Metal-catalyzed benzylic fluorination as a synthetic equivalent to 1,4-conjugate addition of fluoride

Article abstract of DOI:10.1021/jo401796g

We explore in detail the iron-catalyzed benzylic fluorination of substrates containing aromatic rings and electron-withdrawing groups positioned β to one another, thus providing direct access to β-fluorinated adducts. This operationally convenient process can be thought of not only as a contribution to the timely problem of benzylic fluorination but also as a functional equivalent to a conjugate addition of fluoride, furnishing products in moderate to good yields and in excellent selectivity.

Full text of DOI:10.1021/jo401796g

Note
pubs.acs.org/joc
Metal-Catalyzed Benzylic Fluorination as a Synthetic Equivalent to
1,4-Conjugate Addition of Fluoride
Steven Bloom, Seth Andrew Sharber, Maxwell Gargiulo Holl, James Levi Knippel, and Thomas Lectka*
Department of Chemistry, Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, United States
S
* Supporting Information
ABSTRACT: We explore in detail the iron-catalyzed benzylic fluorination of
substrates containing aromatic rings and electron-withdrawing groups positioned
β to one another, thus providing direct access to β-fluorinated adducts. This
operationally convenient process can be thought of not only as a contribution to
the timely problem of benzylic fluorination but also as a functional equivalent to
a conjugate addition of fluoride, furnishing products in moderate to good yields
and in excellent selectivity.
ver the past decade the demand for fluorine-enriched
compounds has risen dramatically. Consequently, a host
convenient route for site-specific β-fluorination. Remarkably,
under our conditions α-fluorinated byproducts were not
observed despite the well-documented background reaction
between Selectfluor and various ketones.11 Also, several
functional groups known for intolerance to Selectfluor persisted
through the reaction conditions very well. Finally, it should be
noted that the reaction is operationally simple and reliable.
We began our studies by examining several well-known,
saturated variants of “Michael acceptors” under catalytic
conditions. To our satisfaction, a host of β-fluorinated products
were obtained in good yields and in outstanding selectivity
(Table 1). Some noteworthy observations include (1) α-
substituted carbonyls demonstrated a preference for syn
addition of fluorine; (2) nitriles, aldehydes, and free acids
were tolerated under our reaction conditions despite a
perceived high propensity for deleterious side reactions with
Selectfluor and various metal catalysts;12 (3) for substrates
possessing multiple benzylic positions 3, 5, 9, and 12,
fluorination of the least substituted carbon is preferred; (4)
difluorination and (5) α-fluorination are negligible. In addition,
1,3-aryl sulfones, ketones, and oxazolidinones were successfully
β-fluorinated, the latter a being potentially useful auxiliary for
developing an asymmetric variant of our reaction. An important
note is that the use of other iron(II) and iron(III) salts or the
corresponding Fe(acac)3 failed to yield any appreciable
quantities of fluorinated product.
O
of fluorination strategies has evolved to aid the modern chemist
in their syntheses.1 Despite a large repertoire of practical
fluorination methods, the 1,4-addition of fluoride to α,β-
unsaturated carbonyl-containing compounds represents a long-
standing problem. Of medicinal interest, hydrogen atoms β to a
carbonyl are often labile and susceptible to enzymatic
decomposition (e.g., in fatty acid catabolism).2 Accordingly,
the replacement of a single hydrogen atom by fluorine has been
shown to increase the chemical integrity of the parent molecule,
improving its lifetime in vivo.3 It therefore stands to reason that
a practical β-fluorination may prove to be a valuable
transformation. Unfortunately, previous efforts exploring the
use of cuprates (copper fluorides) have yet to afford a notable
success, resulting in trace yields or limited selectivity.4 Perhaps
this is no surprise; computationally, employing hybrid-DFT
theory, the addition of dimethylcuprate is predicted to be much
−
more thermodynamically favorable than the addition of CuF2
(Figure 1). We envisioned an indirect approach in the absence
of the alkene to circumvent this issue.5,6 Recently, our lab
published an iron(II)-catalyzed system for the chemoselective
benzylic fluorination of several alkylbenzenes using Selectfluor
as a fluorinating agent.7 Our paper was among the first to
provide a more general solution to what is proving to be a very
timely problem.8 In this note, we explore in detail the iron-
catalyzed benzylic fluorination of substrates containing aromatic
rings and electron-withdrawing groups beta (β) to one another
to yield β-fluorinated products (Figure 2). This process can be
thought of as a functional solution to the long-standing
problem of mild conjugate addition of fluoride, affording
products in good to moderate yields and in excellent selectivity.
