Facile construction of 3-hydroxyphenanthrene-1,4-diones: Key intermediates to tanshinone i and its A-ring-modified analogue

Article abstract of DOI:10.1016/j.tet.2014.03.019

A mild synthetic approach was established allowing for a convenient construction of tricyclic hydroxyphenanthraquinones, the key precursor for total synthesis of tanshinone I. This tandem process includes decarboxylative radical alkylation, intramolecular C-H arylation and one-pot O-demethylation and aromatization. Variously substituted phenylpropanoic acids were well tolerated in this approach, and synthesis of tanshinone I (1) was finally successful in six straight steps in 19% overall yields from commercially available 5-bromovanillin.

Full text of DOI:10.1016/j.tet.2014.03.019

Tetrahedron 70 (2014) 2976e2981
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Facile construction of 3-hydroxyphenanthrene-1,4-diones: key
intermediates to tanshinone I and its A-ring-modified analogue
*
Mingkun Jiao, Chunyong Ding , Ao Zhang
CAS Key Laboratory of Receptor Research, and Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica
(SIMM), Chinese Academy of Sciences, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild synthetic approach was established allowing for a convenient construction of tricyclic hydrox-
yphenanthraquinones, the key precursor for total synthesis of tanshinone I. This tandem process includes
decarboxylative radical alkylation, intramolecular CeH arylation and one-pot O-demethylation and
aromatization. Variously substituted phenylpropanoic acids were well tolerated in this approach, and
synthesis of tanshinone I (1) was finally successful in six straight steps in 19% overall yields from
commercially available 5-bromovanillin.
Received 21 January 2014
Received in revised form 26 February 2014
Accepted 6 March 2014
Available online 14 March 2014
Keywords:
Tanshinone I
Ó 2014 Elsevier Ltd. All rights reserved.
Total synthesis
Radical alkylation
Intracellular CeH arylation
ꢀ
FeisteBenary reaction
1. Introduction
activities, such as cardioprotection, antibacterial, anti-
inflammatory, antioxidant, anti-platelet aggregation and antican-
Tanshinones represent a series of chromophore-containing
abietane-derived diterpenes isolated exclusively from Salvia mil-
tiorrhiza Bunge (Danshen in Chinese), one of the most famous tra-
ditional Chinese medicines (TCMs) for the treatment of
cardiovascular disease, heart failure as well as inflammatory dis-
eases including chronic hepatitis and arthritis.1 Among the tan-
cer properties.2,3 Recently, an increasing attention has been drawn
to tanshinone I due to its unique in vitro and in vivo anticancer
activities.4,5 Synthetically, several methods towards total synthesis
of 1 have been reported since the early 1960s (Scheme 1), including
semi-synthesis from podocarpic acid,6 photochemical aromatic
annulation,7 DielseAlder reaction8 and base-induced photochem-
ical cyclization.9 However, all of these methods suffered from low
yields, not readily available starting materials, harsh reaction con-
ditions, and, most importantly, the impracticality of generating
shinone family, tanshinone
I (1), tanshinone IIA (2), crypto
tanshinone (3) and neo-tanshinlactone (4) (Fig. 1) are the major
bioactive constituents exhibiting various pharmacological
Fig. 1. Structures of four bioactive tanshinones isolated from Danshen.
diversified structural analogues of tanshinone I for structur-
eeactivity relationship study. Therefore, mild and facile synthetic
approaches to access tanshinone I and its analogues are still
wanted.
* Corresponding author. Tel./fax: þ86 (021) 50806035; e-mail address: chding@
simm.ac.cn (C. Ding).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.019

M. Jiao et al. / Tetrahedron 70 (2014) 2976e2981
2977
Scheme 1. Reported approaches for the synthesis of tanshinone I (1).
In our synthetic efforts towards biologically active natural
products,10e13 we developed an efficient method to assemble benzo
[a]anthraquinones from bromoquinones and arylpropionic acid
through a tandem three-step reaction approach, including silver-
catalyzed decarboxylic radical alkylation, palladium-catalyzed cy-
clization and DBU-assisted aromatization.11 As an application of
this method, we also synthesized a series of naphtho[2,3-a]carba-
zole-5,13-diones as well as indole- or benzofuran-fused benzo[a]
carbazole-1,4-diones from indol-3-propanoic acid through a simi-
lar one-pot reaction protocol.12,13 Inspired by these results, we
envisioned that this tandem three-step reaction strategy might be
utilized to construct the A/B/C tricyclic phenanthraquinone frag-
ment of tanshinone I (1), which would eventually lead to a facile
total synthesis of 1. Herein, we describe, for the first time, the ap-
plication of this radical strategy to the synthesis of this key tricyclic
precursor, and subsequent assembly of tanshinone I and its 4-
demethylated analogues.
