Palladium-catalyzed allylic fluorination of cinnamyl phosphorothioate esters

Article abstract of DOI:10.1021/ol302263m

A highly regioselective, Pd-catalyzed allylic fluorination of phosphorothioate esters is reported. This chemistry addresses several limitations of previously reported methods in which elimination and lack of reactivity were problematic. Preliminary mechanistic investigations reveal that these reactions are stereospecific and provide fluorinated products with net retention of stereochemical configuration. In analogy to other Pd-catalyzed allylic substitution reactions, this process likely proceeds through a palladium π-allyl intermediate.

Full text of DOI:10.1021/ol302263m

ORGANIC
LETTERS
2012
Vol. 14, No. 19
5138–5141
Palladium-Catalyzed Allylic Fluorination
of Cinnamyl Phosphorothioate Esters
Andrew M. Lauer and Jimmy Wu*
Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755,
United States
jimmy.wu@dartmouth.edu
Received September 4, 2012
ABSTRACT
A highly regioselective, Pd-catalyzed allylic fluorination of phosphorothioate esters is reported. This chemistry addresses several limitations of
previously reported methods in which elimination and lack of reactivity were problematic. Preliminary mechanistic investigations reveal that these
reactions are stereospecific and provide fluorinated products with net retention of stereochemical configuration. In analogy to other Pd-catalyzed
allylic substitution reactions, this process likely proceeds through a palladium π-allyl intermediate.
Fluorinated compounds are extremely important in
medicinal chemistry.1 For instance, fluorination of
some drugs can impart substantially improved meta-
bolic stability. These therapeutics often exhibit unique
pharmacokinetic properties. Fluorine also plays a
prominent role in medical imaging technologies. For
instance, 18F is the preferred nucleus in positron
emission tomography (PET).2 Because the half-life of
18F is about 110 min, its rapid incorporation into PET
tracers is critical.
carbon centers.4,5 Catalytic nucleophilic fluorinations at the
sp3 centers are quite rare.6 Furthermore, there have been
only a handful of publications describing the transition
metal-catalyzed nucleophilic fluorination of allylic sub-
strates.7 These are summarized in eqs 1À4.
Notwithstanding the importance of fluorine in medi-
cine, the synthesis of CÀF bonds remains an under-
developed area. Noncatalyzed fluorination reactions
have been known for a long time.3 In contrast, only
recently has there been significant progress in the develop-
ment of methods for the transition metal-catalyzed con-
struction of CÀF bonds at either sp2- or sp3-hybridized
€
(1) (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (b)
Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev.
2008, 37, 320. (c) Qui, X.-L.; Xu, X.-H.; Qing, F.-L. Tetrahedron 2010,
66, 789. (d) Kirk, K. L. Org. Process. Res. Dev. 2008, 12, 305.
(2) (a) Miller, P. W.; Long, N. J.; Vilar, R.; Gee, A. D. Angew. Chem.,
Int. Ed. 2008, 47, 8998. (b) Ametamey, S. M.; Honer, M.; Schubiger,
P. A. Chem. Rev. 2008, 108, 1501. (c) Adam, M. J.; Wilbur, D. S. Chem.
Soc. Rev. 2005, 34, 153.
(3) For leading references, see: (a) Yin, J.; Zarkowsky, D. S.;
Thomas, D. W.; Zhao, M. M.; Huffman, M. A. Org. Lett. 2004, 6,
1465. (b) Middleton, W. J. J. Org. Chem. 1975, 40, 574.
(4) For reviews of catalytic fluorination reactions, see: (a) Furuya, T.;
Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470. (b) Lectard, S.;
Hamashima, Y.; Sodeoka, M. Adv. Synth. Catal. 2010, 352, 2708.
In 2010, Doyle and co-workers reported the Pd-
catalyzed dynamic kinetic asymmetric transformation
(DYKAT) of racemic cyclic allylic chlorides (eq 1).8 Soon
r
10.1021/ol302263m
Published on Web 09/21/2012
2012 American Chemical Society