We surmised that this system could also be used as a surrogate
to harsh, traditional methods involving nucleophilic-conjugate
addition with hydrohalic acids,9,10 providing a direct,
Moreover, β-fluorinations of several pharmaceutically effica-
cious scaffolds including cyclamen (3), the 3-phenylpropylester
(9), chalcone (10), and the indane (11) were achieved. Among
these structures, indane (11) proved a particularly interesting
case. By crude 19F NMR, both trans and cis diastereomers are
Received: August 15, 2013
© XXXX American Chemical Society
A
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Note
Figure 1. Computational analysis of cuprates in fluoride conjugate addition.
Degradation of the cis-diastereomer may be likewise expected,
albeit at a much slower rate.
Although applicable to a wide survey of functional groups,
yields trended for highly electron-withdrawing “Michael
acceptors” in the general order COOMe > COOH > SO2Ph
> CN > NO2 (trace amounts). This correlates nicely with
relative σ substituent values, advocating an increased reactivity
of more oxidizable, electron-rich benzylic hydrogens toward
fluorination, an unsurprising finding assuming the possible
involvement of free radicals during the reaction.14,15 To
elucidate the potential for radicals in our reaction, we
envisioned the use of the strained cycloalkane norcarane 16
as a radical clock. Although not a benzylic substrate per se, the
cyclopropane ring is similarly activating. Homolytic cleavage of
a C3 C−H bond should lead to product 17 following a rapid
opening of the cyclopropyl ring and trapping with fluorine
(Figure 4).16 In a similar fashion, α,β-unsaturated aryl ester 18
Figure 2. A synthetic equivalent to fluoride conjugate addition.
produced in a 3:1 ratio. However, upon purification by silica gel
chromatography, only the cis diastereomer can be isolated
(31%). In the case of the anti diastereomer, a rapid
dehydrofluorination occurs to give the unsaturated indene as
1
characterized by H NMR. The instability of the trans isomer
relative to cis is rationalized given the ease of syn-elimination
based on precedent in related systems (see Figure 3).13
Table 1. Survey of Conjugate Addition Products
a
b
Yield determined by 19F NMR using 3-chlorobenzotrifluoride as an internal standard. Isolated as the major benzylic product with minor
flourinated isomers. All reactions were run at room temperature for 24 h unless otherwise stated. Diastereoselectivity is reported as (syn:anti).
B
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Note
Figure 3. Dehydrofluorination of the trans-diastereomer.
General Procedure for the Syntheses of β-Fluorinated
Products. An oven-dried, 10-mL, round-bottom flask equipped with
a stir bar was placed under an atmosphere of N2. Selectfluor (195.0
mg, 0.55 mmol, 2.2 equiv) and Fe(acac)2 (6.0 mg, 0.025 mmol, 0.1
equiv) were added followed by MeCN (3.0 mL). 3-Phenyl-
propiononitrile (32.8 mg, 0.25 mmol, 1 equiv) was then added, and
the mixture allowed to stir overnight. The product was extracted into
CH2Cl2 and washed with water. The organics were dried with MgSO4
and filtered through Celite. The solvents were removed by rotary
evaporation, and the residue was subjected to column chromatography
on silica with a mixture of ethyl acetate/hexanes as eluent to afford 3-
fluoro-3-phenylpropanenitrile as a clear oil (16.4 mg, 44%).
Figure 4. Preliminary evidence for the involvement of radicals during
fluorination.
Computational Methods. The Gaussian 0923 package and
Spartan ‘10 were used for all calculations. Chemical shifts of the
products were computed using Gaussian at the B3LYP/6-311++G**
level.24 Geometry optimizations of organocopper complexes were
determined at the B3LYP/6-31G* (LANL2DZ on Cu) level.
