Direct Access to Acyl Fluorides from Carboxylic Acids Using a Phosphine/Fluoride Deoxyfluorination Reagent System

Article abstract of DOI:10.1021/acs.orglett.9b00197

A fast and simple method for deoxyfluorination of carboxylic acids is presented. The protocol employs commodity chemicals (PPh₃, NBS, fluoride), affording products in excellent yields under mild conditions. Acyloxyphosphonium ion, the key reaction intermediate, was identified by NMR spectroscopic methods. Br?nsted acidic conditions are essential for efficient C-F bond formation. The protocol displays scalability, high functional group tolerance, chemoselectivity, and easy purification of products. Deoxyfluorination of active pharmaceutical ingredients was established.

Full text of DOI:10.1021/acs.orglett.9b00197

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Direct Access to Acyl Fluorides from Carboxylic Acids Using a
Phosphine/Fluoride Deoxyfluorination Reagent System
†
†
†
Socrates B. Munoz, Huong Dang, Xanath Ispizua-Rodriguez, Thomas Mathew,
and G. K. Surya Prakash*
Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California
9
0089-1661, United States
*
S Supporting Information
ABSTRACT: A fast and simple method for deoxyfluorination
of carboxylic acids is presented. The protocol employs
commodity chemicals (PPh , NBS, fluoride), affording
3
products in excellent yields under mild conditions. Acylox-
yphosphonium ion, the key reaction intermediate, was
identified by NMR spectroscopic methods. Brønsted acidic
conditions are essential for efficient C−F bond formation. The protocol displays scalability, high functional group tolerance,
chemoselectivity, and easy purification of products. Deoxyfluorination of active pharmaceutical ingredients was established.
6
7
wing to the special role that organofluorine compounds
play in life and materials sciences, incorporation of
by Olah using cyanuric fluoride or SeF /pyridine complex.
4
1
O
Alternative α-fluoroamine reagents (Ishikawa’s and Petrov’s
reagent, TFFH) were employed in few cases. Other
deoxyfluorination protocols rely on the use of sulfur-based
reagents such as DAST, Deoxo-Fluor, XtalFluor-E, etc.
(Scheme 2). However, application of many of these reagents
8
fluorine through synthetic protocols that enjoy practicality,
operational simplicity, wide functional group compatibility and
ease of access of reagents, is a highly desirable goal. Acyl
fluorides are versatile intermediates in organic synthesis, owing
to their superior stability and distinct reactivity, when
compared to other acyl halides. In this context, acyl fluorides
have been successfully employed in many challenging
9
10
11
Scheme 2. Prior Art for Acyl Fluoride Synthesis and Current
Work
2
amidation and esterification reactions (i.e., with electron-
deficient or sterically encumbered nucleophiles), and they are
ideal intermediates for both solution- and solid-phase peptide
3
synthesis. Furthermore, acyl fluorides stand as convenient
precursors of anhydrous fluoride ion and have been employed
4
in S Ar fluorination chemistry with great success. On the
N
other hand, transition-metal-catalyzed, nondecarbonylative,
and decarbonylative transformations of acyl fluorides have
5
also been developed. In this fashion, their utilization as
5
a−c
5d,e
electrophiles has enabled access to ketones,
aldehydes,
5
d
5f
hydrocarbons, trifluoromethylarenes, and more recently,
5
g
biaryls (Scheme 1 paths A−F).
The known approaches for the preparation of acyl fluorides
directly from carboxylic acids date back to the pioneering work
Scheme 1. Synthetic Utility of Acyl Fluorides
remains limited due to toxicity, environmental pollution,
thermal instability, and/or drastic reaction conditions. Olah’s
12
reagent (HF−pyridine) in combination with DCC has also
been used with low functional group compatibility.