afterward, they described the conversion of acyclic chlo-
rides to enantioenriched branched allylic fluorides (eq 2).9
Nguyen and co-workers discovered that Ir(I) complexes
can catalyze the conversion of trichloroacetimidates to
similar fluorinated products (eq 3).10 Finally, Brown and
Gouverneur reported the Pd-catalyzed fluorination of
primary allylic p-nitrobenzoates (eq 4).11
leaving group are present. This chemistry is complemen-
tary to known methods in that it provides access to
fluorinated compounds previously unattainable by other
transition metal-catalyzed processes.
Despite these elegant advances in the transition metal-
catalyzed construction of CÀF bonds at sp3 centers,
numerous challenges remain. One notable limitation is
that the attempted fluorination of 11 furnished the desired
product in only 5% yield (Scheme 1, eq 5).11 The forma-
tion of diene byproduct is evidently quite problematic
for substrates in which β hydrogens are present. Also, fluo-
rination of 12 was not possible (Scheme 1, eq 5). In fact, a
study by Hintermann and co-workers regarding the Pd-
catalyzed fluorination of related substrate 15 resulted in
none of the expected fluorinated product (Scheme 1, eq 6).12
Referring to 15, Hintermann suggested that under their
reaction conditions, “straightforward allylic fluorination in
a catalytic manner is thus not feasible.”12
Recently, our group has been exploring the chemistry of
phosphorothioate esters.13 We have demonstrated that
their use can afford complementary selectivity as compared
to the utilization of more conventional electrophiles. Because
of our ongoing interest in this rather unusual functional
group, we began our investigation with 16a (Table 1).
Several palladium complexes furnished diene 3 as the
major product (Table 1, entries 1À3). However, the use of
Pd(PPh3)4 as the Pd(0) catalyst led to increased reactivity
and a 60% isolated yield of the desired allylic fluoride 17a
with only 24% of the elimination product (entry 4). We
couldfurtherimproveupontheyieldof17a by employing 8
mol % Pd(dba)2 in conjunction with PPh3 as the ligand
(entry 6). Bidentate phosphine ligands were also investi-
gated; however, poor reactivity was observed (entries 3, 7,
and 8). Of several fluoride sources surveyed, only AgF was
effective in promoting the desired reaction (entries 9À12).
As expected, a control experiment in which the palladium
catalyst was omitted resulted in no reaction (entry 13).
Notably, the application of the optimized conditions
(entry 6) to two of the compounds reported by Brown and
Gouverneur resulted in 1) mostly elimination (only ∼10%
fluorinated product) for 11 and 2) no reaction in the case of
12. These data support the notion that the phosphoro-
thioate ester functional group is critical for successful fluo-
rination of these types of substrates.
Scheme 1. Limitations of Prior Art
Herein, we report the successful Pd-catalyzed fluorina-
tion of secondary allylic phosphorothioate esters 16 (eq 7).
In all but two of these substrates, β hydrogens to the
There are also practical advantages of using phosphor-
othioate esters over the corresponding allylic halides. For
instance, secondary allylic halides (and phosphates), espe-
cially those which can form stabilized carbocations after
ionization, are often thermally unstable and incompati-
ble with silica gel chromatography.14 In contrast, the
corresponding allylic phosphorothioate esters are stable to
moisture, air, and chromatography. They can be stored for
extended periods of time at room temperature without any
noticeable decomposition.
(5) For leading references, see: (a) Watson, D. A.; Su, M.; Teverovskiy,
G.; Zhang, Y.; Garcıa-Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science
´
€
2009, 325, 1661. (b) Noel, T.; Maimone, T. J.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2011, 50, 8900. (c) Hull, K. L.; Anani, W. Q.; Sanford,
M. S. J. Am. Chem. Soc. 2006, 128, 7134. (d) Racowski, J. M.; Gary,
J. B.; Sanford, M. S. Angew. Chem., Int. Ed. 2012, 51, 3414. (e) Wang, X.;
Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 7520. (f) Chan,
K. S. L.; Wasa, M.; Wang, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2011, 50,
9081. (g) Tang, P.; Furuya, T.; Ritter, T. J. Am. Chem. Soc. 2010, 132,
12150. (h) Furuya, T.; Kaiser, H. M.; Ritter, T. Angew. Chem., Int. Ed.
2008, 47, 5993. (i) Furuya, T.; Strom, A. E.; Ritter, T. J. Am. Chem. Soc.
2009, 131, 1662. (j) Furuya, T.; Ritter, T. J. Am. Chem. Soc. 2008, 130,
10060. (k) Yandulov, D. V.; Tran, N. T. J. Am. Chem. Soc. 2007, 129,
1342. (l) Grushin, V. V. Chem.;Eur. J. 2002, 8, 1006. (m) Wu, T.; Yin,
G.; Liu, G. J. Am. Chem. Soc. 2009, 131, 16354. (n) Qiu, S.; Xu, T.; Zhou,
J.; Guo, Y.; Liu, G. J. Am. Chem. Soc. 2010, 132, 2856. (o) Xu, T.; Mu,
X.; Peng, H.; Liu, G. Angew. Chem., Int. Ed. 2011, 51, 8176.
(6) (a) Kalow, J. A.; Doyle, A. G. J. Am. Chem. Soc. 2010, 132, 3268.
(b) Haufe, G.; Bruns, S. Adv. Synth. Catal. 2002, 344, 165. (c) Bruns, S.;
Haufe, G. J. Fluorine. Chem. 2000, 104, 247.
With optimized reaction conditions in hand, we pro-
ceeded to explore its scope with several phosphorothioate
(11) Hollingworth, C.; Hazari, A.; Hopkinson, M. N.; Tredwell, M.;
Benedetto, E.; Huiban, M.; Gee, A. D.; Brown, J. M.; Gouverneur, V.
Angew. Chem., Int. Ed. 2011, 50, 2613.
€
(12) Hintermann, L.; Lang, F.; Maire, P.; Togni, A. Eur. J. Inorg.
Chem. 2006, 1397.
(13) (a) Lauer, A. M.; Mahmud, F.; Wu, J. J. Am. Chem. Soc. 2011,
133, 9119. (b) Han, X.; Zhang, Y.; Wu, J. J. Am. Chem. Soc. 2010, 132,
4104. (c) Robertson, F. J.; Wu, J. J. Am. Chem. Soc. 2012, 134, 2775. (d)
Robertson, F. J.; Wu, J. Org. Lett. 2010, 12, 2668. (e) Han, X.; Wu, J.
Org. Lett. 2010, 12, 5780.
(14) (a) Dieter, R. K.; Gore, V. K.; Chen, N. Org. Lett. 2004, 6, 763.
(b) Yasui, K.; Fugami, K.; Tanaka, S.; Tamaru, Y. J. Org. Chem. 1995,
60, 1365. (c) Carrillo-Marquez, T.; Caggiano, L.; Jackson, R. F. W.;
Grabowska, U.; Rae, A.; Tozer, M. J. Org. Biolmol. Chem 2005, 3, 4117.
(7) For a review of noncatalyzed methods for preparing allylic and
propargylic fluorides, see: Pacheco, M. C.; Purser, S.; Gouverneur, V.
Chem. Rev. 2008, 108, 1943.
(8) Katcher, M. H.; Doyle, A. G. J. Am. Chem. Soc. 2010, 132, 17402.
(9) Katcher, M. H.; Sha, A.; Doyle, A. B. J. Am. Chem. Soc. 2011,
133, 15902.
(10) Topczewski, J. J.; Tewson, T. J.; Nguyen, H. M. J. Am. Chem.
Soc. 2011, 133, 19318.
Org. Lett., Vol. 14, No. 19, 2012
5139

