Cross dehydrogenative coupling via base-promoted homolytic aromatic substitution (BHAS): Synthesis of fluorenones and xanthones

Article abstract of DOI:10.1021/ol4000857

Cross dehydrogenative coupling reactions occurring via base-promoted homolytic aromatic substitutions (BHASs) are reported. Fluorenones and xanthones are readily prepared via CDC starting with readily available ortho-formyl biphenyls and ortho-formyl biphenylethers, respectively. The commercially available and cheap tBuOOH is used as an oxidant. Initiation of the radical chain reaction is best achieved with small amounts of FeCp₂ (0.1 or 1 mol %).

Full text of DOI:10.1021/ol4000857

ORGANIC
LETTERS
2013
Vol. 15, No. 4
928–931
Cross Dehydrogenative Coupling via
Base-Promoted Homolytic Aromatic
Substitution (BHAS): Synthesis of
Fluorenones and Xanthones
Sebastian Wertz, Dirk Leifert, and Armido Studer*
€
Fachbereich Chemie, Organisch-Chemisches Institut, Westfalische
Wilhelms-Universitat, Corrensstrasse 40, 48149 Munster, Germany
€
€
studer@uni-muenster.de
Received January 11, 2013
ABSTRACT
Cross dehydrogenative coupling reactions occurring via base-promoted homolytic aromatic substitutions (BHASs) are reported. Fluorenones
and xanthones are readily prepared via CDC starting with readily available ortho-formyl biphenyls and ortho-formyl biphenylethers, respectively.
The commercially available and cheap tBuOOH is used as an oxidant. Initiation of the radical chain reaction is best achieved with small amounts of
FeCp2 (0.1 or 1 mol %).
Development of selective and efficient CꢀC bond forming
reactions is of great importance in organic chemistry. No
doubt, cross-coupling with two prefunctionalized sub-
strates with the help of transition metal (TM) catalysts
ranks as one of the most powerful approaches for CꢀC
bondformation.1 Asafurtherdevelopment, TM-catalyzed
CꢀH bond activation with subsequent CꢀC bond forma-
tion has gained great attention recently2 and cross-
dehydrogenative coupling (CDC) where prefunctionaliza-
tion of the reacting partners is not necessary has emerged
as an even more atom economic approach for the con-
struction of CꢀC bonds.3 C(sp2)ꢀC(sp2) bond formation,
in particular CꢀH arylation, has been most intensively
investigated along that line. Radical chemistry offers a
valuable alternative to TM-based arylations.4 Recently, a
series of papers on TM-freedirect intra- and intermolecular
radical CꢀH arylations has appeared in the literature.5,6
These processes likely proceed via base-promoted homo-
lytic aromatic substitution (BHAS, Scheme 1).7
Intra- or intermolecular aryl radical addition to an arene
leads to the corresponding cyclohexadienyl adduct radical
which upon deprotonation with an external base provides
a biaryl radical anion. This species acts as a single electron
transfer (SET) reagent for reduction of the starting aryl-
iodide to generate another corresponding aryl radical.
Thereby the radical chain reaction is sustained.7
(4) (a) Vaillard, S. E.; Studer, A. In Encyclopedia of Radicals in
Chemistry, Biology and Materials; Studer, A., Chatgilialoglu, C., Eds.;
Wiley: Chichester, 2012; Vol. 2, pp 1059ꢀ10093. (b) Pratsch, G.; Heinrich,
M. R. Top. Curr. Chem. 2012, 320, 33–60.
(5) Reviews: (a) Yanagisawa, S.; Itami, K. ChemCatChem 2011, 3,
827–829. (b) Shirakawa, E.; Hayashi, T. Chem. Lett. 2012, 41, 130–134.
(6) Selected contributions: (a) Deng, G.; Ueda, K.; Yanagisawa, S.;
Itami, K.; Li, C.-J. Chem.;Eur. J. 2009, 15, 333–337. (b) Sun, C.-L.; Li,
H.; Yu, D.-G.; Yu, M.; Zhou, X.; Lu, X.-Y.; Huang, K.; Zheng, S.-F.;
Li, B.-J.; Shi, Z.-J. Nat. Chem. 2010, 2, 1044–1049. (c) Shirakawa, E.;
Itoh, K.-i.; Higashino, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132,
15537–15539. (d) Roman, D. S.; Takahashi, Y.; Charette, A. B. Org.
Lett. 2011, 13, 3242–3245.
(1) (a) Diederich, F.; Stang, P. J. Eds. Metal-Catalyzed Cross-
Coupling Reactions; Wiley-VCH: New York, 1998. (b) Li, Z.-P.; Bohle,
D.-S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928–8933.
(2) (a) Chen, X.; Engle, K.-M.; Wang, D.-H.; Yu, J.-Q. Angew.
€
Chem., Int. Ed. 2009, 48, 5094–5115. (b) Wencel-Delord, J.; Droge, T.;
Glorius, F. Chem. Soc. Rev. 2011, 40, 4740–4761. (c) Chen, D. Y.-K.;
Youn, S. W. Chem.;Eur. J. 2012, 18, 9452–9474. (d) Yamaguchi, J.;
Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960–
€
9009. (e) Bruckl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Acc. Chem.
Res. 2012, 45, 826–839.
(3) (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335–344. (b) Yeung, C. S.;
Dong, V. M. Chem. Rev. 2011, 111, 1215–1292.
(7) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2011, 50, 5018–
5022.
r
10.1021/ol4000857
Published on Web 02/01/2013
2013 American Chemical Society

