Difluorination of Furonaphthoquinones

Article abstract of DOI:10.1021/acs.joc.7b01064

An unprecedented difluorination reaction was developed based on the furonaphthoquinone skeleton of natural products tanshinones and their analogues. By using Selectfluor as the fluorinating source and H₂O as the hydroxyl source, a wide range of unique polycyclic α,α-difluoro β,β-dihydroxyl para-quinone products were achieved with yields up to 90%. The mechanistic studies revealed that the reaction might undergo tandem multiple electrophilic and nucleophilic substitutions, as well as cleavages of C-O and C-C bonds. This approach not only provides a new method to synthesis of α,α-difluoro ketones, but also affords a series of unique chemotypes for biological activity screening.

Full text of DOI:10.1021/acs.joc.7b01064

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Article
Difluorination of Furonaphthoquinones
Jie Li, Yu Xue, Zhoulong Fan, Chunyong Ding, and Ao Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01064 • Publication Date (Web): 27 Jun 2017
Downloaded from http://pubs.acs.org on June 27, 2017
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Difluorination of Furonaphthoquinones
Jie Li,† Yu Xue,‡ Zhoulong Fan,§,#,ǁ Chunyong Ding,*,§,ǁ and Ao Zhang*,†,§,#,ǁ
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†ShanghaiTech University, Shanghai 201210, China
‡Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
§CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
Shanghai 201203, China
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#State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
Shanghai 201203, China
ǁUniversity of Chinese Academy of Sciences, Beijing 100049, China
*Corresponding Author: aozhang@simm.ac.cn (A. Zhang); chding@simm.ac.cn (C. Ding)
ABSTRACT: An unprecedented difluorination reaction was developed based on the
furonaphthoquinone skeleton of natural products tanshinones and their analogues. By
using Selectfluor as the fluorinating source and H2O as the hydroxyl source, a wide
range of unique polycyclic α,αꢀdifluoro β,βꢀdihydroxyl paraꢀquinone products were
achieved with yields up to 90%. The mechanistic studies revealed that the reaction
might undergo tandem multiple electrophilic and nucleophilic substitutions, as well as
cleavages of CꢀO and CꢀC bonds. This approach not only provides a new method to
synthesis of α,αꢀdifluoro ketones, but also affords a series of unique chemotypes for
biological activity screening.
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INTRODUCTION
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Fluorineꢀcontaining compounds play an intrinsic role in the fields of pharmaceuticals,
agrochemicals, and materials due to their superior physiochemical and biological
properties.1 Among various fluorinated structural motifs, α,αꢀdifluorinated ketone
constitutes a valuable subset of bioactive molecules for drug discovery.2 Indeed, the
two fluorine atoms could make the orthoꢀcarbonyl form a more stable hydrate or
gemdiol with H2O.3 The formed gemdiol compounds generally have increased
aqueous solubility, and some of them also showed good potency against proteolytic
enzymes, such as HIV1 protease, and matrix metalloprotease, by mimicking
tetrahedral transition state involved in peptide hydrolysis.4 Accordingly, incorporation
of the α,αꢀdifluorinated ketone moiety has become a promising strategy for drug
design and lead optimization. However, methods to synthesis of α,αꢀdifluorinated
ketones are very limited. Current reported approaches include: a) transitionꢀmetal
catalyzed α,αꢀdifluorocarbonylation,5 b) direct electrophilic α,αꢀdifluorination,6 and c)
deoxydifluorination of ketones or aldehydes.7 Recently, a few new methods for
α,αꢀdifluorocarbonylation were reported via CꢀC cleavage of 1,3ꢀdicarbonyl
compounds. In 2016, the Pattison group developed an oneꢀpot approach for synthesis
of difluoromethyl ketones through cleavage of trifluoroacetyl fragment (Scheme 1a).8
Very recently, Deng and coworkers described a decarboxylative difluorination
reaction of βꢀketoacids (Scheme 1b).9 Undoubtedly, these methods would spur new
interest in the application of α,αꢀdifluorocarbonylation products. However, available
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approaches, especially for the synthesis of cyclic α,αꢀdifluorinated ketones, remain
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largely elusive.
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Scheme 1. Synthesis of α,αꢀDifluorinated Ketones via CꢀC Bond Cleavage and
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Structures of Representative Tanshinones 1ꢀ3.
Tanshinones, including tanshinone IIA (1a, TanꢀIIA), tanshinone I (2, TanꢀI), and
cryptotanshinone (3, CPT) (Scheme 1d), represent a large class of tetracyclic
furoquinone diterpenoids isolated from traditional Chinese medicinal herb Salvia
miltiorrhiza Bunge, and have demonstrated various pharmacological activities.10
However, further clinical development of tanshinones is hampered by its relative low
potency and poor druggability.11 Thus, structural modification of tanshinones,
especially on the metabolically unstable furoquinone rings C/D is desired.12 In our
continuing structural modification of natural product tanshinones,13 we, herein,
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disclose an unprecedented difluorination reaction of tanshinone analogues for facile
construction of polycyclic α,αꢀdifluorinated ketones (Scheme 1c).