In view of the relative instability of 6-bromo-3-methyl
benzofuran-4,5-dione in path a,14 we decided to start our syn-
thetic effort based on path b with 6-bromo-3-methylbenzofuran-
4,7-dione (6) as the key intermediate. Unfortunately, treating
a mixture of bromoquinone 6 and acid 5 with AgNO3 and
(NH4)2S2O8 at rt delivered no desired product. Elevating the re-
action temperature to 80 ꢀC resulted in decomposition of the
substrate. The failure of this radial alkylation reaction was likely
ascribed to the instability of the furan ring of 6. In this regard, we
switched our synthetic effort of 1 to path c with bromoquinone 7 as
the substrate.
As depicted in Scheme 3, by following a literature procedure,15
BaeyereVilliger oxidation of 5-bromovanillin (8) with sodium per-
carbonate followed by hydrolysis of the ester function afforded 1,4-
hydroquinone 9. Subsequent oxidation of 9 with FeCl3 provided
bromoquinone 7 in 89% overall yield (two steps). Initially, the
commerciallyavailable 3-phenylpropanoic acid was used as a model
substrate to test the feasibility of the radical reaction with 7. To our
delight, decarboxylative radical alkylation of 3-phenylpropanoic
acid with 7 in the presence of 0.3 equiv of AgNO3 and 2 equiv of
(NH4)2S2O8 went through smoothly and delivered the desired in-
termediate 12 in 45% yield. It should be noted that this alkylation
reaction of 7 selectively occurred at the carbon neighbouring to
bromo- other than the carbon close to methoxy group due to the
electronic effects of these two substituents.12,13
2. Results and discussion
The retrosynthetic analysis of 1 was outlined in Scheme 2. Three
possible approaches (path a, b and c) were proposed using different
bromoquinone substrates during the synthesis. All of these paths
included the decarboxylative radical alkylation of bromoquinones
with tolylpropionic acid followed by intracellular CeC coupling and
aromatization reactions as key steps to construct the A/B/C rings of
1. In both paths a and b, the furan ring was introduced prior to the
formation of ring B through the bromoquinone intermediate,
whereas in path c, the furan ring was constructed after the for-
mation of A/B/C ring system.
To further optimize the reaction conditions to achieve better
yield, a number of silver catalysts, variant reagent ratios as well as
other reaction parameters were screened. As summarized in
Table 1, all the silver catalysts initiated the radical alkylation, while
Ag2CO3 and Ag3PO4 proved to be more promising to provide

2978
M. Jiao et al. / Tetrahedron 70 (2014) 2976e2981
Scheme 2. Our retrosynthetic analysis of tanshinone I (1).
Scheme 3. Synthesis of 3-hydroxyphenanthrene-1,4-diones 20e26. Reagents and conditions: (a) sodium percarbonate, THF/H2O, rt, 90%; (b) FeCl3, MeOH/H2O, rt, 99%; (c) Ag3PO4
(30%), (NH4)2S2O8 (2 equiv), CH3CN/H2O, 85 ꢀC, 65e79%; (d) Pd(OAc)2, PPh3, K2CO3, toluene, 110 ꢀC; (e) NaOH, O2, ethanol/H2O, 95 ꢀC, 43e79% (two steps).
With the optimized reaction conditions in hand, we then set out
to explore the substrate scope. A number of arylpropionic acids
were employed with various substituents at the para- or ortho-
positions of the phenyl ring, including methyl, fluoro, tri-
fluoromethyl and methoxyl groups. It was found that all reactions
under the optimized conditions occurred smoothly and furnished
the corresponding products 11e17 in 65e79% yields (Scheme 3),
indicating that various substitutions on the phenyl ring were well
tolerated in the alkylation reaction.