A sulfur(VI) fluoride exchange (SuFEx) reaction employing
benzene-1,3-disulfonyl fluoride was disclosed as part of an
13
amidation protocol. Very recently, Schoenebeck and co-
14
workers delineated a protocol employing Me NSCF as an
4
3
Received: January 16, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00197
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
alternative sulfur-based reagent. However, this reagent is not
commercially available and must be prepared from S8,
TMSCF , and expensive anhydrous Me NF. Considering that
Table 1. Optimization of the Reaction Conditions
3
4
acyl fluorides are inexpensive sources of anhydrous fluoride,
4
including expensive Me NF (Scheme 1, path c), utilization of
4
Me NF-derived Me NSCF in the synthesis of RCOF
4
4
3
b
PPh
NBS
fluoride
yield
(%)
3
derivatives requires further justification. Thus, practical, safe,
and operationally simple methods that enable access to a wide
variety of acyl fluorides are still sought. Due to our long-
entry
solvent
(equiv)
(equiv)
(equiv)
1
2
3
4
5
6
7
DCM
DCM
DCM
DCM
DCM
DCM
DCM
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
3
3
3
2
2
2
2
2
2
2
2
2
2
3
3
3
Et N-3HF (6)
99
27
99
99
0
3
15
Me NF (3)
4
standing interest in organofluorine chemistry, we set out to
develop a convenient and inexpensive protocol for direct
deoxyfluorination of carboxylic acids. Herein, we report a
method that employs readily available commodity chemicals
and offers practical utility and operational simplicity to provide
the corresponding acyl fluorides.
Et N-3HF (3)
Et N-3HF (2)
KF (2)
CsF (2)
3
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
3
0
0
KHF (2)
2
c
1
6
8
KF (2)
CsF (2)
28
0
trace
47
60
98
Recognizing the rich chemistry of phosphorus reagents1
7
9
10
1
1
1
and (acyl)oxyphosphonium ions I in peptide coupling,
c
1
8
19
KHF
2
(2)
Mitsunobu, and Appel reactions, we surmised that such
intermediates could be easily transformed into acyl fluorides
under suitable conditions. To the best of our knowledge, such
a transformation (Scheme 3, eq 1) and the related Appel-type
c
,
d
d
1
2
3
KF (2)
c
,
KHF (2)
2
,
de
KHF (2)
2
a
To a suspension of benzoic acid 1a (0.25 mmol, 1 equiv) and PPh3
in DCM was added solid N-bromosuccinimide (NBS) at 0 °C. After
Scheme 3. Working Hypothesis and Related
Transformations
the mixture was stirred for 15 min at room temperature, fluoride
b
source was added and stirring was continued for 2 h. As determined
1
9
c
d
by F NMR spectroscopy; Reaction time: 17 h; Trifluoroacetic
e
acid (TFA, 2 equiv) was added along with fluoride; Reaction time:
24 h. See the Supporting Information for full details.
quantitative yield (Table 1, entry 13). However, due to its fast
reaction rate and ease of addition, Et N−3HF was used in
3
20c
subsequent studies.
In the optimal protocol, NBS (2.1 equiv) is added to a
fluorination using halophosphonium ions (Scheme 3, eq 2) has
not been reported thus far. This is probably due to the
preferred formation of the strong P−F bond, in contrast to
other P−X bonds (X = Cl, Br, I).
suspension of carboxylic acid 1 and PPh (2 equiv) in DCM at
3
0 °C under air. After the activation step is complete (15 min),
20b
Et N−3HF is added. In this manner, the corresponding acyl
3
fluorides are formed in nearly quantitative yields within a few
hours, and in most cases, they are conveniently isolated
without relying on column chromatography by simply passing
through a short plug of SiO2.
Our experience in superacid-catalyzed transformations and
20a
superelectrophilic activation
led us to hypothesize that
under Brønsted acidic conditions, intermediate I could be
further protonated to enable the desired C−F bond formation.
To interrogate this hypothesis, benzoic acid 1a was selected as
a model substrate, and a variety of fluoride sources in
Application of this system to the deoxyfluorination of
various carboxylic acids illustrates its synthetic scope (Scheme
4). Benzoic acids bearing electron-neutral, electron-donating
combination with PPh /NBS were screened for a direct
deoxyfluorination reaction (Table 1).
(−OMe, −Et, −NMe ), as well as electron-withdrawing
3
2
functionalities (−I, −Br, −F, −Ac) are converted to the
corresponding acyl fluorides in good to excellent yields (2a−i).
The present protocol is compatible with unsaturated
functionalities, as evidenced by the successful preparation of
vinyl substituted acyl fluoride 2d, and cinnamoyl fluorides
After activation of 1a by NBS/PPh (3 equiv each) in DCM
3
and using an excess of Et N−3HF, the desired product,
3
benzoyl fluoride 2a, was obtained in almost quantitative yield
after 2 h (Table 1, entry 1). Utilization of basic Me NF (3
4
21d
equiv) afforded 2a in only 27% yield while generating large
(2n,o).
