Published on Web 02/11/2010

Palladium-Catalyzed Intermolecular Aminofluorination of Styrenes

Shuifa Qiu,† Tao Xu,† Juan Zhou,‡ Yinlong Guo,‡ and Guosheng Liu*,†
State Key Laboratory of Organometallics Chemistry, Shanghai Mass Spectrometry Center, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai, China, 200032
Received November 21, 2009; E-mail: gliu@mail.sioc.ac.cn

Palladium-catalyzed difunctionalization of olefins, such as ami- Table 1. Screening Results: Pd-Catalyzed Fluoroamination of
nooxygenation, diamination, and chloroamination, have been Styrenea
broadly studied.1,2 These reactions provide versatile strategies to
synthesize molecules with vicinal aminoheteroatom substitution.
However, palladium-catalyzed aminofluorination of alkenes, which
is the same strategy for the synthesis of vicinal aminofluorines,3 is Yieldb (%)
quite a challenge. Entry [Pd] (5 mol %) Ligand (5.5 mol %) Solvent 3a 4a
Several groups have recently reported palladium-catalyzed 1 Pd(OAc)2 bathocuproine (BC) dioxane 65 7
fluorination of aromatic compounds.4,5 For instance, Buchwald has 2 Pd(OAc)2 none - 0 0
presented a coupling reaction of aryl triflates with CsF to give 3 Pd(OAc)2 pyridined - 0 0
fluoroarenes.4 Sanford5a and Yu5b have reported the use of 4 Pd(OAc)2 2,2′-bipyridine (BPy) - 0 0
N-fluoropyridinium reagents as a F+ source in the directed fluorina- 5 Pd(OAc)2 1,10-phenanthroline - 0 0
6 Pd(OAc)2 neocuproine (NC) - 44 5
tion of C-H bonds, and Ritter has explored the stoichiometric 7 Pd(OAc)2 6,6′-dimethyl-bpy (DMBPy) - 23 0
fluorination of arylboronates with SelectFluor.5c In most cases, the 8 Pd(OAc)2 bathophenanthroline (BPH) - 11 0
formation of a C-F bond is believed to proceed via a Pd(II/IV) 9 PdCl2 BC - 62 7
catalytic cycle.5d,e Very recently, our group reported a palladium- 10 Pd(PhCN)2Cl2 BC - 52 6
catalyzed intramolecular aminofluorination of alkenes by PhI- 11 Pd(OOCCF3)2 BC - 51 5
(OPiv)2/AgF,6 in which the C-F bond was also formed via 12 Pd(dba)2 BC - 55 6
13 Pd(OAc)2 BC TBME 29 9
reductive elimination from a Pd(IV) intermediate. In contrast, 14 Pd(OAc)2 BC DCE 29 3
Sadighi reported a Au-catalyzed hydrofluorination of alkyne, where 15 Pd(OAc)2 BC toluene 54 5
the formation of the C-F bond resulted from fluorogoldation of 16c Pd(OAc)2 BC dioxane 80 10
the triple bond.7 Herein, we describe a novel palladium-catalyzed
a
intermolecular aminofluorination of styrenes with N-fluoroben- Reaction condition: the reaction conducted in 0.2 mmol scale in 1
zenesulfonimide (NFSI) as the source of nitrogen and fluorine, in mL of solvent. b F NMR yield with trifluoromethylbenzene as internal
which fluoropalladation of styrenes is proposed as the key step to standard. c Ligand BC (7.5 mol %) in 0.5 mL of dioxane. d Pyridine (11
mol %). TBME ) tert-butyl methylether, DCE ) dichloroethane.
construct the C-F bond. In addition, a bidentate nitrogen ligand is
crucial to the success of this reaction. to be the most efficient catalyst; Pd(dba)2, a precursor Pd(0),
exhibited similar reactivity to that of the Pd(II) catalyst (entries 1,
9-12). A blank test showed that no reaction takes place without a
palladium catalyst. Compared with the other solvents, dioxane is
more suitable for the aminofluorination (entries 13-15). It should
be noted that, in most cases, a small amount of side product 4a
was observed. With further optimization, the best yield (80%) was
achieved under the reaction condition with Pd(OAc)2 (5 mol %),
BC (7.5 mol %), styrene (0.2 mmol), and NFSI (0.5 mmol) in
Recently, we explored a palladium-catalyzed hydroamination of dioxane at 0.4 M concentration (entry 16).
styrenes.8 In the presence of isopropyl alcohol and bathocuproine With the standard condition, the substrate scope of the amino-