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RESULTS AND DISCUSSION
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Since the orthoꢀquinone moiety was the major issue causing poor aqueous solubility
of tanshinones, our initial effort was to convert one of the two carbonyls in 1a to
fluoromethyl moiety, a strategy widely used in the drug discovery.14 It was found that
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treating 1a with the fluorinating agent DAST in 1,4ꢀdioxane at 90 C afforded two
α,αꢀdifluorinated ketone products 5 and 6 in 42% and 36% yields, respectively
(Scheme 2). The structures of these two regioisomers were discriminated by HRMS,
NMR and Xꢀrays (Figures S2ꢀS3 and Tables S2ꢀS3 in SI). To improve the
regioselectivity of the two α,αꢀdifluorinated products, other fluorinating agents were
explored as alternatives. To our surprise, when the electrophilic fluorinating agent
selectfluor was used, reaction with 1a in the presence of AgNO3/Na2S2O8 in
CH3CN/H2O provided an unprecedented tricyclic α,αꢀdifluoro ß,ßꢀdihydroxyl
paraꢀquinone product 4a in 51% yield with the furan portion truncated (Scheme 2).
The unique structure of 4a was determined by HRMS and NMR, and further secured
by Xꢀray crystallography (Figure S1 and Table S1 in SI).
Scheme 2. Direct Difluorination of 1a
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In view of the structural novelty of 4a, we decided to optimize the reaction
condition to improve the yield and to explore the substrate scope and limitation as
well. Interestingly, we found that the reaction proceeded even better without
AgNO3/Na2S2O8 leading to 4a in 77% yield (Table 1, entry 2). When other
fluorinating agents were used (entries 3ꢀ5), such as NFSI, NFPYBF4, and
Me3NFPYBF4, the yields were decreased in varying degrees (33~56%). Different
reaction solvents, such as DMF/H2O, and 1,4ꢀdioxane/H2O, were also investigated,
and none of them gave better yields (entries 6ꢀ7). Decreasing or elevating reaction
temperature led to slightly decreased yields (entries 8ꢀ9). Using 2.0 equiv of
selectfluor, the yield was decreased to 52%, and 4.0 equiv of selectfluor also failed to
improve the yield (entries 10ꢀ11). Shorter reaction time resulted in a dramatically
decreased yield (entry 12). Taking together, using 3.0 equiv of selectfluor in
CH3CN/H2O at 80 °C was determined to be the optimal reaction condition for this
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unique difluorination reaction.
Table 1. Optimization of Reaction Conditiona
entry
1c
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8d
9e
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12f
[F] source (equiv)
Selectfluor (3.0)
Selectfluor (3.0)
NFSI (3.0)
NFPYBF4 (3.0)
Me3NFPYBF4 (3.0)
Selectfluor (3.0)
Selectfluor (3.0)
Selectfluor (3.0)
Selectfluor (3.0)
Selectfluor (2.0)
Selectfluor (4.0)
Selectfluor (3.0)
solvent
yield (4a, %)b
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
DMF/H2O
dioxane/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
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aReaction condition: 1a (0.1 mmol), [F] source (equiv), solvent (1 mL, v/v = 1/1), 80 C, 12 h; bIsolated yield; cIn the
presence of AgNO3 (0.1 eqiv)/Na2S2O8 (0.5 eqiv); dAt 70 oC; eAt 90 oC; fReaction time: 6 h.
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With the optimized reaction conditions in hand, we next explored the scope and
limitations. First, a series of Aꢀring substituted tanshinone substrates were
investigated (Scheme 3). It was found that 1b, close analogue of 1a but bearing an
aromatic Aꢀring also isolated from Salvia miltiorrhiza, was tolerant in this reaction to
provide the desired product 4b in 47% yield. Tanshinone analogue 1c with the Aꢀring
bearing a α,βꢀunsaturated ketone function afforded the corresponding product 4c in 88%
yield. For the substrate without the Aꢀring, the reaction still went through and
provided product 4d in 61% yield. In addition, we also investigated the substrates
bearing aryloxy substituents on the Aꢀring. Pentafluorphenyl ester substituent was
tolerant well and provided the corresponding product 4e in 83% yield. Aryl ethers
bearing strong electronꢀwithdrawing substituents (e.g. CF3 and NO2) gave the
corresponding product 4f and 4g in 62% and 60% yields, respectively. In the case of
the substrate with a 4ꢀbromophenyloxy substituent, the yield was much lower (4h,
30%). In addition, a subseries of tanshinones bearing diverse esteric functions were
also tested. Cinnamate substrate was tolerated very well and gave product 4i in 76%
yield. The alkyl acyloxylated derivatives also proceeded well in this reaction and
provided dihydroxydifluorination compounds 4jꢀl in 53ꢀ59% yields. For the aryl
acyloxylated derivatives, the yields were slightly higher (63ꢀ64% yields for 4mꢀn).
However, the naphthoate derivative afforded corresponding product 4o in a lower
yield of 47%.