Table 1. Reaction Optimization Using 1a as a Substrate
Scheme 1. Base-Promoted Homolytic Aromatic Substitution
temp
tBuOOH
initiator
(mol %)
yielda
(%)
entry
(°C)
(equiv)
1
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
50
120
2.0 (aq)
1.0 (aq)
0.1 (aq)
2.2 (aq)
2.2 (dec)
2.2 (dec)
2.2 (dec)
2.2 (dec)
2.2 (dec)
2.2 (dec)
2.2 (dec)
2.2 (dec)
2.2 (dec)
2.2 (dec)
2.2 (dec)
2.2 (dec)
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
19ꢀ31b
21
2
3
4
4
41
5
31ꢀ63b
6
FeCp2 (0.5)
66
However, in all these examples a prefunctionalized
radical precursor (mostly an aryl iodide) has to be chosen
as starting material. Herein we present intramolecular
BHAS of various biphenyl-2-carboxaldehydes which pro-
ceed via acyl radicals8 to give the corresponding fluorenones
representing a radical cross dehydrogenative C(sp2)ꢀC(sp2)
bond forming process.9,10 In contrast to the known BHAS
processes, a halide as a radical leaving group and an external
strong base are not necessary thereby improving the
economy of the overall transformation.
7
FeCl2 (0.5)
62
8
Fe(OAc)2 (0.5)
FeSO4 (0.5)
73
9
60
10
11
12
13
14
15
16
17
CuI (0.5)
26
Pd(OAc)2 (0.5)
Bu4NI (0.5)
22
64
FeCp2 (0.1)
60ꢀ72b
FeCp2 (0.1)
73c
tBuONNOtBu (10)
tBuONNOtBu (10)
tBuOOtBu (100)
52
17
traces
As a substrate for optimization studies we chose
biphenyl-2-carboxyaldehyde 1a. The tert-butoxyl radical
is known to efficiently abstract the hydrogen atom of the
carbonyl in aldehydes, and the commercially available
tBuOOH is readily reduced by SET to the tert-butoxyl
radical and the basic hydroxide anion. Hence, this cheap
reagent should be well suited to act as a reagent for the
planned BHAS reactions. We tested radical CDC of 1a
to give fluorenone (2a) with tBuOOH (aq) as the oxidant
(Table 1).
a Determined by 1H NMR using an internal standard. b Difficult to
reproduce, yields in the range given were obtained. c tBuOOH added in
two batches (aq = aqueous, dec = decane: used as a 5.5 M sol. in dec.).
initiation step which is probably mediated with traces of
TMs.11 We therefore tested the reaction in the presence of
a small amounts of TMs and found that FeCp2 performs
well (entry 6). Good results were achieved with 0.1 mol %
of FeCp2 (72%, entry 13); however yields varied. Upon
adding tBuOOH in two batches a reproducible 73% yield
was obtained (entry 14). Increasing (53% with 1 mol %
FeCp2 under otherwise identical conditions) or decreasing
(∼55%NMR yield with0.02mol % of FeCp2) theinitiator
loading gave worse results, and other Fe(II)-salts also
gave good yields (entries 7ꢀ9). A good yield was achieved
with Fe(OAc)2; however, due to the low solubility of the
acetate in CH3CN, this result was difficult to reproduce.
Therefore, the FeCp2-initiator was regarded as the best
Fe-derivative among this series. CuI or Pd(OAc)2 provided
loweryields(entries10, 11). Agoodresultwasalsoachieved
by using 0.5 mol % of Bu4NI which is well-known to
mediate radical reactions in the presence of tBuOOH
(entry 12).12 tBuONNOtBu could also be used to initiate
this reaction. However, as compared to FeCp2 a signifi-
cantly higher initiator loading had to be used (entry 15),
and at lower temperature the chain was not efficient
(entry 16). With tBuOOtBu in the absence of tBuOOH,
only trace amounts of product were formed (entry 17).
Finally, MeCN was found to be the best suited solvent
as compared to other solvents such as tetrahydrofuran,
dichloroethane, dimethylacetamide, or benzotrifluoride.
In the absence of an external radical initiator with
2.2 equiv of tBuOOH at 90 °C, we obtained 2a in 41%
yield (entry 4). Reducing the amount of tBuOOH led to
lower yields (entries 1ꢀ3).
The yield was higher with nonaqueous tBuOOH; how-
ever, we faced difficulties in reproducing results, and yields
varied between 31 and 63% (entry 5). This is due to the
(8) Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem. Rev.
1999, 99, 1991–2069.
(9) TM-catalyzed CꢀH activation for preparation of fluorenones,
see: (a) Campo, M. A.; Larock, R. C. J. Org. Chem. 2002, 67, 5616–5620.
(b) Zhao, J.; Yue, D.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc.
2007, 129, 5288–5295. (c) Thirunavukkarasu, V. S.; Cheng, C.-H.
Chem.;Eur. J. 2011, 17, 14723–14726. (d) Liu, T.-P.; Liao, Y.-X.;
Xing, C.-H.; Hu, Q.-S. Org. Lett. 2011, 13, 2452–2455. (e) Lockner,
J. W.; Dixon, D. D.; Risgaard, R.; Baran, P. S. Org. Lett. 2011, 13, 5628–
5631. (f) Seo, S.; Slater, M.; Greaney, M. F. Org. Lett. 2012, 14, 2650–
2653. (g) Gandeepan, P.; Hung, C.-H.; Cheng, C.-H. Chem. Commun.
2012, 48, 9379–9381.
(10) TM-free fluorenone synthesis: (a) Denney, D. B.; Klemchuk,
P. P. J. Am. Chem. Soc. 1958, 80, 3289–3290. (b) Barluenga, J.; Trincado,
ꢀ
M.; Rubio, E.; Gonzalez, J. M. Angew. Chem., Int. Ed. 2006, 45, 3140–
3143. (c) Shi, Z.; Glorius, F. Chem. Sci. 2013, 4, 829–833. (d) Matcha, K.;
Antonchick, A. P. Angew. Chem., Int. Ed. 2013, early view, DOI:
10.1002/anie.201208851.
(11) A similar initiation and chain propagation step was recently
suggested for a radical arene trifluoromethylation: Ji, Y.; Brueckl, T.;
Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.; Blackmond, D. G.;
Baran, P. S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 14411–14415.
(12) (a) Uyanik, M.; Okamoto, H.; Yasui, T.; Ishihara, K. Science
2010, 328, 1376–1379. (b) Liu, Z. J.; Zhang, J.; Chen, S. L.; Shi, E.; Xu,
Y.; Wan, X. B. Angew. Chem., Int. Ed. 2012, 51, 3231–3235.
Org. Lett., Vol. 15, No. 4, 2013
929