In these cases, no HF addition across the double
1
9
amounts of Ph PF ( F NMR = δ −39.5), thus corroborating
bond was observed. Halo-substituted benzoic acids (−Br and
3
2
our initial hypothesis (Table 1, entry 2). Subsequent attempts
−F) afford the corresponding products in good yields (2g and
2
1c
have shown that by using a 2:2.1:2 molar ratio of PPh /NBS/
2i, respectively).
Substitution at the ortho-position of
3
Et N−3HF, 2a could be formed in close to quantitative yield.
benzoic acid 1f is tolerated, providing the corresponding
product 2f in 83% yield.
3
Use of other fluoride sources such as KF, CsF, and KHF in
2
DCM was unsuccessful, probably due to solubility issues
Another attractive feature of this method is its scalability:
(
Table 1, entries 5−7). Using MeCN as solvent led only to
preparation of 4-methoxybenzoyl fluoride 2c, a reagent
4
marginal improvements, and large amounts of Ph PF were
employed as anhydrous fluoride source for S Ar fluorinations,
3
2
N
detected in these cases also (Table 1, entries 8−10). As
was performed on a 10 mmol scale and obtained in 70% yield
21a
expected, it was found that, under acidic conditions (TFA, 2
after SiO filtration of the reaction mixture. Thus, Et N−
2
3
equiv), KF and KHF could afford the desired product while
3HF, an acidic and atom-economic fluoride source, could be
efficiently utilized for the preparation of an anhydrous fluoride
surrogate.
2
completely inhibiting the formation of Ph PF (Table 1, entries
3
2
1
1−13). In this fashion, after 24 h, KHF also provided 2a in
2
B
DOI: 10.1021/acs.orglett.9b00197
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 4. Direct Deoxyfluorination of Carboxylic Acids
Heteroaromatic substrates such as picolinic, nicotinic, and
isonicotinic acids were all successfully employed in a tandem
deoxyfluorination/amidation sequence using sterically de-
manding 1-adamantanamine (Ad-NH ) (Scheme 5). All
2
Scheme 5. Tandem Deoxyfluorination/Amidation
Sequence*
*
a
Isolated yields shown; average of two runs. Yield of acyl fluoride
1
9
3a′−c′ as determined by F NMR. See the Supporting Information
for full details.
three isomers underwent the desired transformation, affording
the corresponding pyridine carboxamides (3a−c) in up to 91%
yield, after adding a mixture of Ad-NH and Et N to the
2
3
2
1a
formed acyl fluorides (3a′−c′). This procedure eliminates
the need for isolation of the acyl fluorides and represents a
22
significant advantage over previous synthetic routes. More-
1
7c
over, by employing optimal conditions
for amidation via
acyloxyphosphonium intermediates, 3a was obtained in only
21a
2
6% yield, demonstrating the utility of this tandem one-pot
a
Method A conditions: 1 (0.5 mmol, 1 equiv), PPh (2 equiv), DCM
deoxyfluorination/amidation protocol using sterically encum-
bered amines.
3
(
5 mL), N-bromosuccinimide (NBS, 2.1 equiv), 0 °C to rt,15 min.
b
Then Et N−3HF (2 equiv) rt, 2 h. Method B conditions: using
polymer-bound phosphine reagent in place of PPh . Isolated yields,
To gain a mechanistic understanding of this transformation,
3
3
1
19
3
a series of P and F NMR studies were conducted. Addition
1
9
average of two runs. Yields in parentheses determined by F NMR
spectroscopy, using internal standard. See the Supporting Information
for full experimental details.
of NBS to a solution of PPh in DCM at 0 °C, led to the
3
31
formation of a species with P signal at δ 31.5, assigned to
bromophosphonium ion A. When NBS was added to a mixture
of PPh and 1a, a new signal corresponding to acyloxyphos-
3
phonium ion I appeared at δ 45.2. These species quickly
Next, aliphatic carboxylic acids were tested. In this case,
phenylacetic acid, phenylbutyric acid, and 1-adamantanecar-
boxylic acid were all amenable to the reaction conditions,
affording the corresponding products in good isolated yields
disappeared upon adding Et N−3HF, and appearance of 2a (δ
3
1
7.4) along with small amount of Ph PF (δ −39.3 t, J = 659.6
3
2
19
Hz) was observed in the F NMR spectrum. Furthermore,
independently prepared Ph PF was found to be a chemically
3
2
(
2j−l). Notably, the present protocol exhibited excellent
incompetent species to promote the transformation under the
2
1a,e
chemoselectivity toward −COOH moiety, as demonstrated by
the preparation of 4-hydroxybenzoyl fluoride 2p in 50%
isolated yield.
reaction conditions (DCM, rt).