Table 1
Optimization of radical alkylation reaction condition for 12
Entry Ag
Molar ratio
T (ꢀC) Time (h) Yielda (%)
Next, we turned our attention to the intramolecular cyclization
of bromoquinone 11 through a Pd(OAc)2-catalyzed CeH arylation to
construct the A/B/C tricyclic skeleton of 1 (Scheme 3). By following
our previously developed CeC coupling procedure,11 treating 11
with Pd(OAc)2 (0.45 equiv), PPh3 (0.8 equiv) and K2CO3 (3 equiv) in
refluxing toluene for 12 h yielded the desired cyclization product 18
as the major product, together with a small amount of dehydro-
genated aromatic product 19 that was inseparable from 18 by flash
chromatography. To our delight, after many attempts, we found that
the reaction mixture, without further isolation, was directly treated
with aqueous NaOH solution (1 N) under O2 atmosphere in refluxing
EtOH to complete the dehydrogenation and O-demethylation in one
pot affording the aromatic product 20 in 71% yield as the sole
product (two steps). On the basis of this encouraging result, a series
of tricyclic hydroxyquinones 21e26 were successfully synthesized
in 43e79% yields in a similar fashion. To further verify this method,
indole-3-propionic acids 27 and 28 were used to replace tolylpro-
pionic acids and subjected to the optimized radical alkylation. Benzo
catalysts (10/7/Ag catalyst/oxidant)
1
2
3
4
5
6
7
8
AgNO3
Ag2CO3
AgOAc
Ag3PO4
AgBF4
1.5/1.0/0.3/2.0
1.5/1.0/0.3/2.0
1.5/1.0/0.3/2.0
1.5/1.0/0.3/2.0
1.5/1.0/0.3/2.0
1.5/1.0/0.3/2.0
1.5/1.0/0.3/2.0
1.5/1.0/0.6/2.0
1.5/1.0/0.1/2.0
1.0/1.5/0.3/2.0
1.5/1.0/0.3/2.0
2.0/1.0/0.3/2.0
80
80
80
80
80
80
80
80
80
80
85
85
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.0
2.0
2.0
1.0
0.8
45
58
37
62
50
49
48
63
33
45
61
79
AgClO4
AgOTf
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
9
10
11
12
a
Isolated yields.
product 12 in 58% and 62% yields, respectively (entries 2 and 4). The
best result (79% for 12) was achieved by using 0.3 equiv of Ag3PO4,
2 equiv of (NH4)2S2O8 as well as 2/1 molar ratio of compounds 10
and 7 at 85 ꢀC (entry 12).

M. Jiao et al. / Tetrahedron 70 (2014) 2976e2981
2979
[a]carbazole-1,4-diones 29 and 30 were obtained directly in 62%
4. Experimental section
4.1. General
and 54% yields, respectively. The high efficiency of this one-pot
three-step process (radical alkylationecyclizationearomatization)
is due to the high reactivity of indole-3-propionic acid substrates,
a phenomenon similar to our previous report (Scheme 4).12
All reactions were performed in glassware containing a Teflon-
coated stir bar. All reagents were obtained from commercial sour-
ces and used without further purifications. Melting points were
determined by a X-4 digital display microscopic melting point ap-
paratus and are uncorrected. 1H and 13C NMR spectra were recorded
with tetramethylsilane as an internal reference. Low- and high res-
olution mass spectra were obtained in the EI (70 eV) mode. Flash
column chromatography on silica gel (200e300 mesh) was used for
the routine purification of reactionproducts. The column output was
monitored by TLC on silica gel (100e200 mesh) precoated on glass
plates (10ꢁ50 cm), and spots were visualized by UV light at 254 nm.
Scheme 4. Synthesis of compounds 29 and 30.
4.1.1. 2-Bromo-6-methoxycyclohexa-2,5-diene-1,4-dione
(7). This
compound was prepared according to a literature procedure.15 1
H
With the key precursor 20 successfully prepared, we decided to
NMR (400 MHz, CDCl3):
1H), 3.86 (s, 3H).
d
7.21 (d, J¼2.4 Hz, 1H), 5.97 (d, J¼2.4 Hz,
complete the synthesis of tanshinone I (1) by using the reported
16
ꢀ
FeisteBenary reaction (Scheme 5). Although this one-step syn-
thetic reaction has been claimed in a patent using NH4OAc/HOAc in
refluxing EtOH/toluene,17 repeating this procedure only led to
a complex with trace amount of desired product 1 in our labora-
tory. Extensive investigations indicated that the solvent played
a key impact factor for the conversion of 20 to 1. Using anhydrous
toluene as the solvent, treating 20 with bromo-2-propanone and
NH4OAc at 120 ꢀC in a sealed tube for 10 h successfully provided
tanshinone I (1) in 35% yield as the major product, together with
recovered 20 (30%). Similarly, 4-demethylated analogue 31 was
also achieved in 34% yield under the same reaction condition from
the precursor 21.
