Synthesis of phosphonylated and thiolated indenones by manganese(III)- mediated addition of phosphorus- and sulfur-centered radicals to 1,3-diarylpropynones

Article abstract of DOI:10.1002/ejoc.201100486

Phosphorus- or sulfur-centered radicals generated from the reaction of manganese(III) acetate with dialkyl phosphonates or arylthiols undergo selective additions to conjugated alkynes followed by cyclization and rearomatization to afford 2-phosphonyl- or

Full text of DOI:10.1002/ejoc.201100486

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100486
Synthesis of Phosphonylated and Thiolated Indenones by Manganese(III)-
Mediated Addition of Phosphorus- and Sulfur-Centered Radicals to
1,3-Diarylpropynones
Jun Zhou,[a] Guang-Liang Zhang,[a] Jian-Ping Zou,*[a] and Wei Zhang*[b]
Keywords: Manganese / Heterocycles / Phosphorus / Sulfur / Radicals
Phosphorus- or sulfur-centered radicals generated from the
reaction of manganese(III) acetate with dialkyl phosphonates
or arylthiols undergo selective additions to conjugated al-
kynes followed by cyclization and rearomatization to afford
2-phosphonyl- or 2-thioaryl-substituted indenones in fair to
good yields.
ucts 2 or 3.[19] We recently disclosed the preliminary results
on the reaction of phosphonyl radicals with 1,3-diarylprop-
ynones 4 to form phosphonylated indenones 5.[18] We report
here more detailed information on the development of
Mn(OAc)3-promoted reactions of 1,3-diarylpropynones
with dialkyl phosphonates and arylthiols to form the corre-
sponding 2,3-disubstituted indenones.
Introduction
Substituted indenone compounds have a broad range of
biological activities. They have been used as alcoholic fer-
mentation activators,[1] estrogen binding receptors,[2] ago-
nists in the treatment of diabetes,[3] and fungicides.[4] They
are also intermediates for the synthesis of indanones,[5] in-
denes,[6] and natural products such as steroids[7] and gibber-
ellins.[8] Other than intramolecular Friedel–Crafts reac-
tions,[7] cycloaddition of arylpalladium complexes with al-
kynes introduced by Heck is another powerful method for
the synthesis of substituted indenones.[9] Substrates such as
2-halobenzaldehydes,[10] 2-haloacetophenones,[11] 2-iodo-
benzonitrile,[12] and arylimines[11] have been used for the gen-
eration of arylpalladium complexes. Rhodium complexes
with aroyl chlorides,[13] 2-cyanophenylboronic acids,[14] and
2-halophenylboronic acids[15] have also been used to react
with alkynes for the synthesis of indenones. Very recently,
decomposition of diazabenzotropones under mild heat-
ing[16] and Rh-catalyzed dehydrative trimerization of aryl
aldehydes[17] have been introduced for making indenones.
As part of our continuous effort on the development of
radical reactions promoted by manganese(III) acetate, we
have reported that phosphonyl radicals generated from the
reaction of Mn(OAc)3 with dialkyl phosphonates could re-
act with conjugated alkenes to form phosphonylated E-alk-
enes 1 (Scheme 1).[18] Phosphonyl radicals could also react
with heteroarenes or arenes to form phosphonylated prod-
Scheme 1. Phosphonylations of arenes, heteroarenes, alkenes, and
alkynes.
[a] Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry and Chemical Engineering, Suzhou
University,
Results and Discussion
199 Renai Street, Suzhou, Jiangsu 215123, China
Fax: +86-512-65880335
In our previous paper, we reported that two aryl groups
in 1,3-diarylpropynones 4 are required for the reaction with
phosphonyl radicals to form indenones 5.[18] Reactions of
propynones such as 6a–d all gave complicated mixtures con-
taining regio- and E/Z-isomers of hydrophosphonylation
products.
E-mail: jpzou@suda.edu.cn
[b] Department of Chemistry, University of Massachusetts Boston,
100 Morrissey Boulevard, Boston, MA 02125, USA
Fax: +1-617-287-6030
E-mail: wei2.zhang@umb.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100486.
3412
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3412–3415

