Modular, Metal-Catalyzed Cycloisomerization Approach to Angularly Fused Polycyclic Aromatic Hydrocarbons and Their Oxidized Derivatives

Article abstract of DOI:10.1021/acs.joc.5b00931

Palladium-catalyzed cross-coupling reactions of 2-bromobenzaldehyde and 6-bromo-2,3-dimethoxybenzaldehyde with 4-methyl-1-naphthaleneboronic acid and acenaphthene-5-boronic acid gave corresponding o-naphthyl benzaldehydes. Corey-Fuchs olefination followed by reaction with n-BuLi led to various 1-(2-ethynylphenyl)naphthalenes. Cycloisomerization of individual 1-(2-ethynylphenyl)naphthalenes to various benzo[c]phenanthrene (BcPh) analogues was accomplished smoothly with catalytic PtCl₂ in PhMe. In the case of 4,5-dihydrobenzo[l]acephenanthrylene, oxidation with DDQ gave benzo[l]acephenanthrylene. The dimethoxy-substituted benzo[c]phenanthrenes were demethylated with BBr₃ and oxidized to the o-quinones with PDC. Reduction of these quinones with NaBH₄ in THF/EtOH in an oxygen atmosphere gave the respective dihydrodiols. Exposure of the dihydrodiols to N-bromoacetamide in THF-H₂O led to bromohydrins that were cyclized with Amberlite IRA 400 HO^- to yield the series 1 diol epoxides. Epoxidation of the dihydrodiols with mCPBA gave the isomeric series 2 diol epoxides. All of the hydrocarbons as well as the methoxy-substituted ones were crystallized and analyzed by X-ray crystallography, and these data are compared to other previously studied BcPh derivatives. The methodology described is highly modular and can be utilized for the synthesis of a wide variety of angularly fused polycyclic aromatic hydrocarbons and their putative metabolites and/or other derivatives.

Full text of DOI:10.1021/acs.joc.5b00931

Article
pubs.acs.org/joc
Modular, Metal-Catalyzed Cycloisomerization Approach to Angularly
Fused Polycyclic Aromatic Hydrocarbons and Their Oxidized
Derivatives
Paul F. Thomson,† Damon Parrish,‡ Padmanava Pradhan,† and Mahesh K. Lakshman*,†
†Department of Chemistry, The City College and The City University of New York, 160 Convent Avenue, New York, New York
10031, United States
‡Naval Research Laboratory, Code 6030, 4555 Overlook Avenue, Washington D.C. 20375, United States
S
* Supporting Information
ABSTRACT: Palladium-catalyzed cross-coupling reactions of 2-bromobenzaldehyde and 6-bromo-2,3-dimethoxybenzaldehyde
with 4-methyl-1-naphthaleneboronic acid and acenaphthene-5-boronic acid gave corresponding o-naphthyl benzaldehydes.
Corey−Fuchs olefination followed by reaction with n-BuLi led to various 1-(2-ethynylphenyl)naphthalenes. Cycloisomerization
of individual 1-(2-ethynylphenyl)naphthalenes to various benzo[c]phenanthrene (BcPh) analogues was accomplished smoothly
with catalytic PtCl2 in PhMe. In the case of 4,5-dihydrobenzo[l]acephenanthrylene, oxidation with DDQ gave
benzo[l]acephenanthrylene. The dimethoxy-substituted benzo[c]phenanthrenes were demethylated with BBr3 and oxidized to
the o-quinones with PDC. Reduction of these quinones with NaBH4 in THF/EtOH in an oxygen atmosphere gave the respective
dihydrodiols. Exposure of the dihydrodiols to N-bromoacetamide in THF-H2O led to bromohydrins that were cyclized with
Amberlite IRA 400 HO− to yield the series 1 diol epoxides. Epoxidation of the dihydrodiols with mCPBA gave the isomeric series
2 diol epoxides. All of the hydrocarbons as well as the methoxy-substituted ones were crystallized and analyzed by X-ray
crystallography, and these data are compared to other previously studied BcPh derivatives. The methodology described is highly
modular and can be utilized for the synthesis of a wide variety of angularly fused polycyclic aromatic hydrocarbons and their
putative metabolites and/or other derivatives.
readily applied. One case would be the unavailability of
appropriate precursors for the photocyclization. Thus, alter-
native methods have been developed for the assembly of
molecules containing a phenanthrene subunit. Some represen-
tative examples are cyclization reactions using electrophiles,
such as ICl14 and IBF4,15 Pd-catalyzed annulation,16 intra-
molecular olefin metathesis,17 Friedel−Crafts type reactions of
geminal difluoroalkenes in FSO3H·SbF5 (magic acid),18 Rh(II)-
catalyzed dimerization of carbenes formed from bis tosylhy-
drazones,19 t-BuOK-mediated intramolecular cyclization of 1-
(2-methylaryl)-3,4-dihydronaphthalene-2-carbaldehydes in the
presence of light,20 intramolecular Diels−Alder reaction of
allenyl alcohols obtained by AuCl3-catalyzed rearrangement of
homopropargylic alcohols,21 Ru-catalyzed benzannulation
processes,22 and Pd-mediated C−H bond-activation and
arylation.23 PtCl2, AuCl3, GaCl3, InCl3, as well as designed Pt
INTRODUCTION
■
One of the classical methods for the synthesis of compounds
containing a phenanthrene moiety is oxidative photocycliza-
tion.1−8 In this approach, cis/trans stilbene-like molecules are
subjected to photochemical ring closure to yield dihydroar-
omatic systems, which then undergo oxidation with catalytic I2
and air to yield the fully aromatized final products. The high
value of this method has led to improvements in order to attain
cleaner reactions and better product yields. The most notable
of these improvements are the use of propylene oxide9 or
THF10 as sponges for the liberated HI. More recently, C−H
bond activation to yield substituted stilbenes, followed by
oxidative-photochemical cyclization has been reported, wherein
PhI(OAc)2 was used as the oxidant.11 The power of
photocyclization chemistry is exemplified in the range of
compounds that can be synthesized, and recent reviews provide
relevant representative examples.12,13
Despite the broad applicability of the photocyclization
Received: April 24, 2015
approach, there are scenarios in which this method cannot be
© XXXX American Chemical Society
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Scheme 1. Oxidative Metabolism of Polycyclic Aromatic Hydrocarbons and DNA Damage
Scheme 2. Retrosynthetic Analysis of the Proposed Approach
and Au catalysts have been evaluated for the 6-endo-dig
cyclization of o-ethynylbiaryl systems.24−26 The combination of
PtCl2/PtCl4 has been reported for hydroarylation-cycloisome-
rization.27
RESULTS AND DISCUSSION
■
We chose to demonstrate the metal-mediated cycloisomeriza-
tion approach via the modular synthesis of two remotely
functionalized BcPh derivatives as well as their putative
dihydrodiol and diol epoxide metabolites. The retrosynthetic
analysis is shown in Scheme 2. In fact, this approach has been
used for the synthesis of BcPh in a demonstration of the
chemistry.24
In the present case, the key would be the identification of
suitable building blocks that can be used to modularly assemble
various polycyclic hydrocarbon derivatives, which can then be
elaborated to the oxidized metabolites. In Scheme 2, either
building block could serve as the electrophile in the cross
coupling with the other serving as the nucleophile. Because
various arylboronic acids and related derivatives are readily
available, either commercially or by synthesis, these were
selected as the nucleophiles for the cross-coupling step. Thus,
2-bromobenzaldehyde and 6-bromo-2,3-dimethoxybenzalde-
hyde were chosen as the electrophilic cross-coupling partners.
Whereas the former is commercially available, the latter (a
known compound37) can be readily prepared on a multigram
scale (Scheme 3). Bromination of 2,3-dimethoxybenzyl alcohol
with NBS in THF gave the known 6-bromo-2,3-dimethox-
ybenzyl alcohol (2),38 which upon oxidation with PCC in
CH2Cl2,39 then gave required aldehyde 3.
For studies on the molecular mechanisms of chemical
carcinogenesis by polycyclic aromatic hydrocarbons (PAHs),
simple and facile routes to the hydrocarbons and their
metabolites are necessary. PAHs are products of incomplete
combustion of organic matter and are widely distributed in the
environment. Because of their ubiquitous presence, they pose a
significant health risk. Among this large family of compounds,
alternant hydrocarbons possessing a bay or fjord region are
particularly important. In mammalian systems, bay- and fjord-
region-containing polycyclic aromatic hydrocarbons are meta-
bolically converted to proximate carcinogens, dihydrodiols, by
the combined actions of CYP450 and epoxide hydrolase.28
Further oxidation of the dihydrodiols by CYP450 produces four
isomeric electrophilic diol epoxides, which then covalently
modify DNA.28,29 Dihydrodiols are also implicated in
dihydrodiol dehydrogenase-mediated redox cycles, resulting in
the formation of DNA damaging reactive oxygen species and o-
quinones (Scheme 1).30,31
Substituted chrysenes and benzo[c]phenanthrenes (BcPhs)
have been of significant interest in chemical carcinogenesis and
access to these ring systems is available by photocyclization of
appropriate 1- and 2-styryl naphthalenes, respectively.32−34
Introduction of methoxy substituents into the angular ring then
allows for the conversion of the hydrocarbons to their oxidized
metabolites, the dihydrodiols and diol epoxides, via o-
quinones.33−36 Despite the convenience of the photochemical
approach, availability of starting materials can be a limitation.
Thus, we decided to explore the utility of PtCl2- and AuCl3-
mediated cycloisomerization of o-ethynylbiaryls as a method to
access unusual polycyclic aromatic hydrocarbons and their
putative metabolites.
Scheme 3. Synthesis of 6-Bromo-2,3-
dimethoxybenzaldehyde as a Key Building Block
B
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Scheme 4. Initial Tests on the in Situ Formation of a Boronate Ester and Cross Coupling
Because synthesis of biaryls via in situ formation of
arylboronates has been reported,40 we initially considered the
formation of pinacol boronate esters from aryl halides41 for
cross coupling with bromo aldehyde 3. Along these lines, initial
experiments were conducted on 1-bromonaphthalene as a
representative example (Scheme 4). Reaction of 1-bromonaph-
thalene (4) with bis(pinacolato)diboron was performed using
PdCl2(dppf)/KOAc in DMF at 80 °C, followed by cross
coupling with aldehyde 3 as per the literature.41 Although
product 6 could be obtained in respectable 79−86% yields,
extensive and repeated column chromatography was necessary
to obtain pure product. Thus, this approach was discontinued.