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Scheme 3. Substrate Scope of the AꢀRing of Tanshinonesa
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aReaction condition: 1 or 2 (0.1 mmol), selectfluor (3 equiv), MeCN/H2O (1 mL, v/v = 1/1), 80 oC,
12 h. Isolated yields.
Next, we examined the scope of the C/D ring of tanshinones (Scheme 4).
Interestingly, most of these substrates gave the same product 4a. βꢀChloromethyl
substituent on the Dꢀring (1p) led to the tricyclic product 4a in 35% yield. The
substrate 1q with 16ꢀamino substituent afforded 4a in 40% yield. When the Cꢀ2
position of the Dꢀring was substituted by vinyl or ethyl (1rꢀs), the yields of 4a were
increased to 58ꢀ67%. Unfortunately, the substrate 1t failed to provide product 4a
probably due to electronic effect of the bromoꢀsubstituent. Interestingly, the
difluorinated substrate 5 also participated in the reaction and the corresponding
product 4u was obtained in 90% yield.
Scheme 4. Substrate Scope of the C/DꢀRing Tanshinonesa
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aReaction condition: 1pꢀt, 5 (0.1 mmol), Selectfluor (3 equiv), MeCN/H2O (1 mL, v/v = 1/1), 80
oC, 12 h. Isolated yields.
To gain more insight on the reaction mechanism, as shown in Scheme 5, we
firstly attempted to capture the key intermediate of this reaction. We carried out the
reaction by using 5 as the substrate and quenched in 20 min. To our delight, an
intermediate was successfully isolated in 34% yield and the structure was
demonstrated to be 7u by Xꢀray crystallography (Figure S4 and Table S4 in SI).
Under the standard condition, 7u could be smoothly converted to 4u in 78% yield. In
the meantime, we found that the furyl ringꢀsaturated substrate 3 failed to give the
desired product 4a under the standard reaction, indicating the unsaturated furan
moiety is necessary in the reaction. Finally, we conducted the reaction using 1v as the
substrate, and the leaving fragment 8v was successfully obtained.
Scheme 5. Preliminary Mechanistic Studies
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On the basis of the experiments above, a possible mechanism is proposed in
Scheme 6. Initially, electrophilic substitution of 1 with F+ generated the intermediate I,
which then underwent Michael addition to give the stable intermediate 7 (7u, R1 = Me,
R2 = H). A second electrophilic substitution with F+ occurred at the Cꢀ13 position of 7,
followed by intramolecular nucleophilic cyclization to yield intermediate III (Path a).
Subsequently, hydroxyl anion (OHꢀ) attacked the oxirane ring to generate an unstable
ketal IV, which was then converted to V. Alternatively, as shown in Path b, addition
of H2O to the oxonium ion II led to the opening of the furan ring to give VIII, which
was also transformed to V. Subsequent fragmentation of V released diketone 8 (8v, R1
= Me, R2 = 4ꢀMeOꢀPh), leading to fluoroketone VI. A third electrophilic substitution
with F+ accompanied by ketoneꢀhydration generated the final product 4.
Scheme 6. Proposed Mechanism
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CONCLUSION
In conclusion, we have developed an unprecedented difluorination reaction based on
the furonaphthoquinone skeleton of natural products tanshinones and its analogues. A
wide range of unique polycyclic α,αꢀdifluoro β,βꢀdihydroxyl paraꢀquinone products
were obtained by using Selectfluor as the fluorinating source and H2O as the hydroxyl
source. The mechanistic studies revealed that the reaction might undergo tandem
multiple electrophilic and nucleophilic substitutions, as well as cleavages of CꢀO and
CꢀC bonds. This approach not only provides a new method to synthesis of
α,αꢀdifluoro ketones, but also affords a series of unique chemotypes of tricyclic
α,αꢀdifluoro β,βꢀdihydroxyl paraꢀquinones for biological activity screening.
EXPERIMENTAL SECTION
General Information. All reactions were performed in flameꢀdried sealed tubes.
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Liquids and solutions were transferred with syringes. All solvents and chemical
reagents were obtained from commercial sources and used without further
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purifications. H and 13C NMR spectra were recorded with tetramethylsilane as an
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internal reference. Low and highꢀresolution mass spectra were recorded on EI or ESI
mode. Flash column chromatography on silica gel (200 ꢀ 300 mesh). The column
output was monitored by TLC on silica gel (100 ꢀ 200 mesh) precoated on glass plates
(15 x 50 mm), and spots were visualized by UV light at 254 nM. Starting materials
were synthesized according to previous literatures or obtained from commercial
sources, such as Strem Chemicals, Adamas-beta, Sigma-Aldrich , J&K and TCI,
which were used without further purification.
General procedure for the synthesis of 4aꢀo,4u. A 10 mL sealed tube was charged
with TanꢀIIA substrates (0.1 mmol), Selectfluor (0.3 mmol). MeCN/H2O
(0.5ml/0.5mL) was added, and the resulting mixture was stirred at 80 °C for 12 h.
