861.
Sodium 1,8-Diaza-4,5-diisobutoxy-7-(methoxycarbonyl)-9-meth-
yl-2-anthracenecarboxylate (3-Me). Compound 1 (10.0 g, 22.0
mmol) was placed in a 1 L round-bottomed flask and dissolved in 750
mL of THF/MeOH (75/25 v/v). NaOH (1.01 g, 25.3 mmol, 1.15
equiv) dissolved in MeOH (20 mL) was slowly added to this mixture.
The reaction mixture was then stirred at room temperature for 24 h,
during which time the product precipitated from solution. The white/
yellow solid was collected by filtration and washed with cold MeOH.
The solid was dried under vacuum to give the sodium salt of the
monocarboxylate of 1 (3-Me) as a light yellow solid (9.1 g, 89%). The
compound was used in this form for subsequent reactions. However,
because of the limited solubility of 3-Me in the carboxylate form, for
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures giving NMR spectra for all compounds and figures,
tables, and CIF files giving crystallographic data for 1-Br, 1-
ONO2, 1-OAc, 1-N3, 2-Cl, 2-H2, 2, 2-NH2, 2-SBn, and 2-Br
and the byproducts 2-Clred and 4-dimer. This material is
available free of charge via the Internet at http://pubs.acs.org.
2121
dx.doi.org/10.1021/jo402852m | J. Org. Chem. 2014, 79, 2115−2122

The Journal of Organic Chemistry
Article
(25) Bao, C.; Kauffmann, B.; Gan, Q.; Srinivas, K.; Jiang, H.; Huc, I.
Angew. Chem., Int. Ed. 2008, 47, 4153.
AUTHOR INFORMATION
Corresponding Author
*E-mail for I.H.: i.huc@iecb.u-bordeaux.fr.
■
(26) Berni, E.; Garric, J.; Lamit, C.; Kauffmann, B.; Leg
́
er, J.-M.; Huc,
I. Chem. Commun. 2008, 1968.
(27) Hall, C. M.; Wright, J. B.; Johnson, H. G.; Taylor, A. J. J. Med.
Chem. 1977, 20, 1337.
(28) Cheney, B. V.; Christoffersen, R. E. J. Med. Chem. 1983, 26, 726.
(29) Jain, R.; Caldwell, S. L.; Louie, A. S.; Hicks, R. G. Can. J. Chem.
2006, 84, 1263.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
(30) Zhang, J.; Karabunarliev, S.; Baumgarten, M. Chem. Phys. 1996,
339.
The authors declare no competing financial interest.
(31) Gan, Q.; Shang, J.; Kauffmann, B.; Wang, Y.; Bie, F.; Jiang, H.
Tetrahedron Lett. 2012, 68, 4479.
ACKNOWLEDGMENTS
■
(32) Gan, Q.; Ferrand, Y.; Bao, C.; Kauffmann, B.; Grel
H.; Huc, I. Science 2011, 331, 1172.
́
ard, A.; Jiang,
This work was supported by the European Union’s Seventh
Framework Programme through Marie Curie actions (PIIF-
GA-2010-275209 postdoctoral fellowship to M.L.S.) and
through the European Research Council (Grant Agreements
No. ERC-2012-AdG-320892), by COST action CM0803
(travel grant to N.C.) and by the Fondation Simone et Cino
Del Duca de l’Institut de France (Post-Doctoral Fellowship to
M.L.S.).
(33) Berni, E.; Dolain, C.; Kauffmann, B.; Leger, J.-M.; Zhan, C.;
Huc, I. J. Org. Chem. 2008, 73, 2687.
(34) Berni, E.; Kauffmann, B.; Bao, C.; Lefeuvre, J.; Bassani, D. M.;
Huc, I. Chem. Eur. J. 2007, 13, 8463.
(35) Zewge, D.; Chen, C.-y.; Deer, C.; Dormer, P. G.; Hughes, D. L.
J. Org. Chem. 2007, 72, 4276.
(36) On the basis of the results reported herein, the 9-hydro
derivative reported by Zhu et al. is rather an impurity that has been
mistaken for their desired product: Zhu, H.; Guan, Z.; Zhan, C. Youji
Huaxue 2010, 30, 1716.
(37) Grehn, L.; Ragnarsson, U. Synthesis 1987, 3, 275.
