A general route for 13C-labeled fluorenols and phenanthrenols via palladium-catalyzed cross-coupling and one-carbon homologation

Article abstract of DOI:10.1002/jlcr.3066

A series of ¹³C-labeled polyaromatic hydrocarbons (PAHs), fluorenols and phenanthrenols were synthesized from commercially available ¹³C-labeled starting material giving rise to M + 6 isotopomers. This was accomplished using key pall

Full text of DOI:10.1002/jlcr.3066

Research Article
Received 1 May 2013,
Accepted 2 May 2013
Published online 15 July 2013 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3066
13
A general route for C-labeled fluorenols
and phenanthrenols via palladium-catalyzed
cross-coupling and one-carbon homologation
a
a
a
*
Ruilian Wu, L. A. ‘Pete’ Silks, Morgane Olivault-Shiflett,
Robert F. Williams,a Erick G. Ortiz,a Philip Stotter,a David B. Kimball,a
and Rodolfo A. Martinez
b**
A series of 13C-labeled polyaromatic hydrocarbons (PAHs), fluorenols and phenanthrenols were synthesized from commercially
available 13C-labeled starting material giving rise to M + 6 isotopomers. This was accomplished using key palladium-catalyzed
cross-coupling and one-carbon homologation strategies. The conditions for these reactions were optimized, and the new
chemical routes are efficient in the number of chemical steps, can be scaled to afford gram quantities and occur in good yields
based on the 13C label. These labeled compounds as precursors for more complex PAHs and are useful as internal standards in
mass spectrometry and NMR spectroscopy studies for monitoring environmental contamination and biological exposure to
PAHs and their metabolites.
Keywords: polyaromatic hydrocarbons; palladium-catalyzed cross-coupling; one-carbon homologation; mass spectral standards;
uniformly 13C-labeled benzene and Friedel–Crafts reactions
presence of PAHs in biological systems and the environment
Introduction
by mass spectral methods. This report details our synthetic
Polyaromatic hydrocarbons (PAHs) make up a class of compounds
efforts toward a comprehensive approach to stable isotope
implicated in carcinogenesis and found to be prevalent in the
labeling of PAHs. Because deuterium labeling of PAHs is
problematic in terms of stability (dilution of the label), 13C
environment. The most potent carcinogenic members contain four
to six benzo rings. These PAHs have structural features such as
labeling is required in many cases. Our concept then begins with
a reasonable source of 13C label starting with U-13C benzene.
crowded bay or fjord regions which enhance biological activities
(Figure 1).1
While making mass spectral standards and the studies of PAHs
One of the most potent carcinogens known is derivatives of
and DNA interactions, we needed to synthesize M + 4 labeled
fluorenols and phenanthrenols. There are few existing methods1
the benzo[a]pyrene family. Strong correlation with carcinogenic
for 13C labeling, however for our site-specific labeling, these are
activity is found with oxidized versions of benzo[a]pyrene.
Metabolism by oxidases is found to give rise to epoxides, which
not feasible in terms of both time and cost. Here, we report a
new general route to 13C-labeled fluorenols and phenanthrenols
are more reactive than the parent benzo[a]pyrene. Interestingly,
the enzymatic reactions proceed with high regioselectivities and
by using a key palladium-catalyzed cross-coupling step followed
by a one-carbon homologation (Figure 2).2
stereoselectivities, and these highly reactive intermediates then
proceed to attack cellular targets such as DNA. The covalent
The synthetic route to 9-fluorenol 3 is shown in Scheme 1.
attachment of PAHs to DNA can lead to significant damage to
2-Iodobenzoyl chloride smoothly underwent Friedel–Crafts
the cell. Persistent lesions give rise to cellular signals, lead to
apoptosis. In addition, during replication, transcription errors
can provide a whole host of deleterious cellular events. As
cytoxicity is usually accompanied by gross changes in the
structure of the DNA helix, which serves to block the reading
of the oligomer by RNA and DNA polymerases, mutagenic
lesions can give rise to errors in the transcription process.
We have recently been interested in the study of the process
of the intercalation of PAHs into oligomeric deoxynucleic acids
(DNA), and the effect and extent of soft π•••H–X (X = C, N, O)
and C–H•••O hydrogen bonding interactions have on the
structure of the DNA. In addition, we believe many of these
intermediates are useful in monitoring and quantitating the
aBioenergy and Biome Sciences Group, Biophysical Chemistry Team, Los Alamos
National Laboratory, Los Alamos, NM 87545, USA
bDepartment of Chemistry, New Mexico Highland University, Las Vegas, NM
87701, USA
*Correspondence to: Pete Silks, Bioenergy and Biome Sciences Group, Los Alamos
National Laboratory, Los Alamos, NM 87545, USA.
E-mail: pete-silks@lanl.gov
**Correspondence to: Department of Chemistry and Forensic Science. New
Mexico Highlands University. Room:HSCI-132. Las Vegas, NM 87701.
E-mail: rudy@nmhu.edu
J. Label Compd. Radiopharm 2013, 56 581–586
Copyright © 2013 John Wiley & Sons, Ltd.

R. Wu et al.
Scheme 2. Synthesis of 13C6 3-, 4-, 5- and 6-methox-2-bromobenzophenones.
4-methoxyfluorenone 5a and dehydrohalogenation product
3-methoxybenzophenone in a 2:3 ratio and in low combined yield
(30–40%). Improvement in the selectivity of the reaction was
observed by the addition of triphenylphosphine to the catalyst
affording 5a at higher yield of 76% accompanied with less than
6% of dehydrohalogenation product.