The more traditional cross coupling of boronic acids was
then considered. 4-Methyl-1-naphthaleneboronic acid (7) and
acenaphthene-5-boronic acid (8) were selected for further
elaboration to the respective hydrocarbons as well as the
putative metabolites. Although both boronic acids are
commercially available, they are relatively expensive. Hence,
these were prepared by lithiation of commercially available 1-
bromo-4-methylnaphthalene as well as 5-bromoacenaphthene,
followed by reaction with B(OMe)3, and hydrolysis (89% yield
of compound 7 and 77% yield of compound 8). Each boronic
acid was cross coupled with the bromo aldehydes 3 and 9 using
Pd(PPh3)4 and CsF in DME at reflux. The product structures
and yields are summarized in Table 1.
In earlier work,42 similar biaryl aldehydes were elaborated to
either oxiranes (reaction with Me2SCH2) or methoxyethenes
(reaction with MeOCHPPh3), which upon exposure to
suitable Bronsted or Lewis acids underwent cyclization and
aromatization to polycyclic hydrocarbons. In the present
method, alkynylation was the next step in the sequence.
Initially, the Bestmann−Ohira alkynylation was attempted on
aldehyde 10. Use of dimethyl-2-oxopropylphosphonate (1.2
molar equiv), p-TsN3 (1.2 molar equiv), and K2CO3 (3 molar
equiv), under literature conditions43 led to a 55% isolated yield
of the alkyne. The use of NaH caused a drastic reduction in the
yield (39%). By comparison, the Corey−Fuchs two-step
alkynylation44 gave far superior results (97% yield for the
gem-dibromide and 81% yield for the alkynylation, 78%
overall). Thus, this became the preferred method to access
the requisite cyclization precursors. The overall methodology
up to the cyclization step is shown in Scheme 5.
Generally, good yields were obtained over two steps leading
to alkynyl products 14−17 (56−78%). At this stage, both
AuCl3 and PtCl2 were evaluated for the cyclization. Although 5
mol % AuCl3 in PhMe at 80 °C gave 84% yield of dimethoxy
BcPh 18, the yield of analogue 19 with this catalyst was 59%. In
contrast, 5 mol % PtCl2 in PhMe at 80 °C gave compounds 18
and 19 in comparable yields of 75 and 72%, respectively.
Additional test reactions were conducted on the cyclization of
1-(2-ethynylphenyl)naphthalene. Here, in PhMe at 80 °C,
PtCl2 gave a 69% yield of BcPh, which is comparable to the
yield reported in the literature,24 whereas AuCl3 gave only 45%
yield. On the basis of these results, as well as the hygroscopic
nature of AuCl3, PtCl2 appears to be a suitable catalyst.
Cyclization of alkynes 16 and 17 with PtCl2 led to BcPh
derivatives 20 and 21 in yields of 81 and 69%, respectively.
At this stage, we had completed the synthesis of the
precursors to the putative oxidized metabolites of 5-
methylbenzo[c]phenanthrenene (5-MBcPh), 4,5-dihydro-
benzo[l]acephenanthrylene (H2B[l]A), and the parent hydro-
carbons. As shown in Scheme 6, demethylation of compounds
18 and 19 with BBr3 gave catechols, which were directly
converted to o-quinones 22 and 23, respectively, by oxidation
with PDC. Both quinones showed characteristic fjord-region
quinonoid proton resonances (d, J = 10.5 Hz), which
corresponded well with other quinones of BcPh and its
derivatives.32e,33,34
Table 1. Products of the C−C Cross Coupling and Yields
Reduction of quinones 22 and 23 with NaBH4 in EtOH,
under an oxygen atmosphere,33−35 led to dihydrodiols ( )-24
Scheme 5. Synthesis of the Various Polycyclic Aromatic Hydrocarbons
C
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Scheme 6. Synthesis of the Dihydrodiols and Diol Epoxides of 5-MBcPh and H2B[l]A
and ( )-25, respectively. Diastereoselective conversion of the
dihydrodiols to the diol epoxides, based upon literature
procedures,45 depends upon the trans hydroxyl groups being
predominantly diequatorial. Thus, the conformations of
dihydrodiols 24 and 25 were evaluated by 1H NMR
spectroscopy. In both cases, the hydroxyl groups were
predominantly diequatorially disposed as indicated by the
>11 Hz coupling constant between the carbinol protons in
acetone-d6. This is comparable to the coupling constant
observed for the carbinol protons in BcPh (J = 10.8 Hz in
CD3OD)46 and the 1,4-difluoro derivative (DFBcPh, J = 11.0
Hz in acetone-d6).34 Unlike the dihydrodiol of 1,4-
dimethylbenzo[c]phenanthrene (DMBcPh),33 compounds 24
and 25 did not demonstrate P and M hydrocarbon helicity, and
these were similar to dihydrodiols of BcPh and DFBcPh.
Exposure of dihydrodiols 24 and 25 to N-bromoacetamide
(NBA) in THF-H2O gave the respective bromotriols in 97 and
95% yield. Cyclization of the bromotriols to the series 1 diol
epoxides ( )-26 and ( )-27 was accomplished with the
hydroxide form of Amberlite IRA 400. Yields in the epoxidation
step were 64% for 26 and 60% for 27. Synthesis of the series 2
diol epoxides was accomplished by exposure of the dihydrodiols
to mCPBA in dry THF. Thus, ( )-24 gave ( )-28 in 69% yield
and ( )-25 gave ( )-29 in 80% yield.
in Figure 1). This was further supported by the additional weak
interaction between H-1 and H-4. Similarly, and as compared
to compound ( )-26, in diol epoxide ( )-27, interaction
between H-9 (δ 4.83 ppm) and H-11 (δ 3.90 ppm) and a weak
interaction between H-9 and H-12 (δ 4.45 ppm) were observed
(see the Supporting Information for spectra).
From a conformation standpoint, in the absence of unusual
factors, bay-region series 1 diol epoxides of polycyclic aromatic
hydrocarbons generally exhibit a quasidiaxial arrangement of
the hydroxyl groups, and in the series 2 isomers, these are
quasidiequatorial.28c Typically, series 2 diol epoxides, with
quasiequatorial hydroxyl groups, are tumorigenic, whereas the
series 1 isomers are not.28,29 In the case of BcPh, both series 1
and series 2 diol epoxides exhibit quasidiequatorial hydroxyl
groups due to steric buttressing in the fjord region of the
hydrocarbon.47 Correspondingly, this has important implica-
tions on the biological activity, and the (+)-series 1 BcPh diol
epoxide enantiomer showed high tumor-initiating ability in the
mouse skin model.48 It would therefore be instructive to
compare the conformational preferences of the various diol
epoxides synthesized to date that contain the BcPh scaffold
(Figure 2).
We have not previously synthesized the series 1 diol epoxide
from DMBcPh because of complications related to the P/M
helicity elicited by its dihydrodiol.33 However, we have
synthesized both series 1 and 2 diol epoxides of DFBcPh.34
In comparison to the series 1 diol epoxide of BcPh, the
corresponding diol epoxide from DFBcPh shows a significantly
smaller coupling constant between the carbinol protons (Figure
2), indicative of a predominantly diaxial orientation of the
hydroxyl groups in the latter (the coupling constant between
the carbinol protons for the BcPh series 1 diol epoxide in
acetone-d6 is comparable to that in DMSO-d634). This
difference between the two hydrocarbons is likely due to the
extreme out-of-plane distortion of DFBcPh.34 The series 1 diol
epoxide of benzo[ghi]fluoranthene (B[ghi]F), a compound that
is expected to be more planar than both BcPh and DFBcPh,
surprisingly, also shows a much smaller coupling constant
between its carbinol protons (J = 2.1 Hz),49 identical to that
observed with DFBcPh. By contrast, the hydroxyl group
conformation in the series 1 diol epoxides of both 5-MBcPh
[( )-26)] and H2B[l]A [( )-27)] are comparable to that in
BcPh.
NOESY spectra for the series 1 diol epoxides ( )-26 and
( )-27 were evaluated to support the relative stereochemistry
(Figure 1). For compound ( )-26, NOESY cross peaks
Figure 1. NOESY correlations between protons leading to assign-
ments (dashed blue lines) and relative stereochemical arrangement of
substituents (green ovals).
between the resonance at δ 4.82 ppm and the upfield resonance
of the ABq at δ 7.96 ppm led to the unequivocal assignment of
the former resonance as H-4. The doublet at δ 4.36 ppm was
assigned to H-1 on the basis of its NOESY cross peak with the
doublet at δ 9.19 ppm (H-12), which was coupled to a proton
that produced a triplet resonance. The rest of the
tetrahydrobenzo protons were easily assigned on the basis of
their coupling constants. In diol epoxide ( )-26, the relative
stereochemistry of H-2 (δ 3.95 ppm) and H-4 (δ 4.82 ppm)
was cis based on the NOESY interaction (shown in green ovals
Evaluation of the series 2 diol epoxides (Figure 2) shows a
general uniformity in the hydroxyl group orientation, which are
quasidiequatorial, with the carbinol coupling constants in the
8.0−8.7 Hz range. Remarkably, the more planar B[ghi]F as well
as the highly nonplanar DFBcPh and DMBcPh diol epoxides
have comparable conformations (diastereomeric P and M
D
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Figure 2. Various diol epoxides having the BcPh structure and the coupling constants of their carbinol protons.
Scheme 7. Synthesis of Benzo[l]acephenanthrylene and the Structures of the Related Hydrocarbons Cholanthrene and
Cyclopenta[c,d]pyerene
Figure 3. Crystal structures of several of the synthesized BcPh derivatives.
helical dihydrodiols from DMBcPh have very similar carbinol
coupling constants33). From this evaluation it appears that,
among the BcPh analogues, conformations of the series 1 diol
epoxides have a greater dependence on subtle differences in
molecular structure, whereas the series 2 diol epoxides appear
generally independent of it.
