Regioselective Synthesis of Unsymmetric Tetra- and Pentasubstituted Pyrenes with a Strategy for Primary C-Alkylation at the 2-Position

Article abstract of DOI:10.1021/acs.joc.8b01491

The synthesis of 1,2,4,5- and 1,2,9,10-tetrasubstituted and 1,2,4,5,8-pentasubsutituted pyrenes has been achieved by initially functionalizing the K-region of pyrene. Bromination, acylation, and formylation reactions afford high to moderate levels of regioselectivity, which facilitate the controlled introduction of other functional groups about 4,5-dimethoxypyrene. Access to 4,5-dimethoxypyren-1-ol and 9,10-dimethoxypyren-1-ol enabled a rare, C-2 primary alkyl substitution of pyrene.

Full text of DOI:10.1021/acs.joc.8b01491

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Note
Regioselective Synthesis of Unsymmetric Tetra- and Pentasubstituted
Pyrenes with a Strategy for Primary C-Alkylation at the 2-Position
Ana M. Dmytrejchuk, Sydney N. Jackson, Rolande Meudom, John D. Gorden, and Bradley L. Merner
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01491 • Publication Date (Web): 19 Jun 2018
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The Journal of Organic Chemistry
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Regioselective Synthesis of Unsymmetric Tetra- and Pentasubstituted
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Pyrenes with a Strategy for Primary C-Alkylation at the 2-Position.
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Ana M. Dmytrejchuk, Sydney N. Jackson, Rolande Meudom, John D. Gorden, and Bradley L. Merner*
Department of Chemistry and Biochemistry, Auburn University, Auburn, AL, 36849, USA
ABSTRACT: The synthesis of 1,2,4,5, 1,2,9,10ꢀtetrasubstituted, and 1,2,4,5,8ꢀpentasubsutituted pyrenes has been achieved by
initially functionalizing the Kꢀregion of pyrene. Bromination, acylation, and formylation reactions afford high to modest levels of
regioselectivity, which facilitate the controlled introduction of other functional groups about 4,5ꢀdimethoxypyrene. Access to 4,5ꢀ
dimethoxypyrenꢀ1ꢀol and 9,10ꢀdimethoxypyrenꢀ1ꢀol enabled,
a
rare, Cꢀ2 primary alkyl substitution of pyrene.
The substitution chemistry of pyrene can be highly predictable
based on the nature of electrophilic reagents employed in an
(electrophilic) aromatic substitution (EAS) reaction; however,
controlling selectivity can be an issue.1 It is well known that
the (most) nucleophilic positions of pyrene are the 1, 3 ,6, and
8ꢀpositions and in the presence of small or nonꢀbulky electroꢀ
philes, substitution at these positions is generally afforded
(Scheme 1A).2 While selective monoꢀ and tetrasubstitution
can be achieved, selective di and trisubstitution at these posiꢀ
tions is virtually impossible. In fact, if a selectively di or triꢀ
substituted pyrene is desired it must be prepared using a multiꢀ
step synthetic sequence.3 Such indirect methods for forming
selectively functionalized pyrenes requires the conversion of
[2.2]metacyclophane derivatives into pyrene (Scheme 1B),4
partial reduction of pyrene (b ring hydrogenation) followed by
EAS of the resulting 4,5,9,10ꢀtetrahydropyrene,5 or cyclization
reactions of appropriately substituted biphenyl derivatives
(Scheme 1C).6 Substitution of the 2 or 2 and 7 positions diꢀ
rectly can be accomplished by using large or bulky electroꢀ
philic reagents.1ꢀ3 Particularly, tertꢀbutyl substitution at one of
the a rings of pyrene will block or attenuate further substituꢀ
tion at the neighboring 1 and 3 positions, allowing for selecꢀ
tive functionalization of nucleophilic carbons at the unsubstiꢀ
tuted apical ring (6, 7, and 8ꢀpositions).7 Direct borylation of
the 2 or 2 and 7 positions provides a means for subsequent Cꢀ
C bond formation that does not require quaternization of the
alkyl electrophile (Scheme 1A).8
tions after initial substitution of the Kꢀregion (Scheme 2B) is
reported. This strategy provides access to unsymmetrically
A. Electrophilic aromatic substitution (EAS) of pyrene
2
E
1
3
a
E
E
10
9
4
5
b
b
bulky
small
a
electrophiles
electrophiles
8
6
E
= Br, CHO,
E
= t-Bu, Bpin,
7
C(O)Me, NO2
Me Cl
pyrene
E
non-K-region
(1, 2, 3, 6, 7, & 8)
Me
R
susceptible to subst.;
susceptible to subst.;
difficult to control r.r.
easier to control r.r.
r.r. = regioisomer ratio
B. Unsymmetrical pyrenes with primary C-2 alkylation
R1
R1
R2
I2
DDQ
PhH
PhH, 60 °C
R1
OMe
94%
73%
multistep synthesis
R1 = Me; R2 = t-Bu
R2
R2
C. Symmetrical and unsymmetrical pyrenes via alkyne annulations
R1
R1 R1
R2
R2
R2
R2
The 4, 5, 9, and 10 positions of pyrene, known as the
Kꢀregion, are not as susceptible to EAS reactions and typically
display alkeneꢀlike reactivity.5 This dichotomy in reactivity
has enabled the synthesis of 1,4,5,8ꢀ,9 2,4,5,7ꢀ,10 and 4,5,9,10ꢀ
tetrasubstituted pyrene derivatives (Scheme 2A).11 In all of the
aforementioned cases, the pyrene nucleus was subjected to
difunctionalization reactions after the Kꢀregion was first subꢀ
stituted. Herein, a strategy for the regioselective substitution of
the pyrene nucleus that involves monofunctionalization reacꢀ
TFA
then
TfOH
X
X
PtCl2
X
X
PhMe
52%
63%
R1=R3=
R2= H
X=p-OMeC6H4
t
-Bu
R1=OMe; R3=OBn
R2=CH2NHBoc
X=H
R3
R3
R3
Scheme 1. EAS chemistry of pyrene and indirect synthesis of
symmetrical and unsymmetrical pyrenes.
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substituted pyrene derivatives and sterically hindered or unꢀ
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zyl (Bn) and 2ꢀnaphthyl (Nap) groups could be achieved,13
however, attempts to install bulky silyl groups proved to be
limiting. Alkylation with both TBDPSCl and TIPSCl was
sluggish and did not result in formation of the desired silyl
ethers. Furthermore, isolation 4,5ꢀdihydroxypyrene can be
problematic and thus using the more reactive silyl triflate deꢀ
rivatives was not an option. Indeed, formylation of benzylated
pyrene derivative 1b gave a 4:1 ratio of constitutional isomers,
in favor of 2b (entry 4, Scheme 3). Unfortunately, 1b and 1c
succumbed to dealkylation under Rieche, or Rieche and Vilsꢀ
meierꢀHaak formylation conditions, respectively (entries 3, 5,
and 6, Scheme 3).
1
2
3
4
5
6
7
8
hindered hydroxypyrene derivatives, which can be used for
direct, primary Cꢀallylation of the 2ꢀposition. The latter has
been a longstanding challenge for pyreneꢀbased chemical synꢀ
thesis. The Cꢀallyl unit provides a functional group handle
from which two identical pyrene systems can be brought toꢀ
gether by a metathesis reaction. Furthermore, a regioselectiveꢀ
ly functionalized 1,2,4,5,8ꢀpentasubstituted pyrene derivative
has been synthetized using sequential monofunctionalization
reactions.
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Scheme 2. Synthesis of tetrasubstituted pyrenes via Kꢀregion
substitution.
Selective substitution of the pyrene Kꢀregion can be
achieved using
a
known method to afford 4,5ꢀ
dimethoxypyrene.12 While several groups have used 1a or
related alkoxy pyrenes in the preparation of regioselectively
functionalized pyrene derivatives,10ꢀ12 to the best of our
knowledge, the successful incorporation of a single substituent
or functional group (directly) at the 1ꢀposition of 1a has not
been reported. Access to such a strategy would allow for
preparation of unsymmetrically substituted pyrene derivatives,
which have been limited using direct substitution methods.