Synthesis of Phosphonylated and Thiolated Indenones
Table 1. Synthesis of 3-aryl-2-phophonyl-1-indenones 5.[a]
1,3-Diphenylpropynone (4a) was selected as a model
compound for the optimization of Mn(OAc)3-promoted
phosphonyl radical reactions. The optimization processes
included selection of reaction solvent, variation of reagent
ratio, and changing reaction temperature and time. After
screening a series of solvents including HOAc, MeOH,
EtOH, MeCN, CH2Cl2 and CHCl3, the best solvent was
found to be HOAc. The most suitable reagent ratio was
1:2:3 for 4a/dimethyl phosphonate/Mn(OAc)3. Reaction
temperatures from 60 to 90 °C and reaction times from 30
to 120 min were explored. Almost no reaction occurred at
60 °C. If the reaction time was longer than 60 min at 80 °C,
a complicated mixture was generated. It was found that
80 °C and 30 min gave the best result. Under the optimized
conditions of using 1:2:3 4a/dimethyl phosphonate/
Mn(OAc)3 in acetic acid and heating the mixture at 80 °C
for 30 min, the reaction gave 2,3-disubstituted indenone 5a
in 74% isolated yield (Scheme 2). The structure of 5a has
been confirmed by X-ray crystal structural analysis (Fig-
ure 1).
Scheme 2. Reaction of 1,3-diphenylpropynone with dimethylphos-
phonate.
[a] Reaction conditions: Propynone 4 (1 mmol), dimethylphos-
phonate (2 mmol) and Mn(OAc)3·2H2O (3 mmol) were heated in
HOAc (10 mL) at 80 °C for 30 min in air. The crude product was
purified by flash chromatography. [b] Isolated yield.
Figure 1. X-ray structure of 5a.
Under the optimized conditions, a series of substituted
1,3-diarylpropynones 4 were employed for exploring the
scope and limitation of this reaction. As shown in Table 1,
the substituents on the 1-phenyl ring of 1,3-diarylpropy- tho-substituted at the 1-phenyl ring (Table 1, entries 8–10)
nones have a significant impact on the yields. Electron-do- gave slightly lower yields than corresponding substrates
nating groups increase the yields (Table 1, entries 2, 3, 8), with para-substituents (Table 1, entries 3, 4, 6). Substrates
whereas electron-withdrawing groups decrease the yields with meta-substituents on the 1-phenyl ring could afford
(Table 1, entries 4–6, 9, 10). The NO2-substituted substrate regioisomers. Indeed, we found that reactions of 4m–o each
gave the lowest yield of 33% (Table 1, entry 7). Different gave two isomers (Table 1, entries 13–15). Finally, substrates
from the substituents on the 1-phenyl ring described above, with naphthalenyl, anthracenyl, and furyl instead of 1-
two examples with the substituents on the 3-phenyl ring phenyl all resulted in complicated reaction mixtures
indicated that neither the electron-donating nor the elec- (Table 1, entries 16–18). Probably these aromatic rings do
tron-withdrawing groups had a big impact on the product not have the right electron density, as the phenyl ring does,
yields (Table 1, entries 11, 12). We found that substrates or- to control the regioselectivity during the addition of the
Eur. J. Org. Chem. 2011, 3412–3415
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3413