After cooling to rt, the mixture was extracted with CH2Cl2 (3×5mL). The combined
organic layer was washed with saturated NaCl aqueous solution, dried over Na2SO4,
and concentrated in vacuo to give a brown residue. The residue was purified by
chromatography on silicagel column to furnish the desired compounds 4aꢀo and 4u as
white solids.
2,2ꢀDifluoroꢀ3,3ꢀdihydroxyꢀ8,8ꢀdimethylꢀ2,3,5,6,7,8ꢀhexahydrophenanthreneꢀ1,4ꢀ
1
dione (4a). Yield: 77% (24 mg); H NMR (300 MHz, CDCl3) δ 8.11 (d, J = 8.2 Hz,
1H), 7.87 (d, J = 8.3 Hz, 1H), 4.55 (s, 2H), 3.19 (t, J = 6.3 Hz, 2H), 1.89 – 1.79 (m,
2H), 1.75 – 1.67 (m, 2H), 1.35 (s, 6H); 13C NMR (151 MHz, CDCl3) δ 190.0, 183.4 (t,
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J = 24.6 Hz), 156.3, 142.0, 134.1, 131.9, 129.4, 126.0, 110.6 (t, J = 259.2 Hz), 92.5 (t,
J = 24.4 Hz), 37.5, 35.3, 31.7 (2C), 29.6, 18.9; 19F NMR (471 MHz, CDCl3) δ ꢀ124.76;
HRMS m/z (ESI) calcd for C16H15F2O4 (MꢀH)ꢀ 309.0944, found 309.0938.
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2,2ꢀDifluoroꢀ3,3ꢀdihydroxyꢀ8ꢀmethylꢀ2,3ꢀdihydrophenanthreneꢀ1,4ꢀdione
(4b).
Yield: 47% (14 mg); 1H NMR (300 MHz, CDCl3) δ 9.13 (d, J = 8.2 Hz, 1H), 8.53 (d,
J = 8.8 Hz, 1H), 8.31 (d, J = 9.0 Hz, 1H), 7.75 – 7.67 (m, 1H), 7.61 (d, J = 6.7 Hz,
1H), 4.61 (s, 2H), 2.79 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 190.5, 184.0 (t, J =
25.0 Hz), 136.3, 135.5, 133.3, 133.0, 131.0, 130.7, 130.6, 128.9, 125.6, 122.3, 110.8
(t, J = 259.4 Hz), 93.1 (t, J = 24.3 Hz), 19.9; HRMS m/z (ESI) calcd for C15H11F2O4
(M+H)+ 293.062, found 293.0618.
2,2ꢀDifluoroꢀ3,3ꢀdihydroxyꢀ8,8ꢀdimethylꢀ2,3ꢀdihydrophenanthreneꢀ1,4,7(8H)ꢀtrio
ne (4c). Yield: 88% (28 mg); 1H NMR (300 MHz, CDCl3) δ 8.66 (d, J = 10.4 Hz, 1H),
8.29 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 6.40 (d, J = 10.5 Hz, 1H), 4.54 (s,
2H), 1.49 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 201.2, 190.6, 156.8, 138.1, 132.8,
132.6, 130.6, 129.4, 128.8, 128.6, 110.5 (t, J = 254.5 Hz), 93.0 (t, J = 21.4 Hz), 48.6,
27.4 (2C); HRMS m/s (ESI) calcd for C16H13F2O5 (M+H)+ 323.0726, found 323.0725.
2,2ꢀDifluoroꢀ3,3ꢀdihydroxyꢀ2,3ꢀdihydronaphthaleneꢀ1,4ꢀdione (4d). Yield: 61%
1
(14 mg); H NMR (300 MHz, CDCl3) δ 8.29 – 8.23 (m, 2H), 7.95 – 7.89 (m, 2H),
4.33 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 188.9, 183.1 (t, J = 25.4 Hz), 136.1,
135.7, 133.0, 131.4, 128.6, 128.5, 111.1 (t, J = 260.4 Hz), 92.2 (t, J = 24.6 Hz);
HRMS m/z (ESI) calcd for C10H7F2O4 (M+H)+ 229.0307, found 229.0301.
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2,2ꢀDifluoroꢀ3,3ꢀdihydroxyꢀ8,8ꢀdimethylꢀ5ꢀ(perfluorophenoxy)ꢀ2,3,5,6,7,8ꢀhexah
ydrophenanthreneꢀ1,4ꢀdione (4e). Yield: 83% (41 mg); 1H NMR (300 MHz, CDCl3)
δ 8.31 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H), 6.66 (s, 1H), 4.64 (s, 1H), 4.00 (s,
1H), 2.33 – 2.09 (m, 3H), 1.66 – 1.60 (m, 1H), 1.51 (s, 3H), 1.33 (s, 3H); 13C NMR
(151 MHz, CDCl3) δ 190.6, 182.8 (t, J = 25.2 Hz), 157.1, 142.3 (m), 140.7 (m), 138.9
(m), 137.9 (m), 137.2 (m), 135.0, 134.8, 132.1, 131.4 (m), 130.6, 129.1, 110.4 (t, J =
255.6 Hz), 110.4, 92.9 (t, J = 23.1 Hz), 73.1, 35.5, 31.4, 31.2, 31.0, 24.6; HRMS m/z
(ESI) calcd for C22H14F7O5 (MꢀH)ꢀ 491.0735, found 491.0730.