One of the most useful monofunctionalization reactions of
pyrene is the Rieche formylation, and this reaction has been
employed in the synthesis of several pyreneꢀ1ꢀcarbaldehyde
derivatives.7a,b,d Based on the precedent for 4,5ꢀ
dimethoxypyrene to undergo 1,8ꢀdibromination, leaving the 3
and 6 positions untouched (Scheme 2A), we anticipated that
only 4,5ꢀdimethoxypyreneꢀ1ꢀcarbaldehyde (2a) would be afꢀ
forded upon treatment of 1a with dichloromethyl methyl ether
in the presence of TiCl4. To our surprise, a 1.5:1 ratio of 2a
and 9,10ꢀdimethoxypyreneꢀ1ꢀcarbaldehyde (3a) (effective
substitution at the 3ꢀposition, see pyrene numbering in Scheme
1A) was produced. A VilsmeierꢀHaackꢀtype formylation of
1a produced a slight increase in regioselectivity (2:1 r.r.,
2a:3a) and comparable yield of 75%. To attenuate formylaꢀ
tion at the effective 3ꢀpostiton of 1a, larger substituents were
placed at the 4 and 5 positions. The introduction of both benꢀ
Scheme 3. Synthesis of 1ꢀhydroxypyrenes 4a and 5a
Separation of the mixture of aldehydes afforded from
both formylation protocols was possible, however, tedious
chromatography was required (see Supporting Information).
As such, this mixture (R = Me) was directly subjected to a
Dakin oxidation reaction to afford an easily separable pair of
1ꢀhydroxypyrenes 4a and 5a (Scheme 4). It should be noted
1
that both 4a and 5a are soluble in CDCl3, however, the H
NMR spectrum of 4a is poorly resolved in this solvent. The
faster moving (Rf
=
0.50, 1:4 EtOAc/hexanes) 1ꢀ
1
hydroxypyrene 5a gave a wellꢀresolved H NMR spectrum in
CDCl3 (see Supporting Information). Direct access of 4a
could be achieved by following a slightly modified synthetic
protocol. Treatment of 1a with AcCl and AlCl3 in dichloroꢀ
methane at 0 °C afforded monoacylation product 6 in 87%
yield. The conversion ketone 6 to 4a was not trivial and reꢀ
quired several weeks of optimization. Standard BayerꢀVilliger
oxidation conditions using mꢀCBPA or related peroxy acids
led to either poor yields of the desired acetate ester, or the
formation of numerous unidentified byꢀproducts. Employing a
boric acidꢀmediated protocol that had been reported by Harvey
and coꢀworkers for the synthesis of 1ꢀhydroxypyrene,14 gave
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the desired acetate ester, however, complete consumption of
to be (moderately) susceptible to deallylation. Approximately
10% of 5a was produced in this reaction, along with 18% of
unreacted starting material. The free alcohols of 8 and 12
were sulfonylated to give 9 and 13 in 89% and 51% yields,
respectively. Olefin metathesis in the presence of Grubbs
firstꢀgeneration catalyst gave a 4.7:1 mixture of alkene diaꢀ
stereomers, in the case of 9, which were directly subjected to
transfer hydrogenation using the HoveydaꢀGrubbs secondꢀ
generation catalyst to afford 10 in 55% overall yield. It should
be noted that a oneꢀpot metathesis, transfer hydrogenation
sequence using only the HoveydaꢀGrubbs secondꢀgeneration
catalyst,16 was attempted, however, a much lower yield of 10
was obtained. In the case of triflate 13, a 2.7:1 mixture of
alkene diastereomers was produced when subjected to identiꢀ
cal olefin metathesis conditions. Transfer hydrogenation of
this mixture afforded 14 in 64% yield over two steps.
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3
4
5
6
7
8
the ketone was not achieved, resulting in a low overall yield of
4a. Finally, it was discovered that clean conversion of 1a to 4a
could be achieved by first oxidizing the methyl ketone to the
corresponding acetate ester, in the presence of a catalytic
amount of SeO2 and H2O2,15 followed by direct hydrolysis of
the crude material to afford 4a in 5% overall yield.
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Determination of the regiochemical outcome of the
formylation reaction that produced both 2a and 3a (Scheme 3),
1
was initially made on the basis of H NMR analysis. In parꢀ
ticular, the major constitutional isomer displayed a doublet at
9.38 ppm, which is indicative of a Kꢀregion proton flanked by
an aldehyde group at the 1ꢀposition of pyrene. The absence of
this signal from the minor regioisomer produced in this reacꢀ
tion suggested 9,10ꢀdimethoxypyrenꢀ1ꢀcarbaldehyde as its
structure. Secondly, the assumption that only 1ꢀacetylꢀ4,5ꢀ
dimethoxypyrene was afforded upon acylation of 1a with
AcCl, and matching the NMR data of the hydrolysis product
4a with that obtained from the Dakin oxidation of 2a further
supported the assignment of 2a and 4a. Nonetheless, a single
crystal suitable for Xꢀray crystallographic analysis of 10 was
obtained, allowing for the unambiguous assignment of the
substitution pattern of the tetrasubstituted pyrenes synthesized
(see Supporting Information, Figure SIꢀ2).
Access to triflated pyrenes such as 10 and 14, should
enable the synthesis of arylated derivatives via crossꢀcoupling
reactions. Arylated pyrenes are of importance in the developꢀ
ment of liquid crystalline and optoelectonic, pyreneꢀbased
materials.17 Furthermore, the bridging butyl and butenyl units
can be subjected to benzylic and alyllic oxidation reactions to
afford 1,4ꢀdiketones, which have been used in the synthesis of
macrocyclic benzenoid systems.16a,18 With this in mind, the
synthesis of a pentasubstituted pyrene 18, with both bromide
Scheme 4. Synthesis of primary alkylated, tetrasubstituted
pyrenes 10 and 14.
At this juncture, hydroxypyrenes 4a and 5a were
subjected to an identical fiveꢀstep sequence, which centered on
the installation of a primary Cꢀallyl group at the 2ꢀposition.
Upon Oꢀallylation of 4a under standard conditions, 1ꢀallyloxyꢀ
4,5ꢀdimethoxypyrene (7) was afforded in 87% yield (Scheme
4A). Heating 7 to 190 °C in N,Nꢀdiethylaniline for 6 hours
brought about a Claisen rearrangement that produced 8 in 74%
yield. Subjecting hydroxypyrene 5a to the same twoꢀstep seꢀ
quence produced 12 in comparable yield, however, 11 proved
Scheme 5. Synthesis of 1,2,4,5,8ꢀpentasubstituted pyrene 18.
and triflate crossꢀcoupling handles was pursued. Low temperature
bromination of 1a, followed by acylation of the intermediate
monobromide 15, furnished bromoketone 16 in 70% overall yield
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(Scheme 5). Subjecting 16 to the same reaction sequence as deꢀ
4,5-Dibenzyloxypyrene (1b): Sodium dithionite (0.56 g, 3.2
mmol) and tetrabutylammonium bromide (0.11 g, 0.32 mmol)
were added to a stirred solution of pyreneꢀ4,5ꢀdione (0.25 g,
1.1 mmol) in THF (10 mL) and H2O (10 mL) at room temꢀ
perature. After 15 min., a solution of NaOH (0.52 g, 13
mmol) in water (10 mL) was added to the reaction mixture
followed by benzyl bromide (0.94 g, 5.4 mmol). The resulting
mixture was stirred at room temperature for 12 h. The reacꢀ
tion was diluted with EtOAc (20 mL), the layers were separatꢀ
ed, and the aqueous phase was extracted with EtOAc (3 × 20
mL). The combined organic extracts were washed with H2O
(30 mL) and brine (30 mL), dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was puriꢀ
fied by flash chromatography (2.5 × 18 cm, 50% dichloroꢀ
methane/hexanes) to afford 1b as a light brown solid (0.064 g,
33%) and compound 21 (0.19 g, 54%): Rf = 0.21 (60% diꢀ
chloromethane/hexanes). Compound 21 (0.19 g, 0.60 mmol)
was reꢀsubjected to the alkylation conditions described above
to afford 1b (0.098 g, 39%): Rf = 0.82 (60% dichloroꢀ
scribed above, gave 1,2,4,5,8ꢀpentasubstituted pyrene 17 in 32%
overall yield. Sulfonylation of the free alcohol in 17 afforded
triflate 18 in 57% yield. The substitution pattern of 18, and the
orthogonal nature of aryl bromides and triflates in crossꢀcoupling
and functional group interconversion reactions, will be of great
use in the development of synthetic approaches to piꢀextended
macrocyclic systems, such as carbon nanobelts.