Because we have synthesized H2B[l]AP (21 in Scheme 5), an
isomer of the carcinogen cholanthrene,50 we decided to
dehydrogenate compound 21 to benzo[l]acephenanthrylene
(B[l]AP, 30). Compound 30 is related to cyclopenta[c,d]-
pyrene, a powerful mutagen and carcinogen.51 Exposure of
BcPh derivative 21 to DDQ in PhMe at 80 °C gave B[l]AP
(30) in 72% yield (Scheme 7). Compound 21 has previously
been synthesized in 24−42% yields via a Wittig reaction/
photocyclization approach starting from 1-indanone.52 By
comparison, the three-step yield of 21 obtained herein was
36%. A marginally better yield (by 12%) was obtained for the
conversion of H2B[l]AP (21) to B[l]AP 30 as compared to the
literature.52
To gain greater insight into the new hydrocarbons
synthesized, we undertook X-ray crystallographic analysis.
Figure 3 shows the structures of 5-MBcPh (20), H2B[l]AP
(21), B[l]AP (30), as well as the two dimethoxy compounds 18
and 19. From these structures, the molecular distortion in BcPh
derivatives 18−21 is clearly evident, but compound 30 is
significantly more planar.
Table 2 provides quantitative data on the plane angles
between the four aromatic rings of BcPh, 1,4-DFBcPh, 1,4-
DMBcPh, 5-MBcPh, H2B[l]AP, B[l]AP, as well as the two
methoxy derivatives 18 and 19. As can be seen from the A−D
plane angles of the unsubstituted hydrocarbons in this table,
nonplanarity decreases in the order 1,4-DMBcPh > 1,4-DFBcPh
> BcPh > 5-MBcPh > H2B[l]AP > B[l]AP. What is perhaps
surprising is that a remote substitution, namely a methyl group
at the C-5 position of BcPh, actually produces a decrease in
overall nonplanarity of the BcPh structure by ∼3°. The ethylene
bridge in H2B[l]AP causes a further flattening of the molecule,
and finally, B[l]AP is only distorted by ∼2°. The A−B plane
E
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a
Table 2. Crystallographically Determined Plane Angles in BcPh and its Analogues
a
Data for BcPh, DFBcPh, and DMBcPh were obtained from refs 33 and 34.
angles in BcPh, 1,4-DFBcPh, and 1,4-DMBcPh are in the 10−
12° range. Remote functionalization reduces this angle to <10°.
There are wide variations in the other plane angles. Among the
dimethoxy-substituted compounds, in the case of 3,4-
dimethoxy-8-methyl BcPh 18 there is an increase in overall
molecular nonplanarity as compared to the parent hydrocarbon
20 as seen from the greater A−D plane angle. In contrast, in
corresponding H2B[l]AP derivative 19, the A−D plane angle is
slightly decreased compared to that of its parent hydrocarbon
21.
These data show that the molecular distortion in such
hydrocarbons can be manipulated not only via introduction of
substituents into the angular rings but also via introduction of
more remote substituents. As we have previously shown,33,34
metabolic activation processes are influenced by molecular
distortion with highly nonplanar polycyclic aromatic hydro-
carbons undergoing poorer oxidative metabolism to DNA-
alkylating, angular-ring diol epoxide metabolites. Thus, one is
tempted to propose that the greater planarization of 5-MBcPh
and H2B[l]AP should result in greater metabolic conversion to
the angular-ring metabolites, this of course is not considering
other possible metabolism pathways.
quinone, trans dihydrodiol, as well as the series 1 and series 2
diol epoxides, which are of biological interest. In the context of
the potential biological properties of these new compounds, the
conformational preferences of the newly synthesized series 1
and series 2 diol epoxides have been compared to known data
from other related BcPh derivatives. In addition, we have
comparatively assessed the crystallographically derived molec-
ular structures of the new compounds, as well as those
previously reported. We anticipate the utilization of these new
compounds for metabolism and DNA binding studies, and on
the chemical side, we expect that the methodology will draw
broad interest in organic synthesis approaches.
EXPERIMENTAL SECTION
■
General Experimental Considerations. Thin-layer chromatog-
raphy was performed on 250 μm glass-backed silica gel plates or 200
μm aluminum-foil-backed silica gel plates. Column chromatographic
purifications were performed on 230−400 mesh silica gel.
Commercially available compounds were used without further
purification. THF was distilled over LAH and then redistilled over
Na prior to use. PhMe was distilled over Na. CH2Cl2 and DME were
distilled over CaH2. Hexanes and EtOAc were distilled over anhydrous
CaSO4. Air and/or moisture-sensitive liquids and solutions were
transferred via syringe under inert gas. 1H NMR spectra were recorded
at 500 MHz in the solvents indicated and are referenced to residual
protonated solvent resonances. 13C NMR spectra were recorded at
125 MHz in the solvents indicated and are referenced to the solvent
resonances. Chemical shifts (δ) are reported in parts per million
(ppm), and coupling constants (J) are in hertz (Hz). Standard
abbreviations are used to designate resonance multiplicities.
CONCLUSIONS
■
Herein, we have demonstrated the applicability of Pt-catalyzed
(or in some cases Au-catalyzed) cycloisomerization reactions of
1-(2-ethynylphenyl)naphthalenes to yield benzo[c]-
phenanthrene analogues that are otherwise not easy to access.
The approach utilizes catalysis chemistry for two key
transformations, namely, the synthesis of the biaryl core and
the cyclization step. The method is highly modular wherein the
use of 2-bromobenzaldehyde leads to the parent hydrocarbons,
whereas the easily prepared 6-bromo-2,3-dimethoxybenzalde-
hyde allows access to the oxidative metabolites, such as o-
6-Bromo-2,3-dimethoxybenzyl Alcohol (2).38 In an oven-dried 100
mL round-bottom flask equipped with a magnetic stirring bar was
placed 2,3-dimethoxybenzyl alcohol (1) (4 g, 23.8 mmol) in dry THF
(18 mL). Recrystallized NBS (4.66 g, 26.2 mmol) was added, and the
suspension was stirred at room temperature for 30 min at which time
TLC showed the reaction to be complete. The THF was evaporated
F
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under reduced pressure, and the residue was dissolved in Et2O. The
insoluble succinimide was removed by filtration, and the resulting
ethereal layer was washed twice with 2N aqueous NaOH. The organic
layer was dried over anhydrous Na2SO4, filtered, and evaporated under
reduced pressure. Recrystallization of the product using 1:1 EtOAc-
hexanes yielded a white, gummy solid that needed purification.
Chromatographic purification on a silica gel column packed in hexanes
and eluted with 20% EtOAc in hexanes afforded compound 2 as a
whitish solid (5.33 g, 90% yield). Rf (SiO2/20% EtOAc in hexanes):
0.21; mp 75−76 °C (lit.38 mp 76 °C). 1H NMR (500 MHz, CDCl3): δ
7.27 (d, J = 9.0 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 4.83 (d, J = 7.0 Hz,
2H), 3.90 (s, 3H), 3.85 (s, 3H), 2.32 (t, J = 7.0 Hz, 1H). 13C NMR
(125 MHz, CDCl3): δ 152.3, 148.8, 133.9, 127.9, 114.8, 113.4, 61.7,
60.4, 56.0.
complete. The resulting black reaction mixture was diluted with
EtOAc and washed twice with water. The aqueous layer was extracted
with EtOAc twice. The combined organic layer was dried over
anhydrous Na2SO4 and evaporated under reduced pressure to give an
orange residue. The crude product was chromatographed on a silica
gel column packed in hexanes sequentially eluted with 10% EtOAc in
hexanes and CH2Cl2. Compound 10 was obtained as a yellow-light
brown solid (2.08 g, 83% yield). Rf (SiO2/CH2Cl2): 0.44; mp 146−
148 °C. 1H NMR (500 MHz, CDCl3): δ 9.91 (s, 1H), 8.05 (d, J = 8.5
Hz, 1H), 7.53−7.50 (m, 2H), 7.39 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 7.0
Hz, 1H), 7.22−7.19 (m, 2H), 7.08 (d, J = 8.5 Hz, 1H), 4.01 (s, 3H),
3.98 (s, 3H), 2.74 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 191.2,
152.2, 150.4, 135.4, 135.1, 134.4, 132.6, 132.5, 129.8, 127.4, 127.2,
126.4, 125.93, 125.91, 125.7, 124.5, 116.5, 62.2, 56.2, 19.6. HRMS
(ESI/FTICR) m/z: calcd for C20H18O3Na [M + Na]+, 329.1148;
found, 329.1141.
6-Acenaphthen-5-yl-2,3-dimethoxybenzaldehyde (11). As de-
scribed for the synthesis of compound 10, compound 11 was prepared
by the reaction of 6-bromo-2,3-dimethoxybenzaldehyde (3) (5 g, 20.4
mmol), acenaphthene-5-boronic acid (8) (4.44 g, 22.4 mmol), CsF
(8.68 g, 57.1 mmol), and Pd(PPh3)4 (943 mg, 0.816 mmol) in dry
DME (105 mL). The reaction mixture was stirred at reflux under a
nitrogen atmosphere for 24 h and then worked up as described for
compound 10. Chromatographic purification using a silica gel column
packed in hexanes sequentially eluted with 50% CH2Cl2 in hexanes
and CH2Cl2 afforded compound 11 as a light brownish solid (5.96 g,
92% yield). Rf (SiO2/CH2Cl2): 0.32; mp 122−125 °C. 1H NMR (500
MHz, CDCl3): δ 9.94 (s, 1H), 7.38 (t, J = 7.0 Hz, 1H), 7.31−7.25 (m,
4H), 7.20 and 7.13 (ABq, J = 8.3 Hz, 2H), 4.00 (s, 3H), 3.97 (s, 3H),
3.47−3.41 (m, 4H). 13C NMR (125 MHz, CDCl3): δ 191.4, 152.6,
150.2, 146.2, 146.1, 139.2, 135.0, 132.0, 130.8, 129.8, 129.5, 128.3,
127.4, 120.6, 119.5, 118.8, 116.6, 62.2, 56.2, 30.6, 30.2. HRMS (ESI/
FTICR) m/z: calcd for C21H18O3Na [M + Na]+, 341.1148; found,
341.1149.