Compound Characterization. 3-Fluoro-3-phenylpropaneni-
trile (1). Spectral and analytical data were in agreement with previous
reports.20 Yield: (16.4 mg, 44%).
should be a propitious substrate to probe the generation of
benzylic radicals. It is expected that formation of the
corresponding benzyl radical could lead to the standard
fluorinated product 19 and/or to the more diagnostic product
20 through a cyclization reaction. In both cases, these putative
radical-derived products were observed by 19F NMR analysis of
our reaction mixtures and identified by comparison to known
literature values.17,18 In the case of 16, it should be noted that
the primary fluoride 17 is still the predominant product.
Whereas the formation of 17 is incompatible with an anionic
mechanism, the formation of cyclized product 20 is
incompatible with a cationic mechanism.
In conclusion, a convenient, mild route for the direct
preparation of β-fluorinated, 3-phenyl propanoids has been
presented. This protocol is operationally reliable and highly
chemoselective and has been shown to tolerate a diverse array
of functional groups. What is more, we demonstrate the ability
of our reaction to act as a surrogate in the 1,4-conjugate
addition of fluoride, thus providing an alternative to corrosive
hydrofluoric acid protocols.
3-Fluoro-3-phenylpropanoic Acid (2). Amorphous solid; 1H
NMR (CDCl3) δ 7.46−7.40 (m, 5H), 5.95 (ddd, 1H, J = 46.7, 9.0, 4.0
Hz), 3.12 (ddd, 1H, J = 25.4, 16.4, 8.9 Hz), 2.89 (ddd, 1H, J = 32.4,
16.2, 4.1 Hz); 13C NMR (CDCl3) δ 177.5 (s), 138.4 (d, J = 19.0 Hz),
128.9 (s), 128.7 (s), 128.4 (d, J = 30.7 Hz), 126.4 (s), 125.6 (d, J = 5.9
Hz), 90.4 (d, J = 172.7 Hz), 30.2 (d, J = 90.0 Hz); 19F NMR (CDCl3)
δ −172.4 (ddd, 1F, J = 45.4, 33.0, 13.4 Hz); IR (CH2Cl2) 3065, 1717
cm−1; HRMS (ESI+) calcd for C9H9FO2Na+ 191.0485, found
191.0491. Yield: (20.2 mg, 48%).
3-Fluoro-3-(4-isopropylphenyl)-2-methylpropanal (3). Clear
oil; 1H NMR (CDCl3) δ 9.90 (dd, 1H, J = 2.2, 0.9 Hz), 9.76 (t, 1H, J =
1.2 Hz), 7.50−7.10 (m, 8H), 5.87 (dd, 1H, J = 46.7, 4.7 Hz), 5.57 (dd,
1H, J = 46.5, 8.3 Hz), 3.10−2.75 (m, 4H), 1.25 (d, 6H, J = 7.0 Hz),
1.25 (d, 6H, J = 8.3 Hz), 1.17 (dd, 3H, J = 7.2, 0.8 Hz), 0.96 (d, 3H, J
= 7.2 Hz); 13C NMR (CDCl3) δ 202.2 (d, J = 3.7 Hz), 201.8 (d, J =
4.4 Hz), 195.6 (s), 150.92 (s), 150.0 (s), 149.4 (s), 137.6 (s), 134.9 (d,
J = 20.5 Hz), 134.4 (d, J = 20.5 Hz), 130.3 (s), 126.9 (s), 126.8 (s),
126.7 (s), 126.4 (s), 126.4 (s), 125.6 (s), 125.5 (s), 94.6 (d, J = 172.6
Hz), 92.6 (d, J = 176.4 Hz), 52.5 (d, J = 23.4 Hz), 52.0 (d, J = 23.4
Hz), 34.1 (s), 33.9 (d, J = 4.4 Hz), 23.9 (s), 23.8 (s), 13.3 (s), 11.0 (s),
10.4 (d, J = 6.6 Hz), 8.07 (d, J = 5.1 Hz; 19F NMR (CDCl3) δ −171.5
(dd, 1F, J = 47.4, 15.5 Hz), δ −186.9 (dd, 1F, J = 46.4, 24.7 Hz); IR
(CH2Cl2) 1679 cm−1; HRMS (ESI+) calcd for C13H17FONa+
231.1161, found 231.1169. Yield: (34.9 mg, 67%).
