Site-selective approach to β-fluorination: Photocatalyzed ring opening of cyclopropanols

Article abstract of DOI:10.1002/chem.201501081

To expand upon the recent pioneering reports of catalyzed sp³ C-H fluorination methods, the next rational step is to focus on directing "radical-based fluorination" more effectively. One potential solution entails selective C-C bond activation

Full text of DOI:10.1002/chem.201501081

DOI: 10.1002/chem.201501081
Communication
&
Synthetic Methods
Site-Selective Approach to b-Fluorination:
Photocatalyzed Ring Opening of Cyclopropanols
Steven Bloom, Desta Doro Bume, Cody Ross Pitts, and Thomas Lectka*[a]
cellent mode for directing fluorination, as long as selective for-
mation of the radical cation that prompts CÀC bond scission
can be achieved. Furthermore, expanding on new advance-
ments in the field, we gathered that photochemistry could
play a pivotal role in the development of this tandem ring-
opening/fluorination reaction. Accordingly, herein, we report
a site-selective photochemical approach to synthesizing a varie-
ty of b-fluorinated carbonyl-containing compounds from cyclo-
propanols (Scheme 1).
Abstract: To expand upon the recent pioneering reports
of catalyzed sp3 CÀH fluorination methods, the next ra-
tional step is to focus on directing “radical-based fluorina-
tion” more effectively. One potential solution entails selec-
tive CÀC bond activation as a prelude to selective fluorina-
tion. Herein, we report the tandem photocatalyzed ring-
opening/fluorination reactions of cyclopropanols by
1,2,4,5-tetracyanobenzene (TCB) and Selectfluor to afford
a process tantamount to site-selective b-fluorination of
carbonyl-containing compounds. This new approach pro-
vides a synthetically mild and operationally simple route
to otherwise difficult-to-prepare b-fluorinated products in
good yields and with good-to-excellent regioselectivity.
Remarkably, substrates that contain other usually reactive
(e.g., benzylic) sites undergo ring-opening fluorination
preferably. The versatility of this method to give cyclic b-
fluorides from tertiary cyclopropanols and g-fluoro alco-
hols is also highlighted.
Scheme 1. Site-selective b-fluorination of cyclopropanols.
Over the last two years, great strides have been made in the
development of direct sp3 CÀH monofluorination methods.
However, the methods we[1] and others[2] have reported are
often limited to the derivatization of highly symmetric com-
pounds, such as cycloalkanes, or those containing one activat-
ed site (e.g., benzylic). In substrates that contain many distinct
carbon atoms, the problem of “scattershot” fluorination often
arises, leading to undesirable mixtures of products. Expanding
upon these pioneering initial discoveries, the most logical next
step is to focus on directing sp3 CÀF bond formation more ef-
fectively, which will allow new and desirable passageways to
complex, selectively fluorinated molecules.
Our laboratory recently unveiled a photocatalyzed proce-
dure for the monofluorination of aliphatic[1d] and benzylic[1g]
substrates by using the inexpensive photosensitizer 1,2,4,5-tet-
racyanobenzene (TCB) along with Selectfluor as a source of
atomic fluorine.[4] This work was accompanied by a number of
alternative sp3 CÀH fluorination methods by using photosensi-
tizers, such as fluorenone,[2d] acetophenone,[2f] anthraquino-
ne,[2h] and decatungstate ions.[2k] Preliminary mechanistic ex-
periments on our benzylic substrates suggest that the reaction
proceeds through the formation of a radical-cation intermedi-
ate that is rapidly (if not simultaneously) deprotonated to the
corresponding benzylic radical (subsequently fluorinated by
Selectfluor).[1g] With this in mind, we deduced that a similar
photochemical system may be amendable to substituted cy-
clopropanol-based starting materials, because: 1) these com-
pounds are known to form radical cations under mild irradia-
tion in the presence of photooxidants due to their high-lying
HOMOs[5] (release of strain energy being the thermodynamic
driving force); and 2) the ring opening of radicals generated
from cyclopropanols followed by halogen-atom transfer is
a well-documented process to access b-halo ketones (or
enones).[6] In the calculated structure of the representative radi-
cal cation shown in Figure 1, elongation (to 2.02 ꢀ) of the
Conceptually, two potential routes for a site-selective fluori-
nation event may involve: 1) employing a directing group for
CÀH activation; or 2) exploring selective CÀC activation. In the
latter scenario, the use of CÀC activation as a means to guide
sp3 fluorination is, to our knowledge, uncharted territory.[3] To
examine this possibility, we envisioned that the one-electron
oxidation of highly strained cyclopropanes may serve as an ex-
[a] S. Bloom, D. D. Bume, C. R. Pitts, Prof. Dr. T. Lectka
Department of Chemistry, Johns Hopkins University
3400 North Charles Street, Baltimore, MD 21218 (USA)
E-mail: lectka@jhu.edu
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501081. It contains general experimental
details and characterization data.