J. Zhou, G.-L. Zhang, J.-P. Zou, W. Zhang
SHORT COMMUNICATION
phosphonyl radical and to control the reactivity of the in- phenyl ring slightly disfavored the reactions (Table 2, entries
termediate radical for cyclization to form indenone-type 4–6, 8, 9). The MeO group at the ortho- or para-positions
products. Competitive oxidation of more electron-rich aro- of the 1-phenyl ring gave similar yields (Table 2, entries 3,
matic substrates by Mn(OAc)3 could also contribute to the 7). Electron-donating groups on the 3-phenyl ring of 4 also
formation of the complicated reaction mixture.
gave improved yields (Table 2, entries 10, 11). Interestingly,
A mechanism for the reaction of 1,3-diarylpropynone 4 the reaction of 1-(anthracen-9-yl)-3-phenylpropynone (4q)
to form phosphonylated indenone 5 is proposed in gave product 11q, which has a newly formed six-membered
Scheme 3. The electrophilic dimethylphosphonyl radical is ring, in 60% yield (Table 2, entry 12); this was not the case
more reactive toward the conjugated alkyne than the phenyl in the reaction of the phosphonyl radical (Table 1, entry
ring.[20] Since the α-position of the conjugated alkyne has a 17). The effect of the substituent on the thiophenol was
higher electron density than the β-position, it induces the also examined. A study of three examples of thiophenols
attack of the dimethylphosphonyl radical at the α-position containing para-Me, ortho-Br, and para-NO2 substituents
to generate radical 7, which is then cyclized to form radical indicated that electron-donating groups increased product
8 followed by oxidation to form 9. Deprotonation of 9 af- yields, whereas electron-withdrawing groups decreased the
fords phosphonylated indenone 5.
Table 2. Synthesis of 3-aryl-2-phosphonyl-1-indenones 11.[a]
Scheme 3. A proposed mechanism for the reaction of phosphonyl
radical with 1,3-diarylpropynone 4.
The success of phosphorus-centered radical addition to
propynone to form phosphonylated indenones encouraged
us to extend the reactions to include other heteroatom-cen-
tered radicals. A literature search indicated that reactions
of thiols with Mn(OAc)3 could generate sulfur-centered
radicals.[21] After screening several aliphatic and aromatic
thiols, we found that thiophenol (10a) reacted with 1,3-di-
phenylpropynone (4a) to afford 3-phenyl-2-thiophenyl-1-
indenone (11a) in 57% yield (Scheme 4). Similar reaction
conditions developed for the reaction of phosphonyl radi-
cals could be applied to the reaction of the thiophenoxyl
radical; only the amount of thiol was tripled and the reac-
tion time was doubled. We believe that the reaction of thio-
phenoxyl radical with 1,3-diphenylpropynone should have
a similar reaction mechanism as that of phosphonyl radical
shown in Scheme 3.
Scheme 4. Reaction of 1,3-diphenylpropynone with thiophenol.
The scope for the reactions of propynones 4 with thiols
[a] Reaction conditions: Propynone
4 (1 mmol), thiophenol
10 was explored. The results shown in Table 2 indicate that
electron-donating substituents on the 1-phenyl ring of 1,3-
diphenylpropynones favored the reactions (Table 2, entries
2, 3, 7), whereas electron-withdrawing groups on the 1-
(6 mmol) and Mn(OAc)3·2H2O (3 mmol) were heated in HOAc
(10 mL) at 80 °C for 1 h in air. The crude product was purified by
flash chromatography. [b] Isolated yield.
3414
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3412–3415