EXPERIMENTAL SECTION
■
General. Unless otherwise stated, all reactions were carried out
under strictly anhydrous, air-free conditions under nitrogen. All
solvents and benzylic compounds were dried and distilled by standard
1
methods. H spectra were acquired on a 400 MHz NMR in CDCl3;
13C and 19F spectra were taken on a 300 MHz NMR in CDCl3. The
1H, 13C, and 19F chemical shifts are given in parts per million (δ) with
respect to an internal tetramethylsilane (TMS, δ 0.00 ppm) standard
and/or 3-chlorobenzotrifluoride (δ −64.2 ppm relative to CFCl3).19
NMR data are reported in the following format: chemical shift
(multiplicity (s = singlet, d= doublet, t = triplet, q = quartet, m =
multiplet), integration, coupling constants [Hz]). IR data were
obtained using an FT-IR and standard NaCl cell. High resolution
mass spectra (HRMS) were recorded using ESI-TOF (electrospray
ionization-time-of-flight) mass spectrometry. All measurements were
recorded at 25 °C unless otherwise stated. Characterization of 3-
fluoro-3-phenylpropanenitrile (1),20 methyl-3-fluoro-2-methyl-3-phe-
nylpropanoate (8),21 and 3-fluoro-1,3-diphenylpropan-1-one (10)7
were consistent with the literature precedents. Compounds 4 and 11
are reported as crude spectra due to product decomposition. Spectral
data was processed with ACD/NMR Processor Academic Edition.22
(1-Fluoro-2-(phenylsulfonyl)ethyl)benzene (4). Amorphous
1
solid; H NMR (CDCl3) δ 8.0−7.63 (m, 10H), 6.11 (ddd, 1H, J =
47.5, 9.4, 2.5 Hz), 3.83 (ddd, 1H, J = 22.8, 13.4, 1.7 Hz), 3.49 (ddd,
1H, J = 31.7, 15.3, 2.5 Hz); 13C NMR (CDCl3) δ 139.1 (s), 137.5 (s),
133.9 (s), 133.8 (s), 129.4 (s), 129.3 (s), 128.9 (s), 128.8 (s), 128.3
(s), 128.1 (s), 126.9 (s), 125.5 (d, J = 6.6 Hz), 88.5 (d, J = 177.1 Hz),
62.7 (d, J = 26.4 Hz); 19F NMR (CDCl3) δ −172.1 (ddd, 1F, J = 46.4,
32.0, 13.4 Hz); IR (CH2Cl2) 1087, 1151 cm−1; HRMS (ESI+) calcd for
C14H13FO2SNa+ 287.0518, found 287.0512. Yield: (29.7 mg, 45%).
1
1-Fluoro-1,5-diphenylpentan-3-one (5). Amorphous solid; H
NMR (CDCl3) δ 7.45−7.15 (m, 10H), 6.01 (ddd, 1H, J = 46.9, 8.9,
4.1 Hz), 3.2 (ddd, 1H, J = 14.7, 8.3, 2.5 Hz), 3.0−2.7 (m, 5H); 13C
NMR (CDCl3) δ 205.8 (s), 142.6 (s), 140.7 (s), 139.2 (s), 139.0 (s),
C
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Note
128.9 (s), 128.7 (s), 128.6 (s), 128.5 (s), 128.3 (s), 126.2 (s), 125.5
(s), 125.4 (s), 90.1 (d, J = 165 Hz), 50.1 (d, J = 25.6 Hz), 42.2 (s),
29.4 (s); 19F NMR (CDCl3) δ −173.4 (ddd, 1F, J = 47.4, 32.0, 14.4
Hz); IR (CH2Cl2) 1715 cm−1; HRMS (ESI+) calcd for C17H17FONa+
279.1161, found 279.1168. Yield: (35.9 mg, 56%).