Figure 1. Carcinogenic hot spots in the molecular architecture of benzopyrenes
and derivatives.
However,
for
the
cyclization
of
2-bromo-6-
methoxybenzophenone, use of triphenylphosphine as a ligand
gave rise to a 1:1 mixture of 1-methoxyfluorenone 5a and the
dehydrohalogenation product 2-methoxybenzophenone. By
substituting the phosphorus-based ligand with tricyclohexyl-
phosphine tetrafluoroborate5 the product to by-product ratio
increased to 3:1.
The methoxyl substituted 9-fluorenones 5 were reduced to
fluorenes 6 by palladium on carbon with hydrogen under
pressure and heat at about 60 °C.6 Demethylation of the
methoxy groups using boron tribromide provided the desired
fluorenols 7 (Scheme 5).
Figure 2. Synthesized 13C labeling polyaromatic hydrocarbons.
The synthesis of 9-phenanthrenol 8 started with 9-fluorenone
2 that was constructed according to Scheme 1 using a ring
expansion homologation reaction. 9-Fluorenone 2 reacted with
trimethylsilyldiazomethane in the presence of boron trifluoride
to form the 9-phenanthrenol 8 in one step (Scheme 6).7
Likewise, the synthesis of 1-, 2-, 3- and 4-methoxyphenanthrenes
11 started from the corresponding 1-, 2-, 3- and 4-methoxyfluorenones
5 as shown in Scheme 7.
acylation with uniformly 13C-labeled benzene as illustrated in
Scheme 1. The cyclization of the resulting benzophenone 1
was achieved by palladium (II) acetate catalyzed cross-coupling
to afford 9-fluorenone 2 in good overall yield.3 9-Fluorenol 3
was obtained by reduction of 9-fluorenone 2 with sodium
borohydride.4
3-, 4-, 5-, and 6-Methoxy-2-bromofluorenone 4a, 4b, 4c, 4d
were synthesized from the corresponding methoxy substituted
2-bromobenzoyl chloride. The general synthetic route for the
first step is illustrated in Scheme 2.
The Friedel–Crafts reaction between 4-methoxy-2-bromobenzoyl
chloride and benzene in chlorinated solvents gave rise to the
desired product 4-methoxybenzophenone 4b albeit in diminished
yields (13–35%). Simply by changing the solvent to nitromethane
gave rise to significantly improved yields (72%).
Following the one-carbon homologation, the methoxy
substituted 9-phenanthrenols
9
were converted to the
corresponding aryl triflates 10. Reaction of the aryl triflates with
palladium acetate, triphenyphosphine, triethylamine and formic
acid in DMF gave rise to methoxy substituted phenanthrenes
Cross-coupling of the substituted bromobenzophenone using
palladium acetate as a catalyst afforded the corresponding annulated
fluorenones 5, as illustrated in Scheme 3 in 57–92% yields.
As shown in Scheme 4, the cyclization of 2-bromo-3-
methoxybenzophenone using palladium acetate and sodium
carbonate in N,N-dimethylacetamide gave rise to a mixture of
Scheme 3. Synthesis of 13C6 fluorenones 5.
Scheme 1. Synthesis of 13C6 9-fluorenol 3.
Scheme 4. Synthesis of 13C6 4-methoxyfluorenone 5d.
Copyright © 2013 John Wiley & Sons, Ltd. J. Label Compd. Radiopharm 2013, 56 581–586
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R. Wu et al.
of these PAHs. In addition, these compounds will be useful for
the detection, quantitation and environmental monitoring of
exposures to PAH agents.
Experimental
General
All reactions were carried out under argon. All solvents or reagents were
used as received. Uniformly 13C-labeled benzene was purchased either
from Cambridge Isotope Laboratories, Inc. (Andover, MA, USA) or Isotec,
Inc. (Miamisburg, OH, USA). Flash column chromatography was carried
out using Merck Kieselge 60 (Darmstadt, Germany) (230–400 mesh) silica
gel. Proton and carbon NMR spectra were recorded on Bruker Avance
300 spectrometer (Billerica, MA, USA) using an internal deuterium lock.
Chemical shifts are quoted in parts per million downfield from
tetramethylsilane. Carbon NMR spectra were recorded with broad proton
decoupling. Mass spectra were recorded on a ThermoFinnigan PolarisQ
TraceGC instrument (San Jose, CA, USA), and elemental analyses were
recorded on a ThermoFinnigan Flash 1112 Series EA CHNSO Analyzer.
2-Iodobenzoyl chloride and 2-bromo-5-methoxybenzoyl chloride
were purchased from Aldrich Chemical Company (St. Louis, MO,
USA) and Lancaster Synthesis Inc. (Windham, NH, USA), respectively.
2-Bromo-3-methoxybenzoyl chloride, 2-bromo-4-methoxybenzoyl
chloride and 2-bromo-6-methoxybenzoyl chloride were made from
their corresponding acids by treatment with thionyl chloride.
Scheme 5. Synthesis of 13C6 fluorenol 7.
Scheme 6. Synthesis of 13C6 9-phenanthrenol 8.