2-(4-Methylnaphthalen-1-yl)benzaldehyde (12). As described for
the synthesis of compound 10, compound 12 was prepared by the
reaction of 2-bromobenzaldehyde (9) (1.2 g, 6.49 mmol), 4-methyl-1-
naphthaleneboronic acid 7 (1.33 g, 7.13 mmol), CsF (2.76 g, 18.16
mmol), and Pd(PPh3)4 (300 mg, 0.259 mmol) in dry DME (33 mL).
The reaction mixture was stirred at reflux under a nitrogen atmosphere
for 18 h and then worked up as described for compound 10.
Chromatographic purification using a silica gel column packed in
hexanes sequentially eluted with hexanes and 30% CH2Cl2 in hexanes
afforded compound 12 as a yellow solid (1.34 g, 83% yield). Rf (SiO2/
10% EtOAc in hexanes): 0.62; mp 102−104 °C. 1H NMR (500 MHz,
CDCl3): δ 9.63 (s, 1H), 8.10 (d, J = 7.0 Hz, 1H), 8.09 (d, J = 8.0 Hz,
1H), 7.69 (t, J = 7.5 Hz, 1H), 7.59−7.54 (m, 2H), 7.51 (d, J = 8.5 Hz,
1H), 7.44 (t, J = 6.5 Hz, 2H), 7.40 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 7.0
Hz, 1H), 2.78 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 192.2, 144.6,
135.1, 135.0, 133.7, 133.6, 132.8, 132.5, 131.9, 128.1, 128.0, 127.0,
126.5, 126.4, 126.0, 125.8, 124.5, 19.6. HRMS (ESI/TOF) m/z: calcd
for C18H15O [M + H]+, 247.1117; found, 247.1121.
2-(1,2-Dihydroacenaphthylen-5-yl)benzaldehyde (13). As de-
scribed for the synthesis of compound 10, compound 13 was prepared
by the reaction of 2-bromobenzaldehyde (9) (4.5 g, 24.32 mmol),
acenaphthene-5-boronic acid (8) (5.30 g, 26.75 mmol), CsF (10.34 g,
68.10 mmol), and Pd(PPh3)4 (1.12 g, 0.973 mmol) in dry DME (123
mL). The reaction mixture was stirred at reflux under a nitrogen
atmosphere for 23 h and then worked up as described for compound
10. Chromatographic purification using a silica gel column packed in
hexanes sequentially eluted with hexanes and 50% CH2Cl2 in hexanes
afforded compound 13 as a yellow-orange solid (4.66 g, 74% yield). Rf
(SiO2/CH2Cl2): 0.51; mp 120−122 °C. 1H NMR (500 MHz, CDCl3):
δ 9.72 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.56
(t, J = 7.5 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H),
7.36−7.33 (m, 3H), 7.28 (d, J = 8.5 Hz, 1H), 3.48 (br s, 4H). 13C
NMR (125 MHz, CDCl3): δ 192.4, 146.8, 146.3, 144.1, 139.2, 134.8,
133.6, 131.8, 131.0, 130.8, 130.2, 128.8, 127.9, 127.2, 120.6, 119.8,
118.8, 30.5, 30.2. HRMS (ESI/TOF) m/z: calcd for C19H15O [M +
H]+, 259.1117; found, 259.1119.
6-Bromo-2,3-dimethoxybenzaldehyde (3).37 In an oven-dried 50
mL round-bottom flask equipped with a magnetic stirring bar was
placed 6-bromo-2,3-dimethoxybenzyl alcohol (2) (2 g, 8.09 mmol) in
dry CH2Cl2 (10 mL). The solution was cooled to 0 °C, and PCC
(3.49 g, 16.2 mmol) was added. The orange suspension was stirred at
0 °C for 5 min and then at room temperature for 5 h, at which time
TLC showed the reaction to be complete. The black suspension was
filtered through Celite, and the residue was washed with CH2Cl2. The
filtrate was evaporated under reduced pressure to give a yellowish
solid. The crude product was chromatographed on a silica gel column
packed in hexanes sequentially eluted with 20% CH2Cl2 in hexanes
and 50% CH2Cl2 in hexanes. Compound 3 was obtained as a whitish-
yellow solid (1.43 g, 72% yield). Rf (SiO2/20% EtOAc in hexanes):
0.32; mp 82−83 °C (lit.37a mp 83−85 °C). H NMR (500 MHz,
1
CDCl3): δ 10.37 (s, 1H), 7.37 (d, J = 9.0 Hz, 1H), 6.98 (d, J = 9.0 Hz,
1H), 3.96 (s, 3H), 3.91 (s, 3H). 13C NMR (125 MHz, CDCl3): δ
190.6, 152.9, 152.3, 129.5, 128.7, 117.7, 112.9, 62.5, 56.4.
2,3-Dimethoxy-6-naphthalen-1-yl-benzaldehyde (6). Step 1:
Synthesis of 4,4,5,5-Tetramethyl-2-(naphthalen-1-yl)-1,3,2-dioxa-
borolane. In an oven-dried reaction vial equipped with a magnetic
stirring bar was placed PdCl2(dppf) (29.5 mg, 0.040 mmol) in dry
DMF (4.0 mL). Bis(pinacolato)diboron (342 mg, 1.36 mmol), KOAc,
(360 mg, 3.67 mmol), and 1-bromonaphthalene (4) (254 mg, 1.22
mmol) were added. The vial was flushed with nitrogen gas and allowed
to stir in a sand bath at 80 °C for 14 h, at which time TLC showed
consumption of the starting material and the formation of a new spot.
Rf (SiO2/20% EtOAc in hexanes): 0.13.
Step 2: Synthesis of 2,3-Dimethoxy-6-naphthalen-1-yl-benzalde-
hyde. To the reaction mixture obtained in step 1 were added 6-bromo-
2,3-dimethoxybenzaldehyde (3) (150 mg, 0.612 mmol), 2 M aqueous
Na2CO3 (0.51 mL, 12.2 mmol), and PdCl2(dppf) (29.5 mg, 0.040
mmol). The vial was flushed with nitrogen gas and allowed to stir in a
sand bath at 80 °C for 21 h at which time TLC showed the reaction to
be complete. The mixture was diluted with Et2O and washed twice
with water followed by brine. The organic layer was dried over
anhydrous Na2SO4 and evaporated under reduced pressure to give a
black solid. The crude product was chromatographed several times on
a silica gel column packed in hexanes sequentially eluted with 20%
CH2Cl2 in hexanes and 20% EtOAc in hexanes. Compound 6 was
obtained as a whitish-yellow solid (141 mg, 79% yield). Rf (SiO2/20%
1
EtOAc in hexanes): 0.29; mp 119−121 °C. H NMR (500 MHz,
CDCl3): δ 9.94 (s, 1H), 7.88 (t, J = 8.0 Hz, 2H), 7.51−7.45 (m, 3H),
7.38 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 7.0 Hz, 1H), 7.21 (d, J = 8.0 Hz,
1H), 7.09 (d, J = 8.0 Hz, 1H), 4.02 (s, 3H), 3.98 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ 191.2, 152.9, 150.7, 137.1, 135.2, 133.6, 132.8,
129.9, 128.5, 128.2, 127.7, 127.5, 126.5, 126.1, 125.9, 125.3, 116.7,
62.4, 56.4. HRMS (ESI/TOF) m/z: calcd for C19H17O3 [M + H]+,
293.1172; found, 293.1178.
2,3-Dimethoxy-6-(4-methyl-naphthalen-1-yl)benzaldehyde (10).
In an oven-dried 100 mL round-bottom flask equipped with a
magnetic stirring bar was placed 6-bromo-2,3-dimethoxybenzaldehyde
(3) (2 g, 8.16 mmol) in dry DME (40 mL). 4-Methyl-1-
naphthaleneboronic acid (7) (1.67 g, 8.98 mmol), CsF (3.47 g, 22.8
mmol), and Pd(PPh3)4 (377 mg, 0.326 mmol) were added. The
resulting yellow suspension was stirred at reflux under a nitrogen
atmosphere for 16 h, at which time TLC showed the reaction to be
G
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The Journal of Organic Chemistry
Article
1-(2-Ethynyl-3,4-dimethoxyphenyl)-4-methylnaphthalene (14).
Step 1: Synthesis of 1-[2-(2,2-Dibromovinyl)-3,4-methoxyphenyl]-
4-methylnaphthalene. In an oven-dried 50 mL round-bottom flask
equipped with a magnetic stirring bar was placed PPh3 (7.71 g, 29.4
mmol) in dry CH2Cl2 (8.0 mL). The mixture was cooled to 0 °C;
CBr4 (4.87 g, 14.7 mmol) was added, and the mixture was stirred for
10 min at 0 °C. Aldehyde 10 (1.8 g, 5.87 mmol) dissolved in dry
CH2Cl2 (14.0 mL) was added slowly. The mixture was flushed with
nitrogen gas and allowed to stir at 0 °C for 2 h, at which time TLC
showed the reaction to be complete. The mixture was diluted with
CH2Cl2 and washed twice with brine followed by twice with H2O. The
aqueous layer was extracted twice with CH2Cl2. The combined organic
layer was dried over anhydrous Na2SO4 and evaporated under reduced
pressure to give an orange residue. Chromatographic purification on a
silica gel column packed in CH2Cl2 eluted with CH2Cl2 afforded the
vinyl dibromide as a foamy, yellow solid (2.63 g, 97% yield). Rf (SiO2/
solid (1.06 g, 81% yield). Rf (SiO2/20% EtOAc in hexanes): 0.42; mp
154−156 °C. H NMR (500 MHz, CDCl3): δ 7.44−7.36 (m, 3H),
1
7.32 (d, J = 7.0 Hz, 1H), 7.27 (d, J = 6.0 Hz, 1H), 7.10 and 7.02 (ABq,
J = 8.3 Hz, 2H), 4.01 (s, 3H), 3.94 (s, 3H), 3.44 (br s, 4H), 2.99 (s,
1H). 13C NMR (125 MHz, CDCl3): δ 151.7, 151.4, 145.0, 145.7,
139.3, 136.4, 133.3, 130.4, 129.3, 127.7, 126.3, 121.3, 119.1, 118.7,
117.5, 112.8, 84.5, 78.7, 61.1, 56.1, 30.5, 30.2. HRMS (ESI) m/z: calcd
for C22H18O2Na [M + Na]+, 337.1199; found, 337.1198.