1
2
3
4
5
6
7
8
In conclusion, the regioselective synthesis of 1,2,4,5 and
1,2,9,10ꢀtetrasubstituted pyrenes has been achieved using
sequential monofunctionalization reactions of 4,5ꢀ
dimethoxypyrene. Formylation, followed by Dakin oxidaꢀ
tion, of 4,5ꢀdimethoxypyrene provides access to separable
1ꢀhydroxypyrene derivatives (1,4,5 and 1,9,10 substituted),
while acetylation, followed by BaeyerꢀVilliger oxidation to
a single 1ꢀhydroxyꢀ4,5ꢀdimethoxyprene. The 2 position of
pyrene can be subsequently Cꢀallylated a via Claisen rearꢀ
rangement, which represents a rare example of direct, priꢀ
mary alkylation at the 2ꢀposition of pyrene. A 1,2,4,5,8ꢀ
pentasubstituted pyrene derivative 18, containing both
bromide and triflate crossꢀcoupling handles has been synꢀ
thesized using sequential monofunctionalization reactions.
Finally, olefin metathesis has enabled the synthesis of a
1,4ꢀbis(1ꢀpyrenyl)butane (and butꢀ2ꢀene) derivatives 10
and 14. The conversion such compounds into 1,4ꢀ
diketones and their application piꢀextended macrocycle
synthesis is underway in our laboratory. The synthesis of
these macrocycles will be reported in due course.
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1
methane/hexanes); H NMR (600 MHz, CDCl3) δ 8.54 (d, J =
7.8 Hz, 2H), 8.18 (d, J = 7.7, Hz, 2H), 8.09 (s, 2H), 8.07 –
8.01 (m, 2H), 7.64 (d, J = 7.4 Hz, 4H), 7.47 – 7.44 (m, 4H),
7.42 – 7.38 (m, 2H), 5.43 (s, 4H); 13C{1H}NMR (151 MHz,
CDCl3) δ 144.3, 137.6, 131.1, 128.7, 128.52, 128.50, 128.3,
127.4, 126.1, 124.7, 123.0, 119.7, 75.6; HRMS (ESI) calculatꢀ
ed for C30H23O2 ([M+H]+) m/z = 415.1698, found 415.1701.
4,5-Bis(2-naphthyloxy)pyrene (1c): Sodium dithionite (0.34 g,
1.9 mmol) and tetrabutylammonium bromide (0.065 g, 0.19
mmol) were added to a stirred solution of pyreneꢀ4,5ꢀdione
(0.14 g, 0.59 mmol) in THF (7 mL) and H2O (7 mL) at room
temperature. After 15 min., a solution of KOH (0.27 g, 4.8
mmol) in water (10 mL) was added to the reaction mixture,
followed by 2ꢀ(bromomethyl)naphthalene (0.69 g, 3.1 mmol).
The resulting mixture was stirred at room temperature for 12
h. The reaction was diluted with EtOAc (20 mL), the layers
were separated, and the aqueous phase was extracted with
EtOAc (3 × 20 mL). The combined organic extracts were
washed with H2O (30 mL) and brine (30 mL), dried over
MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by flash chromatography (2.5 × 18
cm, 70% dichloromethane/hexanes) to afford 1c as a white
solid (0.050 g, 17%) and compound 22 (0.020 g, 9%): Rf =
0.28 (60% dichloromethane/hexanes). Compound 22 (0.020
g, 0.053 mmol) was reꢀsubjected to the alkylation conditions
described above to afford 1c (0.010 g, 36%): Rf = 0.80 (60%
dichloromethane/hexanes); 1H NMR (600 MHz, CDCl3) δ
8.65 (d, J = 7.8 Hz, 2H), 8.20 (d, J = 7.6 Hz, 2H), 8.11 (s, 2H),
8.10 – 8.05 (m, 4H), 7.94 – 7.90 (m, 4H), 7.81 (d, J = 7.8 Hz,
2H), 7.78 (d, J = 8.3 Hz, 2H), 7.57 – 7.51 (m, 4H), 5.61 (s,
4H); 13C{1H}NMR (151 MHz, CDCl3) δ 144.5, 135.1, 133.4,
133.2, 131.2, 128.6, 128.4, 128.2, 127.8, 127.5, 127.3, 126.30,
126.25, 126.20, 124.7, 123.1, 119.7, 75.9 (only 18 of 19 carꢀ
bons observed); HRMS (ESI) calculated for C38H27O2
([M+H]+) m/z = 515.2011, found 515.2015.
EXPERIMENTAL SECTION
General experimental conditions: All reactions were run in
flame or ovenꢀdried (120 °C) glassware and cooled under a
positive pressure of ultra high pure nitrogen or argon gas. All
chemicals were used as received from commercial sources,
unless otherwise stated. Anhydrous reaction solvents were
purified and dried by passing HPLC grade solvents through
activated columns of alumina (Glass Contour SDS). All solꢀ
vents used for chromatographic separations were HPLC grade
(hexanes, ethyl acetate and dichloromethane). Chromatoꢀ
graphic separations were preformed using flash chromatogꢀ
raphy, as originally reported by Still and coꢀworkers, on silica
gel 60 (particle size 43ꢀ60 ꢁm), and all chromatography condiꢀ
tions have been reported as diameter × height in centimeters.
Reaction progress was monitored by thin layer chromatogꢀ
raphy (TLC), on glassꢀbacked silica gel plates (pH = 7.0).
TLC plates were visualized using a handheld UV lamp (254
nm or 365 nm) and stained using an aqueous ceric ammonium
molybdate (CAM) solution. Plates were dipped, wiped clean,
and heated from the back. 1H and 13C nuclear magnetic resoꢀ
nance (NMR) spectra were recorded at 400 or 600 MHz, caliꢀ
brated using residual undeuterated solvent as an internal referꢀ
ence (CHCl3, δ 7.27 and 77.2 ppm), reported in parts per milꢀ
lion relative to trimethylsilane (TMS, δ 0.00 ppm), and preꢀ
sented as follows: chemical shift (δ, ppm), multiplicity (s =
singlet, d = doublet, dd = doublet of doublets, ddt = doublet of
doublet of triplets, bs = broad singlet, m = multiplet), coupling
constants (J, Hz), and integration. Highꢀresolution mass specꢀ
trometric (HRMS) data were obtained using a quadrupole
timeꢀofꢀflight (QꢀTOF) spectrometer and electrospray ionizaꢀ
tion (ESI).
