Practical radical cyclizations with arylboronic acids and trifluoroborates

Article abstract of DOI:10.1021/ol2023505

Practical radical cyclizations using organoboronic acids and trifluoroborates take place in water, open to air, and in a scalable fashion employing catalytic silver nitrate and stoichiometric potassium persulfate. Both Pschorr-type cyclizations and tandem radical cyclization/trap cascades are described, illustrating the utility of these mild conditions for the generation of polycyclic scaffolds.

Full text of DOI:10.1021/ol2023505

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5628–5631
Practical Radical Cyclizations with
Arylboronic Acids and Trifluoroborates
Jonathan W. Lockner, Darryl D. Dixon, Rune Risgaard, and Phil S. Baran*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037, United States
pbaran@scripps.edu
Received August 30, 2011
ABSTRACT
Practical radical cyclizations using organoboronic acids and trifluoroborates take place in water, open to air, and in a scalable fashion employing
catalytic silver nitrate and stoichiometric potassium persulfate. Both Pschorr-type cyclizations and tandem radical cyclization/trap cascades are
described, illustrating the utility of these mild conditions for the generation of polycyclic scaffolds.
Radical cyclizations have proven to be a valuable tactic
widely employed in organic synthesis.1 Often, however, the
appeal they exhibit in generating molecular complexity is
attenuated by the drawback of using toxic tin species and
inert (oxygen-free) reaction conditions. In the case of aryl-
centered radicals, diazonium salts serve as one means for
entry into radical processes, although their prepara-
tion and handling offset their synthetic value. Among the
Figure 1. Previously reported intermolecular CꢀH functionali-
recent developments2 aimed at circumventing such draw-
backs, the recently discovered Minisci-type reactivity of
zation of heteroarenes3a and benzoquinones.3b
organoboronic acids3 and trifluoroborates3b,4 (Figure 1)
addresses many of these. Indeed, the conditions involve the
use of ubiquitous boronic acids and cheap inorganic salts
(silver nitrate and potassium persulfate), can be performed
in an open-flask without recourse to high temperatures,
and can be safely conducted on gram scale. In this letter, the
chemistry of aryl radicals derived from boronic acids and
trifluoroborates is explored in an intramolecular setting.
The preparation of tricyclic scaffolds such as dibenzo-
furans and fluorenones has received significant attention,
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r
10.1021/ol2023505
Published on Web 09/16/2011
2011 American Chemical Society