General procedure for the preparation of benzophenones 1
and 4
In a 100-mL round bottom flask, was charged with 2-iodo or 2-
bromomethoxy-substituted benzoyl chloride (10.0 mmol), 1,2-
dichloroethane (10.0 mL), and 13C6 benzene (0.841 g, 10.0 mmol). The
reaction mixture was cooled in an ice bath, and aluminum chloride
(1.467 g, 11.0 mmol) was added in one portion. The mixture was stirred
at 0 °C for 5 min and allowed to warm to room temperature, and stirring
was continued for 1–2 h or until thin layer chromatography (TLC) analysis
showed a complete reaction. Water was slowly added to the reaction
mixture while cooled with an ice bath. The mixture was extracted with
dichloromethane, washed with brine and dried over sodium sulfate,
filtered and concentrated. The residue was purified by flash
chromatography with 3–10% ethyl acetate in hexanes to provide the
desired product.
Scheme 7. Synthesis of 13C6 1-, 2-, 3- and 4-methoxyphenanthrenes 11.
2-Iodobenzophenone 1 (96%)
1H NMR (CDCl3) δ 8.25–8.05 (m, 1H), 8.00–7.95 (dd, J = 8.07, 1.01 Hz,
1H), 7.95–7.82 and 7.42–7.30 (m, 1H), 7.82–7.70 (m, 1H), 7.75–7.52
(m, 1H), 7.50–7.45 (td, J = 7.50, 1.04 Hz, 1H), 7.37–7.30 (dd, J = 7.65,
1.73 Hz, 1H), 7.30–7.20 (m, 1H), 7.25–7.20 (td, J = 7.74, 1.70 Hz, 1H).
13C NMR (CDCl3) δ 197.20 (d, J = 51.77 Hz), 144.33 (d, J = 12.72 Hz),
139.68 (s), 135.8 (td, J = 55.57, 8.43 Hz), 133.80 (td, J = 52.61, 8.52 Hz),
130.50 (td, J = 58.98, 4.54 Hz), 128.50 (td, J = 52.55, 7.79 Hz), 92.19 (s).
HRMS calculated 313.9899, found 313.9894.
11 in good to excellent yields.8 1-, 2-, 3- and 4-Phenanthrenols
12 were obtained by conventional demethylation with boron
tribromide (Scheme 8).
In conclusion, we report an efficient and reliable route to the
synthesis of M + 6 isotope-labeled fluorenols and phenanthrenols
by using uniformly 13C-labeled benzene as the only carbon 13
source. The procedure provides
a quick access to these
compounds. These new stable isotope-labeled PAHs and
intermediates are ideally suited for further elaboration to more
complex and biologically and environmentally important PAHs.
Current efforts in our laboratories are underway for construction
(2-Bromo-3-methoxyphenyl)(phenyl)-methanone 4a (91%)
1H NMR (CDCl3) δ 8.25–8.05 (m, 1H), 7.96–7.85 and 7.32–7.45 (m,
1H), 7.85–7.70 (m, 1H), 7.65–7.53 (m, 1H), 7.38 (dd, J = 8.28,
7.56 Hz, 1H), 7.34–7.20 (m, 1H), 7.24 (dd, J = 8.28, 1.37 Hz, 1H), 6.98
(dd, J = 7.56, 1.35 Hz, 1H), 3.85 (s, 3H). 13C NMR (CDCl3) δ 156.00
(d, J = 15.57 Hz), 135.55 (m), 133.30 (m), 129.85 (m), 128.10 (m),
120.39, 112.62, 108.89, 56.45. HRMS calculated 296.0144, found
296.0141.
(2-Bromo-4-methoxyphenyl)(phenyl)methanone 4b (72%)
1H NMR (CDCl3) δ 8.18–8.05 (m, 1H), 7.95–7.85 and 7.32–7.45 (m, 1H),
7.80–7.70 (m, 1H), 7.65–7.50 (m, 1H), 7.39 (d, J = 8.52 Hz, 1H), 7.30–7.20
(m, 1H), 7.25 (d, J = 2.52 Hz, 1H), 6.97 (dd, J = 8.52, 2.52 Hz, 1H), 3.95 (s,
Scheme 8. Synthesis of 13C6 1-, 2-, 3- and 4-phenanthrenols 12.
J. Label Compd. Radiopharm 2013, 56 581–586
Copyright © 2013 John Wiley & Sons, Ltd.
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R. Wu et al.
3H). 13C NMR (CDCl3) δ 136.51 (m), 132.98 (m), 129.82 (m), 127.91 (m),
118.29, 112.62, 55.31. HRMS calculated 296.0144, found 296.0146.
9-Fluorenol 3 (76%)
To a solution of 9-fluorenone 2 (1.391 g, 7.470 mmol) in methanol (35 mL)
was added sodium borohydride (0.311 g, 8.22 mmol) in one portion at 0 °
C. The mixture was allowed to warm to room temperature and stirred for
0.5 h until TLC analysis showed a complete reaction. The solvent was
removed by rotary evaporation, and the residue was partitioned between
water and ethyl acetate. The organic extracts were dried over sodium
sulfate and concentrated. The residue was purified on silica gel with
5% EtOAC/hexanes to provide 1.068 g (76%) of the title product as a
white solid. 1H NMR (CDCl3) δ 8.05–7.65 (m, 1H), 7.65–7.55 (m, 2H),
7.55–7.25 (m, 3H), 7.25–6.90 (m, 1H), 5.60 (s, 1H), 1.90 (s, 1H). 13C NMR
(CDCl3) δ 145.66 (m), 139.95 (m), 129.14 (m), 127.72 (m), 125.00 (m),
(2-Bromo-5-methoxyphenyl)(phenyl)methanone 4c (94%)
1H NMR (CDCl3) δ 8.22–8.05 (m, 1H), 7.90–7.80 and 7.40–7.28 (m, 1H),
7.80–7.65 (m, 1H), 7.65–7.50 (m, 1H), 7.51 (dd, J = 8.22, 0.88 Hz, 1H),
7.28–7.15 (m, 1H), 6.95–6.85 (m, 2H), 3.80 (s, 3H). 13C NMR (CDCl3)
195.38 (pd, J = 55.66, 3.97 Hz), 158.52 (s), 141.14 (d, J = 12.85 Hz), 135.58
(m), 133.71 (m), 130.03 (m), 128.39 (m), 117.09 (s), 114.02 (s), 109.36 (s),
55.44 (s). HRMS calculated 296.0144, found 296.0142.