4.2. General procedure for compounds 11e17, 29 and 30
through silver-catalyzed radical alkylation
A vigorously stirred mixture of various substituted propanoic
acid (1.0 mmol), 2-bromo-6-methoxy-[1,4]-benzoquinone (217 mg,
0.5 mmol), Ag3PO4 (63 mg, 0.15 mmol) and acetonitrile (5 mL) was
placed in a preheated oil bath at 85 ꢀC, and a solution of (NH4)2S2O8
(228 mg,1.0 mmol) in water (3 mL) was added over a period of 5 min
under N2 by means of a syringe. The resulting mixture was stirred at
the same temperature. After completion of the reaction, as indicated
by TLC, the reaction was quenched with ice and extracted with
CH2Cl2 (3ꢁ20 mL). The combined organic solution was washed with
brine, dried over anhydrous Na2SO4, filtered and evaporated to give
a solid residue. The residue was further purified using chromatog-
raphy developed by CH2Cl2 to afford the desired products.
4.2.1. 3-Bromo-5-methoxy-2-(2-methylphenethyl)cyclohexa-2,5-
diene-1,4-dione (11). Yellow solid (75%), mp 149e152 ꢀC. 1H NMR
(400 MHz, CDCl3):
2.94e2.90 (m, 2H), 2.78e2.74 (m, 2H), 2.42 (s, 3H). 13C NMR
(100 MHz, CDCl3): 183.7, 174.9, 158.4, 149.1, 138.7, 136.3, 133.2,
d 7.20e7.12 (m, 4H), 5.96 (s, 1H), 3.85 (s, 3H),
d
130.5, 129.2, 126.7, 126.2, 107.5, 56.8, 32.1, 31.4, 19.4. MS (EI) 334
(Mþ); HRMS (EI) calcd for C16H15BrO3 (Mþ) 334.0205, found
334.0188.
Scheme 5. Synthesis of 1 and its analogue 31.
3. Conclusion
4.2.2. 3-Bromo-5-methoxy-2-phenethylcyclohexa-2,5-diene-1,4-
dione (12). Yellow solid (79%), mp 138e140 ꢀC. 1H NMR (400 MHz,
In summary, we have developed a mild synthetic approach
CDCl3):
d
7.32e7.20 (m, 5H), 5.96 (s, 1H), 3.85 (s, 3H), 3.00e2.96 (m,
183.7, 174.9,
allowing for
a
convenient construction of tricyclic hydrox-
2H), 2.80e2.76 (m, 2H). 13C NMR (100 MHz, CDCl3):
d
yphenanthraquinone 20, the key precursor for total synthesis of
tanshinone I (1). This tandem process includes decarboxylative
radical alkylation, intramolecular CeH arylation and one-pot O-
demethylation and aromatization. Variously substituted phenyl-
propanoic acids were tolerated very well in this approach, and one-
pot synthesis of benzo[a]carbazole-1,4-diones 29 and 30 was ach-
ieved directly in the radical alkylation reaction. Finally, synthesis of
tanshinone I (1) and its 4-demthylated analogue 31 was completed
158.3, 149.0, 140.5, 133.4, 128.6 (4), 126.5, 107.4, 56.8, 33.9, 33.3. MS
(EI) 320 (Mþ); HRMS (EI) calcd for C15H13BrO3 (Mþ) 320.0048,
found 320.0025.
4.2.3. 3-Bromo-2-(2-fluorophenethyl)-5-methoxycyclohexa-2,5-
diene-1,4-dione (13). Yellow solid (74%), mp 134e137 ꢀC. 1H NMR
(400 MHz, CDCl3):
1H), 3.85 (s, 3H), 3.03e2.99 (m, 2H), 2.88e2.84 (m, 2H). 13C NMR
(125 MHz, CDCl3):
d 7.23e7.17 (m, 2H), 7.07e6.98 (m, 2H), 5.95 (s,
ꢀ
by following a modified FeisteBenary reaction. Compared to the
d
183.7, 174.9, 161.3 (d, J¼245.5 Hz), 158.3, 148.7,
currently available procedures for total synthesis of tanshinone
I,6e9 our protocol started from commercially available starting
material (5-bromovanillin), and furnished the natural product in
six straight steps in 19% overall yields. Our success in the efficient
construction of tricyclic phenanthraquinone compounds provides
133.6, 130.9 (d, J¼4.8 Hz), 128.4 (d, J¼8.2 Hz), 127.2 (d, J¼16.0 Hz),
124.2 (d, J¼3.7 Hz), 115.4 (d, J¼22.0 Hz), 107.5, 56.8, 31.6, 27.3. MS
(EI) 338 (Mþ); HRMS (EI) calcd for C15H12BrFO3 (Mþ) 337.9954,
found 337.9950.
new synthetic potential to easily access novel tanshinone
derivatives.