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2,2ꢀDifluoroꢀ3,3ꢀdihydroxyꢀ8,8ꢀdimethylꢀ5ꢀ(3ꢀ(trifluoromethyl)phenoxy)ꢀ2,3,5,6,7
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,8ꢀhexahydrophenanthreneꢀ1,4ꢀdione (4f). Yield: 62% (29 mg); H NMR (300
MHz, CDCl3) δ 8.29 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.45 (t, J = 7.8 Hz,
1H), 7.29 – 7.24 (m, 2H), 7.20 (m, 1H), 6.40 (t, J = 3.3 Hz, 1H), 4.63 (s, 1H), 4.07 (s,
1H), 2.19 – 2.01 (m, 3H), 1.62 (m, 1H), 1.48 (s, 3H), 1.35 (s, 3H); 13C NMR (126
MHz, CDCl3) δ 190.2, 183.0 (t, J = 25.1 Hz), 157.6, 156.7, 136.4, 134.3, 132.4, 131.9
(q, J = 32.8 Hz), 131.0, 130.2, 128.5, 124.0 (q, J = 272.4 Hz), 119.0, 118.0 (q, J = 3.8
Hz), 112.9 (q, J = 3.8 Hz), 110.5 (t, J = 264.6 Hz), 92.9 (t, J = 25.2 Hz), 68.7, 35.4,
31.8, 31.0, 31.0, 22.9; HRMS m/z (ESI) calcd for C23H19F5O5Na (M+Na)+ 493.1045,
found 493.1052.
2,2ꢀDifluoroꢀ5ꢀ(3ꢀfluoroꢀ4ꢀnitrophenoxy)ꢀ3,3ꢀdihydroxyꢀ8,8ꢀdimethylꢀ2,3,5,6,7,8ꢀ
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hexahydrophenanthreneꢀ1,4ꢀdione (4g). Yield: 60% (28 mg); H NMR (400 MHz,
CDCl3) δ 8.32 (d, J = 8.4 Hz, 1H), 8.14 (t, J = 9.1 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H),
6.85 (dq, J = 7.7, 2.5 Hz, 2H), 6.39 (t, J = 3.3 Hz, 1H), 4.53 (s, 1H), 4.26 (s, 1H), 2.13
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(m, 3H), 1.67 – 1.62 (m, 1H), 1.49 (s, 3H), 1.36 (s, 3H); 13C NMR (126 MHz, CDCl3)
δ 190.3, 182.9 (t, J = 25.1 Hz), 163.5 (d, J = 10.9 Hz), 157.7 (d, J = 265.8 Hz), 156.7,
135.0, 134.7, 132.7, 130.9 (d, J = 6.7 Hz), 130.7, 129.0, 128.1, 111.5 (d, J = 2.52 Hz),
110.5 (d, J = 258.3 Hz), 104.6 (d, J = 24.2 Hz), 92.8 (t, J = 24.4 Hz), 69.9, 35.4, 31.6,
31.1, 30.9, 23.1; HRMS m/z (ESI) calcd for C22H18F3NO7Na (M+Na)+ 488.0928,
found 488.0923.
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5ꢀ(4ꢀBromophenoxy)ꢀ2,2ꢀdifluoroꢀ3,3ꢀdihydroxyꢀ8,8ꢀdimethylꢀ2,3,5,6,7,8ꢀhexahy
drophenanthreneꢀ1,4ꢀdione (4h). Yield: 30% (14 mg); 1H NMR (300 MHz, CDCl3)
δ 8.27 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 7.9 Hz, 2H), 6.92 (d,
J = 8.0 Hz, 2H), 6.31 (s, 1H), 2.20 – 1.92 (m, 3H), 1.62 – 1.55 (m, 1H), 1.47 (s, 3H),
1.34 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 190.3, 183.0 (t, J = 25.0 Hz), 156.7,
156.6, 136.6, 134.2, 132.5 (2C), 132.3, 131.2, 128.4, 117.7 (2C), 113.6, 110.6 (dd, J =
264.7, 254.3 Hz), 93.0 (dd, J = 26.2, 22.6 Hz), 68.7, 35.4, 31.9, 31.0 (2C), 22.8;
HRMS m/z (ESI) calcd for C22H18BrF2O5 (MꢀH)ꢀ 479.0311, found 479.0305.