1-(2-Ethynylphenyl)-4-methylnaphthalene (16). Step 1: Synthesis
of 1-(2-(2,2-Dibromovinyl)phenyl)-4-methylnaphthalene. As de-
scribed for the synthesis of compound 14, the vinyl dibromide was
prepared using PPh3 (6.39 g, 24.36 mmol), CBr4 (4.04 g, 12.18
mmol), and aldehyde 12 (1.2 g, 4.87 mmol) in dry CH2Cl2 (18 mL) at
0 °C for 2 h. Workup as described for compound 14 and
chromatographic purification on a silica gel column packed in hexanes
and eluted with hexanes afforded the vinyl dibromide as a yellow oily
solid (1.939 g, 99% yield). Rf (SiO2/50% CH2Cl2 in hexanes): 0.76. 1H
NMR (500 MHz, CDCl3): δ 8.07 (d, J = 8.5 Hz, 1H), 7.81−7.79 (m,
1H), 7.55−7.33 (m, 7H), 7.22 (d, J = 7.5 Hz, 1H), 6.94 (s, 1H), 2.76
(br s, 3H). 13C NMR (125 MHz, CDCl3): δ 140.1, 136.9, 136.1, 135.4,
134.5, 132.6, 131.8, 131.1, 128.8, 128.2, 127.3, 127.2, 126.6, 126.0,
125.8, 125.7, 124.4, 90.6, 19.6.
Step 2: Synthesis of 1-(2-Ethynylphenyl)-4-methylnaphthalene
(16). As described for the synthesis of compound 14, compound 16
was prepared from the vinyl dibromide (2.08 g, 5.17 mmol) using a 1.6
M solution of n-BuLi in hexanes (8.07 mL, 12.92 mmol) in dry THF
(12 mL) at −78 °C for 5 h and then for 1 h at room temperature.
Workup as described for compound 14 and chromatographic
purification on a silica gel column packed in hexanes and eluted
with hexanes afforded compound 16 as an orange-yellow solid (773
mg, 62% yield). Rf (SiO2/20% EtOAc in hexanes): 0.61; mp 72−74
°C. 1H NMR (500 MHz, CDCl3): δ 8.06 (d, J = 8.5 Hz, 1H), 7.67 (d,
J = 7.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.51 (t, J = 7.0 Hz, 1H),
7.46−7.42 (m, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.0 Hz, 2H),
2.76 (s, 4H). 13C NMR (125 MHz, CDCl3): δ 143.7, 136.8, 134.2,
134.2, 133.2, 132.6, 131.9, 131.0, 128.5, 127.2, 126.9, 126.8, 126.0,
125.5, 124.3, 122.6, 82.7, 80.2, 19.9. HRMS (EI/TOF) m/z: calcd for
C19H14 [M]+, 242.1096; found, 242.1094.
1
20% EtOAc in hexanes): 0.56. H NMR (500 MHz, CDCl3): δ 8.04
(d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.51 (t, J = 7.0 Hz, 1H),
7.39 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 7.0 Hz, 1H), 7.23 (d, J = 7.0 Hz,
1H), 7.07−7.02 (m, 3H), 3.95 (s, 3H), 3.88 (s, 3H), 2.74 (s, 3H). 13C
NMR (125 MHz, CDCl3): δ 152.1, 146.2, 135.9, 134.0, 133.9, 132.8,
132.7, 131.9, 130.9, 127.2, 126.65, 126.61, 126.0, 125.50, 125.47,
124.4, 112.2, 93.7, 61.1, 55.9, 19.6.
Step 2: Synthesis of 1-(2-Ethynyl-3,4-dimethoxyphenyl)-4-meth-
ylnaphthalene (14). In an oven-dried 25 mL three-neck round-
bottom flask equipped with a magnetic stirring bar was placed the vinyl
dibromide obtained in step 1 (200 mg, 0.433 mmol) in dry THF (1.0
mL) under a nitrogen atmosphere. The mixture was cooled to −78 °C,
and a 1.6 M solution of n-BuLi in hexanes (0.68 mL, 1.08 mmol) was
added dropwise. The mixture was allowed to stir at −78 °C for 5 h and
then for 1 h at room temperature, at which time TLC showed the
reaction to be complete. The mixture was quenched with cold water
and extracted with Et2O three times. The combined organic layer was
dried over anhydrous Na2SO4 and evaporated under reduced pressure
to give an orange-yellow oily solid. Chromatographic purification on a
silica gel column packed in hexanes eluted with 10% EtOAc in hexanes
afforded compound 14 as a yellowish-white solid (106 mg, 81% yield).
1
Rf (SiO2/20% EtOAc in hexanes): 0.38; mp 155−156 °C. H NMR
5-(2-Ethynylphenyl)-1,2-dihydroacenaphthene (17). Step 1: Syn-
thesis of 5-(2-(2,2-Dibromovinyl)phenyl)-1,2-dihydroacenaphthene.
As described for the synthesis of compound 14, the vinyl dibromide
was prepared using PPh3 (12.69 g, 48.39 mmol), CBr4 (8.02 g, 24.19
mmol), and aldehyde 13 (2.5 g, 9.68 mmol) in dry CH2Cl2 (35 mL) at
0 °C for 2 h. Workup as described for compound 14 and
chromatographic purification on a silica gel column packed in hexanes
and eluted with hexanes afforded the vinyl dibromide as a yellow solid
(500 MHz, CDCl3): δ 8.04 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz,
1H), 7.51 (t, J = 7.0 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.36 and 7.32
(ABq, J = 6.8 Hz, 2H), 7.04 and 7.01 (ABq, J = 8.8 Hz, 2H), 4.00 (s,
3H), 3.95 (s, 3H), 2.93 (s, 1H), 2.74 (s, 3H). 13C NMR (125 MHz,
CDCl3): δ 151.8, 151.2, 137.1, 136.4, 134.0, 132.5, 132.2, 127.1, 126.9,
126.4, 125.9, 126.5, 126.4, 124.2, 117.8, 112.7, 84.5, 78.5, 61.1, 56.1,
19.6. HRMS (ESI/FTICR) m/z: calcd for C21H18O2Na [M + Na]+,
325.1199; found, 325.1197.
1
(3.774 g, 94% yield). Rf (SiO2/50% CH2Cl2 in hexanes): 0.68. H
5-(2-Ethynyl-3,4-dimethoxyphenyl)acenaphthene (15). Step 1:
Synthesis of 5-[2-(2,2-Dibromovinyl)-3,4-dimethoxyphenyl]-
acenaphthene. As described for the synthesis of compound 14, the
vinyl dibromide was prepared from PPh3 (824 mg, 3.14 mmol), CBr4
(521 mg, 1.57 mmol), and aldehyde 11 (200 mg, 0.628 mmol) in dry
CH2Cl2 (2.3 mL) at 0 °C over 2 h. Workup as described for
compound 14 and chromatographic purification on a silica gel column
packed in hexanes sequentially eluted with 50% CH2Cl2 in hexanes
and CH2Cl2 afforded the vinyl dibromide as a foamy, yellow solid (284
NMR (500 MHz, CDCl3): δ 7.81−7.79 (m, 1H), 7.46−7.42 (m, 2H),
7.42−7.37 (m, 2H), 7.34−7.27 (m, 4H), 7.01 (s, 1H), 3.49−3.43 (m,
4H). 13C NMR (125 MHz, CDCl3): δ 146.2, 146.1, 139.5, 139.3,
137.2, 135.1, 133.1, 131.0, 130.1, 129.5, 129.0, 128.3, 128.1, 127.1,
120.9, 119.5, 118.8, 90.4, 30.5, 30.2.
Step 2: Synthesis of 5-(2-Ethynylphenyl)-1,2-dihydroacenaph-
thylene (17). As described for the synthesis of compound 14,
compound 17 was prepared from the vinyl dibromide (3.5 g, 8.45
mmol) using a 1.6 M solution of n-BuLi in hexanes (13.2 mL, 21.13
mmol) in dry THF (20 mL) at −78 °C for 5 h and then for 1 h at
room temperature. Workup as described for compound 14 and
chromatographic purification on a silica gel column packed in hexanes
and eluted with hexanes afforded compound 17 as a whitish-yellow
solid (1.282 g, 60% yield). Rf (SiO2/10% EtOAc in hexanes): 0.53; mp
86−87 °C. 1H NMR (500 MHz, CDCl3): δ 7.68 (d, J = 7.5 Hz, 1H),
7.45 (t, J = 7.0 Hz, 2H), 7.43−7.36 (m, 4H), 7.34 (d, J = 7.5 Hz, 1H),
7.29−7.28 (m, 1H), 3.55 (br s, 4H), 2.84 (s, 1H). 13C NMR (125
MHz, CDCl3): δ 146.1, 146.0, 143.1, 139.3, 133.7, 133.4, 130.9, 130.1,
129.2, 128.5, 127.8, 127.1, 122.2, 121.2, 119.2, 118.7, 83.0, 80.1, 30.6,
30.2. HRMS (ESI/TOF) m/z: calcd for C20H15 [M + H]+, 255.1168;
found, 255.1170.
1
mg, 96% yield). Rf (SiO2/20% EtOAc in hexanes): 0.47. H NMR
(500 MHz, CDCl3): δ 7.38−7.34 (m, 2H), 7.30−7.28 (m, 3H,
superimposed with the CHCl3 resonance), 7.14 (s, 1H), 7.12 (d, J =
8.0 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 3.95 (s, 3H), 3.87 (s, 3H),
3.48−3.40 (m, 4H). 13C NMR (125 MHz, CDCl3): δ 152.0, 146.1,
145.6, 139.4, 134.1, 133.0, 132.3, 130.7, 130.2, 129.4, 127.8, 126.6,
120.9, 119.1, 118.7, 112.21, 112.20, 93.6, 61.0, 55.9, 30.5, 30.1.