I
4.2.4. 3-Bromo-2-(4-fluorophenethyl)-5-methoxycyclohexa-2,5-
diene-1,4-dione (14). Yellow solid (73%), mp 130e132 ꢀC. 1H NMR

2980
M. Jiao et al. / Tetrahedron 70 (2014) 2976e2981
(400 MHz, CDCl3):
d
7.23e7.18 (m, 2H), 7.01e6.95 (m, 2H), 5.96 (s,
evaporated to give a solid residue. Without further purification, the
residue was dissolved in ethanol (5 mL), and the resulting solution
was heated at 95 ꢀC in the presence of aqueous NaOH solution (1 N,
10 mL) under O2 atmosphere (O2 balloon) for 30 min. After cooling
to rt, the reaction mixture was acidified with 2 N HCl (6 mL) and
extracted with EtOAc (3ꢁ20 mL). The combined organic solution
was washed with brine, dried over anhydrous Na2SO4, filtered and
evaporated to give a solid residue. The residue was further purified
using chromatography developed by 10% methanol in CH2Cl2 to
afford the desired products.
1H), 3.85 (s, 3H), 2.97e2.93 (m, 2H), 2.78e2.74 (m, 2H). 13C NMR
(100 MHz, CDCl3):
d
183.6, 174.8, 161.7 (d, J¼244.2 Hz), 158.4, 148.8,
136.1,133.5,130.0 (2),115.5,115.3,107.4, 56.8, 33.3, 33.0. MS (EI) 338
(Mþ); HRMS (EI) calcd for C15H12BrFO3 (Mþ) 337.9954, found
337.9957.
4.2.5. 3-Bromo-5-methoxy-2-(2-(trifluoromethyl)phenethyl)cyclo-
hexa-2,5-diene-1,4-dione (15). Yellow solid (65%), mp 143e145 ꢀC.
1H NMR (400 MHz, CDCl3):
d
7.63 (d, J¼7.9 Hz, 1H), 7.52e7.48 (m,
1H), 7.43 (d, J¼7.5 Hz, 1H), 7.35e7.31 (m, 1H), 5.98 (s, 1H), 3.86 (s,
3H), 3.05e2.94 (m, 4H). 13C NMR (125 MHz, CDCl3):
183.7, 174.9,
d
4.3.1. 3-Hydroxy-8-methylphenanthrene-1,4-dione
(20). Orange
9.29
158.4, 148.5, 139.2, 133.8, 132.1, 131.5, 128.7 (q, J¼29.9 Hz), 126.7,
126.1 (q, J¼5.7 Hz),124.6 (q, J¼274.3 Hz), 107.52, 56.9, 33.0, 30.4. MS
(EI) 388 (Mþ); HRMS (EI) calcd for C16H12BrF3O3 (Mþ) 387.9922,
found 387.9919.
solid (71%), mp 209e212 ꢀC. 1H NMR (400 MHz, DMSO-d6):
d
(d, J¼8.8 Hz, 1H), 8.48 (d, J¼8.8 Hz, 1H), 8.09 (d, J¼8.8 Hz, 1H),
7.69e7.65 (m,1H), 7.54 (d, J¼6.9 Hz,1H), 6.11 (s,1H), 2.70 (s, 3H). 13
C
NMR (125 MHz, DMSO-d6):
d 184.8, 184.1, 160.7, 135.2, 134.6, 132.3,
131.7, 129.9, 129.7, 128.9, 125.5, 124.8, 121.3, 107.8, 19.5. MS (EI) 238
(Mþ); HRMS (EI) calcd for C15H10O3 (Mþ) 238.0630, found
238.0630.
4.2.6. 3-Bromo-5-methoxy-2-(4-(trifluoromethyl)phenethyl)cyclo-
hexa-2,5-diene-1,4-dione (16). Yellow solid (69%), mp 124e126 ꢀC.
1H NMR (400 MHz, CDCl3):
d
7.56 (d, J¼8.1 Hz, 2H), 7.38 (d, J¼8.1 Hz,
2H), 5.97 (s, 1H), 3.86 (s, 3H), 3.01e2.96 (m, 2H), 2.86e2.82 (m, 2H).
13C NMR (125 MHz, CDCl3):
183.6, 174.7, 158.5, 148.5, 144.6, 133.7,
4.3.2. 3-Hydroxyphenanthrene-1,4-dione (21). Red solid (79%). 1H
d
NMR (400 MHz, DMSO-d6):
d
9.42 (d, J¼8.9 Hz, 1H), 8.37 (d,
128.9 (3), 125.6, 124.4 (q, J¼272.3 Hz), 107.4 (2), 56.9, 33.6, 32.8. MS
(EI) 388 (Mþ); HRMS (EI) calcd for C16H12BrF3O3 (Mþ) 387.9922,
found 387.9904.