(2-Bromo-6-methoxyphenyl)(phenyl)methanone 4d (78%)
1H NMR (CDCl3) δ 8.30–8.00 (m, 1H), 8.00–7.85 and 7.35–7.20 (m, 1H), 119.90 (m), 75.0 (bd, J = 46.45 Hz). HRMS calculated 188.0933, found
7.85–7.70 (m, 1H), 7.70–7.50 (m, 1H), 7.50–7.20 (m, 3H), 7.00 (dd, 188.0927. Anal. Calcd for 13C612C7H10O: C, 86.14; H, 5.36. Found: C, 86.24;
J = 8.00, 1.15 Hz, 1H), 3.75 (s, 3H). 13C NMR (CDCl3) δ 157.61, 136.10 H, 5.38.
(m), 133.80 (m), 129.63 (m), 128.54 (m), 124.77, 109.91, 56.03. HRMS
calculated 296.0144, found 296.0149.
General procedure for the preparation of methoxyfluorene 6
In a 100 mL Parr hydrogenation reaction, bottle was charged with
fluorenone 5 (0.497 g, 2.30 mmol) and absolute ethanol (25 mL). One
General procedure for the preparation of fluorenones 2 and 5
drop of concentrated sulfuric acid was added followed by addition of
10% Pd/C (0.113 g). The mixture was heated with a heating tape and
hydrogenated at 55 psi at 65 °C (wall temperature) for 2.5 h and at room
temperature for 1 h. TLC showed a complete reaction. The mixture was
filtered to remove the catalyst, and the filtrate was concentrated. The
residue was partitioned between ethyl acetate and water, washed with
5% sodium bicarbonate and brine. The organic layers were combined
and dried over sodium sulfate. The solvent was removed under reduced
pressure, and the residue was purified on silica gel with 1–2% ethyl
acetate/hexanes to provide the title product.
For 2-iodobenzophenone,
a mixture of 2-iodobenzophenone 1
(3.023, 9.600 mmol) and palladium acetate (0.211 g, 0.940 mmol) in
N-methylimidazole (9.6 mL) was heated to reflux overnight. For 2-
bromobenzophenone, a mixture of methoxy 2-bromobenzophenone
(3.340 g, 11.26 mmol), palladium acetate (0.3800 g, 1.689 mmol) and
sodium carbonate (2.148 g, 20.27 mmol) in N,N-dimethylacetamide
(20 mL) was heated to reflux overnight. The mixture was cooled
to room temperature, and water was added. The mixture was
extracted with ethyl acetate, and the organic extracts were washed
with 2 M HCl, dried over sodium sulfate and concentrated. The
residue was purified on silica gel with 2% EtOAc/hexanes to
provide the desired compound.
4-Methoxyfluorene 6a (88%)
1H NMR (CDCl3) δ 8.54–8.40 and 7.87–7.76 (m, 1H), 8.0–7.87 (m, 1H), 7.74–
7.48 (m, 1H), 7.40–7.23 (m, 1H), 7.20 (d, J = 7.51 Hz, 1H), 7.16–7.00 (m, 1H),
6.93 (d, J = 8.16 Hz, 1H), 4.00 (s, 3H). 13C NMR (CDCl3) δ 141.48 (m), 134.11
(m), 126.26 (m), 124.22 (m), 117.32, 110.51, 108.63, 55.32, 29.70. HRMS
calculated 202.1089, found 202.1091.
9-Fluorenone 2 (73%)
1H NMR (CDCl3) δ 8.00–7.90 and 7.46–7.36 (m, 1H), 7.87–7.73 (m, 1H), 7.70
and 7.28 (br d, J = Hz, 1H), 7.66–7.48 (m, 3H), 7.35–7.28 (m, 1H), 7.30–7.18
and 7.14–6.98 (m, 1H). 13C NMR (CDCl3) δ 144.38 (m), 134.76 (m), 129.09
(m), 124.21 (m), 120.23 (m). HRMS calculated 186.0776, found 186.0773.
3-Methoxyfluorene 6b (93%)
1H NMR (CDCl3) δ 8.10–7.77 (m, 1H), 7.77–7.50 (m, 1H), 7.47 (d, J = 8.28 Hz,
1H), 7.35 (t, J = 2.66Hz, 1H), 7.18–7.02 (m, 1H), 6.91 (dd, J = 8.28, 2.49 Hz,
1H), 3.92 (s, 3H). 13C NMR (CDCl3) δ 144.48 (m), 141.71 (m), 127.19 (m),
126.50 (m), 125.02 (m), 119.89 (m), 113.98, 113.36, 111.05, 104.98, 55.71,
42.32 (td, J = 296.48, 32.73 Hz).