These observations are in
17
full agreement with previous literature reports. On the basis
of these observations, the following mechanistic pathway is
proposed (Scheme 6).
To further illustrate the synthetic scope of this method, a
series of active pharmaceutical ingredients (APIs) bearing the
−
COOH functionality was subjected to the reaction
Scheme 6. Mechanistic Hypothesis
conditions. Gratifyingly, complex structures bearing double
bonds, sulfonamide, indole, keto, nitrile, and thiazole
functionalities all afforded the corresponding acyl fluoride
analogues in high isolated yields (Scheme 4, bottom section).
In pursuit of easier purification of products, we substituted
PPh3 with the commercially available, polymer-bound
phosphine reagent. The acyl fluoride 2h was obtained in
comparable yield (95% by 19F NMR, 72% isolated yield),
following purification much easier than before. Similarly,
amino acid fluoride bearing the acid-stable Fmoc- protecting
group Fmoc-Phe-F 2q was prepared in 50% isolated yield
Oxidation of PPh by NBS generates a bromophosphonium
3
ion A, which reacts with RCOOH derivatives 1, affording
acyloxyphosphonium intermediate I. Under acidic conditions,
I could be protonated, followed by fluoride attack at the C−
1
9
(
97% by F NMR). As mentioned above, purification of
products is easily achieved by simply filtering off the resin,
21a,b
followed by a simple workup procedure
method B).
(Scheme 4,
acyl moiety, giving rise to RCOF products and Ph PO. In the
3
case of basic fluoride sources, generation of RCOF is minor
C
DOI: 10.1021/acs.orglett.9b00197
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
and fluoride attack at the P-center of I, affording Ph PF , seems
to be the dominant pathway.
In conclusion, a practical and convenient protocol for a
direct deoxyfluorination of carboxylic acids, using a phospho-
M.; Ritter, T. Nature 2016, 534, 369. (d) Schimler, S. D.; Cismesia,
M. A.; Hanley, P. S.; Froese, R. D. J.; Jansma, M. J.; Bland, D. C.;
Sanford, M. S. J. Am. Chem. Soc. 2017, 139, 1452.
3
2
(
5) (a) Zhang, Y.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 15964.
b) Ogiwara, Y.; Maegawa, Y.; Sakino, D.; Sakai, N. Chem. Lett. 2016,
5, 790. (c) Ogiwara, Y.; Sakino, D.; Sakurai, Y.; Sakai, N. Eur. J. Org.
(
4
rus-based reagent system, in combination with Et N−3HF as
3
fluoride ion source was developed. This protocol employs
inexpensive commodity chemicals and enables facile access to
a wide array of substituted acyl fluorides possessing various
functional groups. The greater significance of this method is
further emphasized by its scalability (demonstrated by the fast
and successful preparation of 2c, a common source of
anhydrous fluoride) and applicability to a tandem deoxyfluori-
nation/amidation sequence. Utilization of this protocol for the
deoxyfluorination of several active pharmaceutical ingredients
bearing −COOH as substrates was also successfully estab-
lished. Application of this approach to deoxyfluorination of
alcohols will be reported elsewhere.
Chem. 2017, 2017, 4324. (d) Ogiwara, Y.; Sakurai, Y.; Hattori, H.;
Sakai, N. Org. Lett. 2018, 20, 4204. (e) Braden, R.; Himmler, T. J.
Organomet. Chem. 1989, 367, C12. (f) Keaveney, S. T.; Schoenebeck,
F. Angew. Chem., Int. Ed. 2018, 57, 4073. (g) Malapit, C. A.; Bour, J.
R.; Brigham, C. E.; Sanford, M. S. Nature 2018, 563, 100.