J¼8.5 Hz, 1H), 8.08 (d, J¼8.0 Hz, 1H), 8.07 (d, J¼8.2 Hz, 1H),
7.83e7.79 (m, 1H), 7.74e7.70 (m, 1H), 6.15 (s, 1H). 13C NMR
(125 MHz, DMSO-d6):
d 185.0, 183.9, 160.2, 135.7, 135.6, 132.6,
130.3, 129.3, 129.1, 128.3, 126.6, 125.2, 121.5, 108.0. MS (EI) 224
(Mþ); HRMS (EI) calcd for C14H8O3 (Mþ) 224.0473, found
224.0475.
4.2.7. 3-Bromo-5-methoxy-2-(2-methoxyphenethyl)cyclohexa-2,5-
diene-1,4-dione (17). Yellow solid (72%), mp 161e163 ꢀC. 1H NMR
(400 MHz, CDCl3):
d
7.19 (m,1H), 7.13 (dd, J¼7.4,1.7 Hz,1H), 6.87 (m,
1H), 6.82 (d, J¼8.2 Hz,1H), 5.93 (s,1H), 3.84 (s, 3H), 3.81 (s, 3H), 2.99
4.3.3. 8-Fluoro-3-hydroxyphenanthrene-1,4-dione
(22). Orange
9.26
(dd, J¼8.7, 6.6 Hz, 2H), 2.83 (dd, J¼8.8, 6.5 Hz, 2H). 13C NMR
solid (50%), mp 227e239 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d
(100 MHz, CDCl3):
d
183.6, 175.0, 158.2, 157.6, 149.7, 133.0, 130.2,
(d, J¼8.9 Hz, 1H), 8.53 (d, J¼8.8 Hz, 1H), 8.18 (d, J¼8.8 Hz, 1H),
128.7, 127.9, 120.6, 110.3, 107.4, 56.8, 55.4, 31.5, 28.8. MS (EI) 350
(Mþ); HRMS (EI) calcd for C16H15BrO4 (Mþ) 350.0154, found
350.0154.
7.86e7.78 (m, 1H), 7.58 (dd, J¼10.5, 7.8 Hz, 1H), 6.18 (s, 1H). 13C NMR
(100 MHz, DMSO-d6):
d
184.7, 183.5, 160.2, 157.9 (d, J¼252.5 Hz),
133.1, 130.5, 130.4 (d, J¼4.0 Hz), 127.30 (d, J¼7.1 Hz), 125.4 (d,
J¼16.2 Hz), 125.3, 123.1 (d, J¼4.0 Hz), 122.3, 112.2 (d, J¼19.2 Hz),
108.2. MS (EI) 242 (Mþ); HRMS (EI) calcd for C14H7FO3 (Mþ)
242.0379, found 242.0384.
4.2.8. 2-Methoxy-11-methyl-1H-benzo[a]carbazole-1,4(11H)-dione
(29). Red solid (62%), mp 236e239 ꢀC. 1H NMR (400 MHz, DMSO-
d6):
d
8.60 (d, J¼7.9 Hz, 1H), 8.29 (d, J¼7.8 Hz, 1H), 7.90 (d, J¼7.9 Hz,
1H), 7.73 (d, J¼8.3 Hz, 1H), 7.64e7.60 (m, 1H), 7.37e7.33 (m, 1H),
4.3.4. 6-Fluoro-3-hydroxyphenanthrene-1,4-dione
(23). Orange
11.71
6.30 (s, 1H), 3.91 (s, 3H), 3.89 (s, 3H). 13C NMR (125 MHz, DMSO-d6):
solid (43%), mp 223e225 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d
d
184.7, 179.7, 161.7, 144.7, 138.8, 130.8, 129.8, 128.3, 125.6, 121.2,
(br s, 1H), 9.11 (d, J¼12.7 Hz, 1H), 8.41 (d, J¼8.2 Hz, 1H), 8.22e8.16
121.1, 120.9, 117.5, 117.2, 110.9, 107.9, 56.6, 35.4. MS (EI) 291 (Mþ);
(m, 1H), 8.03 (d, J¼8.6 Hz, 1H), 7.69e7.62 (m, 1H), 6.15 (s, 1H). 13
C
HRMS (EI) calcd for C18H13NO3 (Mþ) 291.0895, found 291.0896.
NMR (100 MHz, DMSO-d6):
d
184.7, 183.5, 163.0 (d, J¼245.2 Hz),
159.9, 135.7, 133.2, 133.8, 132.1 (d, J¼10.1 Hz), 130.2 (d, J¼11.1 Hz),
124.5 (d, J¼6.1 Hz), 121.0, 118.4 (d, J¼26.3 Hz), 110.2 (d, J¼25.3 Hz),
108.2. MS (EI) 242 (Mþ); HRMS (EI) calcd for C14H7FO3 (Mþ)
242.0379, found 242.0376.