4,5-Dimethoxypyrene-1-carbaldehyde
(2a)
and
9,10-
dimethoxypyrene-1-carbaldehyde (3a): POCl3 (9.8 g, 64
mmol) was added dropwise to a stirred 0 °C solution of Nꢀ
methylformanilide (4.3 g, 32 mmol) in 1,2ꢀdichlorobenzene
(15 mL). After 10 min., the cooling bath was removed and a
solution of 4,5ꢀdimethoxypyrene (2.66 g, 10.1 mmol) in 1,2ꢀ
dichlorobenzene (10 mL) was added. The reaction was then
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heated at 90 °C. After 48 h, the reaction mixture was poured
Rf = 0.20 (20% EtOAc/hexanes); 1H NMR (400 MHz,
CD3OD) δ 8.35 (d, J = 9.1 Hz, 1H), 8.29 – 8.23 (m, 2H), 7.98
(dd, J = 7.8, 1.2 Hz, 1H), 7.94 – 7.87 (m, 2H), 7.51 (d, J = 8.5
Hz, 1H), 4.14 (s, 3H), 4.09 (s, 3H); 13C{1H}NMR (101 MHz,
CD3OD) δ 151.7, 145.0, 142.0, 131.8, 128.8, 125.7, 125.1,
124.2, 123.01, 122.91, 121.04, 120.70, 119.92, 118.80,
117.78, 112.4, 60.1, 59.9; HRMS (ESI) calculated for
C18H15O3 ([M+H]+) m/z = 279.1021, found 279.1009.
1
2
3
4
5
6
7
8
into ice, neutralized with 1 M NaOH, and diluted with EtOAc
(60 mL). The layers were separated, and the aqueous phase
was extracted with EtOAc (2 × 60 mL). The combined organꢀ
ic extracts were washed with brine (80 mL), dried over
MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by flash chromatography (5 cm × 15
cm; 80% dichloromethane/hexanes) to afford a mixture of 2a
and 3a (2:1 r.r) as a yellow solid (2.2 g, 75%): Rf = 0.31 (80%
dichloromethane/hexanes); a small portion of 2a was isolated
9,10-Dimethoxypyren-1-ol (5a): isolated as a yellow solid
1
1
9
from a single chromatography fraction and characterized: H
(0.058 g, 29%): Rf = 0.50 (20% EtOAc/hexanes); H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (600 MHz, CDCl3) δ 10.74 (s, 1H), 9.41 (d, J = 9.2 Hz,
1H), 8.60 (dd, J = 7.8, 1.1 Hz, 1H), 8.56 (d, J = 8.1 Hz, 1H),
8.45 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 9.2 Hz, 1H), 8.25 (dd, J =
7.6, 1.1 Hz, 1H), 8.11 – 8.07 (m, 1H), 4.26 (s, 3H), 4.18 (s,
3H); 13C{1H}NMR (151 MHz, CDCl3) δ 193.4, 147.8, 144.3,
133.4, 132.1, 131.2, 131.0, 130.6, 128.3, 127.1, 126.9, 126.6,
123.2, 122.9, 122.5, 121.7, 118.9, 61.6, 61.4; HRMS (ESI)
calculated for the mixture of constitutional isomers C19H15O3
([M+H]+) m/z = 291.1021, found 291.1057.
(400 MHz, CDCl3) δ 10.01 (s, 1H), 8.30 (dd, J = 7.7, 1.2 Hz,
1H), 8.07 – 8.00 (m, 2H), 7.99 – 7.93 (m, 1H), 7.91 (d, J = 8.9
Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H),
4.29 (s, 3H), 4.14 (s, 3H); 13C{1H}NMR (101 MHz, CDCl3) δ
153.2, 145.6, 143.9, 132.2, 128.7, 127.7, 126.9, 126.5, 124.7,
124.6, 124.5, 124.3, 124.0, 117.7, 115.3, 112.7, 62.1, 61.1;
HRMS (ESI) calculated for C18H15O3 ([M+H]+) m/z =
279.1021, found 279.1021.
1-(4,5-Dimethoxypyren-1-yl)ethanone (6): Acetyl chloride
(0.065 g, 0.84 mmol) was added to a stirred 0 °C solution of
AlCl3 (0.25 g, 1.7 mmol) and 4,5ꢀdimethoxypyrene (0.20 g,
0.76 mmol) in dichloromethane (8 mL). After 15 min., the
reaction mixture was poured into ice water (10 mL), the layers
were separated, and the aqueous phase was extracted with
dichloromethane (3 × 10 mL). The combined organic extracts
were washed with a saturated solution of NaHCO3 (20 mL)
and brine (20 mL), dried over MgSO4, filtered and concentratꢀ
ed under reduced pressure. The residue was purified by flash
chromatography (2.5 × 15 cm, dichloromethane) to afford 6 as
a bright yellow solid (0.20 g, 87%): Rf = 0.12 (80% dichloroꢀ
4,5-Dibenzyloxypyrene-1-carbaldehyde (2b) and 9,10-
dibenzyloxypyrene-1-carbaldehyde (3b): POCl3 (0.022 g, 0.14
mmol) was added dropwise to a stirred 0 °C solution of Nꢀ
methylformanilide (0.009 g, 0.07 mmol) in 1,2ꢀ
dichlorobenzene (0.6 mL). After 10 min., the cooling bath
was removed and the temperature was increased to 80 °C.
After 15 min., a solution of 1b (0.010 g, 0.024 mmol) in 1,2ꢀ
dichlorobenzene (0.3 mL) was added and the reaction was
heated at 80 °C for 24 h. The reaction mixture was cooled to
room temperature, diluted with dichloromethane (10 mL), then
poured into ice water (10 mL), and the layers were separated.
The aqueous phase was extracted with dichloromethane (3 × 5
mL). The combined organic extracts were washed with brine
(25 mL), dried over MgSO4, filtered and concentrated under
reduced pressure. The residue was purified by flash chromaꢀ
tography (1.3 × 18 cm; 60% dichloromethane/hexanes) to
afford an inseparable mixture of constitutional isomers 2b and
3b (3.8:1 r.r) as a yellow solid (0.0084 g, 84%): Rf = 0.36
1
methane/hexane); H NMR (600 MHz, CDCl3) δ 9.09 (d, J =
9.3 Hz, 1H), 8.58 (d, J = 7.8 Hz, 1H), 8.49 (d, J = 8.3 Hz, 1H),
8.43 (d, J = 8.3 Hz, 1H), 8.25 – 8.18 (m, 2H), 8.11 – 8.06 (m,
1H), 4.26 (s, 3H), 4.21 (s, 3H), 2.92 (s, 3H); 13C{1H}NMR
(151 MHz, CDCl3) δ 202.3, 146.7, 144.2, 131.8, 131.5, 130.6,
129.9, 129.7, 128.4, 127.7, 126.7, 125.8, 125.1, 123.3, 122.7,
120.9, 118.3, 61.5, 61.4, 30.7; HRMS (ESI) calculated for 6
C20H17O3 ([M+H]+) m/z = 305.1178, found 305.1190.
1
(60% dichloromethane/hexanes); H NMR (600 MHz, CDCl3)
δ 11.51 (s, 1H), 10.77 (s, 3H), 9.47 (d, J = 9.2 Hz, 4H), 8.66
(d, J = 7.8 Hz, 4H), 8.63 – 8.61 (m, 5H), 8.52 (d, J = 8.1 Hz,
1H), 8.46 (d, J = 8.1 Hz, 4H), 8.34 (d, J = 9.2 Hz, 4H), 8.30
(d, J = 7.6 Hz, 4H), 8.27 (d, J = 7.6 Hz, 1H), 8.23 – 8.18 (m,
3H), 8.13 – 8.08 (m, 7H), 7.63 – 7.60 (m, 18H), 7.50 – 7.48
(m, 3H), 7.47 – 7.43 (m, 19H), 7.42 – 7.38 (m, 10H), 5.53 (s,
2H), 5.49 (s, 7H), 5.41 (s, 7H), 5.29 (s, 2H); HRMS (ESI)
calculated for the mixture of constitutional isomers C31H23O3
([M+H]+) m/z = 443.1647, found 443.1642.