3-(3-Fluoro-3-phenylpropanoyl)oxazolidin-2-one (6). Amor-
phous solid; 1H NMR (CDCl3) δ 7.47−7.35 (m, 5H), 6.05 (ddd, 2H, J
= 47.1, 9.0, 3.4 Hz), 4.49−4.39 (m, 2H), 4.16−4.0 (m, 2H), 3.8 (ddd,
1H, J = 16.7, 9.2, 3.0 Hz), 3.36 (ddd, 1H, J = 32.8, 16.7, 3.4 Hz); 13C
NMR (CDCl3) δ 169.3 (s), 153.5 (s), 138.7 (d, J = 19.8 Hz), 128.8 (d,
J = 2.2 Hz), 128.6 (s), 128.5 (d, J = 8.0 Hz), 125.7 (d, J = 6.6 Hz), 90.0
(d, J = 172 Hz), 62.2 (s), 42.8 (d, J = 27.1 Hz), 42.5 (s); 19F NMR
(CDCl3) δ −173.6 (ddd, 1F, J = 47.4, 33.0, 13.4 Hz); IR (CH2Cl2)
1706, 1783 cm−1; HRMS (ESI+) calcd for C12H12FNO3Na+ 260.0699,
found 260.0691. Yield: (30.2 mg, 51%).
Ethyl-3-(4-chlorophenyl)-3-fluoropropanoate (13). Spectral
and analytical data were in agreement with previous reports.25 Yield:
(21.9 mg, 38%).
Ethyl-3-(3-methoxyphenyl)-3-fluoropropanoate (14). Spec-
tral and analytical data were in agreement with previous reports.25
Yield: (24.3 mg, 43%).
Ethyl-3-(4-bromophenyl)-3-fluoropropanoate (15). Spectral
and analytical data were in agreement with previous reports.25 Yield:
(27.5 mg, 40%).
ASSOCIATED CONTENT
* Supporting Information
■
S
Characterization data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
2-(Fluoro(phenyl)methyl)cyclohexanone (7). Clear oil; 1H
NMR (CDCl3) δ 7.56−7.25 (m, 10H), 6.09 (dd, 1H, J = 46.5, 4.1
Hz), 5.87 (dd, J = 45.2, 7.7 Hz), 3.26−1.52 (m, 18H); 13C NMR
(CDCl3) δ 209.9 (d, J = 2.9 Hz), 209.4 (d, J = 2.9 Hz), 139.2 (d, J =
20.5 Hz), 137.6 (d, J = 20.5 Hz), 130.3 (s), 128.6 (d, J = 2.9 Hz),
128.4 (s), 128.3 (s), 128.1 (s), 128.0 (d, J = 1.5 Hz), 126.6 (d, J = 7.3
Hz), 125.5 (d, J = 8.0 Hz), 92.3 (d, J = 174.2 Hz), 90.8 (d, J = 170.5
Hz), 56.3 (d, J = 5.1 Hz), 56.1 (d, J = 5.9 Hz), 42. Three (s), 29.9 (d, J
= 5.1 Hz), 28.1 (s), 27.5 (s), 27.2 (s), 26.6 (d, J = 5.9 Hz), 24.5 (d, J =
2.2 Hz), 23.8 (s); 19F NMR (CDCl3) δ −96.9 (dd, J = 1492.9, 12.4
Hz), −95.2 (dd, J = 990.8, 12.4 Hz), −172.3 (dd, 1F, J = 45.4, 15.5
Hz), −191.6 (dd, 1F, J = 45.4, 21.7 Hz); IR (CH2Cl2) 1721 cm−1;
HRMS (ESI+) calcd for C13H15FONa+ 229.1005, found 229.1009.
Yield: (28.9 mg, 56%).
AUTHOR INFORMATION
Corresponding Author
*E-mail: lectka@jhu.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
T.L. thanks the PRF-ACS and NSF (CHE 1152996) for
support.
REFERENCES
■
Methyl 3-Fluoro-2-methyl-3-phenylpropanoate (8). Spectral
and analytical data were in agreement with previous reports.21 Yield:
(33.8 mg, 69%).