7,7ꢀDifluoroꢀ6,6ꢀdihydroxyꢀ1,1ꢀdimethylꢀ5,8ꢀdioxoꢀ1,2,3,4,5,6,7,8ꢀoctahydrophen
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anthrenꢀ4ꢀyl cinnamate (4i). Yield: 76% (35 mg); H NMR (300 MHz, CDCl3) δ
8.27 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 16.0 Hz, 1H), 7.46 (m,
2H), 7.35 (m, 3H), 6.57 (s, 1H), 6.35 (d, J = 16.0 Hz, 1H), 5.24 (s, 1H), 5.18 (s, 1H),
2.25 – 2.05 (m, 3H), 1.73 – 1.64 (m, 1H), 1.49 (s, 3H), 1.32 (s, 3H); 13C NMR (151
MHz, CDCl3) δ 191.2, 183.3 (t, J = 25.5 Hz), 167.2, 157.1, 146.2, 135.0, 134.1, 134.0
(2C), 132.4, 131.5, 130.7 (2C), 128.9, 128.6, 128.3, 117.3, 110.8 (t, J = 259.7 Hz),
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93.6 (t, J = 24.3 Hz), 67.3, 35.5, 32.2, 31.5, 31.3, 24.8; HRMS m/z (ESI) calcd for
C25H21F2O6 (MꢀH)ꢀ 455.1312, found 455.1303.
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anthrenꢀ4ꢀyl acetate (4j). Yield: 59% (22 mg); H NMR (300 MHz, CDCl3) δ 8.19
(d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 6.36 (s, 1H), 4.79 (m, 2H), 2.09 – 1.93
(m, 6H), 1.63 – 1.51 (m, 1H), 1.40 (s, 3H), 1.25 (s, 3H); 13C NMR (126 MHz, CDCl3)
δ 190.9, 171.1, 157.0, 135.1, 134.0, 132.2, 131.6, 128.5, 93.4, 67.1, 35.4, 32.1, 31.5,
31.2, 24.7, 21.2; HRMS m/z (ESI) calcd for C18H17F2O6 (MꢀH)ꢀ 367.0999, found
367.0998.
7,7ꢀDifluoroꢀ6,6ꢀdihydroxyꢀ1,1ꢀdimethylꢀ5,8ꢀdioxoꢀ1,2,3,4,5,6,7,8ꢀoctahydrophen
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anthrenꢀ4ꢀyl propionate (4k). Yield: 55% (21 mg); H NMR (300 MHz, CDCl3) δ
8.25 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 6.45 (s, 1H), 4.98 (s, 2H), 2.29 (q, J
= 7.6 Hz, 2H), 2.20 – 2.02 (m, 3H), 1.69 – 1.64 (m, 1H), 1.46 (s, 3H), 1.31 (s, 3H),
1.10 (t, J = 7.5 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 191.1, 183.2 (t, J = 25.3 Hz),
174.7, 157.0, 135.0, 134.0, 132.2, 131.5, 128.5, 113.1 – 108.3 (t, J = 259.6 Hz), 93.4
(t, J = 24.3 Hz), 66.9, 35.4, 32.1, 31.5, 31.3, 27.8, 24.7, 9.1; HRMS m/z (ESI) calcd
for C19H19F2O6 (MꢀH)ꢀ 381.1155, found 381.1154.
7,7ꢀDifluoroꢀ6,6ꢀdihydroxyꢀ1,1ꢀdimethylꢀ5,8ꢀdioxoꢀ1,2,3,4,5,6,7,8ꢀoctahydrophen
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anthrenꢀ4ꢀyl cyclopropanecarboxylate (4l). Yield: 53% (21 mg); H NMR (300
MHz, CDCl3) δ 8.17 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 6.41 (s, 1H), 4.84
(s, 1H), 4.81 (s, 1H), 2.14 – 1.99 (m, 3H), 1.66 – 1.59 (m, 1H), 1.53 (s, 3H), 1.42 (s,
3H), 1.25 (s, 3H), 0.93 – 0.86 (m, 2H), 0.83 – 0.76 (m, 2H); 13C NMR (126 MHz,
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CDCl3) δ 191.3, 183.2 (t, J = 25.3 Hz), 175.3, 157.0, 134.7, 133.8, 132.8, 131.1, 128.5,
112.9 – 108.6 (t, J = 254.2 Hz), 93.8 – 93.3 (t, J = 22.6 Hz), 66.9, 35.4, 32.2, 31.7,
31.3, 24.8, 13.2, 8.9, 8.8; HRMS m/z (ESI) calcd for C20H19F2O6 (MꢀH)ꢀ 393.1155,
found 393.1147.
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7,7ꢀDifluoroꢀ6,6ꢀdihydroxyꢀ1,1ꢀdimethylꢀ5,8ꢀdioxoꢀ1,2,3,4,5,6,7,8ꢀoctahydrophen
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anthrenꢀ4ꢀyl benzoate (4m). Yield: 63% (27 mg); H NMR (400 MHz, CDCl3) δ
8.26 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.2 Hz, 3H), 7.55 (t, J = 7.2 Hz, 1H), 7.40 (t, J =
7.5 Hz, 2H), 6.76 (s, 1H), 4.82 (s, 1H), 4.79 (s, 1H), 2.32 – 2.16 (m, 3H), 1.75 (m,
1H), 1.50 (s, 3H), 1.35 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 191.2, 183.4 – 182.9 (t,
J = 25.3 Hz), 166.6, 157.1, 134.9, 134.0 (2C), 133.4 (2C), 132.6, 131.4, 129.7 (2C),
128.6, 128.5, 93.7 – 93.2 (t, J = 26.2 Hz), 67.6, 35.5, 32.4, 31.6, 31.4, 24.9; HRMS
m/z (ESI) calcd for C23H19F2O6 (MꢀH)ꢀ 429.1155, found 429.1174.