Alternative synthesis of 4,5-dimethoxypyren-1-ol (4a): SeO2
(0.001 g, 0.001 mmol) and a 30% solution (w/w) of hydrogen
peroxide in water (0.13 mL, 1.1 mmol) were added to a stirred
50 °C solution of 6 (0.086 g, 0.28 mmol) in tꢀBuOH (3 mL).
After 4 h, the reaction mixture was cooled to room temperaꢀ
ture, poured into water (30 mL) and further diluted with diꢀ
chloromethane (15 mL). The layers were separated, and the
aqueous phase was extracted with dichloromethane (3 × 15
mL). The combined organic extracts were washed with water
(50 mL) and brine (50 mL), dried over MgSO4, filtered and
concentrated under reduced pressure to afford 23 as a light
4,5-Dimethoxypyren-1-ol (4a):
Concentrated H2S2O4 (5
drops) and a 35% solution (w/w) of hydrogen peroxide in waꢀ
ter (5 drops) were added to a stirred solution of 2a and 3a (2:1
r.r, 0.212 g, 0.731 mmol) in 1:1 methanol/dichloromethane (8
mL) at room temperature. After 4 h, the reaction mixture was
poured into water (50 mL), the layers were separated, and the
aqueous phase was extracted with dichloromethane (3 × 35
mL). The combined organic extracts were sequentially
washed with water (2 × 30 mL), a saturated solution of Naꢀ
HCO3 (60 mL) and brine (60 mL), dried over MgSO4, filtered
and concentrated under reduced pressure. The residue was
purified by flash chromatography (2.5 × 18 cm; 10%
EtOAc/hexanes) to afford 4a as a brown solid (0.11 g, 52%):
1
brown solid: Rf = 0.45 (dichloromethane); H NMR (400
MHz, CDCl3) δ 8.63 – 8.39 (m, 2H), 8.16 (d, J = 7.7, 1H),
8.13 – 8.07 (m, 2H), 8.05 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 8.5
Hz, 1H), 4.23 (s, 3H), 4.22 (s, 3H) 2.58 (s, 3H); 13C{1H}NMR
(101 MHz, CDCl3) δ 170.0, 144.7, 144.6, 144.1, 130.9, 128.6,
128.1, 126.7, 126.5, 124.8, 123.8, 123.1, 122.7, 120.1, 119.91,
119.86, 119.6, 61.2, 21.2; HRMS (ESI) calculated for
C20H17O4 ([M+H]+) m/z = 321.1127, found 321.1111. Potassiꢀ
um carbonate (0.64 g, 4.6 mmol) was added to a stirred soluꢀ
tion of 23 in MeOH (20 mL) at room temperature. After 30
min., the reaction mixture was poured into ice water (10 mL)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
and neutralized with 1 M HCl (10 mL), the layers were sepaꢀ
Page 6 of 9
6.6 Hz, 1H), 5.33 – 5.26 (m, 2H), 4.23 – 4.21 (m, 6H), 4.00 (d,
2H); 13C{1H}NMR (151 MHz, CDCl3) δ 145.8, 144.1, 140.1,
135.5, 131.4, 130.5, 129.7, 128.55, 128.52, 126.9, 125.7,
124.7, 122.9, 122.2, 121.3, 120.9, 120.1, 119.0 (JCꢀF = 318
Hz), 117.8, 61.41, 61.39, 35.4; HRMS (ESI) calculated for
C22H16O5F3S ([MꢀH]−) m/z = 449.0676, found 449.0667.
1
2
3
4
5
6
7
8
rated and the aqueous phase was extracted with dichloroꢀ
methane (3 × 10 mL). The combined organic extracts were
washed with a saturated solution of NaHCO3 (20 mL), dried
over MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by flash chromatography (1.3 cm ×
15 cm, dichloromethane) to afford 4a as a light yellow solid
(0.042 g, 54% overall).
1,4-Bis(1-(trifluorometanesulfonyl)oxy-4,5-dimethoxypyren-2-
yl)butane (10): HoveydaꢀGrubbs secondꢀgeneration catalyst
(0.010 g, 0.016 mmol) and NaBH4 (0.025 g, 0.66 mmol) were
added to stirred solution of 19 (0.110 g, 0.126 mmol) in 1:9
methanol/dichloromethane (14 mL). After 2 h, the reaction
mixture was poured into water (30 mL) and further diluted
with 1 M HCl (15 mL). The resulting mixture was extracted
with dichloromethane (3 × 10 mL), and the combined organic
extracts were washed with brine (20 mL), dried over MgSO4,
filtered and concentrated under reduced pressure. The residue
was purified by flash chromatography (1.3 × 15 cm; 40% diꢀ
chloromethane/hexanes) to afford 10 as an offꢀwhite solid
(0.070 g, 70% BORSM, 0.010 g of 19): Rf = 0.21 (40% diꢀ
1-Allyloxy-4,5-dimethoxypyrene (7): K2CO3 (0.126 g, 0.912
mmol) and allyl bromide (0.11 g, 0.91 mmol) were added to a
stirred solution of 4a (0.168 g, 0.603 mmol) in DMF (13 mL)
at room temperature. After 2 h, the reaction mixture was
poured into water (100 mL) and further diluted with 1 M HCl
(50 mL). The resulting mixture was extracted with EtOAc (5
× 20 mL), the combined organic extracts were washed with 1
M HCl (3 × 30 mL) and a saturated solution of NaHCO3 (50
mL), dried over MgSO4, filtered and concentrated under reꢀ
duced pressure. The residue was purified by flash chromatogꢀ
raphy (2.5 cm × 15 cm; 50% dichloromethane/hexanes) to
afford 7 as a yellow solid (0.15 g, 87%): Rf = 0.39 (50% diꢀ
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
chloromethane/hexanes); H NMR (600 MHz, CDCl3) δ 8.55
1
chloromethane/hexanes ); H NMR (600 MHz, CDCl3) δ 8.53
(d, J = 7.9, 1.1 Hz, 2H), 8.40 (s, 2H), 8.26 (d, J = 9.2 Hz, 2H),
8.23 – 8.17 (m, 4H), 8.13 – 8.07 (m, 2H), 4.22 (s, 6H), 4.19 (s,
6H), 3.32 (t, 4H), 2.12 – 2.02 (m, 4H); 13C{1H}NMR (151
MHz, CDCl3) δ 148.1, 142.9, 140.1, 133.6, 130.7, 130.6,
128.6, 127.8, 126.6, 126.4, 126.0, 125.7, 123.0, 122.2, 121.2,
120.3, 117.9 (JCꢀF = 318 Hz), 61.7, 60.8, 30.5, 30.2; HRMS
(ESI) calculated for C42H33O10F6S2 ([M+H]+) m/z = 875.1419,
found 875.1459.
(d, J = 9.1 Hz, 1H), 8.46 – 8.39 (m, 2H), 8.11 (d, J = 7.6 Hz,
1H), 8.08 – 8.00 (m, 2H), 7.55 (d, J = 8.6 Hz, 1H), 6.27 (ddt, J
= 17.3, 10.4, 5.1 Hz, 1H), 5.62 (dd, J = 17.3, 1.6 Hz, 1H), 5.42
(dd, J = 10.6, 1.5 Hz, 1H), 4.94 – 4.85 (m, 2H), 4.26 (s, 3H),
4.22 (s, 3H); 13C{1H}NMR (151 MHz, CDCl3) δ 152.6, 145.1,
143.0, 133.5, 131.8, 129.2, 126.5, 126.4, 124.3, 123.9, 123.2,
122.3, 121.4, 120.8, 120.1, 118.9, 117.8, 109.7, 69.9, 61.3,
61.2; HRMS (ESI) calculated for C21H19O3 ([M+H]+) m/z =
319.1334, found 319.1348.