Scheme 2. Suggested Mechanism
leads to the biaryl radical anion C. Deprotonation is
facilitated by the neighboring carbonyl group. Indeed, it
was previously shown that cyclohexadienyl radicals bearing
acidifying nitrile or carbonyl functionalities are deprotonated
by a weak base.14 Cthen reduces tBuOOH by SET to provide
fluorenone 2 and the chain propagating tert-butoxyl radical
along with the basic hydroxide anion.11 We assume that as
side reactions the biaryl radical anion C and the cyclohex-
adienyl radical B can also reduce the Fe(III)-complex gener-
ated in the initiation step thereby regenerating the initiator.15
This is likely the reason why only very small amounts of the
radical initiator are necessary in these chain reactions.
Experimental proof for the involvement of acyl radicals
was obtained by running the reaction in the presence of
TEMPO (1 equiv). The TEMPO-ester 4 was isolated in
36% yield, and 2a was not formed (eq 1). Moreover, in
order to evaluate the possibility whether cyclohexadienyl
radicals of type B can reduce tBuOOH by SET prior to
deprotonation, we ran a control experiment on iodide 5
which is a typical substrate in BHAS reactions.7
Figure 1. Fluorenone synthesis: substrate scope (isolated yields).
To document the substrate scope, various formylated
biaryls were reacted under optimized conditions (2.2 equiv
of tBuOOH, 0.1 mol % FeCp2, CH3CN) to the corre-
sponding fluorenones (Figure 1). Electron-donating
and -withdrawing substituents at the para-position of
the radical accepting arene in the biphenyl moiety were
tolerated, and fluorenones 2bꢀf were isolated in good
yields (68ꢀ84%). As expected for a radical process, the
meta-substituted congener reacted with low regioselectivity
(see 2m). We further showed that the formyl carrying arene
moiety in the biphenyl substrate can bear electron-donating
and -withdrawing substituents (2hꢀj and 2e) and also sub-
strates, where both arenes carry substituents, provided the
corresponding CDC products in good yields (2k, 2l). Inter-
estingly, the naphthyl derivative afforded, along with the
targeted fluorenone 2n, ketone 3in good overall yield (82%).
The suggested mechanism for the fluorenone synthesis
is depicted in Scheme 2. Initiation occurs by reducing
tBuOOH with FeX2 to give the tert-butoxyl radical along
with an Fe(III)-complex. The tert-butoxyl radical then
abstracts the H-atom from the aldehyde to giveacyl radical
A which attacks the arene to generate the cyclohexadienyl
radical B.13 Deprotonation with the basic hydroxide anion
To generate the necessaryaryl radical from the iodide we
added Et3SiH which is known to be readily converted to
(13) Acyl radicals are known to react intramolecularily with hetero-
ꢀ
arenes: (a) Miranda, L. D.; Cruz-Almanza, R.; Pavon, M.; Alva, E.;
(14) Wang, C.; Russell, G. A.; Trahanovsky, W. S. J. Org. Chem.
1998, 63, 9956–9959.
(15) These processes can only be side reactions since we obtained in
some cases good results also in the absence of the Fe-initiator (see
Table 1).
Muchowski, J. M. Tetrahedron Lett. 1999, 40, 7153–7157. (b) Allin,
S. M.; Barton, W. R. S.; Bowman, W. R.; McInally, T. Tetrahedron Lett.
2001, 42, 7887–7890. (d) A review on intermolcular acyl radical addi-
tions to heteroarenes: Minisci, F. Synthesis 1973, 1–24. Minisci, F. Top.
Curr. Chem. 1976, 62, 1–48.
930
Org. Lett., Vol. 15, No. 4, 2013