Step 2: Synthesis of 5-(2-Ethynyl-3,4-dimethoxyphenyl)-
acenaphthene (15). As described for the synthesis of compound
14, compound 15 was prepared from the vinyl dibromide (1.99 g, 4.19
mmol) using a 1.6 M solution of n-BuLi in hexanes (6.54 mL, 10.5
mmol) in dry THF (10 mL) at −78 °C for 5 h and then for 1 h at
room temperature. Workup as described for compound 14 and
chromatographic purification on a silica gel column packed in hexanes
eluted with 10% EtOAc in hexanes afforded compound 15 as a yellow
3,4-Dimethoxy-8-methylbenzo[c]phenanthrene (18). Using PtCl2.
In an oven-dried reaction vial equipped with a magnetic stirring bar
H
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The Journal of Organic Chemistry
Article
was placed alkyne 14 (40 mg, 0.132 mmol) in dry PhMe (0.6 mL).
PtCl2 (1.8 mg, 6.77 μmol) was added. The vial was flushed with
nitrogen gas, and the mixture was allowed to stir in a sand bath at 80
°C for 17 h, at which time TLC showed the reaction to be complete.
The mixture was filtered through Celite, and the residue was washed
with CH2Cl2. Chromatographic purification on a silica gel column
packed in hexanes eluted with 50% CH2Cl2 in hexanes afforded
compound 18 as a yellow solid (29.8 mg, 75% yield).
1H), 8.02 (d, J = 8.0 Hz, 1H), 7.88 and 7.83 (ABq, J = 8.5 Hz, 2H),
7.72−7.68 (m, 2H), 7.65 (s, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.50 (d, J =
7.0 Hz, 1H), 3.53−3.48 (m, 4H). 13C NMR (125 MHz, CDCl3): δ
146.1, 145.1, 139.2, 133.7, 132.8, 131.3, 129.0, 128.6, 128.3, 127.7,
127.3, 127.0, 126.2, 125.3, 124.8, 123.5, 120.6, 120.2, 30.7, 29.4.
HRMS (ESI/TOF) m/z: calcd for C20H15 [M + H]+, 255.1168; found,
255.1170.
8-Methylbenzo[c]phenanthrene-3,4-dione (22). Step 1: Deme-
thylation. In an oven-dried 15 mL two-neck round-bottom flask
equipped with a magnetic stirring bar was placed catechol dimethyl
ether 18 (30.24 mg, 0.1 mmol) in dry CH2Cl2 (1.5 mL) under a
nitrogen atmosphere. The mixture was cooled to −70 °C, and a 1 M
solution of BBr3 in pentane (0.3 mL, 0.3 mmol) was added. The
purple-pink suspension was stirred at −70 °C for 5 min, then allowed
to warm to room temperature and stirred for 2 h. TLC showed
completion of the reaction, and the mixture was by quenched with ice
and cold water. The mixture was diluted with CH2Cl2, and the layers
were separated. The organic layer was washed several times with brine
and cold water. The organic layer was dried over anhydrous Na2SO4
and evaporated under reduced pressure to give the crude catechol as a
reddish solid. Rf (SiO2/CH2Cl2): 0.16.
Using AuCl3. In an oven-dried reaction vial equipped with a
magnetic stirring bar was placed alkyne 14 (30 mg, 0.100 mmol) in dry
PhMe (0.43 mL). AuCl3 (1.5 mg, 4.94 μmol) was added. The vial was
flushed with nitrogen gas, and the mixture was allowed to stir in a sand
bath at 80 °C for 24 h, at which time TLC showed the reaction to be
complete. Workup as described above and chromatographic
purification on a silica gel column packed in hexanes and eluted
with 50% CH2Cl2 in hexanes afforded compound 18 as a yellow solid
(25.3 mg, 84% yield). Rf (SiO2/50% CH2Cl2 in hexanes): 0.28; mp
1
143−144 °C. H NMR (500 MHz, CDCl3): δ 9.08−9.06 (m, 1H),
8.80 (d, J = 9.3 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.17−8.15 (m, 1H),
7.76 (d, J = 8.5 Hz, 1H), 7.67−7.65 (m, 3H), 7.40 (d, J = 9.5 Hz, 1H),
4.07 (s, 3H), 4.06 (s, 3H), 2.80 (s, 3H). 13C NMR (125 MHz,
CDCl3): δ 148.6, 143.3, 133.2, 132.3, 132.3, 130.3, 129.6, 128.9, 128.4,
127.1, 127.0, 126.5, 125.7, 125.5, 124.42, 124.39, 120.7, 113.5, 61.4,
56.6, 19.7. HRMS (ESI/FTICR) m/z: calcd for C21H18O2Na [M +
Na]+, 325.1199; found, 325.1198.
Step 2: Oxidation. In an oven-dried 25 mL three-neck round-
bottom flask equipped with a magnetic stirring bar was placed the
crude catechol (27.43 mg, 0.1 mmol) in dry CH2Cl2 (2 mL). The
mixture was cooled to 0 °C, and PDC (104.4 mg, 0.3 mmol) was
added. The mixture was stirred at room temperature for 4 h, at which
time TLC showed the reaction to be complete. The mixture was
filtered through Celite, and the reddish orange filtrate was evaporated
under reduced pressure to give a reddish solid. This product was
chromatographed on a silica gel column packed in CH2Cl2 and
sequentially eluted with CH2Cl2 and 5% MeOH in CH2Cl2.
Compound 22 was obtained as a reddish-orange solid (22.3 mg,
82% yield). Rf (SiO2/5% MeOH in CH2Cl2): 0.82; mp 204−210 °C
9,10-Dimethoxy-4,5-dihydrobenzo[l]acephenanthrylene (19).
Using PtCl2. As described for the synthesis of compound 18,
compound 19 was prepared by a reaction of alkyne 15 (30 mg,
0.095 mmol) and PtCl2 (1.27 mg, 4.77 μmol) in dry PhMe (0.42 mL)
at 80 °C over 21 h. Workup and chromatographic purification on a
silica gel column packed in hexanes and eluted with 50% CH2Cl2 in
hexanes afforded compound 19 as a yellow solid (21.7 mg, 72% yield).
Using AuCl3. As described for the synthesis of compound 18,
compound 19 was prepared by a reaction of alkyne 15 (30 mg, 0.095
mmol) and AuCl3 (1.45 mg, 4.78 μmol) in dry PhMe (0.42 mL) at 80
°C over 29 h. Workup and chromatographic purification on a silica gel
column packed in hexanes and eluted with 50% CH2Cl2 in hexanes
afforded compound 19 as a yellow solid (17.8 mg, 59% yield). Rf
(SiO2/20% EtOAc in hexanes): 0.32; mp 154−155 °C. 1H NMR (500
MHz, CDCl3): δ 9.01 (d, J = 9.0 Hz, 1H), 8.84 (d, J = 8.5 Hz, 1H),
8.23 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.66 (t, J = 7.0 Hz,
1H), 7.63 (s, 1H), 7.47 (d, J = 7.0 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H),
4.07 (d, 3H), 4.06 (d, 3H), 3.52−3.48 (m, 4H). 13C NMR (125 MHz,
CDCl3): δ 148.5, 146.1, 144.4, 139.3, 132.5, 128.8, 128.5, 128.2, 128.1,
126.9, 126.8, 124.9, 123.43, 123.37, 120.5, 120.4, 120.2, 113.6, 61.4,
56.6, 30.7, 29.4. HRMS (ESI/FTICR) m/z: calcd for C22H18O2Na [M
+ Na]+, 337.1199; found, 337.1195.
1
(dec. with charring). H NMR (500 MHz, DMSO-d6): δ 8.39 (d, J =
10.5 Hz, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.11
(d, J = 8.5 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.81 (dt, J = 1.0, 8.0 Hz,
1H), 7.76 (dt, J = 1.0, 8.0 Hz, 1H), 7.71 (s, 1H), 6.51 (d, J = 10.5 Hz,
1H), 2.72 (s, 3H). 13C NMR (125 MHz, DMSO-d6): δ 180.6, 178.9,
143.7, 137.1, 137.0, 133.3, 131.9, 130.5, 129.6, 129.2, 128.6, 128.4
128.1, 126.4, 126.3, 126.1, 125.7, 125.1, 19.4. HRMS (ESI/TOF) m/z:
calcd for C19H13O2 [M + H]+, 273.0910; found, 273.0912.
4,5-Dihydrobenzo[l]acephenanthrylene-9,10-dione (23). Step 1:
Demethylation. As described for the synthesis of compound 22,
compound 23 was prepared from catechol dimethyl ether 19 (31.4 mg,
0.1 mmol) using a 1 M solution of BBr3 in pentane (0.3 mL, 0.3
mmol) in dry CH2Cl2 (1.5 mL). Workup gave a reddish-orange solid
of the crude catechol. Rf (SiO2/CH2Cl2): 0.07.
5-Methylbenzo[c]phenanthrene (20). As described for the syn-
thesis of compound 18, compound 20 was prepared by a reaction of
alkyne 16 (771 mg, 3.183 mmol) and PtCl2 (42.3 mg, 0.159 mmol), in
dry PhMe (14 mL) at 80 °C over 24 h. Workup and chromatographic
purification on a silica gel column packed in hexanes and eluted with
hexanes afforded compound 20 as a yellow solid (626 mg, 81% yield).
Rf (SiO2/hexanes): 0.18; mp 74−76 °C. 1H NMR (500 MHz,
CDCl3): δ 9.14 (d, J = 8.5 Hz, 1H), 9.07 (d, J = 8.5 Hz, 1H), 8.20−
8.18 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.77
(d, J = 8.5 Hz, 1H), 7.71−7.65 (m, 4H), 7.59 (t, J = 7.6 Hz, 1H), 2.82
(s, 3H). 13C NMR (125 MHz, CDCl3): δ 133.3, 133.1, 133.1, 130.8,
130.5, 130.2, 128.5, 128.4, 127.9, 127.5, 127.1, 126.5, 126.4, 126.1,
125.8, 125.7, 125.4, 124.4, 19.8. HRMS (ESI/TOF) m/z: calcd for
C19H15 [M + H]+, 243.1168; found, 243.1168.