1-Allyloxy-9,10-dimethoxypyrene (11): K2CO3 (0.091 g, 0.66
mmol) and allyl bromide (0.08 g, 0.7 mmol) were added to a
stirred solution of 5a (0.061 g, 0.22 mmol) in DMF (7 mL) at
room temperature. After 20 h, the reaction mixture was
poured into water (20 mL) and further diluted with 1 M HCl
(25 mL). The resulting mixture was extracted with diethyl
ether (3 × 15 mL), the combined organic extracts were washed
with brine (40 mL), dried over MgSO4, filtered and concenꢀ
trated under reduced pressure. The residue was purified by
4,5-Dimethoxy-2-(2-propen-1-yl)pyren-1-ol (8): Compound 7
(0.105 g, 0.331 mmol) was dissolved in N,Nꢀdiethylaniline
(0.2 mL) and heated to 190 °C. After 12 h, the solvent was
evaporated under a gentle stream of nitrogen and the residue
was purified by flash chromatography (1.3 × 15 cm; 10%
EtOAc/hexanes) to afford 8 as an offꢀwhite solid (0.078 g,
1
74%): Rf = 0.27 (10% EtOAc/hexanes); H NMR (600 MHz,
CDCl3) δ 8.47 – 8.21 (m, 3H), 8.16 – 7.89 (m, 3H), 6.22 (ddt,
J = 16.6, 10.1, 6.2 Hz, 1H), 5.94 – 5.89 (m, 1H), 5.39 – 5.29
(m, 2H), 4.24 (s, 3H), 4.19 (s, 3H), 3.89 (bs, 2H);
13C{1H}NMR (151 MHz, CDCl3) δ 148.8, 145.0, 143.1, 136.4,
131.42, 128.9, 126.7, 126.3, 123.9, 123.5, 123.1, 122.7, 122.2,
121.4, 120.8, 119.6, 118.9, 117.7, 61.4, 61.2, 37.0; HRMS
(ESI) calculated for C21H19O3 ([M+H]+) m/z = 319.1334, found
319.1336.
flash chromatography (1.3 × 15 cm; 40% dichloroꢀ
methane/hexanes) to afford 11 as a light brown solid (0.045 g,
1
98%): Rf = 0.22 (40% dichloromethane/hexanes); H NMR
(400 MHz, CDCl3) δ 8.40 (d, J = 7.5 Hz, 1H), 8.11 – 7.85 (m,
5H), 7.60 (d, J = 8.5 Hz, 1H), 6.40 – 6.23 (m, 1H), 5.62 (d, J =
17.2 Hz, 1H), 5.41 (d, J = 10.1 Hz, 1H), 4.89 (d, J = 5.6 Hz,
2H), 4.23 (s, 3H), 4.10 (s, 3H); 13C{1H}NMR (101 MHz,
CDCl3) δ 153.6, 146.9, 146.3, 133.7, 132.0, 128.8, 127.6,
126.5, 126.0, 125.8, 125.39, 125.35, 124.2, 123.6, 118.4,
118.1, 118.0, 112.7, 71.4, 70.0, 61.5; HRMS (ESI) calculated
for C21H19O3 ([M+H]+) m/z = 319.1334, found 319.1324.
1-(Trifluorometanesulfonyl)oxy-4,5-dimethoxy-2-(2-propen-1-
yl)pyrene (9): Triflic anhydride (0.14 g, 0.35 mmol) and pyriꢀ
dine (0.03 g, 0.3 mmol) were added to a stirred 0 °C solution
of 8 (0.056 g, 0.18 mmol) in dichloromethane (3.5 mL). The
cooling bath was removed and 10 min. later the reaction mixꢀ
ture was poured into 1 M HCl (30 mL). The resulting mixture
was extracted with dichloromethane (3 × 15 mL), the comꢀ
bined organic extracts were washed with and brine (35 mL),
dried over MgSO4, filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography
(1.3 × 12 cm; 20% dichloromethane/hexanes) to afford 9 as a
yellow solid (0.071 g, 89%): Rf = 0.32 (20% dichloroꢀ
methane/hexanes); 1H NMR (600 MHz, CDCl3) δ 8.54 (d, J =
7.8, 1.1 Hz, 1H), 8.41 (s, 1H), 8.28 (d, J = 9.2 Hz, 1H), 8.22 –
8.15 (m, 2H), 8.10 – 8.02 (m, 1H), 6.17 (ddt, J = 16.1, 10.6,
9,10-Dimethoxy-2-(2-Propen-1-yl)pyren-1-ol (12):
Comꢀ
pound 11 (0.229 g, 0.719 mmol) was dissolved in N,Nꢀ
diethylaniline (0.3 mL) and heated to 190 °C. After 9 h, the
solvent was evaporated under a gentle stream of nitrogen and
the residue was purified by flash chromatography (1.3 × 15
cm; 40% dichloromethane/hexanes) to afford 12 as a dark
yellow solid (0.13 g, 62% BORSM, 0.022 g recovered of 11
and 0.041 g of 5a): Rf = 0.35 (40% dichloromethane/hexanes);
1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 8.28 (d, J = 7.2
Hz, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.98 – 7.88 (m, 3H), 7.84
(d, J = 8.8 Hz, 1H), 6.24 (ddt, J = 16.7, 10.1, 6.5 Hz, 1H), 5.24
– 5.13 (m, 2H), 4.30 (s, 3H), 4.14 (s, 3H), 3.81 (d, J = 6.4 Hz,
ACS Paragon Plus Environment

Page 7 of 9
The Journal of Organic Chemistry
2H); 13C{1H}NMR (101 MHz, CDCl3) δ 151.1, 145.7, 144.1,
The residue was dissolved in dichloromethane (10 mL) and
cooled to 0 °C, followed by addition of acetyl chloride (0.031
g, 0.42 mmol) and AlCl3 (0.14 g, 0.83 mmol). After 30 min.,
the reaction mixture was directly poured into ice water (20
mL), the layers were separated and the aqueous phase was
extracted with dichloromethane (3 × 10 mL). The combined
organic extracts were washed water (20 mL) and brine (20
mL), dried over MgSO4, filtered and concentrated under reꢀ
duced pressure. The residue was purified by flash chromatogꢀ
raphy (1.3 × 18 cm; 50% dichloromethane/hexanes) to afford
16 as a bright yellow solid (0.10 g, 70%): Rf = 0.29 (60% diꢀ
chloromethane/hexanes); 1H NMR (600 MHz, CDCl3) δ 9.09
(d, J = 9.6 Hz, 1H), 8.51 – 8.45 (m, 2H), 8.41 (d, J = 8.2 Hz,
1H), 8.36 (d, J = 8.4 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 4.24 (s,
3H), 4.19 (s, 3H), 2.91 (s, 3H); 13C{1H}NMR (151 MHz,
CDCl3) δ 201.9, 146.1, 143.9, 131.7, 131.4, 130.6, 129.3,
128.8, 128.08, 128.01, 127.8, 126.4, 123.6, 122.4, 121.2,
120.9, 118.8, 61.4, 61.2, 30.5; HRMS (ESI) calculated for
C20H16BrO3 ([M+H]+) m/z = 383.0283, found 383.0276.
1
2
3
4
5
6
7
8
137.1, 131.9, 128.5, 127.5, 127.4, 126.17, 126.14, 124.5,
124.4, 124.2, 123.9, 123.5, 117.7, 116.0, 112.4, 62.2, 61.2,
34.8; HRMS (ESI) calculated for C21H19O3 ([M+H]+) m/z =
319.1334, found 319.1319.
1-(Trifluorometanesulfonyl)oxy-2-(2-Propen-1-yl)-9,10-
dimethoxypyrene (13): Triflic anhydride (0.22 g, 0.60 mmol)
was added to a stirred 0 °C solution of 12 (0.064 g, 0.20
mmol) in pyridine (2 mL). The cooling bath was removed and
the temperature increased to 40 °C. After 4 h, the reaction
mixture was cooled to room temperature, diluted with diꢀ
chloromethane (10 mL), and poured into 1 M HCl (50 mL).