Figure 2. Pschorr-type cyclization using organotrifluoroborates as radical precursors.a
owing to their presence in natural products and com-
pounds of medicinal interest.5 One of the earliest means
for access to such molecules involves the radical-based
method known as the Pschorr cyclization,6 which dates
back to 1896. This powerful transformation relies upon an
arenediazonium salt as a radical precursor and typically
employs superstoichiometric iron or copper salts for radi-
cal generation. Figure 2 illustrates the invention and scope
of a “borono-Pschorr” reaction that obviates the need for
potentially dangerous arenediazonium salt preparation.
Additionally, this method complements Pd-mediated pro-
cesses recently described by Harvey,7a Fagnou,7b and
Glorius.7c A variety of functional groups are tolerated,
such as nitriles, esters, and Lewis basic heteroatoms, and
products are obtained in synthetically useful yields. Con-
comitant benzylic oxidation is observed, and this can be
exploited to increase step economy. For instance, fluor-
enone (7) was obtained from a diarylmethane precursor
under the standard conditions.
(5) (a) Wang, W.; Snieckus, V. J. Org. Chem. 1992, 57, 424–426. (b)
Cone, M. C.; Melville, C. R.; Gore, M. P.; Gould, S. J. J. Org. Chem.
1993, 58, 1058–1061. (c) Jones, W. D., Jr.; Ciske, F. L. J. Org. Chem.
1996, 61, 3920–3922. (d) Kaniwa, K.; Ohtsuki, T.; Yamamoto, Y.;
Ishibashi, M. Tetrahedron Lett. 2006, 47, 1505–1508. (e) Yu, M.;
Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 2783–2785. (f) Ye,
Y. Q.; Koshino, H.; Onose, J.; Yoshikawa, K.; Abe, N.; Takahashi, S.
Org. Lett. 2009, 11, 5074–5077. (g) Kemnitzer, W.; Sirisoma, N.; Jiang,
S.; Kasibhatla, S.; Crogan-Grundy, C.; Tseng, B.; Drewe, J.; Cai, S. X.
Bioorg. Med. Chem. Lett. 2010, 20, 1288–1292. (h) Teng, H.; Thakur,
G. A.; Makriyannis, A. Bioorg. Med. Chem. Lett. 2011, 21, 5999–6002.
(6) (a) Pschorr, R. Ber. 1896, 29, 496–501. (b) Leake, P. H. Chem.
Rev. 1956, 56, 27–48. (c) Cano-Yelo, H.; Deronzier, A. J. Chem. Soc.,
Perkin Trans. 2 1984, 1093–1098. (d) Wassmundt, F. W.; Kiesman, W. F.
J. Org. Chem. 1995, 60, 196–201. (e) Yasuda, N.; Huffman, M. A.; Ho,
G.-J.; Xavier, L. C.; Yang, C.; Emerson, K. M.; Tsay, F.-R.; Li, Y.;
Kress, M. H.; Rieger, D. L.; Karady, S.; Sohar, P.; Abramson, N. L.;
DeCamp, A. E.; Mathre, D. J.; Douglas, A. W.; Dolling, U.-H.;
Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1998, 63, 5438–5346.
(f) Moorthy, J. N.; Samanta, S. J. Org. Chem. 2007, 72, 9786–9789.
The boronic acid is installed onto the substrate through
lithiumꢀhalogen exchange followed by borate trapping,8
or by transition-metal-mediated borylation.9 For a sub-
strate bearing a pinacol boronate ester, conversion to the
trifluoroborate salt is accomplished by treatment with
(7) (a) ArOTf, cat. PdCl2(Ph3P)2, 145 °C: Wang, J.-Q.; Harvey, R. G.
Tetrahedron 2002, 58, 5927–5931. (b) ArH, cat. Pd(OAc)2, PivOH,
120 °C: Liegault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou,
K. J. Org. Chem. 2008, 73, 5022–5028. (c) ArCO2H, cat. Pd(TFA)2,
Ag2CO3, 150 °C: Wang, C.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009,
131, 4194–4195.
(8) Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Cai, D.;
Larsen, R. D.; Reider, P. J. J. Org. Chem. 2002, 67, 5394–5397.
(9) Billingsley, K. L.; Buchwald, S. L. J. Org. Chem. 2008, 73, 5589–
5591.
Org. Lett., Vol. 13, No. 20, 2011
5629

