γ-carbonyl quinones: Radical strategy for the synthesis of evelynin and its analogues by C-H activation of quinones using cyclopropanols

Article abstract of DOI:10.1021/ol402229m

Cyclopropanols, on oxidative ring opening with AgNO₃-K ₂S₂O₈ in DCM-H₂O at room temperature and under open flask conditions, produced β-keto radicals which were successfully added to quinones to furni

Full text of DOI:10.1021/ol402229m

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
γ‑Carbonyl Quinones: Radical Strategy
for the Synthesis of Evelynin and
Its Analogues by CÀH Activation
of Quinones Using Cyclopropanols
Andivelu Ilangovan,*,† Shanmugasundar Saravanakumar,†,‡ and
Subramani Malayappasamy†
School of Chemistry, Bharathidasan University, Tiruchirappalli 620024, India and
Syngene International Ltd., Bangalore 560 099, India
ilangovanbdu@yahoo.com
Received August 6, 2013
ABSTRACT
Cyclopropanols, on oxidative ring opening with AgNO3ÀK2S2O8 in DCMÀH2O at room temperature and under open flask conditions, produced
β-keto radicals which were successfully added to quinones to furnish γ-carbonyl quinones. This mild method has been applied to the synthesis of
cytotoxic natural products, 4,6-dimethoxy-2,5-quinodihydrochalcone and evelynin.
Quinone motifs are prevalent in a number of naturally
occurring biologically active compounds.1 As a result of
their unique structure, quinones carry out important bio-
logical functions such as oxidative phosporylation and
bioenergetic transport.2 Interest in synthetic variations of
quinones has been steadily increasing as the naturally occur-
ring quinones reveal a wide variety of biological activit-
ies such as antibiotic,3a anticancer,3b antimalarial,3c anti-
tumor,3d and antidiabetic,3e besides playing a vital role in
cellular metabolism. Since quinones possess redox properties,
their efficacy has been exploited in the industry as dyes and
pigments.4 In synthetic organic chemistry, quinones found
their use as dienophiles in DielsÀAlder reactions,5 oxidat-
ions,6 and as ligands in coordination chemistry.7
Even though quinones have captured human attention
for a longtime, there are only limited methodsavailable for
the functionalization of quinones. For example, demethyl-
asterriquinone B1 was prepared by Lewis acid catalysis
followed by reoxidation with DDQ.8a Similarly, aryl-
substituted 1,4-quinones have been synthesized from
electron-rich arenes by conjugate addition followed by in
situ dehydrogenation strategy.8b The other well-known
method for CÀC bond formation, such as Heck coupling,
faced hardship as a result of competing complex formation
bypalladium aswellaspooraccessibility of haloquinones.9
† Bharathidasan University.
‡ Syngene International Ltd.
(1) Thomson, R. H. Naturally Occurring Quinones IV; Blackie
Academic: London, 1997.
(2) Morton, R. A. Biochemistry of Quinones; Academic Press: New
York, 1965.
(5) Lee, J.; Mei, H. S.; Snyder, J. K. J. Org. Chem. 1990, 55, 5013–
5016.
(6) The Chemistry of Quinonoid Compounds; Patai, S., Rappoport, Z.,
Eds.; Wiley: New York, 1974; Vol. 1.
(7) Kharisova, B. I.; Mendez-Rojasb, M. A.; Garnovskiic, A. D.;
Ivakhnenkoc, E. P.; Ortiz-Mendezd, U. J. Coord. Chem. 2002, 55
745–770.
(8) (a) Pirrung, M. C.; Liu, Y.; Deng, D.; Halstead, D. K.; Li, Z.;
May, J. F.; Wedel, M.; Austin, D. A.; Webster, N. J. G. J. Am. Chem.
Soc. 2005, 127, 4609. (b) Zhang, H.-B.; Liu, L.; Chen, Y.-J.; Wang, D.;
Li, C.-J. Adv. Synth. Catal. 2006, 348, 229–235.
(3) (a) Koyama, J. Recent Pat. Anti-Infect. Drug Discovery 2006, 1,
113–125. (b) Sendl, A.; Chen, J. L.; Jolad, S. D.; Stoddart, C.; Rozhon,
E.; Nanakorn, W.; Balick, M.; Kernan, M. J. Nat. Prod. 1996, 59, 808–
811. (c) Silva, A. J. M.; Netto, C. D.; Pacienza-Lima, W.; Torres-Santos,
E. C.; Rossi-Bergmann, B.; Maurel, S.; Valentin, A.; Costa, P. R. R.
J. Braz. Chem. Soc. 2009, 20, 176–182. (d) Kang, K.-H.; Lee, K.-H.;
Kim, M.-Y.; Choi, K.-H. J. Biol. Chem. 2001, 276, 24638–24644. (e) He,
K.; Chan, C.-B.; Liu, X.; Jia, Y.; Luo, H. R.; France, A. S; Liu, Y.;
Wilson, W. D.; Ye, K. J. Biol. Chem. 2011, 286, 37379–37388.
(4) Bechtold, T. In Handbook of Natural Colorants; Bechtold, T.,
Mussak, R., Eds.; Wiley: New York, 2009; pp 151À182.
(9) Lysons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 677.
r
10.1021/ol402229m
XXXX American Chemical Society