Table 1. Reaction Optimization Studies
Table 2. Scope of Allylic Fluorination
a As determined by 1H NMR spectroscopy. b Isolated yield. Purified
product was contaminated with diene as they coelute on silica gel
chromatography. Reported yield is of 17a only and was calculated on
the basis of the ratio of 17a versus 18a, as determined by 1H NMR
spectroscopy. c Used 16 mol % of ligand.
esters (Table 2). For most substrates, optimal yields were
obtained using 8 mol % of Pd(dba)2; however, compounds
17a and 17g were isolated in good yield with only 2 mol %
of catalyst (entry 1 and 7). In all cases, fluorination
was accompanied by dienes 18aÀm as minor products.
Sterically hindered phosphorothioate esters also gave
good yields for the desired allylic fluoride (entries 3
and 4). In addition, excellent regioselectivity was ob-
served for all cases with the exception of the tert-
butyl substrate (entry 4). Fluorination was amenable to
electron-withdrawing and electron-donating substituents
(entries 7, 8, 10, 11, and 13). The reaction was also
compatible with various functional groups. These include
esters, ethers, and thiophene (entries 8À11). Notably, a
TIPS (triisopropylsilyl) ether remained intact during the
reaction (entry 12), further highlighting the mildness
of this method. This methodology is most suited to
cinnamyl-derivedphosphorothioate esters since we believe
that the aromatic group is instrumental in dictating the
formation of the observed regioisomer of the product.
It should be noted that in their neat forms, many allylic
fluorides, especially those possessing γ substituents that
can stabilize carbocations, are sensitive to acid and in some
cases even to borosilicate glass.15 It is therefore possible
that some of the yields in Table 2 may be diminished as a
result of the isolation process.
a As determined by 1H NMR spectroscopy of unpurified reaction
mixture, b Due to volatility and instability of the product, the yield was
determined via 1H NMR spectroscopy of the crude reaction mixture
using 1,2-dimothoxypropane as an internal standard. c 2 mol % of
Pd(dba)2 and 6 mol % of PPh3 d Isolated as a 1:1 mixture of regiosomers.
e Purified products were contaminated with varying amounts of diene
(coelutes with product). Reported yields are of the fluorinated products
and were calculated based on the ratio of product vs diene, as determined
by 1H NMR spectroscopy.
Several experiments were performed to gain some
mechanistic insight. First we subjected a 2:1 mixture of
phosphorothioate esters 19 and 20 to the optimized
conditions (eq 8). This reaction provided allylic fluo-
ride 17a as the exclusive regioisomer. The formation of
only 17a suggests a mechanism wherein a Pd π-allyl
complex undergoes rapid πÀσÀπ isomerization. This is
(15) Lee, E.; Yandulov, D. V. J. Fluorine Chem. 2009, 130, 474.
(16) Obtained via preparatory SFC separation using a Chiralcel
AD-H column (performed by Lotus Separations, Princeton, NJ).
5140
Org. Lett., Vol. 14, No. 19, 2012