The layers were separated and the aqueous phase was extractꢀ
ed with dichloromethane (3 × 15 mL), the combined organic
extracts were washed with 1 M HCl (20 mL), a saturated soluꢀ
tion of NaHCO3 (20 mL) and brine (20 mL), dried over
MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by flash chromatography (1.3 × 15
cm; 20% dichloromethane/hexanes) to afford 13 as a light
yellow solid (0.046 g, 51%): Rf = 0.23 (20% dichloroꢀ
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8-Bromo-4,5-dimethoxy-2-(2-propen-1-yl)pyren-1-ol
(17):
1
methane/hexanes); H NMR (600 MHz, CDCl3) δ 8.54 (d, J =
Compound 26 (0.29 g, 0.74 mmol) was dissolved in N,Nꢀ
diethylaniline (2 mL) and heated to 190 °C. After 48 h, the
solvent was evaporated under a gentle stream of nitrogen and
the residue was purified by flash chromatography (2.5 × 18
cm; 50% dichloromethane/hexanes) to afford 17 as an offꢀ
white solid (0.21 g, 74%): Rf = 0.33 (50% dichloroꢀ
methane/hexanes); HRMS (ESI) calculated for C21H17BrO3
([M]+) m/z = 396.0361, found 396.0365. The 1H and 13C NMR
spectra for 17 were poorly resolved. As such, it was subjected
to triflation and characterized at a later stage – see below.
7.7 Hz, 1H), 8.18 (d, J = 7.5 Hz, 1H), 8.10 – 8.01 (m, 3H),
7.99 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 6.12 – 6.08
(m, 1H), 5.37 – 5.25 (m, 2H), 4.32 (s, 3H), 3.99 (s, 3H), 3.95
(d, J = 7.0 Hz, 2H); 13C{1H}NMR (151 MHz, CDCl3) δ 148.4,
143.2, 140.1, 135.7, 131.6, 131.0, 130.8, 128.8, 128.1, 126.8,
126.7, 126.3, 126.1, 123.4, 122.3, 121.4, 120.5, 119.1 (JCꢀF
=
317 Hz), 118.0, 61.9, 61.1, 34.6; HRMS (ESI) calculated for
C22H18O5F3S ([M+H]+) m/z = 451.0827, found 451.0825.
1,4-Bis(1-(trifluorometanesulfonyl)oxy-9,10-dimethoxypyren-
2-yl)butane (14): 14: HoveydaꢀGrubbs secondꢀgeneration
catalyst (0.0005 g, 0.0009 mmol) and NaBH4 (0.006 g, 0.1
mmol) were added to stirred solution of 20 (0.025 g, 0.029
mmol) in 1:9 methanol/dichloromethane (1.5 mL). After 2 h,
the reaction mixture was poured into water (25 mL) and dilutꢀ
ed with 1 M HCl (15 mL). The resulting mixture was extractꢀ
ed with dichloromethane (3 × 12 mL), the combined organic
extracts were washed with brine (20 mL), dried over MgSO4,
filtered and concentrated under reduced pressure. The residue
was purified by flash chromatography (0.5 × 10 cm; 40% diꢀ
chloromethane/hexanes) to afford 14 as an offꢀwhite solid
(0.012 g, 95%): Rf = 0.30 (40% dichloromethane/hexanes); 1H
NMR (600 MHz, CDCl3) δ 8.52 (d, J = 7.8, 1.2 Hz, 2H), 8.17
(d, J = 8.0, 7.6 Hz, 2H), 8.08 – 8.02 (m, 4H), 7.99 (s, 2H),
7.91 (d, J = 8.9 Hz, 2H), 4.29 (s, 6H), 3.90 (s, 6H), 3.26 (t, J =
6.8 Hz, 4H), 2.10 – 1.94 (m, 4H); 13C{1H}NMR (151 MHz,
CDCl3) δ 148.1, 142.9, 140.1, 133.6, 130.7, 130.6, 128.6,
127.8, 126.6, 126.4, 126.0, 125.7, 123.0, 122.2, 121.2, 120.3,
118.9 (JCꢀF = 317 Hz), 61.7, 60.8, 30.5, 30.2, 29.7; HRMS
(ESI) calculated for C42H32O10F6S2Na ([M+Na]) m/z =
897.1239, found 897.1194.
Triflate 18: Trifluoromethanesulfonic anhydride (0.03 g, 0.1
mmol) and pyridine (0.01 g, 0.1 mmol) were added to a stirred
0 °C solution of 17 (0.021 g, 0.053 mmol) in dichloromethane
(1.5 mL). After 10 min., the reaction mixture was diluted with
dichloromethane (5 mL) and neutralized with 1 M HCl (10
mL). The layers were separated and the aqueous phase was
extracted with dichloromethane (3 × 7 mL). The combined
organic extracts were washed with 1 M HCl (10 mL), Naꢀ
HCO3 (10 mL), and brine (10 mL), dried over MgSO4, filtered
and concentrated under reduced pressure. The residue was
purified by flash chromatography (0.5 × 10 cm; dichloroꢀ
methane) to afford 18 as a yellow solid (0.027 g, 57%): Rf =
1
0.78 (dichloromethane); H NMR (600 MHz, CDCl3) δ 8.58
(d, J = 9.4 Hz, 1H), 8.43 (s, 1H), 8.41 – 8.35 (m, 2H), 8.30 (d,
J = 8.3 Hz, 1H), 6.13 (ddt, J = 16.7, 9.9, 6.7 Hz, 1H), 5.31 –
5.25 (m, 2H), 4.22 – 4.18 (m, 6H), 3.98 (d, J = 6.6 Hz, 2H);
13C{1H}NMR (151 MHz, CDCl3) δ 145.3, 144.0, 140.1, 135.0,
132.1, 130.9, 128.9, 128.6, 128.2, 128.0, 124.5, 123.2, 122.1,
121.9, 121.6, 121.5, 120.7, 118.8 (JCꢀF = 253 Hz), 117.9, 61.32,
61.27, 35.2; HRMS (ESI) calculated for C22H17BrF3O5S
([M+H]+) m/z = 528.9932, found 528.9926.
1-(8-Bromo-4,5-dimethoxypyren-1-yl)ethanone (16): Bromine
(0.06 g, 0.4 mmol) was added dropwise to a stirred –78 °C
solution of 4,5ꢀdimethoxypyrene (0.10 g, 0.38 mmol) in diꢀ
chloromethane (20 mL). After 10 min., the reaction mixture
was directly poured into an aqueous saturated solution of
Na2SO3 (10 mL), and the resulting mixture was extracted with
dichloromethane (3 × 10 mL). The combined organic extracts
were washed with water (20 mL) and brine (20 mL), dried
over MgSO4, filtered and concentrated under reduced pressure.
Alkene 19: Grubbs firstꢀgeneration catalyst (0.001 g, 0.001
mmol) was added to a stirred 40 °C solution of 9 (0.020 g,
0.043 mmol) in dichloromethane (0.8 mL). After 12 h, the
reaction mixture was cooled to room temperature and the solꢀ
vent was evaporated under reduced pressure. The residue was
purified by flash chromatography (1.3 × 10 cm; 30% diꢀ
chloromethane/hexanes) to afford 19 (dark yellow solid, 0.014
g, 78%, 4.7:1 d.r) as an inseparable mixture of diastereomers:
Rf = 0.27 (35% dichloromethane/hexanes); 1H NMR (400
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MHz, CDCl3) δ 8.52 – 8.48 (m, 5H), 8.43 – 8.40 (m, 1H), 8.37
tion of NaHCO3 (50 mL), dried over MgSO4, filtered and conꢀ
centrated under reduced pressure to afford 25 as a light brown
solid (0.393 g, 82%): Rf = 0.24 (dichloromethane); HRMS
(ESI) calculated for C18H13BrO3 ([M]+) m/z = 356.0048, found
1
2
3
4
5
6
7
8
(s, 5H), 8.28 – 8.23 (m, 6H), 8.18 (d, J = 1.4 Hz, 5H), 8.16 (d,
J = 1.1 Hz, 5H), 8.07 – 7.94 (m, 9H), 6.19 – 6.15 (m, 1H),
6.02 – 5.96 (m, 5H), 4.15 (s, 14H), 4.13 – 4.10 (m, 2H), 4.07 –
4.04 (m, 18H), 4.02 – 3.98 (m, 13H); 13C{1H}NMR (151
MHz, CDCl3) δ 145.8, 145.6, 144.1, 144.0, 140.1, 139.9,
131.8, 131.7, 130.5, 130.3, 130.2, 129.7, 129.42, 129.41,
128.62, 128.55, 128.43, 128.38, 127.0, 126.8, 125.7, 125.6,
124.7, 124.4, 122.9, 122.5, 122.2, 121.9, 121.3, 121.0, 120.80,
120.72, 120.2, 120.1, 119.8, 117.9, 61.4, 61.28, 61.25, 61.15,
34.4, 29.9, 29.1; HRMS (ESI) calculated for C42H31O10F6S2
([M+H]+) m/z = 873.1263, found 873.1262.