4-Methoxy-9-fluorenone 5a (76%)
1H NMR (CDCl3) δ 8.20–8.05 and 7.80–7.65 (m, 1H), 8.00–7.85 and 7.05–6.90
(m, 1H), 7.65–7.45 (m 1H), 7.45–7.15 (m 3H), 7.15–7.05 (m, 1H), 4.00 (s, 3H).
13C NMR (CDCl3) δ 144.06 (m), 134.94 (m), 133.73 (m), 128.21 (m), 124.91
(m), 123.71 (m), 117.99, 116.74, 55.83. HRMS calculated 216.0882, found
216.0882.
2-Methoxyfluorene 6c (89%)
1H NMR (CDCl3) 8.05–7.76 (m, 1H), 7.72 (dd, J = 8.36, 2.27 Hz, 1 H)
and 7.70–7.38 (m, 1H), 7.38–7.17 (m, 1H), 7.17–7.02 and 6.94–6.75
(m, 1H), 6.98 (dd, J = 8.36, 2.27 Hz, 1H), 3.92 (s, 3H). 13C NMR
(CDCl3) δ 160.00, 142.71 (m), 141.47 (m), 128.32 (m), 126.82 (m),
125.30 (m), 119.03 (m), 115.00, 113.00, 111.40, 110.60, 56.49, 41.5
(td, J = 230.05, 32.56 Hz). HRMS calculated 202.1089, found
202.1088.
3-Methoxy-9-fluorenone 5b (57%)
1H NMR (CDCl3) δ 7.99–7.83 and 7.45–7.33 (m, 1H), 7.83–7.70 (m, 1H),
7.69–7.50 and 7.13–6.95 (m, 1H), 7.65 (d, J = 8.23 Hz, 1H), 7.29–7.13 (m,
1H), 7.10–7.00 (m, 1H), 6.77 (dd, J = 8.22, 2.09 Hz, 1H), 3.95 (s, 3H). 13C
NMR (CDCl3) δ 165.53 (d, J = 4.93 Hz), 143.48 (m), 135.45 (m), 134.350
(m), 129.40 (dtm), 123.96 (m), 120.22 (m), 113.68, 113.09, 107.23, 55.93.
2-Methoxy-9-fluorenone 5c (92%)
1-Methoxyfluorene 6d (80%)
1H NMR (CDCl3) δ 7.94–7.80 and 7.56–7.44 (m, 1H), 7.78–7.63 (m, 1H), 7.41
(dd, J = 8.19, 3.15 Hz, 1H), 7.41–7.30 and 7.03–6.89 (m, 1H), 7.21 (d,
J = 2.46 Hz, 1H), 7.00 (dd, J = 8.16, 2.52 Hz, 1H), 3.85 (s, 3H). 13C NMR
(CDCl3) δ 193.82 (br d, J = 54.10 Hz), 160.76, 158.68, 144.81 (m), 134.48
(m), 127.76 (m), 124.17 (m), 119.47 (m), 109.29, 5.67. HRMS calculated
216.0882, found 216.0886.
1H NMR (CDCl3) δ 8.11–7.98 and 7.89–7.78 (m, 1H), 7.70–7.27 (m, 4 H)
and 7.21–6.93 (m, 1H), 6.84 (dd, J = 7.89, 0.82 Hz, 1H), 3.93 (s, 3H),
3.83 (br s, 1H). 13C NMR (CDCl3) δ 142.6 (m), 126.7 (m), 125.0 (m),
120.1 (m), 112.7, 108.5, 55.3, 34.2 (d, J = 44.9 Hz). HRMS calculated
216.0882, found 216.0882.
General procedure for the preparation of fluorenol 7
1-Methoxy-9-fluorenone 5d (58%)
1H NMR (CDCl3) δ 8.25–8.02 and 7.35–7.15 (m, 1H), 7.90–7.67 (m, 1H), To
a solution of 3-methoxyfluorene 6c (0.433 g, 2.14 mmol) in
7.67–7.46 (m, 1H), 7.56–7.47 (m 1H), 7.47–7.35 (m, 1H), 7.12–7.05 (m, dichloromethane (10.0 mL) was added dropwise 1.0-M boron tribromide
1H), 6.92 (dd, J = 68.6, 8.5 Hz, 1H), 3.75 (s, 3H). 13C NMR (CDCl3) δ 157.61, in dichloromethane (2.36 mL, 2.36 mmol) at 0 °C. The mixture was
134.65 (m), 132.97 (m), 129.77 (m), 128.10 (m), 124.01, 120.98, 55.61.
allowed to warm to room temperature and stirred for 1 h or until the
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J. Label Compd. Radiopharm 2013, 56 581–586

R. Wu et al.
TLC showed a complete reaction. Methanol was added to decompose
excess boron tribromide while cooled at 0 °C. The solvent was removed
under reduced pressure, and the residue was adsorbed on silica gel
and purified by flash chromatography with 10% ethyl acetate in hexanes
to provide the title product 7c (0.334 g, 83%).
4-Methoxyphenanthrenols 9a (88%)
1H NMR (CDCl3) δ 10.10–9.10 (m, 1H), 9.10–7.90 (m, 2H), 7.90–7.30 (m, 3H),
7.30–7.10 (m, 2H), 4.18, 4.16 (two s, 3H). 13C NMR (CDCl3) δ 140.33 (m),
135.79 (m), 132.81 (m), 130.04 (m), 128.42 (m), 56.20.