consistent with other Pd-catalyzed mechanisms for
allylic substitution.
configuration. This is opposite to the predictive model
invoked by Trost and co-workers for hard and/or unstabi-
lized nucleophiles.17 It is unclear how or why fluoride, which
is widely regarded as a hard nucleophile,18 would exhibit this
mode of reactivity. However, these results are consistent with
what Doyle and co-workers observed in their studies of the
enantioselective fluorination of allylic chlorides.8
Preliminary data suggest that silver coordination may
play an important role in these reactions. While AgF
itself is sparingly soluble in THF, the addition of
phosphorothioate ester 16a promotes a noticeable in-
crease in solubility of the silver salt. Furthermore, the
19F and 31P NMR spectra of a mixture of 16a and AgF
indicate the presence of a new species. The addition of
PPh3 to AgF had no visible effect on solubility or the
19F and 31P NMR spectra. We believe this NMR data is
suggestive of some type of coordination between AgF
and 16a. This interaction may facilitate the requisite
ionization of the phosphorothioate ester.
Using enantiopure phosphorothioate (S)-16 (>99%
ee),16 compound (S)-17a was generated in only 60% ee
(Table 3, entry 1). However, at partial conversion, the
enantioenrichment of 17a was substantially improved
(92% ee, entry 2). Longer reaction times did not further
diminish its enantioenrichment or have an appreciable
effect on yield (entry 3).
Table 3. Stereospecific Allylic Fluorinations
In summary, we have reported a highly regioselective
Pd-catalyzed allylic fluorination of phosphorothioate es-
ters. This chemistry addresses several limitations of pre-
viously reported methods in which diene formation and
lack of reactivity were problematic. The mildness of the
reaction conditions are demonstrated by its functional
group tolerance.
Acknowledgment. J.W. acknowledges financial support
provided by Dartmouth College and an NSF CAREER
Award (CHE-1052824).
a As determined by HPLC analysis with a Chiralcel OD-H column.
b Isolated yields. c Reaction halted at partial conversion of (S)-16a. d Not
determined.
Supporting Information Available. Experimental pro-
cedures and spectra for all previously unreported com-
pounds.This material is available free of charge via the
Internet at http://pubs.acs.org.
The fluorination products for all three entries in Table 3
were produced with net retention of stereochemical
(17) (a) Trost, B. M.; Machacek, M. R.; Aponick, A. Acc. Chem. Res.
2006, 39, 747. (b) Trost, B. M.; Zhang, T.; Sieber, J. D. Chem. Sci. 2010,
1, 427. (c) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. (d)
Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258.
(18) Parr, R. G.; Pearson, R. G. J. Am. Chem. Soc. 1983, 105, 7512.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 19, 2012
5141