1
356.0041. The H and 13C NMR spectra for 25 were poorly
resolved. As such it was subjected to allylation and characterꢀ
ized at a later stage – see below.
1-Allyloxy-8-bromo-4,5-dimethoxypyrene (26): NaH (0.031 g,
1.3 mmol) and allyl bromide (0.17 g, 1.4 mmol) were added to
a stirred solution of 25 (0.29 g, 0.82 mmol) in DMF (22 mL)
at room temperature. After 30 min., the reaction mixture was
poured into water (20 mL) and neutralized with 1 M HCl (20
mL). The resulting mixture was extracted with dichloroꢀ
methane (3 × 15 mL), the combined organic extracts were
washed with water (40 mL) and a saturated solution of Naꢀ
HCO3 (40 mL), dried over MgSO4, filtered and concentrated
under reduced pressure. The residue was purified by flash
chromatography (2.5 × 18 cm; dichloromethane) to afford 26
as a yellow solid (0.30 g, 91%): Rf = 0.70 (dichloromethane);
1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 9.4 Hz, 1H), 8.43
(d, J = 8.7 Hz, 1H), 8.38 (d, J = 9.4 Hz, 1H), 8.25 – 8.20 (m,
2H), 7.58 (d, J = 8.7 Hz, 1H), 6.26 (ddt, J = 17.3, 10.4, 5.1 Hz,
1H), 5.60 (dd, J = 17.3, 1.6 Hz, 1H), 5.41 (dd, J = 10.6, Hz,
1H), 4.95 – 4.88 (m, 2H), 4.22 (s, 3H), 4.16 (s, 3H);
13C{1H}NMR (151 MHz, CDCl3) δ 152.8, 144.9, 142.4, 133.2,
130.4, 130.0, 128.7, 124.9, 124.2, 123.6, 122.9, 122.2, 120.8,
120.6, 119.3, 118.6, 117.8, 110.0, 69.7, 61.2, 61.1; HRMS
(ESI) calculated for C21H18BrO3 ([M+H]+) m/z = 397.0439,
found 397.0422.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Alkene 20: Grubbs firstꢀgeneration catalyst (0.003 g, 0.003
mmol) was added to a stirred 40 °C solution of 13 (0.047 g,
0.10 mmol) in dichloromethane (0.8 mL). After 12 h, the reꢀ
action mixture was cooled to room temperature and the solꢀ
vent was evaporated under reduced pressure. The residue was
purified by flash chromatography (1.3 × 15 cm; 30% diꢀ
chloromethane/hexanes) to afford 20 (light yellow solid, 0.031
g, 67%, 2.7:1 d.r.) as an inseparable mixture of diastereomers:
Rf = 0.38 (30% dichloromethane/hexanes); 1H NMR (600
MHz, CDCl3 δ 8.54 (d, J = 7.7 Hz, 4H), 8.20 (d, J = 7.5 Hz,
3H), 8.16 (d, J = 7.6 Hz, 1H), 8.12 – 8.04 (m, 10H), 7.99 (d, J
= 9.0 Hz, 5H), 7.81 (d, J = 8.8 Hz, 1H), 6.12 – 6.08 (m, 1H),
6.02 – 5.97 (m, 3H), 4.32 – 4.27 (m, 12H), 4.18 – 4.14 (m,
2H), 4.04 – 3.98 (m, 6H), 3.95 (s, 3H), 3.89 (s, 9H);
13C{1H}NMR (151 MHz, CDCl3) δ 148.44, 148.41, 143.1,
140.12, 140.09, 131.9, 131.0, 130.9, 130.8, 130.6, 129.6,
128.87, 128.80, 128.06, 128.04, 126.9, 126.71, 126.5, 126.26,
126.20, 126.18, 125.9, 123.4, 122.34, 122.29, 121.53, 121.46,
120.51, 120.50, 120.1, 118.0, 61.9, 61.02, 60.99, 33.6, 28.3;
HRMS (ESI) calculated for C42H31O10F6S2 ([M+H]+) m/z =
873.1263, found 873.1257.
ASSOCIATED CONTENT
Supporting Information
1H and 13C NMR spectra for all new compounds, and crystalꢀ
lographic data, including CIFs. This material is available free
of charge via the Internet at http://pubs.acs.org.
8-Bromo-4,5-dimethoxypyren-1-ol (25): SeO2 (0.009 g, 0.08
mmol) and a 30% solution (w/w) of hydrogen peroxide in
water (1.0 mL, 12 mmol) were added to a stirred 50 °C soluꢀ
tion of 6 (0.89 g, 2.9 mmol) in tꢀBuOH (12 mL). After 3 days,
the reaction mixture was cooled to room temperature, poured
into water (30 mL) and further diluted with dichloromethane
(15 mL). The layers were separated, and the aqueous phase
was extracted with dichloromethane (3 × 15 mL). The comꢀ
bined organic extracts were washed with water (50 mL) and
brine (50 mL), dried over MgSO4, filtered and concentrated
under reduced pressure. The residue was purified by flash
chromatography (2.5 × 18 cm, 80% dichloromethane/hexane)
to afford 24 (0.533 g, 57%): Rf = 0.48 (80% dichloroꢀ
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: blm0022@auburn.edu.
Author Contributions
The manuscript was written through contributions of all auꢀ
thors. All authors have given approval to the final version of
the manuscript.
1
methane/hexanes); H NMR (600 MHz, CDCl3) δ 8.53 (d, J =
Notes
8.5 Hz, 1H), 8.47 (d, J = 9.4 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H),
8.27 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 9.3 Hz, 1H), 7.85 (d, J =
8.5 Hz, 1H), 4.21 (s, 3H), 4.19 (s, 3H), 2.58 (s, 3H);
13C{1H}NMR (151 MHz, CDCl3) δ 170.0, 144.7, 144.4, 144.2,
130.7, 129.4, 128.2, 126.8, 123.9, 123.2, 123.1, 121.8, 120.7,
120.5, 120.4, 119.8, 61.30, 61.27, 21.3; HRMS (ESI) calculatꢀ
ed for 24 C20H16BrO4 ([M+H]+) m/z = 399.0232, found
399.0215. Compound 24 was dissolved in MeOH (20 mL)
and K2CO3 (0.641 g, 4.64 mmol) was added, the resulting
mixture was stirred for 30 min. The reaction mixture was
directly poured into ice water (50 mL) and neutralized with 1
M HCl (40 mL), the layers were separated and the aqueous
phase was extracted with dichloromethane (3 × 30 mL). The
combined organic extracts were washed with a saturated soluꢀ
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This material is based upon work supported by the National
Science Foundation under Grant Number (CHEꢀ1654691).
The authors are also grateful to Auburn University, the Colꢀ
lege of Sciences and Mathematics, and the Department of
Chemistry and Biochemistry. We also thank Umicore for
generous catalyst donations.
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