3-Methoxyphenanthrenols 9b (89%)
4-Fluorenol 7a (80%)
1H NMR (CDCl3) δ 8.90–7.70 (m, 4H), 7.70–7.50 (m, 1H), 7.50–7.25 (m, 1H),
7.25–6.90 (m, 1H), 4.09, 4.03 (two s, 3H). 13C NMR (CDCl3) δ 136.14 (m),
130.78 (m), 126.74 (m), 124.18 (m), 122.14 (m), 55.45, 55.33 (two s).
1H NMR (CDCl3) δ 8.47–8.35 and 7.50–7.40 (m, 1H), 7.95–7.76 (m, 1H),
7.76–7.50 (m, 1H), 7.40–6.90 (m, 3H), 6.90–6.77 (m, 1H ), 4.00 (br, s, 2H).
13C NMR (CDCl3) δ 141.54 (m), 135.01 (m), 128.38 (m), 126.38 (m),
124.28 (m), 117.61, 113.66, 37.24 (br d, J = 43.47 Hz). Anal. Calcd for
13C162C7H10O: C, 86.14; H, 5.36. Found: C, 85.71; H, 5.60.
2-Methoxyphenanthrenols 9c (84%)
1H NMR (CDCl3) δ 9.20–8.35 (m, 1H), 8.35–7.70 (m, 3H), 7.70–7.35 (m 2H),
7.30–7.20 (m, 1H), 7.20–6.90 (m, 1H), 4.07, 4.04 (two s, 3H). 13C NMR
(CDCl3) δ 135.78 (m), 133.43 (m), 130.99 (m), 126.68 (m), 124.66(m),
122.73 (m).
3-Fluorenol 7b (83%)
1H NMR (CDCl3) δ 8.08–7.78 (m, 1H), 7.78–7.54 (m, 1H), 7.54–7.46 and
7.38–7.25 (m, 1H), 7.25–6.90 (m, 1H), 7.44 (d, J = 8.08 Hz, 1H), 7.30 (t,
J = 3.03 Hz, 1 H), 6.84 (dd, J = 8.08, 2.37 Hz, 1H). 13C NMR (CDCl3) 144.36
(m), 141.25 (m), 126.46 (m), 124.87 (m), 119.80 (m), 114.06 (m), 36.13 (br
d, J = 38.15 Hz). HRMS calculated 188.0933, found 188.0929.
1-Methoxyphenanthrenols 9d (75%)
1H NMR (CDCl3) δ 9.58 and 9.02–8.54 (m, 1H), 8.49–7.69(m, 3H), 7.69–7.42
(m, 2H), 7.20–6.90 (m, 2H), 4.16, 4.06 (two s, 3H). 13C NMR (CDCl3) δ 133.4
(m), 130.9 (m), 126.6 (m), 125.0 (m), 124.1 (m), 122.9 (m), 116.7 (s), 106.6
(s), 56.1 (s).
2-Fluorenol 7c (91%)
1H NMR (CDCl3). δ 8.00–7.89 and 7.84–7.70 (m, 1H), 7.64 (dd, J = 8.17,
2.25 Hz, 1H), 7.60–6.92 (m, 3H), 7.05 (s, 1H), 6.85 (dd, J = 8.17, 2.25 Hz,
1H), 3.85 (s). 13C NMR (CDCl3) δ 142.3 (m, 1C), 125.9 (m, 3C), 119.2 (m,
1C), 37.1 (br d, J = 41.7 Hz). HRMS calculated 188.0933, found 188.0930.
General procedure for the preparation of
methoxyphenanthrenyl tosylate 10
To a solution of methoxyphenanthrenol 9b (1.084 g, 4.710 mmol) in
dichloromethane (80.0 mL) was added triethylamine (1.43 g, 14.1 mmol)
followed by triflic anhydride (3.99 g, 14.1 mmol) at 0 °C. The mixture
was allowed to warm to room temperature and stirred for 2–3 h or until
TLC showed a complete reaction. The reaction mixture was washed with
5% sodium bicarbonate, brine and extracted with dichloromethane. The
combined organic extracts were dried with sodium sulfate. The solvent
was removed under reduced pressure, and the residue was purified on
silica gel with 5% ethyl acetate in hexanes to provide the title product
(1.35 g, 79%).
1-Fluorenol 7d (88%)
1H NMR (CDCl3) δ 8.09–7.99 and 7.90–7.78 (m, 1H), 7.73–7.24 (m, 4H),
7.24–6.92 (m, 1H), 6.77 (d, J = 7.89, 0.77 Hz, 1H), 3.85 (d, J = 3.34 Hz, 2H).
13C NMR (CDCl3) δ 142.2 (m), 126.8 (m), 125.1 (m), 120.1 (m), 33.3 (br d,
J = 40.7 Hz).
9-Phenanthrenol 8 (63%)
To a solution of 9-fluorenone 2 (0.372 g, 2.00 mmol) in dichloromethane
(20.0 mL) was added dropwise boron trifluoride (0.38 mL, 1.12 mmol) at
À78 °C followed by dropwise addition of 2.0 M trimethylsilyl
diazomethane in hexanes (41.5 mL, 3.0 mmol). The mixture was stirred
at À78 °C for 1 h or until TLC showed a complete reaction. Water was
added to the reaction mixture, and the layers were separated. The
aqueous layer was extracted with dichloromethane. The combined
organic layers were washed with brine and dried over sodium sulfate.