the corresponding ortho-hydroxybenzophenone deriva-
tives, resulting from ipso attack of the acyl radical and
subsequent cleavage of the CꢀO bond providing stabilized
phenoxyl radicals. We found that substrates bearing
electron-donating and -withdrawing substituents at the
para-position of the radical accepting arene moiety
afforded similar yields showing that electronic effects
exerted by the acyl radical acceptor on the cyclization are
weak (8aꢀe). The meta-methyl derivative gave the two
regioisomeric xanthones 8h and 8h0 in a 1.9:1 ratio in-
dicating the radical nature of the cyclization process.
Surprisingly, 8g was isolated as a single regioisomer albeit
in a moderate yield.
Scheme 3. Xanthone Synthesis via Radical CDC (isolated
yields)
In summary, we have presented CDC reactions occur-
ring via base-promoted homolytic aromatic substitutions
(BHASs). BHASs have gained great attention during the
past four years.6,7 However, all of these reports deal with
the use of aryl iodides as radical precursors. Moreover, in
the known BHAS reactions a stoichiometric amount of
base is necessary and reactions are generally conducted
under harsh conditions. Our protocol does not require any
additional base, and the commercially available oxidant
(tBuOOH) is cheap. We showed that radical reactions
are very efficient since only a small amount of initiator is
necessary to run these processes (long chains) which are
experimentally easy to conduct. The concept presented
herein gives some guidelines for the design of new BHASs.
Et3Si radicals in the presence of tert-butoxyl radicals.
The Si-centered radicals provide aryl radicals by iodine
abstraction from the corresponding aryl iodide. As shown
in eq 2, the targeted product 6 was not identified by
GC-analysis.16 This experiment supports our assumption
that cyclohexadienyl radical D, which is a reasonable
model for B, does not efficiently reduce tBuOOH.
We also tested whether the radical BHAS can be applied
to other CDC reactions and found that xanthones
are readily prepared under similar conditions from the
aldehydes 7aꢀh. Chains were shorter, and a higher initia-
tor loading (1 mol % FeCp2) was necessary. As compared
to the fluorenone synthesis, generally lower yields were
achieved (Scheme 3). As side products we always identified
Acknowledgment. This work was supported by the pro-
gram “Sustainable Chemical Synthesis (SusChemSys)”
which is cofinanced by the European Regional Develop-
ment Fund (ERDF) and the state of North Rhine-
Westphalia, Germany, under the Operational Program
“Regional Competitiveness and Employment” 2007ꢀ2013.
Supporting Information Available. Experimental details
and characterization data for the products. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(16) To make sure that the Fe-initiator does not interfere with the Si-
chemistry we ran the experiment in the absence of the FeCp2 initiator.
Repeating the reaction with FeCp2 under otherwise identical conditions
gave 6 in 14% yield (determined by GC). This control experiment
indicates that the cyclohexadienyl radical D gets slowly oxidized by
the Fe(III)-complex but not by tBuOOH. However, that chain reaction
is not efficient.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
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