(1) (a) Cahard, D.; Xu, X.; CouveBonnaire, S.; Pannecoucke, X.
Chem. Soc. Rev. 2010, 39, 558−568. (b) Purser, S.; Moore, P. R.;
Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320−330.
(2) (a) Campbell, N. H.; Smith, D. L.; Reszka, A. P.; Neidle, S.;
O’Hagan, D. Org. Biomol. Chem. 2011, 9, 1328−1331. (b) Tang, W.;
Borel, A. G.; Fujimiya, T.; Abbott, F. S. Chem. Res. Toxicol. 1995, 8,
671−682.
(3) (a) Ojima, I. Fluorine in Medicinal Chemistry and Chemical
Biology; Wiley-Blackwell: Chichester, U.K., 2009. (b) Liu, P.; Sharon,
A.; Chu, C. K. J. Fluorine Chem. 2008, 129, 743−766. (c) Smart, B. E.
J. Fluorine Chem. 2001, 109, 3−11. (d) Park, B. K.; Kitteringham, N. R.
Drug Metab. Rev. 1994, 26, 605−643. (e) Chambers, R. D. Fluorine in
Organic Chemistry; Wiley: New York, 1973.
2-Phenylpropyl 3-Fluoro-3-phenylpropanoate (9). Clear oil;
1H NMR (CDCl3) δ 7.44−7.20 (m, 20H), 5.97−5.80 (m, 2H), 4.40−
4.20 (m, 4H), 3.25−2.65 (m, 6H), 1.33 (d, 3H, J = 0.8 Hz), 1.31 (d,
3H, J = 0.8); 13C NMR (CDCl3) δ 169.5 (s), 142.9 (d, J = 2.2 Hz),
138.6 (d, J = 19.8 Hz), 128.8 (d, J = 2.2 Hz), 128.7 (s), 128.5 (d, J =
1.5 Hz), 127.3 (s), 126.8 (d, J = 1.5 Hz), 125.6 (dd, J = 6.6, 2.2 Hz),
90.6 (d, J = 171.3 Hz), 69.9 (d, J = 4.4 Hz), 42.4 (dd, J = 28.5, 2.9 Hz),
38.9 (s), 17.7 (s); 19F NMR (CDCl3) δ −172.2 (m, 1F); IR (CH2Cl2)
1738 cm−1; HRMS (ESI+) calcd for C13H15FONa+ 229.1005, found
229.1009. HRMS (ESI+) calcd for C18H19FO2Na+ 309.1267, found
309.1272. Yield: (41.5 mg, 58%).
(4) For a review of cuprates in conjugate additions, see: (a) Silva, E.
M. P.; Silva, A. M. S. Synthesis 2012, 44, 3109−3128. (b) Mori, S.;
Nakamura, E. Modern Organocopper Chemistry; Wiley-VCH Verlag
GmbH: Weinheim, 2002; pp 315−346. (c) Ullenius, C.; Christenson,
B. Pure Appl. Chem. 1988, 60, 57−64.
(5) Our group has recently published a direct method for alkane
fluorination: Bloom, S.; Pitts, C. R.; Miller, D. C.; Haselton, N.; Holl,
M. G.; Urheim, E.; Lectka, T. Angew. Chem., Int. Ed. 2012, 51, 10580−
10583. Groves et al. have likewise published on a catalytic method for
alkane fluorination using a manganese porphyrin, iodosylbenzene as an
oxidant, and AgF as a source of fluoride anion: Liu, W.; Huang, X.;
Cheng, M.-J.; Nielsen, R. J.; Goddard, W. A., III; Groves, J. T. Science
2012, 337, 1322−1325.
(6) (a) Sanford et al. have recently developed a ligand directed
palladium-catalyzed benzylic fluorination of N-containing heterocycles:
McMurtrey, K. B.; Racowski, J. M.; Sanford, M. S. Org. Lett. 2012, 14,
4094−4097. (b) Groves et al. and Inoue et al. have also reported
direct methods for benzylic fluorination: Liu, W.; Groves, J. T. Angew.
Chem., Int. Ed. 2013, 52, 6024−6027. (c) Amaoka, Y.; Nagatomo, M.;
Inoue, M. Org. Lett. 2013, 15, 2160−2163.