(BC), Pd(OAc)2 could catalyze the reaction of styrene with NFSI fluorination reaction was investigated with a variety of vinyl arenes
to afford the desired product 2a in a good yield (eq 1). Surprisingly, (Table 2). Compared to styrene, the reactions of p-, m-, and
in the absence of the alcohol, a significant amount of compound o-methylstyrene afforded 3b, 3c, and 3d at 80%, 70%, and 61%
3a was isolated with a small amount of difluoroamine 4a (eq 2). yields, respectively. Styrenes 1e-1h with a halide in the benzene
To increase the yield of aminofluorination, several experiments were ring underwent intermolecular aminofluorination to afford the
further investigated (Table 1). In comparison with BC (entry 1), corresponding products 3e-3h at moderate to good yields, in which
none of the desired product was observed without a ligand (entry there is no obvious halide effect on the reactivity. Furthermore,
2), or with various common nitrogen ligands, such as pyridine, with different protected p-hydroxystyrenes 1i-1k, similar results
bipyridine, and 1,10-phenanthroline (entries 3-5). A lower yield were obtained. However, the reaction of substrates 1l-1o containing
of 3a was observed when other more sterically hindered ligands, electron-withdrawing groups, such as ester, nitrile, nitro and trifluoro
neocuproine (NC) and 6,6′-dimethyl-bpy, were employed in the groups, exhibited slightly lower reactivity. The internal alkenes,
reaction mixture (entries 6-7). However, bathophenanthroline such as 1p-1r, were proven to be good substrates for the
(BPH) which lacks the ortho-methyl groups was a poor ligand for transformation to generate products 3p-3r with excellent regiose-
this reaction (entry 8). Under these reaction conditions mentioned lectivity but with a moderate level of diastereoselectivity.9 It is
above, aminofluorination product 3a was isolated as the single noteworthy that the reaction of diene trans-1s exhibited very good
regioisomer (entries 1, 6-8). After screening, Pd(OAc)2 was proven chemoselectivity, where aminofluorination exclusively occurred in
the activated double bond. However, the unactivated olefins, such
†
State Key Laboratory of Organometallics Chemistry. as 1-octene and allylbenzene, have no reactivity for the amino-
‡
Shanghai Mass Spectrometry Center. fluorination reaction.
2856 9 J. AM. CHEM. SOC. 2010, 132, 2856–2857 10.1021/ja909716k  2010 American Chemical Society
 COMMUNICATIONS
a
Table 2. Palladium-Catalyzed Aminofluorination of Styrenes styrene, which is similar to the addition of Pd hydride to styrene,14
gives a palladium species IV. The following oxidation of IV by
NFSI gives a Pd(IV) intermediate V, which conducts reductive
elimination to form a C-N bond (pathway A).2f,15 However, an
alternative pathway cannot be excluded currently: the benzylic-Pd
intermediate IV undergoes nitrogen nucleophilic attack to afford
product 3 (pathway B).14a,16 It is worth noting that both catalytic
cycles involve fluoropalladation of styrenes as a key step to
construct C-F bonds.
In conclusion, we have developed a novel palladium-catalyzed
intermolecular oxidative aminofluorination of vinyl arenes, in which
NFSI functioned not only as a fluorination but also as an amination
reagent. The reaction afforded vicinal fluoroamine products with
very high regioselectivity. This transformation may involve fluo-
ropalladation of styrene as a key step for C-F bond formation.
Further mechanistic research is in progress.
Acknowledgment. Dedicated to Prof. Li-Xin Dai on the occasion
of his 85th birthday. This work was supported by CAS, NSFC
(20821002, 20872155 and 20972175), 973-program (2009CB825300),
and STCSM (08PJ1411600 and 08dj1400100).