(6) Olah, G. A.; Nojima, M.; Kerekes, I. Synthesis 1973, 1973, 487.
(7) Olah, G. A.; Nojima, M.; Kerekes, I. J. Am. Chem. Soc. 1974, 96,
9
(
7
25.
8) (a) Wong, C. G.; Rando, R. R. J. Am. Chem. Soc. 1982, 104,
374. (b) Petrov, V. A.; Swearingen, S.; Hong, W.; Petersen, W. C. J.
Fluorine Chem. 2001, 109, 25. (c) Carpino, L. A.; El-Faham, A. J. Am.
Chem. Soc. 1995, 117, 5401.
(9) (a) Middleton, W. J. J. Org. Chem. 1975, 40, 574. (b) Kaduk, C.;
Wenschuh, H.; Beyermann, M.; Forner, K.; Carpino, L. A.; Bienert,
M. Lett. Pept. Sci. 1996, 2, 285.
ASSOCIATED CONTENT
■
*
S
Supporting Information
(10) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H.
J. Org. Chem. 1999, 64, 7048.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00197.
(
11) (a) Beaulieu, F.; Beauregard, L.-P.; Courchesne, G.; Couturier,
M.; LaFlamme, F.; L’Heureux, A. Org. Lett. 2009, 11, 5050.
b) L’Heureux, A.; Beaulieu, F.; Bennett, C.; Bill, D. R.; Clayton,
(
Experimental procedures as well as NMR spectra and
characterization data (PDF)
S.; LaFlamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.;
Couturier, M. J. Org. Chem. 2010, 75, 3401.
(12) Chen, C.; Chien, C. T.; Su, C. H. J. Fluorine Chem. 2002, 115,
7
5.
AUTHOR INFORMATION
■
(13) Smedley, C. J.; Barrow, A. S.; Spiteri, C.; Giel, M.-C.; Sharma,
Corresponding Author
P.; Moses, J. E. Chem. - Eur. J. 2017, 23, 9990.
(14) Scattolin, T.; Deckers, K.; Schoenebeck, F. Org. Lett. 2017, 19,
*E-mail: gprakash@usc.edu.
5
740.
ORCID
(15) (a) Prakash, G. K. S.; Papp, A.; Munoz, S. B.; May, N.; Jones, J.-
P.; Haiges, R.; Esteves, P. M.; Mathew, T. Chem. - Eur. J. 2015, 21,
Thomas Mathew: 0000-0002-2896-1917
G. K. Surya Prakash: 0000-0002-6350-8325
Author Contributions
†S.B.M., H.D., and X.I.-R. contributed equally to this work.
10170. (b) Munoz, S. B.; Aloia, A. N.; Moore, A. K.; Papp, A.;
Mathew, T.; Fustero, S.; Olah, G. A.; Surya Prakash, G. K. Org.
Biomol. Chem. 2016, 14, 85. (c) Prakash, G. K. S.; Zhang, Z.; Wang,
F.; Munoz, S.; Olah, G. A. J. Org. Chem. 2013, 78, 3300. (d) Prakash,
G. K. S.; Munoz, S. B.; Papp, A.; Mathew, T.; Olah, G. A. Asian J. Org.
Chem. 2012, 1, 146. (e) Munoz, S. B.; Ni, C.; Zhang, Z.; Wang, F.;
Shao, N.; Mathew, T.; Olah, G. A.; Prakash, G. K. S. Eur. J. Org. Chem.
Notes
The authors declare no competing financial interest.
2
017, 2017, 2322. (f) Munoz, S. B.; Krishnamurti, V.; Barrio, P.;
Mathew, T.; Prakash, G. K. S. Org. Lett. 2018, 20, 1042.
g) Krishnamurti, V.; Munoz, S. B.; Ispizua-Rodriguez, X.;
Vickerman, J.; Mathew, T.; Prakash, G. K. S. Chem. Commun. 2018,
4, 10574.
16) (a) Cadogan, J. Organophosphorus Reagents in Organic Synthesis;
ACKNOWLEDGMENTS
Financial support by the Loker Hydrocarbon Research
Institute is gratefully acknowledged.
■
(
5
(
REFERENCES
Academic Press: London, 1979. (b) Allen, D. W. Organophosphorus
Chemistry 2011, 40, 1.