(38) Kandalkar, S. R.; Kaduskar, R. D.; Ramaiah, P. A.; Barawkar, D.
A.; Bhuniya, D.; Deshpande, A. M. Tetrahedron Lett. 2013, 54, 414.
(39) Hayashi, M. Chem. Rec. 2008, 8, 252.
(40) Zhou, J.; Matos, M.-C.; Murphy, P. V. Org. Lett. 2011, 13, 5716.
(41) Vala, M.; Szczepanski, J.; Oomens, J. Int. J. Mass. Spectrom. 2011,
308, 181.
REFERENCES
■
(1) Goodman, C. M.; Choi, S.; Shandler, S.; DeGrado, W. F. Nat.
Chem. Biol. 2007, 3, 252.
(2) Guichard, G.; Huc, I. Chem. Commun. 2011, 47, 5933.
(3) Montalvo, G.; Waegele, M. M.; Shandler, S.; Gai, F.; DeGrado,
W. F. J. Am. Chem. Soc. 2010, 132, 5616.
(4) Dohm, M. T.; Mowery, B. P.; Czyzewski, A. M.; Stahl, S. S.;
Gellman, S. H.; Barron, A. E. J. Am. Chem. Soc. 2010, 132, 7957.
(5) Zhao, Y.; Zhong, Z. J. Am. Chem. Soc. 2006, 127, 17894.
(6) Odriozola, I.; Kyritsakas, N.; Lehn, J.-M. Chem. Commun. 2004,
62.
(7) Jamieson, A. G.; Russell, D.; Hamilton, A. D. Chem. Commun.
2012, 48, 3709.
(8) Cheng, P.-N.; Spencer, R.; Woods, J. R.; Glabe, C. G.; Nowick, J.
S. J. Am. Chem. Soc. 2012, 134, 14179.
(9) Appella, D. H.; Christianson, L. A.; Karle, I. L.; Powell, D. R.;
Gellman, S. H. J. Am. Chem. Soc. 1996, 118, 13071.
(10) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001,
101, 3219.
(11) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. Biodivers. 2004,
1, 1111.
(12) Li, X.; Wu, Y. D.; Yang, D. Acc. Chem. Res. 2008, 41, 1428.
(13) Stone, M. T.; Heemstra, J. M.; Moore, J. S. Acc. Chem. Res. 2006,
39, 11.
(14) Leung, S. Y.-L.; Tam, A. Y.-Y.; Tao, C.-H.; Chow, H. S.; Yam, V.
W.-W. J. Am. Chem. Soc. 2012, 134, 1047.
(15) Azeroual, S.; Surprenant, J.; Lazzara, T. D.; Kocun, M.; Tao, Y.;
Cuccia, L. A.; Lehn, J.-M. Chem. Commun. 2012, 48, 2292.
(16) Cuccia, L. A.; Ruiz, E.; Lehn, J.-M.; Homo, J. C.; Schmutz, M.
Chem. Eur. J. 2002, 8, 3448.
(17) Fremaux, J.; Fischer, L.; Arbogast, T.; Kauffmann, B.; Guichard,
G. Angew. Chem., Int. Ed. 2011, 50, 11382.
(18) Mousseau, J. J.; Xing, L.; Tang, N.; Cuccia, L. A. Chem. Eur. J.
2009, 15, 10030.
(19) Zhang, D-.W.; Zhao, X.; Hou, J.-L.; Li, Z.-T. Chem. Rev. 2012,
112, 5271.
(20) Huc, I. Eur. J. Org. Chem. 2004, 17.
(21) Yamato, K.; Kline, M.; Gong, B. Chem. Commun. 2012, 48,
12142.
(22) Juwarker, H.; Suk, J.-m.; Jeong, K.-S. Chem. Soc. Rev. 2009, 38,
3316.
́
(23) Ferrand, Y.; Kendhale, A. M.; Kauffmann, B.; Grelard, A.; Marie,
C.; Blot, V.; Pipelier, M.; Dubreuil, D.; Huc, I. J. Am. Chem. Soc. 2010,
132, 7858.
(24) Bao, C.; Gan, Q.; Kauffmann, B.; Jiang, H.; Huc, I. Chem. Eur. J.
2009, 15, 11530.
2122
dx.doi.org/10.1021/jo402852m | J. Org. Chem. 2014, 79, 2115−2122