These drawbacks make an alternate approach, radical cou-
pling, an attractive protocol for making substituted quinones
by CÀH functionalization of quinones. The major advan-
tages of radical chemistry such as excellent reactivity, mild
conditions, functional group tolerance, and more atom
economy make the metal-mediated radical strategy attrac-
tive for an ideal chemical synthesis. The radical strategy was
utilized in the preparation of arylated and alkylated qui-
nones from boronic acids10a,b and diazonium species.10c
Oxidative decarboxylation approach by Kochi11a and
Minisci11b was followed for the generation of radicals, which
was used for the functionalization of naphthaquinones with
amino acids.11c The major problems associated with the
Minisci reaction are the modest yields and lack of selectivity.
developed from cyclopropanols. Even though the reaction
of cyclopropanols with electron-deficient alkenes was studied
as a multicomponent reaction,13 their reactivity with quinones
has not been explored until now.
The reaction between 1-phenylcyclopropanol and 1,4-
benzoquinone was explored to find the optimal reaction
conditions, and the results are summarized in Table 1.
Table 1. Screening Experiments
isolated
entry
1
reagent(s)
Mn(OAc)3
solvent
AcOH
time (min) yield (%)
90
95
60
70
52
48
65
61
(2.2 equiv)
Mn(OAc)3
(2.2 equiv)
2
3
4
MeOHÀAcOH
(9:1)
AgNO3 (0.2 equiv)/ CH2Cl2ÀH2O
K2S2O8 (3 equiv) (1:1)
FeSO4 (0.5 equiv)/ CH2Cl2ÀH2O
K2S2O8 (3 equiv)
CAN (2.2 equiv)
(1:1)
Cyclopropanols are versatile compounds which can be a
repertoire for various classes of synthetic molecules such as
azaheterocycles,12a β-substituted ketones,12b allyl chlorides,12c
and other products by virtue of the strain energy associated
with the three-membered ring. After Kulinkovich discovered
that the reaction between esters and Grignard reagents in the
presence of Ti(OPri)4 produced cyclopropanols,15 a plethora
of reactions have started emerging on these synthetically
useful intermediates. The ring opening of cyclopropanols by
the one-electron oxidants such as Mn salts,12a CAN,12b Ag(I)
with persulfate,13 etc. under mild conditions delivers reactive
radical species, β-keto radicals. Though it is possible to
generate such radicals from β-keto acids by oxidative dec-
arboxylation, harsh conditions (high temperature and acidic)
are required to get the desired reaction. Considering the
intrinsic reactivity of these radicals, a milder method is
essential to limit the formation of other potential side products
and also to have a broad substrate scope. On the basis of the
above facts, we envisioned that a mild method can be
5
6
MeOH
60
60
traces
traces
FeSO4 (0.5 equiv)/ MeOHÀH2O
TBHP (3 equiv)
7
AgNO3 (0.2 equiv)/ ACN
MnO2 (3 equiv)
60
30
Although Mn(OAc)3 was successful in bringing the desired
conversion, its success is marred with a slower reaction and
considerable amounts of disubstitution. K2S2O8 reacted
rapidly to produce the monosubstituted product in the
presence of catalytic amounts of AgNO3 as well as FeSO4,
but AgNO3 looked superior because of short reaction time
and better yield. The other oxidants, CAN and TBHP,
produced a mixture of side products along with traces of
desired product. MnO2 delivered a lower yield and was found
to be less efficient for this reaction. After the study of the
results from the screening experiments, AgNO3 (20 mol %)
and K2S2O8 (3 equiv) in DCMÀH2O (1:1, v/v) was found to
be the best condition to investigate the further scope of the
reaction.
(10) (a) Fujiwara, Y.; Domingo, V.; Seiple, I. B.; Gianatassio, R.; Bel,
M. D.; Baran, P. S. J. Am. Chem. Soc. 2011, 133, 3292–3295. (b) Wang,
J.; Wang, S.; Wang, G.; Zhang, J.; Yu, X.-Q. Chem. Commun. 2012, 48,
11769–11771. (c) Lamblin, M.; Naturale, G.; Dessolin, J.; Felpin, F.-X.
Synlett 2012, 23, 1621–162.
The required cyclopropanols were prepared in good
yields by the Kulinkovich reaction,15 as per Scheme 1.
(11) (a) Anderson, J. M.; Kochi, J. K. J. Am. Chem. Soc. 1970, 92,
1651–1959. (b) Minisci, F.; Vismara, E.; Fontana, F.; Morini, G.;
Serravalle, M.; Giordana, C. J. Org. Chem. 1986, 51, 4411–4416. (c)
Commandeur, C.; Chalumeau, C.; Dessolin, J.; Laguerre, M. Eur. J.
Org. Chem. 2007, 3045–3052.
Scheme 1. Preparation of Cyclopropanols
(12) (a) Wang, Y.-F.; Chiba, S. J. Am. Chem. Soc. 2009, 131, 12570–
12572. (b) Jiao, J.; Nguyen, L. X.; Patterson, D. R.; Flowers, R. A. Org. Lett.
2007, 9, 1323–1326. (c) Kulinkovich, O. G.; Kozyrkov, Y. Y.; Bekish, A. V.;