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b-fluorinated ketones and other fluorinated products; evident-
ly, selective b-fluorination is only achievable under photocata-
lytic conditions. Moreover, other NÀF reagents were also exam-
ined and found to give lower yields. With these findings in
mind, we decided to examine a variety of cyclopropanols de-
rived from vinyl and allyl cycloalkanes, as well as aryl com-
pounds. In each instance, b-fluorinated products were ob-
tained in good to moderate yields and with excellent regiose-
lectivity (Table 1).
Figure 1. Calculated structure of trans-1,2-dimethylcyclopropanol radical
cation (wB97xD/cc-pVTZ, MeCN dielectric).
Remarkably, the reaction is highly selective toward CÀC
bond cleavage/fluorination over direct sp3 CÀH fluorination,
despite the previous application of a similar system to aliphatic
fluorination.[1d] Compounds 1–4 contain multiple potential flu-
orination sites on the cyclopentane, cyclohexane, and cyclooc-
tane rings, but only trace ring fluorination products were ob-
served in the 19F NMR spectra of the crude products, avoiding
the aforementioned issue of scattershot fluorination. Addition-
ally, the selective formation of b-fluorinated compounds 5–7
reflects the tendency of cyclopropanols to direct the fluorina-
tion event. Benzylic starting compounds of 6 and 7 offer
a much tougher test than 5, but even in the presence of
a more activated benzylic site, CÀC bond cleavage is still fa-
vored, providing b-fluorinated products in upwards of 72%
yield, although trace amounts of putative benzylic products
are observed in some cases.
weakest CÀC bond between the C(Me)(OH) and C(H)(Me) frag-
ments is observed. Thus, proton loss should regioselectively
afford b-carbonyl radicals that can be subsequently fluorinated.
Additionally, cyclopropanols represent attractive substrates for
fluorination, because they are readily accessible (e.g., through
the Simmons–Smith[7] and Kulinkovich[8] reactions) and are suit-
ably reactive, a feature borne of their high-strain energy.
Beyond proof-of-concept, note that the target b-fluorinated
carbonyl-containing compounds are synthetically and medici-
nally useful. For example, the incorporation of a single fluorine
atom at the b-position has been shown to influence the con-
formational integrity of cyclic amines and amides,[9] prevent
mitochondrial b-oxidation of fatty acids,[10] and serve as an ade-
quate positron emission tomography (PET) probe for elucidat-
ing a number of biosynthetic and metabolic pathways.[11] Con-
sequently, a number of methods have emerged pertaining to
the targeted synthesis of b-
Upon isolation, we observed a propensity for some of the
molecules to undergo elimination to form enones when chro-
fluorinated carbonyl com-
pounds.[1c,f,g,12,13] It stands to
reason that the development
of an alternative, photocata-
lytic route to b-fluorides from
cyclopropanols would be
highly desirable, providing
a much needed tool in the
armamentarium of the me-
dicinal chemist.
Table 1. Survey of b-fluoroketones and g-fluoroalcohols.
To begin our studies, we
selected 2-cyclohexyl-1-meth-
ylcyclopropanol for screening
purposes. Gratifyingly, UV ir-
radiation (l=302 nm) with
catalytic TCB (10 mol%) and
Selectfluor (2.2 equiv) at
room temperature gave the
b-fluoride 1, derived from
preferential scission of the
most substituted CÀC bond,
in 54% yield. Note that in
the absence of TCB, no fluori-
nated products were ob-
served. In addition, heating
of 2-cyclohexyl-1-methylcy-
clopropanol and Selectfluor
in MeCN gave an approxi-
mately 1:1 mixture of a- and
All reactions were performed under an inert atmosphere of N2 and irradiated with either a UV pen lamp (l=
302 nm) or Rayonet reactor (l=300 nm) for 16h. [a] Isolated as the major fluorinated product with minor fluorinat-
ed isomers. [b] Crude reaction mixture redissolved in THF and stirred with LiAlH4 (5.0 equiv) for 2 min. Isolated as
a mixture of diastereomers. [c] Substrate for which xanthone was used as the photocatalyst.