■
(
1) (a) Hiyama, T. In Organofluorine Compounds: Chemistry and
Applications; Springer-Verlag: Berlin, 2000. (b) Beg
́
ue,
́
J.-P.; Bonnet-
(17) (a) El-Faham, A.; Albericio, F. Chem. Rev. 2011, 111, 6557.
Delpon, D. In Bioorganic and Medicinal Chemistry of Fluorine; Wiley-
VCH: Weinheim, 2008. (c) Catalan, S.; Munoz, S. B.; Fustero, S.
Chimia 2014, 68, 382.
2) (a) Schindler, C. S.; Forster, P. M.; Carreira, E. M. Org. Lett.
010, 12, 4102. (b) Due-Hansen, M. E.; Pandey, S. K.; Christiansen,
E.; Andersen, R.; Hansen, S. V. F.; Ulven, T. Org. Biomol. Chem. 2016,
4, 430.
3) (a) Carpino, L. A.; Sadat-Aalaee, D.; Chao, H. G.; DeSelms, R.
(b) Barstow, L. E.; Hruby, V. J. J. Org. Chem. 1971, 36, 1305.
(c) Froyen, P. Synth. Commun. 1995, 25, 959. (d) Froyen, P.
Tetrahedron Lett. 1997, 38, 5359. (e) Ramaiah, M. J. Org. Chem. 1985,
50, 4991. (f) Froyen, P. Phosphorus, Sulfur Silicon Relat. Elem. 1994,
91, 145. (g) Froyen, P. Phosphorus, Sulfur Silicon Relat. Elem. 1994, 89,
̃
57. (h) Cuevas-Yanez, E.; García, M. A.; de la Mora, M. A.;
Muchowski, J. M.; Cruz-Almanza, R. Tetrahedron Lett. 2003, 44, 4815.
(i) Castro, B. R. Org. React. 1983, 29, 1.
́
(
2
1
(
H. J. Am. Chem. Soc. 1990, 112, 9651. (b) Carpino, L. A.; Beyermann,
M.; Wenschuh, H.; Bienert, M. Acc. Chem. Res. 1996, 29, 268.
(18) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40,
2380. (b) Mitsunobu, O. Synthesis 1981, 1981, 1.
(
c) Prabhu, G.; Narendra, N.; Basavaprabhu, V.; Panduranga, V.;
(19) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801.
(20) (a) Olah, G. A.; Prakash, G. K. S.; Molnar, A.; Sommer, J.
Superacid Chemistry, 2nd ed.; Wiley, 2009. (b) If all reagents are
Sureshbabu, V. V. RSC Adv. 2015, 5, 48331 and references cited
therein .
(4) (a) Ryan, S. J.; Schimler, S. D.; Bland, D. C.; Sanford, M. S. Org.
present at the onset, formation of Ph PF takes place and no desired
3 2
Lett. 2015, 17, 1866. (b) Cismesia, M. A.; Ryan, S. J.; Bland, D. C.;
Sanford, M. S. J. Org. Chem. 2017, 82, 5020. For related work on
deoxyfluorination of phenols, see: (c) Neumann, C. N.; Hooker, J.
product is observed. (c) Use of lesser amounts of PPh /NBS/Et N−
3
3
3HF also affords the expected products, albeit in longer reaction times
(>20 h).
D
DOI: 10.1021/acs.orglett.9b00197
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
21) (a) See the Supporting Information for full details.
b) Polymer-bound phosphine was used only for easy purification;
in all these cases, PPh3 also affords the corresponding products.
c) Compound 2i exhibits instability toward silica gel, preventing its
(
(
isolation. (d) Isolated yields of these products were low due to their
high volatility. (e) For deoxyfluorination of alcohols using Ph PF
3
2
under drastic conditions, see: Kobayashi, Y.; Akashi, C. Chem. Pharm.
Bull. 1968, 16, 1009.
(22) (a) Danilenko, G. I.; Mokhort, N. A.; Trinus, F. P. Pharm.
Chem. J. 1976, 10, 1036. (b) Morimoto, H.; Fujiwara, R.; Shimizu, Y.;
Morisaki, K.; Ohshima, T. Org. Lett. 2014, 16, 2018.
E
DOI: 10.1021/acs.orglett.9b00197
Org. Lett. XXXX, XXX, XXX−XXX