7,7ꢀDifluoroꢀ6,6ꢀdihydroxyꢀ1,1ꢀdimethylꢀ5,8ꢀdioxoꢀ1,2,3,4,5,6,7,8ꢀoctahydrophen
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anthrenꢀ4ꢀyl 4ꢀmethylbenzoate (4n). Yield: 64% (28 mg); H NMR (300 MHz,
CDCl3) δ 8.26 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.2 Hz, 2H),
7.18 (d, J = 8.0 Hz, 2H), 6.71 (s, 1H), 5.02 (s, 1H), 4.92 (s, 1H), 2.37 (s, 3H), 2.30 –
2.13 (m, 3H), 1.73 (m, 1H), 1.50 (s, 3H), 1.35 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
191.3, 183.2 (t, J = 25.4 Hz), 166.8, 157.1, 144.3, 134.9, 133.9 (2C), 132.7, 131.3,
129.8, 129.2, 128.6 (2C), 126.8, 113.0 – 108.5 (t, J = 254.8 Hz), 93.8 – 93.3 (t, J =
25.7 Hz), 67.4, 35.5, 32.4, 31.6, 31.4, 24.9, 21.7; HRMS m/z (ESI) calcd for
C24H21F2O6 (MꢀH)ꢀ 443.1312, found 443.1312.
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anthrenꢀ4ꢀyl 2ꢀnaphthoate (4o). Yield: 47% (23 mg); 1H NMR (300 MHz, CDCl3) δ
8.48 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H), 7.98 – 7.80 (m, 5H), 7.55 (m, 2H), 6.80 (s, 1H),
4.85 (s, 1H), 4.75 (s, 1H), 2.36 – 2.17 (m, 3H), 1.83 – 1.73 (m, 1H), 1.53 (s, 3H), 1.37
(s, 3H); 13C NMR (151 MHz, CDCl3) δ 191.2, 183.2 (t, J = 25.3 Hz), 166.8, 157.2,
135.7, 135.1, 134.1, 132.5, 132.4, 131.5, 131.4, 129.4, 128.7, 128.6, 128.3, 127.8,
126.8, 126.8, 125.1, 112.6 – 108.9 (t, J = 254.8 Hz), 93.7 – 93.3 (t, J = 25.5 Hz), 67.9,
35.5, 32.5, 31.6, 31.4, 24.9; HRMS m/z (ESI) calcd for C27H21F2O6 (MꢀH)ꢀ 479.1312,
found 479.1317.
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2,2,4,4ꢀTetrafluoroꢀ3,3ꢀdihydroxyꢀ8,8ꢀdimethylꢀ3,4,5,6,7,8ꢀhexahydrophenanthre
nꢀ1(2H)ꢀone (4u). Yield: 90% (30 mg); 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J =
8.5 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 3.80 (s, 2H), 3.11 (t, J = 5.6 Hz, 2H), 1.90 –
1.79 (m, 2H), 1.74 – 1.68 (m, 2H), 1.34 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 182.5
(t, J = 24.2 Hz), 156.5, 138.3, 131.2, 130.2 (t, J = 22.7 Hz), 127.03 (t, J = 6.3 Hz),
125.4, 116.7 (t, J = 253.3 Hz), 109.4 (t, J = 256.7 Hz), 92.2 (t, J = 24.0 Hz), 38.0, 35.5,
31.9 (2C), 27.6 (t, J = 5.4 Hz), 19.1; HRMS m/z (ESI) calcd for C16H15F4O3 (MꢀH)ꢀ
331.0963, found 331.0959.
Synthesis of compounds 5 and 6. A 10 mL sealed tube was charged with TanꢀIIA
substrates (0.1 mmol), DAST (0.3 mmol). Dry 1,4ꢀdioxane (2.0ml) was added, and
the resulting mixture was stirred at 90 °C for 12h. After cooling to room temoerature,
the mixture was extracted with CH2Cl2 (3×5ml). The combined organic layer was
washed with saturated NaCl aqueous solution, dried over Na2SO4, and concentrated in
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vacuo to give a yellow residue. The residue was purified by chromatography on
silicagel column to furnish the desired compounds 5 and 6 as yellow solids.