Synthesis of Phosphonylated and Thiolated Indenones
yield (Table 2, entries 14–16). In this reaction series, we suc-
ceeded in obtaining single crystals of 11f for X-ray analysis
to confirm its structure (Figure 2).
[1]
[2]
[3]
R. L. Frank, H. Eklund, J. W. Richter, C. R. Vanneman, A. N.
Wennerberg, J. Am. Chem. Soc. 1944, 66, 1–4.
G. M. Anstead, J. L. Ensign, C. S. Peterson, J. A. Katzenellen-
bogen, J. Org. Chem. 1989, 54, 1485–1491.
J. H. Ahn, M. S. Shin, S. H. Jung, S. K. Kang, K. R. Kim, S. D.
Rhee, W. H. Jung, S. D. Yang, S. J. Kim, J. R. Woo, J. H. Lee,
H. G. Cheon, S. S. Kim, J. Med. Chem. 2006, 49, 4781–4784.
G. P. Jourdan, B. A. Dreikorn, R. E. Hackler, H. R. Hall, W. R.
Arnold in Synthesis and Chemistry of Agrochemicalals II, ACS
Symposium Series, American Chemical Society, Washington
DC, 1991, p. 566.
[4]
[5]
[6]
H. E. Zimmerman, J. Am. Chem. Soc. 1956, 78, 1168–1173.
E. N. Aleaao, D. G. Tombari, A. F. Ibanez, I. G. Y. Moltrasio,
J. M. Aguirre, Can. J. Chem. 1991, 69, 1166–1170.
a) A. Chatterjee, S. Banerjee, Tetrahedron 1970, 26, 2599–2608;
b) H. Martens, G. Hoornaert, Synth. Commun. 1972, 2, 147–
156.
[7]
[8]
[9]
H. O. Hoouse, J. K. Larson, J. Org. Chem. 1968, 33, 448–451.
a) W. Tao, L. J. Silverberg, A. L. Rheingold, R. F. Heck, Orga-
nometallics 1989, 8, 2550–2559.
Figure 2. X-ray structure of 5-bromo-3-phenyl-2-thiophenyl-1-ind-
enone (11f).
[10]
[11]
R. C. Larock, M. J. Doty, S. Cacchi, J. Org. Chem. 1993, 58,
4579–4583.
a) J. Vicente, J. A. Abad, J. Gil-Rubio, Organometallics 1996,
15, 3509–3519; b) J. Vicente, J. A. Abad, B. Lopez-Pelaez, E.
Martınez-Viviente, Organometallics 2002, 21, 58–67.
Conclusions
[12] a) R. C. Larock, Q. Tian, A. A. Pletnev, J. Am. Chem. Soc.
1999, 121, 3238–3239; b) A. A. Pletnev, Q. Tian, R. C. Larock,
J. Org. Chem. 2002, 67, 9276–9287.
[13] K. Kokubo, K. Matsumasa, M. Miura, M. Nomura, J. Org.
Chem. 1996, 61, 6941–6946.
[14] T. Miura, M. Murakami, Org. Lett. 2005, 7, 3339–3341.
[15] T. Morimoto, K. Yamasaki, A. Hirano, K. Tsutsumi, N. Ka-
gawa, K. Kakiuchi, Y. Harada, Y. Fukumoto, N. Chatani, T.
Nishioka, Org. Lett. 2009, 11, 1777–1780.
[16] Y. Matsuya, H. Katayanagi, T. Ohdaira, Z. L. Wei, T. Kondo,
H. Nemoto, Org. Lett. 2009, 11, 1361–1364.
[17] Y. Kuninobu, T. Matsuki, K. Takai, Org. Lett. 2010, 12, 2948–
2950.
[18] X. Q. Pan, J. P. Zou, G. L. Zhang, W. Zhang, Chem. Commun.
2010, 46, 1721–1723.
[19] a) X. J. Mu, J. P. Zou, Q. F. Qian, W. Zhang, Org. Lett. 2006,
8, 5291–5293; b) W. Xu, J.-P. Zou, W. Zhang, Tetrahedron Lett.
2010, 51, 2639–2643.
[20] Reviews on P-centered radicals: a) D. Leca, L. Fensterbank, E.
Lacote, M. Malacria, Chem. Soc. Rev. 2005, 34, 858–865; b) S.
Marque, P. Tordo, Top. Curr. Chem. 2005, 250, 43–76.
[21] a) V. H. Nguyen, H. Nishino, S. Kajikawa, K. Kurosawa, Tetra-
hedron 1998, 54, 11445–11460; b) X. J. Mu, J. P. Zou, R. S.
Zeng, J. C. Wu, Tetrahedron Lett. 2005, 46, 4345–4347.
Received: April 6, 2011
We have developed a new protocol for the synthesis of 2-
phosphonyl indenones and 2-thioaryl indenones from the
reactions of 1,3-diarylpropynones with dialkylphosphon-
ates and thiophenols, respectively. Mn(OAc)3-induced for-
mation of phosphonyl and thiophenoxyl radicals is followed
by regioselective addition to 1,3-diarylpropynones, after
which cascade cyclization, oxidation, and deprotonation
take place to form the desired products in fair to good
yields. Compared to reactions of Pd or Rh complexes with
alkynes to form 2,3-disubstituted indenones, the new reac-
tions have reasonable scope, proceed under mild conditions,
and do not require heavy-metal catalysts.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterizations of new com-
1
pounds with copies of H NMR and 13C NMR spectra.
Acknowledgments
J. P. Z. thanks the National Natural Science Foundation of China
for financial support (No. 20772088).
Published Online: May 24, 2011
Eur. J. Org. Chem. 2011, 3412–3415
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3415