Step 2: Oxidation. As described for the synthesis of compound 22,
compound 23 was prepared by oxidation of the crude catechol (28.6
mg, 0.1 mmol) with PDC (112.7 mg, 0.3 mmol) in dry CH2Cl2 (2.0
mL). Workup and chromatographic purification on a silica gel column
packed in CH2Cl2 and eluted with CH2Cl2 afforded compound 23 as a
dark red solid (22.5 mg, 79% yield). Rf (SiO2/5% MeOH in CH2Cl2):
1
0.81; mp 159−162 °C (dec. with charring). H NMR (500 MHz,
acetone-d6): δ 8.84 (d, J = 10.5 Hz, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.18
(d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.76 (t, J = 7.0 Hz, 1H),
7.74 (d, J = 7.0 Hz, 1H), 7.65 (s, 1H), 6.58 (d, J = 10.5 Hz, 1H), 3.54−
3.48 (m, 4H). 13C NMR (125 MHz, DMSO-d6): δ 180.0, 178.0, 149.5,
146.8, 143.7, 139.6, 139.3, 135.9, 133.1, 130.7, 129.3, 127.7, 127.4,
125.9, 125.6, 123.7, 120.3, 119.9, 30.6, 29.4. HRMS (ESI/TOF) m/z:
calcd for C20H13O2 [M + H]+, 285.0910; found, 285.0914.
4,5-Dihydrobenzo[l]acephenanthrylene (21).52 As described for
the synthesis of compound 18, compound 21 was prepared by the
reaction of alkyne 17 (1.07 g, 4.207 mmol) and PtCl2 (56 mg, 0.210
mmol) in dry PhMe (18 mL) at 80 °C over 24 h. Workup and
chromatographic purification on a silica gel column packed in hexanes
sequentially eluted with hexanes and 10% CH2Cl2 in hexanes afforded
compound 21 as a pale reddish-brown solid (716 mg, 69% yield). Rf
(SiO2/hexanes): 0.16; mp 125−126 °C (lit.52 mp 123−124). 1H NMR
(500 MHz, CDCl3): δ 9.30 (d, J = 8.5 Hz, 1H), 8.94 (d, J = 8.5 Hz,
( )-Trans-8-methyl-3,4-dihydrobenzo[c]phenanthrene-3,4-diol
(( )24). In an oven-dried 200 mL round-bottom flask equipped with a
magnetic stirring bar was placed quinone 22 (134.8 mg, 0.5 mmol) in
dry THF (9 mL) and EtOH (60 mL). The mixture was cooled to 0
°C, sparged with O2 for 15 min, and then NaBH4 (187.3 mg, 5.0
mmol) was added portionwise. The yellow mixture was allowed to stir
at room temperature while being sparged with O2 for 4 h and was then
allowed to stir under an O2 balloon for 15 h protected from light. The
mixture was again cooled to 0 °C, sparged with O2 for 15 min, and
I
DOI: 10.1021/acs.joc.5b00931
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
another aliquot of NaBH4 (187.3 mg, 5.0 mmol) was added
portionwise. The mixture was allowed to stir at room temperature
while being sparged with O2 for 5 h, at which time TLC showed the
reaction to be complete. The mixture was concentrated to a third of its
volume. The addition of ice and cold water resulted in a creamy yellow
suspension. The mixture was transferred to a separatory funnel; EtOAc
was added to dissolve the solids, and the mixture was washed three
times with H2O. The organic layer was dried over anhydrous Na2SO4
and evaporated under reduced pressure to give a whitish-orange solid.
This solid was suspended in cold Et2O and sonicated to yield
dihydrodiol ( )-24 as a whitish solid, which was collected by filtration
were observed to sharpen upon exchange with D2O: 4.82 (d, J = 9.0
Hz, 1H), 4.36 (d, J = 4.5 Hz, 1H), 3.95 (dd, J = 2.0, 4.5 Hz, 1H), 3.84
(dd, J = 2.0, 9.0 Hz, 1H). 13C NMR (125 MHz, acetone-d6): δ 136.4,
133.4, 132.5, 132.40, 132.37, 130.2, 129.2, 127.8, 127.1, 126.7, 125.8,
124.8, 124.6, 113.9, 72.4, 72.1, 62.4, 50.9, 19.0. HRMS (ESI/TOF) m/
z: calcd for C19H16O3Na [M + Na]+, 315.0992; found, 315.0992.
( )-11β,12β-Epoxy-4,5,9,10,11,12-hexahydrobenzo[l]acephenan-
thrylene-9β,10α-diol (( )-27). Step 1: Synthesis of ( )-11α-Bromo-
4,5,9,10,11,12-hexahydrobenzo[l]acephenanthrylene-9β,10α,12β-
triol. In an oven-dried reaction vial equipped with a magnetic stirring
bar was placed dihydrodiol ( )-26 (30.0 mg, 0.104 mmol) in dry THF
(4.4 mL) and H2O (2.2 mL). Recrystallized N-bromoacetamide (17.2
mg, 0.124 mmol) was added, and the mixture was allowed to stir at
room temperature under subdued light for 19 h, at which time TLC
showed the reaction to be complete. The orange mixture was
evaporated to half its volume, diluted with Et2O, and washed
sequentially with H2O and brine. The organic layer was dried over
anhydrous Na2SO4 and evaporated under reduced pressure to give a
reddish-white solid. Trituration with cold Et2O containing a little
hexanes afforded the bromo triol as a pale reddish-white solid (39.1
mg, 95% yield). Rf (SiO2/5% MeOH in CH2Cl2): 0.16.
1
(104.5 mg, 76% yield). Rf (SiO2/5% MeOH in CH2Cl2): 0.35. H
NMR (500 MHz, acetone-d6): δ 8.63 (d, J = 8.0 Hz, 1H), 8.13 (d, J =
8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.71−
7.64 (m, 2H), 7.61 (s, 1H), 7.27 (d, J = 10.5 Hz, 1H), 6.31 (dd, J =
1.5, 10.0 Hz, 1H), 4.73 (d, J = 11.5 Hz, 1H), 4.69 (br d, J = 5.5 Hz,
1H), 4.64 (br d, J = 11.5 Hz, 1H), 4.42 (br, 1H), 2.73 (s, 3H). 13C
NMR (125 MHz, DMSO-d6): δ 137.9, 133.4, 133.0, 132.21, 132.20,
130.2, 129.0, 128.8, 127.4, 127.1, 126.9, 126.8, 126.4, 125.6, 124.9,
74.9, 71.4, 19.7. HRMS (ESI/TOF) m/z: calcd for C19H16O2Na [M +
Na]+, 299.1043; found, 299.1043.
Step 2: Cyclization to ( )-11β,12β-Epoxy-4,5,9,10,11,12-
hexahydrobenzo[l]acephenanthrylene-9β,10α-diol (( )-27). In an
oven-dried reaction vial equipped with a magnetic stirring bar was
placed the bromo triol obtained above (39.1 mg, 0.101 mmol) in dry
THF (4.0 mL). Amberlite IRA 400 HO− (615.1 mg) was added and
the mixture was stirred at room temperature under subdued light for 4
h, at which time TLC showed the reaction to be complete. The
Amberite was filtered off, and the filtrate obtained was evaporated
under reduced pressure to give a yellowish-white solid. Trituration
with cold Et2O afforded diol epoxide ( )-27 as a pale yellowish-white
solid (18.7 mg, 60% yield). Rf (SiO2/5% MeOH in CH2Cl2): 0.32. 1H
NMR (500 MHz, acetone-d6 + 1 drop DMSO-d6): δ 8.80 (d, J = 8.5
Hz, 1H), 8.00 and 7.95 (ABq, J = 8.3 Hz, 2H), 7.65 (t, J = 7.8 Hz, 1H),
7.59 (s, 1H), 7.55 (d, J = 7.0 Hz, 1H), 5.19 (br, 2H), 4.83 (d, J = 9.5
Hz, 1H), 4.45 (d, J = 4.4 Hz, 1H), 3.90 (dd, J = 2.0, 4.4 Hz, 1H), 3.68
(dd, J = 2.0, 9.5 Hz, 1H), 3.48−3.39 (m, 4H). 13C NMR (125 MHz,
acetone-d6 + 1 drop DMSO-d6): δ 156.5, 146.2, 145.6, 144.2, 139.2,
138.9, 129.7, 128.5, 128.0, 127.6, 124.2, 123.5, 121.7, 119.8, 73.1, 71.9,
61.9, 50.2, 30.2, and one resonance embedded in the acetone-d6
resonance. HRMS (ESI/TOF) m/z: calcd for C20H16O3Na [M +
Na]+, 327.0992; found, 327.0997.
( )-1α,2α-Epoxy-3α,4β-dihydroxy-8-methyl-1,2,3,4-tetrahydro-
benzo[c]phenanthrene (( )-28). In an oven-dried 10 mL round-
bottom flask equipped with a magnetic stirring bar was placed
dihydrodiol ( )-24 (20.0 mg, 72.38 μmol) in THF (4 mL). The
mixture was cooled to −78 °C, and purified mCPBA (125.8 mg, 0.729
mmol) was added. The mixture was allowed to warm to room
temperature and stirred for 2 h, at which time TLC showed the
reaction to be complete. The mixture was evaporated to a third of its
volume and diluted with EtOAc. The mixture was washed twice with
each cold 1 M NaOH, H2O, and brine. The organic layer was dried
over anhydrous Na2SO4 and evaporated under reduced pressure to
give a yellowish-white solid. Trituration with cold Et2O afforded diol
epoxide ( )-28 as a pale yellowish-white solid (14.6 mg, 69% yield). Rf
(SiO2/5% MeOH in CH2Cl2): 0.37. 1H NMR (500 MHz, acetone-d6):
δ 8.79 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.5
Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.75 (dt, J = 1.5, 8.5 Hz, 1H), 7.72
(dt, J = 1.5, 8.5 Hz, 1H), 7.65 (s, 1H), 4.89 (br, 1H, D2O
exchangeable), 4.87 (d, J = 8.5 Hz, 1H), 4.80 (d, J = 4.5 Hz, 1H), 4.64
(br, 1H, D2O exchangeable), 3.96 (br d, J = 8.5 Hz, 1H), 3.81 (dd, J =
1.8, 4.5 Hz, 1H), 2.75 (s, 3H). The following resonances were
observed to sharpen upon exchange with D2O: 4.84 (d, J = 8.5 Hz,
1H), 4.78 (d, J = 4.0 Hz, 1H), 3.96 (dd, J = 2.0, 8.5 Hz, 1H), 3.81 (dd,
J = 2.0, 4.5 Hz, 1H). 13C NMR (125 MHz, acetone-d6): δ 139.8, 133.4,
133.3, 132.2, 132.1, 130.5, 128.2, 127.6, 126.8, 126.6, 125.2, 124.5,
123.4, 72.3, 70.6, 57.2, 54.7, 54.1, 18.8. HRMS (ESI/TOF) m/z: calcd
for C19H16O3Na [M + Na]+, 315.0992; found, 315.0995.