3-Fluoro-1,3-diphenylpropan-1-one (10). Spectral and analyt-
ical data were in agreement with previous reports.7 Yield: (34.8 mg,
61%).
Methyl 1-Fluoro-2,3-dihydro-1H-indene-2-carboxylate (11).
1
Clear oil; H NMR (CDCl3) δ 7.55−7.28 (m, 7H), 7.28−7.15 (m,
1H), 6.31 (dd, 1H, J = 56.3, 5.1 Hz), 6.06 (dd, 1H, J = 56.9, 4.7 Hz)
3.84 (s, 3H), 3.80 (s, 3H), 3.73−3.05 (m, 6H); 13C NMR (CDCl3) δ
173.2 (d, J = 5.9 Hz), 170.5 (d, J = 3.7 Hz), 156.6 (s), 143.9 (d, J = 5.1
Hz), 141.5 (t, J = 5.9 Hz), 138.8 (d, J = 19.0 Hz), 138.0 (d, J = 16.1
Hz), 130.7 (d, J = 4.4 Hz), 130.0 (d, J = 2.9 Hz), 127.3 (dd, J = 18.3,
2.9 Hz), 126.0 (d, J = 2.9 Hz), 125.1 (dd, J = 41.7, 1.5 Hz), 125.2 (d, J
= 2.9 Hz), 124.3 (s), 98.1 (d, J = 180.8 Hz), 95.5 (d, J = 178.6 Hz),
52.3 (d, J = 19.0 Hz), 50.9 (d, J = 21.9 Hz), 49.7 (d, J = 23.4 Hz), 43.5
(s), 36.2 (s), 32.9 (dd, J = 144.9, 1.5 Hz); 19F NMR (CDCl3) δ
−163.9 (dd, 1F, J = 58.8, 24.7 Hz), −167.0 (dd, 1F, J = 55.7, 30.9 Hz);
IR (CH2Cl2) 1740 cm−1; HRMS (ESI+) calcd for C11H11FO2Na+
217.0641, found 217.0637. Yield: (34.5 mg, 71%).
1
Methyl 3-Fluoro-2,3-diphenylpropanoate (12). Clear oil; H
NMR (CDCl3) δ 7.50−7.08 (m, 20H), 6.11−5.90 (m, 2H), 4.18−4.06
(m, 2H), 3.83 (s, 4H), 3.56 (s, 2H); 13C NMR (CDCl3) δ 171.9 (s),
170.9 (s), 137.9 (s), 137.7 (s), 136.9 (s), 136.6 (s), 134.6 (s), 133.4
(s), 133.3 (s), 128.9 (d, J = 23.0 Hz), 128.7 (d, J = 24.2 Hz), 128.3 (s),
128.1 (s), 126.7 (m), 92.8 (d, J = 178.4 Hz), 92.3 (d, J = 177.8 Hz),
58.7 (d, J = 26.9 Hz), 52.5 (s), 52.3 (s); 19F NMR: −167.6 (dd, 1F, J =
45.4, 8.3 Hz), −178.2 (dd, 1F, J = 46.4, 13.4 Hz); IR (CH2Cl2) 1737
cm−1; HRMS (ESI+) calcd for C16H15FO2Na+ 281.0954, found
281.0959. Yield: (48.4 mg, 75%).
(7) Bloom, S.; Pitts, C. R.; Woltornist, R.; Griswold, A.; Holl, M. G.;
Lectka, T. Org. Lett. 2013, 15, 1722−1724.
(8) The popularity of iron catalysts for the direct functionalization of
nonactivated sp3 C-H bonds has grown considerably in recent years.
For representative examples, see: (a) Sekine, M.; llies, L.; Nakamura,
E. Org. Lett. 2013, 15, 714−717. (b) Paradine, S. M.; White, M. C. J.
Am. Chem. Soc. 2012, 134, 2036−2039. (c) Song, C.-X.; Cai, G.-X.;
D
dx.doi.org/10.1021/jo401796g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Farrell, T. R.; Jiang, Z.-P.; Li, H.; Gan, L.-B.; Shi, Z.-J. Chem. Commun.