aqueous KHF2 followed by repeated evaporation with
MeOHꢀH2O (1:1 v/v) to remove pinacol.10
Given the durability of pinacol boronate esters under a
variety of conditions, we secured (as proof-of-principle)
three examples of fluorenone synthesis utilizing a bifunc-
tional reagent, 2-formylphenylboronic acid pinacol ester
(Figure 3). Direct addition of an aryl Grignard, followed
by treatment with aqueous KHF2, provided radical cycli-
zation precursors which, upon exposure to Agþ/S2O8
,
2ꢀ
furnished the corresponding fluorenones. Such a strategy
can prove useful in situations where a masked radical
precursor is carried through subsequent steps and then
unmasked for the radical cyclization step.
Figure 3. Three-step sequence to fluorenones.
Vicinal olefin difunctionalization, in which multiple
carbonꢀcarbon bonds are forged in concert, is a valuable
tactic for complexity generation in synthesis.11 Such a
process is exemplified by the results in Figure 4. In this
tandem radical cyclization/benzoquinone trap protocol,
5-exo, 6-exo, and 6-endo radical cyclizations are combined
with an intermolecular radical capture.12 The trend in
isolated yields (for products 16ꢀ23) suggests that increas-
ing degrees of olefin substitution attenuate the efficiency of
the tandem process. Importantly, this protocol stands in
contradistinction to the more classic tributyltin hydride
based radical cyclization and the palladium-catalyzed
Heck-type process, both of which were found to be in-
compatible with the use of benzoquinone in this context.13
Incidentally, we have isolated benzofuranone (24) in a
control experiment (in the absence of 1,4-benzoquinone).
In lieu of a competent radical trapping agent, oxygen
from the air intercepts the radical intermediate. This,
Figure 4. Tandem radical cyclization/trap using 1,4-benzoqui-
none as the terminating radicophile.
accompanied by benzylic CꢀH oxidation of the substrate,
leads to oxidative carbonꢀcarbon bond cleavage.14,15
While the results described in this letter demonstrate a
capacity for performing open-flask radical cyclizations,
it is important to note its limitations. Although high che-
moselectivity has been observed under these biphasic
conditions,3 persulfate (S2O82ꢀ) is a strong oxidizing agent
and therefore motifs such as benzylic CꢀH bonds and
vicinal diols may not be compatible. Radical ring closure
and intermolecular radicophile capture must outpace the
capture of oxygen (O2) or H-abstraction (either from an
intramolecular donor or from solvent). Such considera-
tions must be taken into account when planning a reaction
using the Agþ/S2O82ꢀ system.16
(10) (a) Darses, S.; Michaud, G.; Genet, J.-P. Eur. J. Org. Chem.
1999, 1875–1883. (b) Bagutski, V.; Ros, A.; Aggarwal, V. K. Tetrahedron
2009, 65, 9956–9960.
The mechanism by which an organoboronic acid gives
rise to a reactive radical species upon exposure to Agþ/
(11) Ho, T.-L. Tandem Organic Reactions; Wiley-Interscience: New
York, 1992; pp 398ꢀ415.
2ꢀ
S2O8 will be the subject of future work. The working
hypothesis involves (1) Agþ-mediated decomposition of
(12) Other examples of quinones in radical capture: (a) Demchuk,
O. M.; Pietrusiewicz, K. M. Synlett 2009, 7, 1149–1153. (b) Luthy, M.;
Darmency, V.; Renaud, P. Eur. J. Org. Chem. 2011, 547–552.
(13) A standard Bu3SnH reaction was performed using 1-(allyloxy)-
2-bromobenzene in the presence of 1,4-benzoquinone. Analysis by TLC
and 1H NMR showed only recovered bromide and no cyclization
product. Similar results were obtained upon performing a Pd-catalyzed
Heck cyclization reaction using 1-(allyloxy)-2-bromobenzene in the
presence of 1,4-benzoquinone.
(16) (a) Snyder, H. R.; Kuck, J. A.; Johnson, J. R. J. Am. Chem. Soc.
1938, 60, 105–111. (b) Lewin, A. H.; Cohen, T. J. Org. Chem. 1967, 32,
3844–3850. (c) Minisci, F.; Citterio, A.; Giordano, C. Acc. Chem. Res.
1983, 16, 27–32. (d) Karady, S.; Cummins, J. M.; Dannenberg, J. J.; del
Rio, E.; Dormer, P. G.; Marcune, B. F.; Reamer, R. A.; Sordo, T. L.
Org. Lett. 2003, 5, 1175–1178.
(14) Benzofuranone was not observed in reactions containing 1,4-
benzoquinone.
(15) It is known that persulfate can cleave vicinal diols: Kumar, A. J.
Am. Chem. Soc. 1981, 103, 5179–5182.
(17) A similar proposal has previously been put forth in which
phenylcarbonyloxy radical (generated in situ) attack at boron leads to
carbonꢀboron bond homolysis: Cadot, C.; Cossy, J.; Dalko, P. I. Chem.
Commun. 2000, 1017–1018.
5630
Org. Lett., Vol. 13, No. 20, 2011

