Unstrained C-C bond activation and directed fluorination through photocatalytically-generated radical cations

Article abstract of DOI:10.1039/c5sc01973g

Expanding the repertoire of controlled radical fluorination techniques, we present a photosensitized unstrained C-C bond activation/directed monofluorination method using Selectfluor and 9-fluorenone. The reaction is amenable to the opening of multiple 1-acetal-2-aryl substituted rings to yield ω-fluoro carboxylic acids, esters, alcohols, and ketones with relative ease. Initial mechanistic insight suggests radical ion intermediates.

Full text of DOI:10.1039/c5sc01973g

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Unstrained C–C bond activation and directed
fluorination through photocatalytically-generated
radical cations†
Cite this: DOI: 10.1039/c5sc01973g
Cody Ross Pitts, Michelle Sheanne Bloom, Desta Doro Bume, Qinze Arthur Zhang
*
and Thomas Lectka
Expanding the repertoire of controlled radical fluorination techniques, we present a photosensitized
unstrained C–C bond activation/directed monofluorination method using Selectfluor and 9-fluorenone.
The reaction is amenable to the opening of multiple 1-acetal-2-aryl substituted rings to yield u-fluoro
carboxylic acids, esters, alcohols, and ketones with relative ease. Initial mechanistic insight suggests
radical ion intermediates.
Received 2nd June 2015
Accepted 22nd June 2015
DOI: 10.1039/c5sc01973g
www.rsc.org/chemicalscience
The foundation of organic chemistry lies on C–C bond forma- putative one-electron photoxidant and proper placement of
tion; it is the spirit of total synthesis, the valued ability to create either acetal or methoxy moieties on the rings.6 The concept is
intricate molecules from simple, cheap starting materials. simple – if the substrate undergoes a one-electron oxidation, the
Alternatively, selective C–C bond cleavage (C–C bond activation, die is cast and the C–C bond productively elongates to form a
in modern parlance) is more seldom discussed, as it is osten- stable radical (e.g., benzylic or tertiary) and resonance stabilized
sibly a difficult undertaking and its importance is less imme- cation. Both the Albini7 and Perrott8 laboratories have shown
diately intuitive to students of organic chemistry. Yet, the eld photosensitized opening of rings followed by hydrogenation.
of C–C bond activation1 is beginning to receive a considerable Considering these precedents, we imagined that uorination of
amount of attention in the contemporary world as chemists are a radical cation should be possible instead, thus allowing highly
nding unique opportunities to construct complex molecules selective sp3 C–F formation (Scheme 1).
via C–C fragmentation that are not easily accessible by other
Our initial screen for reaction conditions began with 6-
means. For instance, our laboratory,2 among others,3 has phenyl-1,4-dioxaspiro[4.5]decane. We examined a variety of
recently become interested in using cyclopropane ring-opening putative photoxidants in MeCN (300 nm light provided by a
chemistry to, in turn, achieve site-selective uorination. In any Rayonet reactor) in the presence of Selectuor. Upon assessing
event, it would seem that the application of this chemistry to the viability of such conventional photoxidants as 1,4-dicyano-
larger ring systems (5, 6, etc.) that are more readily accessible, benzene,8 1,2,4,5-tetracyanobenzene,9 xanthone,10 anthraqui-
but experience relatively little angle strain, is more ambitious. none,11 acetophenone,12 and 9-uorenone,13 we quickly found
However, the ability to use substituted cyclopentane and the most success with 2.2 equiv. of Selectuor and 0.2 equiv. of
cyclohexane rings (or perhaps larger rings) as synthons en route 9-uorenone in producing the desired ring-opened, uorinated
to more complex molecules would prove handy and funda- product by 19F NMR (Table 1). It is important to point out that
mentally interesting to synthetic chemists, especially with similar conditions used by our laboratory in the C–C cleavage/
respect to uorine chemistry. Given the mechanistic insight uorination of cyclopropane compounds resulted in a signi-
provided by our laboratory and others on the uorination of cantly lower yield when applied to this unstrained substrate
alkyl radicals vis-a-vis C–H activation (or other approaches ), (Table 1, Entry 2). Remarkably, the 19F NMR yield was compa-
we postulated that site-selective uorination via unstrained C–C rable when a 14 Watt compact uorescent light bulb was used
fragmentation might be achieved through the photochemical
4
5
`
generation of radical cations with the appropriate substituents.