Matiushenkov, E. A.; Lysenko, I. L. Synthesis 2005, 1713–1717.
(15) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A.;
Pritytskaya, T. S. J. Org. Chem. USSR (Engl. Transl.) 1989, 25, 2027.
(b) Kulinkovich, O. G.; Meijer, A. D. Chem. Rev. 2000, 100, 2789.
(13) Chiba, S.; Cao, Z.; Bialy, S. A. A. E.; Narasaka, K. Chem. Lett.
2006, 18–19.
A wide range of cyclopropanols were reacted with 1,4-
benzoquinone under the optimized conditions, and the
results are shown in Figure 1.
B
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To have a further understanding of the scope of qui-
nones, the reaction was performed with a variety of sub-
stituted quinones (Figure 2). Sterically hindered substrates
(3k and 3r) failed to react under these circumstances,
whereas the trisubstituted quinone (3m and 3n) reacted
slowly and furnished lower yields. Electron-donating
methoxy group (3f and 3g) helped the reaction by produ-
cing higher amounts of the desired product. Due to a
probable steric influence, only a lesser amount of the
product was isolated from 1,2-naphthaquinone. To our
surprise, a free hydroxyl group survived the oxidative
reaction conditions and also generated good yields. To
add to the fruitfulness of the method, the cytotoxic natural
products 4,6-dimethoxy-2,5-quinodihydrochalcone14a (3f)
and evelynin (3g)14b were prepared with over 70% yield,
thus outperforming the earlier method with β-ketoacid
where only ∼5% of evelynin was isolated.
The mechanistic pathway is portrayed in Scheme 2,
which is in consistent with the general method of oxidative
ring opening of cyclopropanols and a radical addition to
quinones. Sulfate radical ion 5, produced by the action of
Ag(I) on persulfate 4, reacts with cyclopropanols to form
an cyclopropoxy radical 6 which opens up to form β-keto
radical 7. This radical adds to quinones by providing a
radical intermediate 8 which undergoes reoxidation with
Ag(II) tohand overthe finalproduct3 aswellasregenerate
Ag(I).
Figure 1. Scope of the reaction between 1,4-benzoquinone and
cyclopropanols. Reaction conditions: 1 (0.55 mmol), 2 (0.5 mmol),
AgNO3 (0.1 mmol), K2S2O8 (1.5 mmol), 4 mL of CH2Cl2ÀH2O
(1:1, v/v), 25 °C, 60 min. Yields of isolated products.
Scheme 2. Plausible Mechanism
In conclusion, a convenient method for the preparation
of diverse γ-carbonyl quinones has been developed by
CÀH activation of quinones using cyclopropanols and a
AgNO3/K2S2O8 oxidant system. The reactivity of β-keto
radicals is rapid, and hence a protection and deprotection
strategy is not generally required. This new method has
also been successful for the preparation of cytotoxic
natural products, 4,6-dimethoxy-2,5-quinodihydrochalcone
(3f) and evelynin (3g), and a series of highly substituted
γ-carbonyl quinones in high yield. The reaction conditions
are mild and tolerable to several sensitive functional
groups, flexible to extend to different substrates, and
Figure 2. Scope of the reaction between 1,4-benzoquinone and
cyclopropanols. Reaction conditions:
(0.5 mmol), AgNO3 (0.1 mmol), K2S2O8 (1.5 mmol), 4 mL of
CH2Cl2ÀH2O (1:1, v/v), 25 °C, 60 min. Yields of isolated
products.
1 (0.55 mmol), 2
All the reactions underwent a clean reaction to deliver
the desired product in good yields. The reaction conditions
are well-tolerated by chloro (3b) and methoxy (3c) sub-
stituents. Aromatic cyclopropanols gavemarginallyhigher
yields than the aliphatic ones.
(14) (a) Lan, Y.-H.; Leu, Y.-L.; Peng, Y.-T.; Thang, T.-D.; Lin,
C.-C.; Bao, B. Planta Med. 2011, 77, 2019–2022. (b) Peng, J.; Jackson,
E. M.; Babinski, D. J.; Risinger, A. L.; Helms, G.; Frantz, D. E.;
Mooberry, S. L. J. Nat. Prod. 2010, 73, 1590–1592.
Org. Lett., Vol. XX, No. XX, XXXX
C

employ cheap and readily available reagents. We trust that
this method looks attractive and that the new chemical
entities made by this strategy might be useful scaffolds in
various scientific applications.
facilities. We thank DST-FIST for the use of NMR facility at
the School of Chemistry, Bharathidasan University.
Supporting Information Available. Detailed experimen-
tal procedures and copies of 1H and 13C NMR spectra of
all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. S.S. thanks Dr. R. Senthilkumaran
(Syngene International Ltd.) for his valuable advice,
Dr. G. Manickam (Syngene International Ltd.) for his sup-
port, and Syngene International Ltd. for providing research
The authors declare no competing financial interest.
D
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