S2O82ꢀ to give SO4•ꢀ, (2) attack at boron by SO4•ꢀ, and (3)
carbonꢀboron bond homolysis.17
be safely conducted on gram scale.20,21 With the
emergence of noncryogenic22 and CꢀH borylation23
protocols to complement classic methods for prepar-
ing organoboron species, we anticipate increased use
of boronic acids and trifluoroborates as radical pre-
cursors in synthesis.
We emphasize that this open-air18 radical chemistry
does not involve high temperatures and avoids the use
of toxic and/or expensive metals. Additionally, this
method circumvents recourse to potentially hazar-
dous entities such as arenediazonium salts,19 and can
(18) It was found that conducting these Agþ/S2O82ꢀ reactions under
a nitrogen atmosphere did not result in an appreciable difference in yield.
(19) Arenediazonium salts are also utilized in Meerwein arylation of
electron-deficient olefins: Heinrich, M. R.; Wetzel, A.; Kirchstein, M.
Org. Lett. 2007, 9, 3833–3835. We have performed a vicinal difunctio-
nalization of acrylonitrile employing 4-methoxyphenylboronic acid and
TEMPO, obtaining the oxyarylation product in 50% yield. See Support-
ing Information and:Dickschat, A.; Studer, A. Org. Lett. 2010, 12, 3972–
3974.
(20) Representative experimental procedure for Pschorr-type cycliza-
tion: To a solution of aryltrifluoroborate (0.1 mmol, 1.0 equiv) in
trifluorotoluene (0.5 mL) and water (0.5 mL) was added silver(I) nitrate
(0.02 mmol, 0.2 equiv). Potassium persulfate (0.3 mmol, 3.0 equiv) was
added in one portion, and the reaction mixture was stirred vigorously at
60 °C for 60 min. The mixture was extracted with EtOAc (5 ꢁ 3 mL). The
organic layers were combined, dried over Na2SO4, filtered, and con-
centrated in vacuo. Purification by silica gel chromatography (hexanes/
EtOAc) afforded the product.
(21) Representative experimental procedure for tandem radical cycli-
zation/trap: To a solution of 1,4-benzoquinone (0.1 mmol, 1.0 equiv) in
trifluorotoluene (0.5 mL) and water (0.5 mL) were added arylboronic
acid (0.15 mmol, 1.5 equiv), silver(I) nitrate (0.02 mmol, 0.2 equiv), and
potassium persulfate (0.3 mmol, 3.0 equiv). The reaction mixture was
stirred vigorously at 60 °C for 60 min, diluted with EtOAc (3 mL), and
washed with 5% aqueous NaHCO3 (3 mL). The layers were separated,
and the aqueous layer was extracted with EtOAc (3 ꢁ 3 mL). The organic
layers were combined, dried over Na2SO4, filtered, and concentrated in
vacuo. Purification by silica gel chromatography (hexanes/Et2O) af-
forded the product.
Acknowledgment. We thank Dr. D.-H. Huang (TSRI)
and Dr. L. Pasternack (TSRI) for NMR spectroscopic
assistance, Dr. G. Siuzdak (TSRI) for assistance with
mass spectrometry, and Paul T. Hernandez (TSRI) for
valuable technical assistance. Financial support for this
work was provided by Amgen, Bristol-Myers Squibb,
Leo Pharma, University of Copenhagen Faculty of
Pharmaceutical Sciences, Glutarget, and the NIH/
NIGMS (GM-073949).
Supporting Information Available. Experimental pro-
cedures, copies of all spectral data, and full character-
ization. This material is available free of charge via the
Internet at http://pubs.acs.org.
(22) Molander, G. A.; Trice, S. L. J.; Dreher, S. D. J. Am. Chem. Soc.
2010, 132, 17701–17703.
(23) (a) Liskey, C. W.; Wei, C. S.; Pahls, D. R.; Hartwig, J. F. Chem.
Commun. 2009, 37, 5603–5605. (b) Chotana, G. A.; Vanchura, B. A., II.;
Tse, M. K.; Staples, R. K.; Maleczka, R. E., Jr.; Smith, M. R., III. Chem.
Commun. 2009, 37, 5731–5733. (c) Mkhalid, I. A. I.; Barnard, J. H.;
Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890–
931.
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