In fact, there is literature precedent (albeit with limited
examples) for selective formation of 1,5- and 1,6-radical cations
from 5- and 6-membered rings, respectively, employing a
Department of Chemistry, Johns Hopkins University, Baltimore, MD, USA. E-mail:
Lectka@jhu.edu
† Electronic supplementary information (ESI) available: NMR spectra and
computational data. See DOI: 10.1039/c5sc01973g
Scheme 1 Concept for selective C–C fragmentation/C–F formation.
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as the light source instead, denoting the use of visible light as a
more accessible alternative. Also note that none of the desired
uorinated product formed in the absence of light or 9-uo-
renone, and heating the substrate with Selectuor in MeCN to
100 ꢀC only resulted in minor a-uoro ether products (Scheme
2).14 Upon aqueous workup, we found that the resultant
ethylene glycol ester was susceptible to varying degrees of
oxidation in the presence of Selectuor and thus proved diffi-
cult to isolate. Consequently, we altered the workup procedure
to conduct a mild saponication with 5.0 equiv. aq. LiOH,15 in
order to form the more easily isolable (and more synthetically
useful) carboxylic acid 1 in 60% yield (Scheme 3).16
Scheme 2 Control reaction.
We then surveyed a variety of substrates to probe the ster-
eoelectronic dependence on each substituent (Table 2). Inter-
estingly, there was no evidence of C–C fragmentation/
uorination of 1,4-dioxaspiro[4.5]decane or 6-methyl-1,4-diox-
aspiro[4.5]decane, suggesting that the aryl group may be
essential to stabilize a putative radical cation enough for
productive cleavage. In support of this claim, the extent of C–C
bond elongation calculated for each radical cation at B3PW91/6-
311++G** (MeCN) follows the trend in radical stability (2ꢀ
Scheme 3 Standard reaction conditions.
ꢀ
ꢀ
˚
˚
˚
benzylic (2.94 A) [ 2 (1.94 A) > 1 (1.64 A)).
On the other hand, we found that traditional non-aryl reso-
nance stabilizers in the a-position (i.e. –OMe, –NPhth, and
–COOEt) proved ineffective for C–C bond fragmentation/uo-
rination. The corresponding N,O-acetal also failed to produce
any of the desired product under reaction conditions unless the
nitrogen atom was substituted with an electron-withdrawing
group (e.g. an acetyl group). Still, the acylated N,O-acetal per-
formed less well than the O,O-acetal. The ideal substituents for
C–C fragmentation/uorination are therefore an aryl moiety
and the easily accessible O,O-acetal.17
Preceding our evaluation of substrate scope, the success of
the aq. LiOH quench for the isolation of the u-uoro carboxylic
acid from 6-phenyl-1,4-dioxaspiro[4.5]decane also prompted a
brief investigation of other quenching reagents as means to
isolate molecules with diverse functional groups directly from
the same reaction. To our satisfaction, quenching with either
5.0 equiv. aq. LiOMe or 6.0 equiv. LiAlH4 (with the crude
reaction mixture redissolved in anhydrous THF) affords the u-
uoro ester 2 or u-uoro alcohol 3 and in comparable yields
(Table 3).
Further assessment of the scope of the reaction revealed
several interesting features. For one, conditions are easily
amenable to gram scale synthesis with no major sacrice in
yield, as highlighted in Table 3, demonstrating the practicality
of this method. In terms of electronic effects, the aryl substit-
uent may be adorned with mildly electron donating (4–5),
mildly electron withdrawing (6–8), or electron neutral groups
(the extremes typically perform less favorably, e.g. –OMe and
–CF3); the system is also tolerant of polyaromatic substituents
such as naphthalene (9). Regarding the chemoselectivity of the
reaction, only the desired C–C bond fragments in the presence
of other aliphatic and aryl-substituted acetal functional groups
(10–11). Even more exceptionally, if other secondary benzylic
Table 2 Screening for substituents
Table 1 Screening for photoxidants
X
Y
Z
19F NMR Yield (%)
Entry
Photoxidant
19F NMR Yield (%)
O
O
O
O
O
O
O
O
O
O
O
O
O
O
NH
NAc
H
Me
Ph
OMe
NPhth
COOEt
Ph
0
0
60
0
0
0
1
2
3
4
5
6
7
—
0
30
31
28
23
33
60
1,2,4,5-Tetracyanobenzene
1,4-Dicyanobenzene
Acetophenone
Anthraquinone
Xanthone
0
50
9–Fluorenone
Ph
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Table 3 Substrate scopea
Substrate
Product
Yield (%)
Substrate
Product
Yield (%)
60 (52) 54 gram scale
59b
55c
51
42 (40)
28d
64 (58)
70 (68)
54 (49)
63
40
58e (60)
56e
30
47
28f
a
Unless otherwise stated, all reactions were conducted using Selectuor (2.2 equiv.) and 9-uorenone (0.2 equiv.) in anhydrous MeCN under UV-
irradiation (300 nm, Rayonet reactor) and inert N2 atmosphere for 12 h, followed by dilution with H2O and 25 min of stirring with LiOH (5.0 equiv.)