The solvent was removed under reduced pressure, and the residue was
purified on silica gel with 30% ethyl acetate in hexanes to provide the
title product 8 (0.254 g, 63%). 1H NMR (CDCl3) δ 9.05–8.55 (m, 2H),
8.55–8.30 (m, 1H), 8.30–7.90 (m, 1H), 7.90–7.65 (m, 2H), 7.65–7.50 (m,
1H), 7.50–7.20 (m, 1H), 7.10–6.95 (m, 1H). 13C NMR (CDCl3) δ 136.02 (m),
131.53 (m), 126.68 (m), 122.46 (m). HRMS calculated 200.0933, found
200.0937.
4-Methoxyphenanthrenyl triflate 10a (72%)
1H NMR (CDCl3) δ 10.0–6.80 (m, 8H), 4.07 (s, 3H). 13C NMR (CDCl3) δ 135.36
(m), 132.37 (m), 129.61 (m), 127.61 (m), 55.80.
3-Methoxyphenanthrenyl triflate 10b (71%)
1H NMR (CDCl3) δ 9.00–7.80 (m, 4H), 7.80–7.30 (m, 4H), 4.03, 4.02 (two s,
3H). 13C NMR (CDCl3) δ 160.00 (d, J = 16.1 Hz), 131.99 (m), 129.53 (m),
128.22 (m), 126.83 (m), 124.42 (m), 122.59 (m), 109.00 (d, 3.0 Hz),
101.83, 55.68, 55.62 (two s). HRMS calculated 362.0531, found 362.0526.
2-Methoxyphenanthrenyl triflate 10c (79%)
1H NMR (CDCl3) δ 9.00–7.80 (m, 5H), 7.80–7.45 (m, 2H), 7.41, 7.35 (two dd,
J = 9.08, 2.50 Hz, 1H), 4.07, 4.08 (two s, 3H). 13C NMR (CDCl3) δ 160.00 (dd,
J = 13.5, 4.7 Hz), 131.11 (m), 127.97 (m), 127.41 (m), 125.70 (m), 122.93 (m),
121.59 (m), 55.57, 55.55(two s), 42.56. HRMS calculated 362.0531, found
362.0528.
General procedure for the preparation of
methoxyphenanthrenols 9
1-Methoxyphenanthrenyl triflate 10d (59%)
To a solution of 2-methoxyfluorenone 5c (1.211 g, 5.600 mmol) in
dichloromethane (56 mL) was added dropwise boron trifluoride
(1.192 g, 8.400 mmol) at À20 °C. A solution of 2.0 M trimethylsilyl
diazomethane (4.2 mL, 8.4 mmol) in hexanes was diluted with
dichloromethane (40 mL) and then added dropwise via cannula to the
previous reaction mixture. The reaction mixture was stirred at this
temperature for 2 h or until the TLC showed a complete reaction. Water
was added and the layers were separated. The aqueous layer was
extracted with dichloromethane, and the combined organic layers were
washed with brine and dried over sodium sulfate. The solvent was
removed under reduced pressure, and the residue was purified on silica
1H NMR (CDCl3) δ 9.06–8.87 and 8.54–8.40 (m, 1H), 8.40–7.86 (m, 3H),
7.76–7.38 (m, 3H), 7.21–7.08 (m, 1H), 4.09 (s, 3H). 13C NMR (CDCl3) δ
131.3 (m), 129.7 (m), 127.7 (m), 127.3 (m), 123.1 (m), 121.1 (m), 115.1,
114.5, 112.0, 108.0, 106.2, 55.4, 55.0.
General procedure for the preparation of
methoxyphenanthrene 11
A stirred mixture of 4-methoxyphenanthrenyl triflate 10a (1.258 g,
3.470 mmol), palladium acetate (0.030 g, 0.13 mmol), triphenylphosphine
gel with 5% ethyl acetate in hexanes to provide the title product (0.0703 g, 0.266 mmol), triethylamine (2.107 g, 20.82 mmol) and formic
(1.084 g, 84%).
acid (0.55 mL, 85% in water) in dimethyl formamide (12.0 mL) was heated
J. Label Compd. Radiopharm 2013, 56 581–586
Copyright © 2013 John Wiley & Sons, Ltd.
www.jlcr.org

R. Wu et al.
to 80–85 °C overnight, cooled to room temperature, and water was
added. The layers were separated and the aqueous layer was extracted
with ethyl acetate. The combined organic layers were washed with brine
and dried over sodium sulfate. The solvent was removed under reduced
pressure, and the residue was purified on silica gel with 5% ethyl acetate
hexanes, v/v, using 60 A silica gel, to provide the title product 11d
(0.655 g, 88%).
2-Hydroxyphenanthrene 12c (70%)
1H NMR (CDCl3) δ 8.93–8.82 and 8.41–8.30 (m, 1H), 8.63 (dd, J = 8.6, 2.6 Hz,
1H), 8.22–7.51 (m, 4H), 7.48–7.22 (m, 3H), 4.99 (br s, 1H). 13C NMR (CDCl3)
δ 130.3, 128.2, 126.4, 125.1, 121.5. HRMS calculated 200.0933, found
200.0928.
1-Hydroxyphenanthrene 12d (90%)
1H NMR (CDCl3) δ 9.05–8.86 and 8.53–8.39 (m, 1H), 8.38–7.60 (m, 5H),
7.60–7.33 (m, 2H), 7.02 (d, J = 7.7 Hz), 5.37 (br s). 13C NMR (CDCl3) δ
131.1 (m), 128.1 (m), 126.6 (m), 125.8 (m), 123.4 (m), 122.7 (m), 119.5,
115.1, 110.2.