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matographed on silica or alumi-
na under neutral, acidic, or basic
conditions. It is important to
note that elimination can be
minimized by using flash chro-
matography on acidic florisil,
which allowed us to isolate most
b-fluorinated products with typi-
cally ꢀ5% eliminated by-prod-
ucts. In particularly sensitive
cases, we found that a reductive
workup by using LiAlH4 allows
effective isolation of the corre-
sponding g-fluoro alcohols after
Scheme 2. Tandem ring expansion/b-fluorination to access cycloheptanone or cycloheptanol core.
purification by chromatography
on silica gel in approximately 1:1
diastereomeric ratio (8–11).
To probe the selectivity of the reaction in situations when in-
discriminate fluorination could be especially problematic, we
turned our attention to cyclopropanols possessing linear ali-
phatic side chains. These compounds could conceivably serve
as precursors to b-fluorinated fatty acids, proteo-counterparts
of which are frequently metabolized by oxidative cleavage of
a b-CÀH bond.[14] The selective inclusion of a single fluorine
atom at the b-position could therefore prove particularly
useful in deterring this pathway.[15] Furthermore, monofluori-
nated lipids have found considerable use as probes for study-
ing the interaction between drugs or peptides and lipid mem-
branes.[16] Toward this effort, we found that 10-, 14-, and 20-
carbon b-fluorinated ketones 11–13 could be prepared from
the respective cyclopropanols.
a ring-expanded b-fluoride. For a representative example, we
selected cyclopropanol 15, because tandem ring expansion/flu-
orination should give b-fluorocycloheptanone. Cycloheptanone
cores are present in pharmaceuticals, such as bencyclane,
a spasmolytic agent and vasodilator, as well as a vital constitu-
ent in many fragrances and polymers (Scheme 2).[19] In this in-
stance, photochemical fluorination proceeded smoothly to
give b-fluorocycloheptanone 16 in 52% yield, as was deter-
mined by 19F NMR analysis (regioselectivity 38:1). This product
was isolated more effectively after purification by chromatog-
raphy on silica gel as the corresponding g-fluoro alcohol.
Finally, a general mechanistic proposal for the reaction is
shown in Scheme 3. Photoexcitation of TCB is known to yield
Polyfluorination and direct ali-
phatic fluorination were not
competitive with b-fluorination,
because compounds 11–13 were
isolated in 65–85% yield.
In another example, ring
opening/fluorination of a non-
natural steroid, a methyl-litho-
cholate derivative,[17] was found
to give the primary fluoride 14
in 28% yield. As was expected,
yields for primary b-fluorides
Scheme 3. Proposed mechanism for photocatalyzed site-selective b-fluorination.
were often lower than secon-
dary, a possible result of the di-
minished stability of primary rad-
icals compared to secondary, but they are still accessible by
this method. In an effort to improve these results, we found
that replacement of TCB by xanthone as the active photocata-
lyst provided moderate increases in yields. Terminal alkyl fluo-
rides have been shown to be effective reagents for inexpensive
nickel or copper-catalyzed cross-coupling reactions,[18] but
direct syntheses through sp3 CÀC or CÀH activation are ex-
tremely limited due to preparative difficulty.
a powerful oxidant that, in this instance, putatively abstracts
an electron from the substrate.[20] The resultant cyclopropanol
radical cation prompts CÀC bond elongation while relieving
ring strain (Figure 1); this is accompanied by proton loss to se-
lectively afford a b-carbonyl radical. As was expected, Select-
fluor can then act as an atomic source of fluorine to directly
fluorinate the radical.[1e,4] Lastly, the Selectfluor radical cation
retrieves the electron from the TCB radical anion, as well as
the excess proton from the reaction medium, thus generating
an ammonium salt by-product and regenerating the TCB cata-
lyst.
At this point, we considered alternative applications for this
method. We explored the use of a tertiary cyclopropanol that
could undergo oxidative ring opening/fluorination to give
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Acknowledgements
T.L. thanks the NSF (CHE 1152996) for support.
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Keywords: CÀC activation · cyclopropanols · fluorination ·
photochemistry · radical ions
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Received: March 19, 2015
Published online on && &&, 0000
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COMMUNICATION
The tandem photocatalyzed ring-open-
ing/fluorination reactions of cyclopropa-
nols by 1,2,4,5-tetracyanobenzene (TCB)
and Selectfluor to afford a process tan-
tamount to site-selective b-fluorination
of carbonyl-containing compounds are
reported (see scheme).
&
Synthetic Methods
S. Bloom, D. D. Bume, C. R. Pitts,
T. Lectka*
&& – &&
Site-Selective Approach to b-
Fluorination: Photocatalyzed Ring
Opening of Cyclopropanols
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