( )-Trans-4,5,9,10-tetrahydrobenzo[l]acephenanthrylene-9,10-
diol (( )-25). As described for the synthesis of dihydrodiol ( )-24,
dihydrodiol ( )-25 was prepared by reduction of quinone 23 (180
mg, 0.633 mmol) with NaBH4 (239.5 mg, 6.33 mmol) added
portionwise in two equal aliquots, in THF (10.5 mL) and EtOH (72.5
mL), in the presence of O2 over 24 h. The crude yellow solid obtained
upon workup as described for ( )-24 was suspended in cold Et2O and
sonicated to afford dihydrodiol ( )-25 as an off-white solid, which was
collected by filtration (144.5 mg, 79% yield). Rf (SiO2/5% MeOH in
1
CH2Cl2): 0.26. H NMR (500 MHz, acetone-d6): δ 8.41 (d, J = 8.0
Hz, 1H), 7.92 and 7.85 (ABq, J = 7.8 Hz, 2H), 7.62 (t, J = 8.0 Hz, 1H),
7.54 (s, 1H), 7.52−7.47 (m, 2H), 6.34 (d, J = 10.5 Hz, 1H), 4.75 (d, J
= 11.5 Hz, 1H), 4.67 (br, J = 5.0 Hz, 1H), 4.60 (d, J = 11.5 Hz, 1H),
4.40 (br, 1H), 3.48−3.41 (m, 4H). 13C NMR (125 MHz, DMSO-d6):
δ 145.7, 143.9, 139.1, 137.1, 134.7, 133.6, 129.9, 128.7, 128.2, 128.1,
126.4, 124.9, 124.5, 124.4, 121.9, 120.1, 74.9, 71.4, 30.6, 28.9. HRMS
(ESI/TOF) m/z: calcd for C20H16O2Na [M + Na]+, 311.1043; found,
311.1043.
( )-1β,2β-Epoxy-3α,4β-dihydroxy-8-methyl-1,2,3,4-tetrahydro-
benzo[c]phenanthrene (( )-26). Step 1: Synthesis of ( )-2α-Bromo-
8-methyl-1β,3α,4β-trihydroxyl-1,2,3,4-tetrahydrobenzo[c]phenan-
threne. In an oven-dried reaction vial equipped with a magnetic
stirring bar was placed dihydrodiol ( )-24 (20.0 mg, 72.38 μmol) in
dry THF (3.0 mL) and H2O (1.5 mL). Recrystallized N-
bromoacetamide (29.95 mg, 0.217 mmol) was added, and the mixture
was stirred at room temperature under subdued light for 25 h, at which
time TLC showed the reaction to be complete. The orange mixture
was evaporated to half its volume, diluted with Et2O, and washed
sequentially with H2O and brine. The organic layer was dried over
anhydrous Na2SO4 and evaporated under reduced pressure to give a
yellowish-white solid. Trituration with cold Et2O containing a little
hexanes afforded the bromo triol as a white solid (26.2 mg, 97% yield).
Rf (SiO2/5% MeOH in CH2Cl2): 0.20.
Step 2: Cyclization to ( )-1β,2β-Epoxy-3α,4β-dihydroxy-8-meth-
yl-1,2,3,4-tetrahydrobenzo[c]phenanthrene (( )-26). In an oven-
dried reaction vial equipped with a magnetic stirring bar was placed the
bromo triol obtained above (15.3 mg, 40.99 μmol) in dry THF (1.6
mL). Amberlite IRA 400 HO− (248.5 mg) was added, and the mixture
was stirred at room temperature under subdued light for 4 h, at which
time TLC showed the reaction to be complete. The Amberite was
filtered off, and the filtrate obtained was evaporated under reduced
pressure to give a white solid. Trituration with cold Et2O afforded diol
epoxide ( )-26 as a white solid (7.7 mg, 64% yield). Rf (SiO2/5%
MeOH in CH2Cl2): 0.39. 1H NMR (500 MHz, acetone-d6): δ 9.19 (d,
J = 7.5 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.98 and 7.96 (ABq, J = 8.3
Hz, 2H), 7.76−7.69 (m, 2H), 7.68 (s, 1H), 4.87 (br, 1H, D2O
exchangeable), 4.82 (d, J = 9.0 Hz, 1H), 4.66 (br, 1H, D2O
exchangeable), 4.36 (d, J = 4.0 Hz, 1H), 3.95 (dd, J = 2.0, 4.5 Hz, 1H),
3.84 (dd, J = 1.5, 9.0 Hz, 1H), 2.74 (s, 3H). The following resonances
( )-11α,12α-Epoxy-4,5,9,10,11,12-hexahydrobenzo[l]ace-
phenanthrylene-9β,10α-diol (( )-29). In an oven-dried 10 mL round-
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DOI: 10.1021/acs.joc.5b00931
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The Journal of Organic Chemistry
Article
bottom flask equipped with a magnetic stirring bar was placed
dihydrodiol ( )-25 (30.0 mg, 0.104 mmol) in THF (6 mL). The
mixture was cooled to −78 °C, and purified mCPBA (179.5 mg, 1.04
mmol) was added. The mixture was allowed to warm to room
temperature and stirred for 2 h, at which time TLC showed the
reaction to be complete. The mixture was evaporated to a third of its
volume and diluted with EtOAc. The mixture was washed twice with
each cold 1 M NaOH, H2O, and brine. The organic layer was dried
over anhydrous Na2SO4 and evaporated under reduced pressure to
give a yellowish-white solid. Trituration with cold Et2O afforded diol
epoxide ( )-29 as a pale yellowish-white solid (25.5 mg, 80% yield). Rf
Institutes of Health Grant G12MD007603 from the National
Institute on Minority Health and Health Disparities. We thank
(the late) Dr. Cliff Soll (Hunter College) for some of the
HRMS analyses and Mr. Hari Akula (City College) for his
assistance.
REFERENCES
■
(1) Mallory, F. B.; Wood, C. S.; Gordon, J. T.; Lindquist, L. C.;
Savitz, M. L. J. Am. Chem. Soc. 1962, 84, 4361−4362.
(2) Moore, W. A.; Morgan, D. D.; Stermitz, F. R. J. Am. Chem. Soc.
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(3) Wood, C. S.; Mallory, F. B. J. Org. Chem. 1964, 29, 3373−3377.
(4) Mallory, F. B.; Wood, C. S.; Gordon, J. T. J. Am. Chem. Soc. 1964,
86, 3094−3102.
(5) Mallory, F. B.; Mallory, C. W. J. Am. Chem. Soc. 1972, 94, 6041−
6048.
1
(SiO2/5% MeOH in CH2Cl2): 0.11. H NMR (500 MHz, acetone-d6
+ 1 drop DMSO-d6): δ 8.50 (d, J = 8.5 Hz, 1H), 7.93 and 7.89 (ABq, J
= 8.4 Hz, 2H), 7.63 (t, J = 7.8 Hz, 1H), 7.55−7.52 (m, 2H), 4.97 (d, J
= 4.5 Hz, 1H), 4.77 (d, J = 8.0 Hz, 1H), 3.95 (dd, J = 2.0, 8.0 Hz, 1H),
1
3.79 (dd, J = 2.0, 4.5 Hz, 1H), 3.47−3.39 (m, 4H). H NMR (500
MHz, THF-d8): δ 8.50 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H),
7.78 (d, J = 8.3 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.48−7.42 (m, 2H),
4.92 (d, J = 4.4 Hz, 1H), 4.88 (d, J = 5.1 Hz, 1H), 4.70 (dd, J = 4.5, 8.5
Hz, 1H), 4.59 (d, J = 6.0 Hz, 1H), 3.82−3.77 (m, 1H), 3.68 (dd, J =
1.9, 4.5 Hz, 1H), 3.47−3.34 (m, 4H). 13C NMR (125 MHz, THF-d8):
δ 146.2, 144.4, 139.9, 135.3, 130.1, 129.9, 129.0, 128.8, 128.3, 128.0,
124.6, 124.1, 122.1, 120.1, 73.2, 71.6, 57.3, 54.5, 31.1, 29.5. HRMS
(ESI/TOF) m/z: calcd for C20H16O3Na [M + Na]+, 327.0992; found,
327.0992.
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equipped with a magnetic stirring bar was placed 4,5-dihydrobenzo-
[l]acephenanthrylene (21) (25.4 mg, 0.1 mmol) in dry PhMe (1 mL).
DDQ (29.5 mg, 0.13 mmol) was added; the vial was flushed with
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alumina and 3/4 silica gel packed in hexanes and eluted with hexanes.
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Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 7.14 (d, J = 5.0 Hz, 1H). 13C NMR
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ASSOCIATED CONTENT
* Supporting Information
■
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1H and 13C NMR spectra for compounds 2, 3, 6, 10−23,
( )-24−( )-29, and 30, NOESY spectra for ( )-26 and
( )-27, details of the X-ray crystallographic analysis, ORTEP
figures, and CIF files for compounds 18−21 and 30. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.joc.5b00931.
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3760. (b) Collins, S. K.; Grandbois, A.; Vachon, M. P.; Cote, J. Angew.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: mlakshman@ccny.cuny.edu.
■
(19) Xia, Y.; Liu, Z.; Xiao, Q.; Qu, P.; Ge, R.; Zhang, Y.; Wang, J.
Angew. Chem., Int. Ed. 2012, 51, 5714−5717.
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Fernandes, M. A.; de Koning, C. B. Org. Biomol. Chem. 2004, 2, 3504−
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a National Institutes of Health
SCORE subproject Grant S06 GM008168 and a PSC CUNY
award to M.K.L. P.F.T. was supported via a Ruth L. Kirschstein
National Research Service Award F31 GM082025 from the
National Institutes of Health and via the NIH RISE program.
Infrastructural support at CCNY was provided by National
K
DOI: 10.1021/acs.joc.5b00931
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