to yield carboxylic acids. Isolated yields reported. Yields in parentheses are from reactions using a visible light source (14 Watt CFL). b Quenched
with LiOMe (5.0 equiv.). c Upon reaction completion, reaction mixture was concentrated, redissolved in anhydrous THF, and stirred with LiAIH4 (6.0
d
equiv.) for an additional 1 h. Acetal removed during workup/isolation. e Isolated as a 1 : 1 mixture of diastereomers. f 19F NMR yield.
positions are present on the substrate, barely any direct sp3 C–H lower in this instance, it exhibits the ability of this method to
benzylic uorination is observed, as C–C fragmentation domi- access u-uoro-u-aryl ketones in addition to u-uoro-u-aryl
nates.18 This is exemplied in the b-phenyl-substituted a-tetra- carboxylic acids, esters, and alcohols. On another note, the
lone derivative 12, which, along with the cis-decalin derivative acetal functional group can act as an unconventional “leaving
13, additionally exemplies the utility of this method in form- group” concomitant with uorine installation (16), if the
ing complex, substituted rings (e.g. benzene and cyclohexane) desired reaction does not call for the opening of a ring.
from commercially available polycyclic substrates. Lastly, to our
Although our initial efforts focused primarily on cleavage of
knowledge, none of the products we present have been ever-pervasive 6-membered rings, we subsequently examined
synthesized using direct sp3 C–H benzylic uorination methods the application to both smaller and larger rings (Table 4). Both
to date.
5- and 7-membered rings (also common in natural products)
We also provide an example where C–C fragmentation/uo- underwent ring-opening/uorination with very similar efficacy
rination can be accomplished from an aryl substituted tertiary to the 6-membered rings vide supra (17 and 18). Remarkably,
alcohol, in lieu of the acetal (15). Although the yield is slightly the reaction also proved amenable to 8- and 12-membered rings
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Table 4 Application to 5-, 7-, 8-, and 12-membered ringsa
uorination of the larger rings may also offer a distinct advan-
tage over existing sp3 C–H benzylic uorination methods, as
these substrates are not prone to competitive sp3 C–H uori-
nation along the chain under our specied conditions.
Entry
Substrate
Product
Yield (%)
58 (62)
Finally, as a preliminary mechanistic probe, we conducted a
few competition experiments to obtain relative rate data, as the
effect of structural modications on reaction rate should
provide information about reactive intermediates,20 viz. the
postulated radical cation. In support of our hypothesis, the
competition experiments (Scheme 4) resulted in a larger ratio of
the product substituted with a mildly electron donating group
(tBu) relative to the electron neutral product, as well as smaller
relative ratios of the products substituted with electron with-
drawing groups (Cl and CF3). In the most extreme case, hardly
any CF3-substituted product was formed in the presence of the
electron neutral species. This suggests a better ability of elec-
tron donating groups to stabilize an electron decient inter-
mediate.21 To further investigate the substituent effects on the
postulated radical cation, we calculated a series of isodesmic
equations.22 In each case, we consistently found a more stable
radical cation with the more electron rich substitution at
B3PW91/6-311++G** (Scheme 5).23
1
2
3
57 (53)
46
4
30
a
Isolated yields reported. Yields in parentheses are from reactions
using a visible light source (14 Watt CFL).
Conclusions
All in all, this photosensitized C–C bond cleavage reaction
provides a mild, unique opportunity for the monouorination
of complex substrates, effortlessly opening classically stable
rings in the presence of light. While initial mechanistic studies
support the idea of a radical cation intermediate (based on
substituent effects and DFT calculations), extensive studies are
currently underway to provide a full Hammett analysis, KIE
studies, computations, and spectroscopic data.
Acknowledgements
T. L. would like to thank the NSF (CHE 1152996) for support.
Scheme 4 Intermolecular competition experiments.
Notes and references
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´
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