2009, 6002−6004.
(9) German, L. S.; Knunyantz, I. L. Angew. Chem., Int. Ed. Engl. 1969,
8, 349−356.
(10) Jacobs, W. A.; Heidelberger, M. J. Am. Chem. Soc. 1917, 39,
1465−1466.
(11) (a) Stavber, G.; Zupan, M.; Stavber, S. Synlett 2009, 4, 589−594.
(b) Stavber, G.; Zupan, M. Tetrahedron Lett. 1996, 37, 3591−3594.
(12) (a) Peng, W.; Shreeve, J. M. Tetrahedron Lett. 2005, 46, 4905−
́
4909. (b) Nyffeler, P. T.; Duron, S. G.; Burkhart, M. D.; Vincent, S. P.;
Wong, C. H. Angew. Chem. 2005, 117, 196−217; Angew. Chem., Int. Ed.
2005, 44, 192−212.
(13) (a) Hudlicky, M. Collect. Czech. Chem. Commun. 1991, 56,
́
1680−1689. (b) Bartsch, R. A.; Zavada, J. Chem. Rev. 1980, 80, 453−
494. (c) Sicher, J. Angew. Chem., Int. Ed. 1972, 11, 200−214.
(14) For a complete table of σ values, see: (a) Datta, D. J. J. Phys. Org.
Chem. 1991, 4, 96−100. (b) McDaniel, D. H.; Brown, H. C. J. Org.
Chem. 1958, 23, 420−427.
(15) Iron acetylacetonates are known to participate in radical based
transformations. See: (a) Barker, T. J.; Boger, D. L. J. Am. Chem. Soc.
2012, 134, 13588−13591. (b) Xue, Z.; Poli, R. J. Polym. Sci., Part A:
Polym. Chem. 2013, 51, 3494−3504. (c) Zhao, J.; Fang, H.; Han, J.;
Pan, Y. Beilstein J. Org. Chem. 2013, 9, 1718−1723.
(16) Sammis et al. in pioneering work have shown that alkyl radicals
can be trapped in the presence of electrophilic fluorinating reagents to
yield fluorinated products. See: Rueda-Becerril, M.; Sazepin, C. C.;
Leung, J. C.; Okbinoglu, T.; Kennepohl, P.; Paquin, J. F.; Sammis, G.
M. J. Am. Chem. Soc. 2012, 134, 4026−4029.
(17) For spectral data of 2A see: Morikawa, T.; Uchida, J.; Hasegawa,
Y.; Takeo, T. Chem. Pharm. Bull. 1991, 39, 2462−2464.
(18) For specral data of 1B see: Liu, W.; Huang, X.; Groves, J. T.;
Cheng, M.-J.; Nielsen, R. J.; Goddard, W. A., III. Science 2012, 37,
1322−1325.
(19) Naumann, D.; Kischkewitz, J. J. Fluorine Chem. 1990, 47, 283−
299.
(20) Guolin, C.; Chau, J. N.; Dominguez, C.; Lu, Y.; Rishton, G. M.
Patent US2003/195221 A1, 2003.
(21) Ayi, A. I.; Remli, M.; Guedj, R. J. Fluorine Chem. 1981, 17, 127−
144.
(22) ACD/NMR Processor Academic ed., version 12.0; Advanced
Chemistry Development, Inc.: Toronto, ON, Canada, 2012; www.
acdlabs.com.
(23) Huczynski, A.; Rutkowski, J.; Brzezinski, B. Struct. Chem. 2011,
22, 627−634.
(24) Merrick, J. P.; Moran, D.; Radom, L. J. Phys. Chem. A 2007, 111,
11683−11700.
(25) (a) Ayi, A. I.; Condom, R.; Wade, T. N.; Guedj, R. J. Fluorine
Chem. 1979, 14, 437−454. (b) Ayi, A. I.; Condom, R.; Maria, P. C.;
Wade, T. N.; Guedj, R. Tetrahedron 1978, 19, 4507−4510.
E
dx.doi.org/10.1021/jo401796g | J. Org. Chem. XXXX, XXX, XXX−XXX