10,10ꢀDifluoroꢀ1,6,6ꢀtrimethylꢀ7,8,9,10ꢀtetrahydrophenanthro[1,2ꢀb]furanꢀ11(6H
)ꢀone (5). Yield: 42% (13 mg); 1H NMR (300 MHz, CDCl3) δ 7.64 (d, J = 8.1 Hz, 1H),
7.46 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 3.13 (t, J = 5.9 Hz, 2H), 2.19 (s, 3H), 1.84 –
1.75 (m, 2H), 1.70 – 1.60 (m, 2H), 1.30 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 189.0
(t, J = 26.3 Hz), 161.4, 149.6, 140.9, 139.1, 130.1, 128.4 (t, J = 22.6 Hz), 121.8 (t, J =
6.3 Hz), 120.0, 119.5, 115.2, 108.8 (t, J = 248.4 Hz), 37.9, 34.4 , 31.6 (2C), 26.7 (t, J
=4.6 Hz), 18.7, 8.3; 19F NMR (471 MHz, CDCl3) δ ꢀ103.23 (s); HRMS m/z (ESI)
calcd for C19H19F2O2 (M+H)+ 317.1335, found 317.1332.
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11,11ꢀDifluoroꢀ1,6,6ꢀtrimethylꢀ6,8,9,11ꢀtetrahydrophenanthro[1,2ꢀb]furanꢀ10(7H
)ꢀone (6). Yield: 36% (11 mg); 1H NMR (300 MHz, CDCl3) δ 7.64 (d, J = 8.1 Hz,
1H), 7.46 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 3.13 (t, J = 5.9 Hz, 2H), 2.19 (s, 3H), 1.84
– 1.75 (m, 2H), 1.70 – 1.60 (m, 2H), 1.30 (s, 6H); 13C NMR (126 MHz, CDCl3) δ
188.0 (t, J = 25.5 Hz), 151.8 (t, J = 11.34 Hz), 148.0, 142.7, 140.6, 133.6, 128.0 (t, J =
2.52 Hz), 122.6, 120.2, 118.6, 115.3 (t, J = 27.7 Hz), 107.2 (t, J = 240.8 Hz), 37.5,
34.1, 31.4 (2C), 29.3, 18.7, 7.8; 19F NMR (471 MHz, CDCl3) δ ꢀ102.30; HRMS m/z
(EI) calcd for C19H18F2O2 (M+) 316.1275, found 316.1277.
2,10,10ꢀTrifluoroꢀ1ꢀhydroxyꢀ1,6,6ꢀtrimethylꢀ1,6,7,8,9,10ꢀhexahydrophenanthro[1
,2ꢀb]furanꢀ11(2H)ꢀone (transꢀ7u). A 10 mL sealed tube was charged with 5 (0.1
mmol), Selectfluor (0.3 mmol). MeCN/H2O (0.5ml/0.5mL) was added, and the
resulting mixture was stirred at 80 °C for 20 min. After cooling to rt, the mixture was
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extracted with CH2Cl2 (3×5mL). The combined organic layer was washed with
saturated NaCl aqueous solution, dried over Na2SO4, and concentrated in vacuo to
give a brown residue. The residue was purified by chromatography on silicagel
column to furnish the desired compounds 7u as a white solid in 34% yield (12 mg);
1H NMR (300 MHz, CDCl3) δ 7.60 (s, 2H), 6.12 (d, J = 60.3 Hz, 1H), 3.13 (t, J = 6.0
Hz, 2H), 2.76 (s, 1H), 1.82 (m, 2H), 1.78 (d, J = 4.5 Hz, 3H), 1.70 (t, J = 5.1 Hz, 2H),
1.33 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 180.9 (t, J = 26.2 Hz), 170.3, 153.7,
139.8, 131.9 (t, J = 22.7 Hz), 130.3, 122.9, 120.0 (t, J = 5.9 Hz), 118.4 (d, J = 245.2
Hz), 112.7, 108.4 (t, J = 248.4 Hz), 80.0 (d, J = 25.1 Hz), 38.1, 35.1, 32.0, 32.0, 27.0
(t, J = 4.5 Hz), 19.4 (d, J = 9.6 Hz), 18.9; 19F NMR (471 MHz, CDCl3) δ ꢀ101.43 –
ꢀ103.19 (m), ꢀ130.57 – ꢀ130.63 (m), ꢀ130.70 – ꢀ130.75 (m); HRMS m/z (ESI) calcd
for C19H19F3O3 (M+H)+ 353.1359, found 353.1365.
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ASSOCIATED CONTENT
Supporting Information
1
Copies of H and 13C NMR spectra for all products, and CIF file for compound 4a
(CCDC 1544780), 5 (CCDC 1545567), 6 (CCDC 1545568) and 7u (CCDC 1544777).
This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel (A. Zhang): +86 (021) 50806035; Fax: +86 (021) 50806035;
aozhang@simm.ac.cn;
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*Tel (C. Ding): +86 (021) 50806035; Fax: +86 (021) 50806035; Eꢀmail:
chding@simm.ac.cn;
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Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by grants from National Natural Science Foundation of
China (81373277, 81402790). Supporting from the International Cooperative Program
(GJHZ1622) and Key Program of the Frontier Science (160621) of the Chinese
Academy of Sciences, the Shanghai Commission of Science and Technology
(16XD1404600, 14431905300, 14431900400) are also highly appreciated.
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