4.2.9. 11-Benzyl-2-methoxy-1H-benzo[a]carbazole-1,4(11H)-dione
(30). Red solid (54%), mp 189e192 ꢀC. 1H NMR (400 MHz, DMSO-
d6):
d
8.67 (d, J¼7.9 Hz, 1H), 8.33 (d, J¼7.8 Hz, 1H), 7.93 (d, J¼8.0 Hz,
1H), 7.67 (d, J¼8.4 Hz, 1H), 7.58e7.54 (m, 1H), 7.38e7.34 (m, 1H),
7.18e7.15 (m, 3H), 6.84 (dd, J¼7.8, 1.5 Hz, 2H), 6.26 (s, 1H), 5.88 (s,
4.3.5. 3-Hydroxy-8-(trifluoromethyl)phenanthrene-1,4-dione
(24). Yellow solid (59%), mp 193e195 ꢀC. 1H NMR (300 MHz,
2H), 3.86 (s, 3H). 13C NMR (125 MHz, DMSO-d6):
d 184.9, 180.5,
161.4, 144.8, 138.5, 138.1, 131.5, 130.9, 128.8 (3), 127.4, 126.8 (2),
126.5, 122.2, 121.7, 121.6, 118.3, 118.2, 112.1, 108.3, 57.1, 50.4. MS (EI)
367 (Mþ); HRMS (EI) calcd for C24H17NO3 (Mþ) 367.1208, found
367.1215.
DMSO-d6):
1H), 8.29 (d, J¼7.7 Hz, 1H), 8.20 (d, J¼7.3 Hz, 1H), 7.95 (t, J¼8.2 Hz,
1H), 6.20 (s, 1H). 13C NMR (125 MHz, DMSO-d6):
184.3, 183.4,
160.3, 132.5, 131.8, 130.4, 130.1, 130.0, 128.6, 127.1 (q, J¼6.3 Hz),
126.0, 125.0 (q, J¼30.0 Hz), 124.3 (q, J¼274.7 Hz), 123.7, 108.2. MS
(EI) 292 (Mþ); HRMS (EI) calcd for C15H7F3O3 (Mþ) 292.0347, found
292.0351.
d
11.85 (br s, 1H), 9.72 (d, J¼9.1 Hz, 1H), 8.51 (d, J¼8.8 Hz,
d
4.3. General procedure for compounds 20e26 through in-
tracellular CeH arylation followed by one-pot O-demethyla-
tion and aromatization
4.3.6. 3-Hydroxy-6-(trifluoromethyl)phenanthrene-1,4-dione
(25). Yellow solid (59%), mp 210e212 ꢀC. 1H NMR (300 MHz,
A mixture of various bromoquinones (0.5 mmol), Pd(OAc)2
(51 mg, 0.225 mmol), PPh3 (105 mg, 0.4 mmol), K2CO3 (207 mg,
1.5 mmol) and anhydrous toluene (5 mL) was refluxed under N2 for
12 h. The reaction mixture was diluted with water (20 mL) and
extracted with CH2Cl2 (3ꢁ20 mL). The combined organic solution
was washed with brine, dried over anhydrous Na2SO4, filtered and
DMSO-d6):
(d, J¼8.5 Hz,1H), 8.18 (d, J¼8.6 Hz,1H), 7.95 (d, J¼8.7 Hz,1H), 6.17 (s,
1H). 13C NMR (100 MHz, DMSO-d6):
184.9, 184.0, 160.5, 137.1,
d
11.77 (br s, 1H), 9.77 (s, 1H), 8.47 (d, J¼8.5 Hz, 1H), 8.30
d
135.8, 133.6, 131.2, 130.1 (q, J¼32.3 Hz), 128.4, 126.3, 124.8 (q,
J¼6.1 Hz), 124.7 (q, J¼273.7 Hz), 124.3, 123.8, 108.7. MS (EI) 292

M. Jiao et al. / Tetrahedron 70 (2014) 2976e2981
2981
(Mþ); HRMS (EI) calcd for C15H7F3O3 (Mþ) 292.0347, found
Supplementary data
292.0344.
These data include all NMR spectra for the compounds de-
scribed in this paper. Supplementary data related to this article can
be found at http://dx.doi.org/10.1016/j.tet.2014.03.019.