4-Methoxyphenanthrene 11a (88%)
1H NMR (CDCl3) δ 10.10–9.30 (m, 1H), 8.40–7.30 (m, 7H), 7.30–7.10 (m, 1H),
4.20 (s, 3H). 13C NMR (CDCl3) δ 131.16, 129.24, 128.17, 127.12, 126.05,
125.60, 121.13 (d, J = 2.3 Hz), 107.89 (d, J = 0.13 Hz), 55.30.
3-Methoxyphenanthrene 11b (90%)
Acknowledgements
1H NMR (CDCl3) δ 9.00–8.00 (m, 3H), 8.00–7.50 (m, 4H), 7.50–7.10 (m, 2H),
4.00 (s, 3H). 13C NMR (CDCl3) δ 158.23, 130.70, 128.45, 126.04, 122.08,
117.06 (d, J = 3.9 Hz), 108.47 (d, J = 1.8 Hz), 55.39. HRMS calculated
200.0933, found 200.0927.
We gratefully acknowledge the support of this work by the CDC
(R-2589-03-0) and the Los Alamos National Laboratory LDRD
program (Silks: 20060317 ER: X9DN, Understanding the Process
of Intercalation Using Stable Isotope Labeled Polyaromatic
Hydrocarbons (PAHs) and Oligomeric DNA; the Quantitation of
Weak Bonding in DNA).
2-Methoxyphenanthrene 11c (100%)
1H NMR (CDCl3) δ 9.05–8.30 (m, 1H), 8.30–7.50 (m, 6H), 7.50–7.20 (m, 2H),
4.05 (s, 3H). 13C NMR (CDCl3) δ 158.41 (d, J = 4.9 Hz), 132.38 (m), 129.60
(m), 128.63 (m), 126.68 (m), 125.91 (m), 122.49 (m), 116.70, 103.89,
55.47. HRMS calculated 214.1089, found 214.1092.
Conflict of Interest
The authors did not report any conflict of interest.
1-Methoxyphenanthrene 11d (93%)
1H NMR (CDCl3) δ 9.04–8.91 and 8.52–8.40 (m, 1H), 8.39–7.32 (m, 7H), 7.06
(d, J = 7.8 Hz), 4.09 (s, 3H). 13C NMR (CDCl3) δ 133.5 (m), 126.6 (m), 124.8
(m), 124.1 (m), 122.9 (m), 116.70, 106.6, 56.1.
References
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General procedure for the preparation of
hydroxyphenanthrene 12
[2] For 1-, 2-, 3-, and 4-fluorenols, see: M. A. Salvadora, P. J. Coelho,
H. D. Burrows, M. M. Oliveira, L. M. Carvalho, Helv. Chim. Acta 2004,
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Ota, H. Hiratsuka, Y. Mori, S. Tanaka, J. Org. Chem. 1985, 50(25),
5105. For 9-hydroxyphenanthrene, see: J. N. Chatterjea, A. K.
Sinha, C. Bhakta, S. N. Mukherjee, Indian J. Chem. Sec. B 1979,
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M. Hallett, A. A. Etheredge, J. Grainger, D. G. Patterson Jr.,
To a solution of methoxyphenanthrene 11c (0.854 g, 3.99 mmol) in
dichloromethane (18.0 mL) was added dropwise 1.0-M boron tribromide
in dichloromethane (4.39 mL, 4.39 mmol) at 0 °C. The mixture was
allowed to warm to room temperature and stirred for 1–2 h or until the
TLC showed a complete reaction. Methanol was added to the reaction
mixture to decompose excess boron tribromide while cooled at 0 °C.
The solvent was removed under reduced pressure. The residue was
adsorbed on silica gel and purified using silica gel chromatography
using10% ethyl acetate/hexanes, v/v, to provide the title product
(0.558 g, 70%).
4-Hydroxyphenanthrene 12a (90%)
1H NMR (CDCl3) δ 10.15–9.20 (m, 1H), 8.40–7.30 (m, 7H), 7.20–6.90 (m, 1H),
6.00–5.30 (br s, 1H). 13C NMR (CDCl3) δ 131.46 (m), 129.58 (m), 128.44 (m),
122.72 (m), 126.47 (m), 125.80 (m), 121.74 (d, J = 2.46 Hz), 113.22 (d,
J = 2.72 Hz). Anal. Calcd. for 13C612C8H10O: C, 86.97; H, 5.04. Found: C,
84.51; H, 5.40.
Polycyclic Aromatic Compounds 2008, 28, 434. For
a general
review see R. G. Harvey, Polycyclic Aromatic Hydrocarbons:
Chemistry and Carcinogenicity, 2009, Cambridge University Press,
Cambridge, 667.
3-Hydroxyphenanthrene 12b (60%)
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Flaim, J. Med. Chem. 1986, 29, 1904.
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[8] J. M. Fu, V. Snieckus, Can. J. Chem. 2000, 78, 905.
1H NMR (CDCl3) δ 9.00–8.25 (m, 2H), 8.25–7.50 (m, 4H), 7.50–7.20 (m, 3H).
13C NMR (CDCl3) δ 130.85 (m), 128.76 (m), 126.29 (m), 122.09 (m), 116.72
(d, J = 4.16 Hz), 111.90 (d, J = 2.76 Hz). HRMS calculated 200.0933, found
200.0927. Anal. Calcd. for 13C612C8H10O: C, 86.97; H, 5.04. Found: C,
85.65; H, 5.26.
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Copyright © 2013 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2013, 56 581–586