a Supporting Information Available: Detailed experimental proce-

Reactions were conducted in 0.4 mmol scale; isolated yield. b The
dures and analytical data for all new compounds. This material is
data in parentheses are the ratio of anti:syn. c The ratio of trans:cis.
available free of charge via the Internet at http://pubs.acs.org.
Scheme 1. Possible Catalytic Cycles for Fluoroamination of
Styrenes References
(1) For reviews on the oxidative amination of olefins, see: (a) Jensen, K. H.;
Sigman, M. S. Org. Biomol. Chem. 2008, 6, 4083–4088. (b) Kotov, V.;
Scarborough, C. C.; Stahl, S. S. Inorg. Chem. 2007, 46, 1910–1923.
(2) For selective examples for Pd-catalyzed difunctionalization, see: (a)
Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005, 127,
7690–7691. (b) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179–
7181. (c) Desai, L. V.; Sanford, M. S. Angew. Chem. 2007, 119, 5839–
5842. (d) Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am.
Chem. Soc. 2005, 127, 14586–14587. (e) Michael, F. E.; Sibbald, P. A.;
Cochran, B. M. Org. Lett. 2008, 10, 793–796. (f) Sibbald, P. A.; Michael,
F. E. Org. Lett. 2009, 11, 1147–1149. (g) Rosewall, C. F.; Sibbald, P. A.;
Liskin, D. V.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 9488–9489.
(3) Molecules bearing a vicinal aminofluorine moiety have been extensively
used as important building blocks in pharmaceuticals; see: McCarthy, J. R.
Fluorine in Drug Design: A Tutorial ReView; 17th Winter Fluorine
Conference; St. Pete Beach, FL, 2005.
(4) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; Garcı́a-Fortanet, J.;
Although the mechanistic details of this transformation are not Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661–1664.
clear at the moment, some preliminary studies indicated that (5) For palladium-catalyzed fluorination of arenes, see: (a) Hull, K. L.; Anani,
W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134–7135. (b) Wang,
fluoropalladation of styrene may be involved in the C-F bond X.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 7520–7521. (c)
formation (Scheme 1).10 As mentioned above, the reaction of Furuya, T.; Kaiser, H. M.; Ritter, T. Angew. Chem., Int. Ed. 2008, 47,
styrene afforded a small amount of byproduct 4a, which is probably 5993–5996. For mechanistic studies, see: (d) Ball, N. D.; Sanford, M. S.
J. Am. Chem. Soc. 2009, 131, 3796–3797. (e) Furuya, T.; Ritter, T. J. Am.
derived from aminofluorination of β-fluorostyrene 5a generated Chem. Soc. 2008, 130, 10060–10061.
from fluoropalladation of styrene and β-hydride elimination (Heck (6) Wu, T.; Yin, G.; Liu, G. J. Am. Chem. Soc. 2009, 131, 16354–16355.
type reaction).11 In addition, when an excess of styrene reacted (7) Akana, J. A.; Bhattacharyya, K. X.; Müller, P.; Sadighi, J. P. J. Am. Chem.
Soc. 2007, 129, 7736–7737.
with NFSI, a small amount of β-fluorostyrene 5a was observed (8) Xu, T.; Qiu, S.; Liu, G. Unpublished results.
(eq 3), which can be subject to further reaction with NFSI to give (9) The ratio of diastereoisomers of 3q was slightly effected by ligand choice,
4a in a good yield (73%, eq 4). Furthermore, the stoichiometric for instance, BC 88% (4:1), BPH 62% (2:1), NC 75% (3.5:1), DMBPy
44% (1.2:1).
reaction of BC, Pd(dba)2 with NFSI generated a Pd(II) complex 6, (10) There is no obvious effect on aminofluorination of styrene by addition of
which was characterized by 19F NMR (a broad single peak at -381 2,4-dinitrophenol or 1,4-hydroquinone, which suggests against a radical
ppm), 1H NMR, and mass spectroscopy.12 When excess styrene mechanism. For the mechanism involving a β-fluorocarbocation intermedi-
ate that is also less likely, see the Supporting Information for details.
1a (20 equiv) was further added, products 3a and 5a were generated (11) Although fluoropalladation of alkenes is unknown, the fluorogoldation of
in 10% and 9% yields, respectively (eq 5).13 alkyne have been reported; see ref 7.
(12) Some examples of PdFX (X ) Ar or F) complexes are stabilized by
nitrogen-containing ligands, see refs 5d-5e and Grushin, V. V.; Marshall,
W. J. J. Am. Chem. Soc. 2009, 131, 918–919.
(13) In the absence of BC, the stoichiometric reaction only afforded product 5a
in 8% yield. See the Supporting Information for the analysis.
(14) For selective examples, see: (a) Hartwig, J. F. Pure. Appl. Chem. 2004,
76, 507–516. (b) Gligorich, K. M.; Cummings, S. A.; Sigman, M. S. J. Am.
Chem. Soc. 2007, 129, 14193–14195.
(15) The intramolecular hydroamination of styrene takes place with NFSI as
oxidant, but no reaction occurs with oxygen as sole oxidant. The observation
indicated that the C-N bond formation is more likely to proceed through
the Pd(II/IV) cycle; see ref 8.
(16) The π-benzyl-Pd intermediate IV has been invoked by Stahl to explain
the regioselectivty of oxidative amination of styrenes; see: (a) Timokhin,
V. I.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 17888–17893. For amination
Based on the above observations, a possible catalytic cycle is of the benzylic-Pd complex, see: (b) Johns, A. M.; Tye, J. W.; Hartwig,
J. F. J. Am. Chem. Soc. 2006, 128, 16010–16011.
shown in the Scheme 1: first, the oxidation of the Pd(0) complex
II by NFSI generates Pd(II) species III; then fluoropalladation of JA909716K

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