4.3.7. 3-Hydroxy-8-methoxyphenanthrene-1,4-dione (26). Red solid
(59%), mp 185e187 ꢀC. 1H NMR (400 MHz, DMSO-d6):
d 8.97 (d,
J¼8.8 Hz, 1H), 8.59 (d, J¼8.5 Hz, 1H), 8.03 (d, J¼8.7 Hz, 1H), 7.70 (t,
J¼8.2 Hz, 1H), 7.16 (d, J¼7.4 Hz, 1H), 6.13 (s, 1H), 4.01 (s, 3H). 13C
NMR (125 MHz, DMSO-d6): d 184.9, 183.7, 160.3, 155.0, 132.9, 130.9,
References and notes
130.4, 129.0, 127.5, 124.8, 120.8, 118.4, 108.0, 106.7, 55.9. MS (EI) 254
(Mþ); HRMS (EI) calcd for C15H10O4 (Mþ) 254.0579, found 254.0579.
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A mixture of 3-hydroxyphenanthrene-1,4-diones (0.1 mmol),
bromo-2-propanone (69 mg, 0.5 mmol), NH4OAc (8 mg, 0.1 mmol)
and anhydrous toluene (5 mL) in a sealed tube was heated to 120 ꢀC
for 10 h in the dark. After cooling to rt, the reaction mixture was
acidified with 1 N HCl (3 mL) and extracted with CH2Cl2 (3ꢁ20 mL).
The combined organic solution was washed with brine, dried over
anhydrous Na2SO4, filtered and evaporated to give a solid residue.
The residue was further purified using chromatography developed
by CH2Cl2 to afford the desired products.
4.4.1. 1,6-Dimethylphenanthro[1,2-b]furan-10,11-dione
solid (35%). 1H NMR (300 MHz, CDCl3):
(1). Red
9.23 (d, J¼8.8 Hz, 1H), 8.28
d
(d, J¼8.8 Hz,1H), 7.78 (d, J¼8.8 Hz,1H), 7.54 (t, J¼8.1 Hz,1H), 7.34 (d,
J¼7.2 Hz, 1H), 7.29 (s, 1H), 2.68 (s, 3H), 2.29 (s, 3H). 13C NMR
(150 MHz, CDCl3):
d 183.5, 175.6, 161.2, 142.0, 135.2, 133.6, 133.0,
132.8, 130.7, 129.6, 128.4, 124.8, 123.1, 121.8, 120.5, 118.7, 19.9, 8.9.
MS (EI) 276 (Mþ); HRMS (EI) calcd for C18H12O3 (Mþ) 276.0786,
found 276.0789.
5. Xu, L.; Feng, J. M.; Li, J. X.; Zhu, J. M.; Song, S. S.; Tong, L. J.; Chen, Y.; Yang, X. Y.;
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4.4.2. 1-Methylphenanthro[1,2-b]furan-10,11-dione (31). Red solid
(34%), mp 226e229 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d
9.28 (d,
1149e1152.
J¼8.8 Hz, 1H), 8.31 (d, J¼8.5 Hz, 1H), 8.00 (d, J¼8.2 Hz, 1H), 7.83 (d,
8. Inouye, Y.; Kakisawa, H. Bull. Chem. Soc. Jpn. 1969, 42, 3318e3323.
9. Huot, R.; Brassard, P. Can. J. Chem. 1974, 52, 88e94.
J¼8.5 Hz, 1H), 7.80 (s, 1H), 7.73 (t, J¼7.7 Hz, 1H), 7.59 (t, J¼7.2 Hz,
1H), 2.20 (s, 3H). 13C NMR (150 MHz, DMSO-d6):
d 182.2, 174.8,
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5693e5696; (e) Wang, D.; Jia, X.; Zhang, A. Org. Biomol. Chem. 2012, 10,
7027e7030; (f) Zhang, X.; Jiang, X.; Ding, C.; Yao, Q.; Zhang, A. Org. Biomol.
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159.9, 143.2, 136.9, 134.0, 131.6, 130.6, 129.5, 129.4, 127.2, 125.8,
122.7, 120.8, 120.3, 118.9, 8.6. MS (EI) 262 (Mþ); HRMS (EI) calcd for
C
17H10O3 (Mþ) 262.0630, found 262.0633.
Acknowledgements
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We gratefully acknowledge financial support from Chinese
National Sciences Foundation (81125021, 81373277), the “In-
terdisciplinary Cooperation Team” Program for Science and Tech-
nology Innovation (CAS), and the support from the State Key
Laboratory of Drug Research (SIMM1302KF-08), Shanghai Institute
of Materia Medica.
17. Jing, H.; Li, H.; Mao, J.; Ma, W.; Chen, Y.; Liu, S. CN102702302 (A), 2012.