Platinum(II)-catalyzed cross-coupling of polyfluoroaryl imines

Article abstract of DOI:10.1021/ol702591b

The introduction of fluorine into an organic molecule imparts unique physicochemical properties. Not surprisingly, fluorine is increasingly incorporated into new drugs and agrochemicals. However, aryl fluoride building blocks are only available through sy

Full text of DOI:10.1021/ol702591b

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5629-5631
Platinum(II)-Catalyzed Cross-Coupling of
Polyfluoroaryl Imines
Tongen Wang, Brian J. Alfonso, and Jennifer A. Love*
Department of Chemistry, 2036 Main Mall, UniVersity of British Columbia,
VancouVer, British Columbia V6T 1Z1, Canada
jenloVe@chem.ubc.ca
Received October 29, 2007
ABSTRACT
The introduction of fluorine into an organic molecule imparts unique physicochemical properties. Not surprisingly, fluorine is increasingly
incorporated into new drugs and agrochemicals. However, aryl fluoride building blocks are only available through synthesis. The ability to
cross-couple polyfluoroaromatics selectively could provide a convenient route to functionalized fluoroaromatics. We report herein the first
examples of Pt-catalyzed cross-coupling of aryl fluorides. The methylated products can potentially serve as precursors to a wide range of
functionalized fluorinated small molecules.
The introduction of fluorine into an organic molecule imparts
unique physicochemical properties, including high metabolic
stability, solubility, and lipophilicity, as well as the ability
to hydrogen bond.1 Recent estimates suggest that up to 20%
of new drugs and approximately 30% of new agrochemicals
contain fluorine;1c,2 in particular, two of the world’s top 10
best-selling drugs in 2005 (Pfizer’s Lipitor and Johnson &
Johnson’s Risperdal) contain aryl fluorides. To date, fewer
than 40 organofluoride natural products have been isolated,
none of which contain an aryl fluoride.3 Consequently, the
building blocks used to generate aryl fluoride containing
pharmaceuticals and materials must be obtained through
synthesis. The ability to cross-couple polyfluoroaromatics
selectively could provide a convenient route to functionalized
fluoroaromatics. Toward this goal, we report herein the
selective methylation of a series of polyfluorinated imines.
This work represents the first examples of Pt-catalyzed cross-
coupling of aryl fluorides. These results also provide rare
examples of sp2-sp3 coupling of aryl fluorides. Moreover,
the methylated products can serve as precursors to a wide
range of functionalized fluorinated small molecules.
Catalytic cross-coupling of aryl fluorides has been a long-
standing goal in organometallic chemistry, in part because
of the challenge of activating the strong C-F bond.4,5 Of
the catalytic C-C bond forming reactions using aryl
fluorides, Ni and Pd catalysts have been the most extensively
explored.6-8 However, these processes generally work only
with monofluoroarenes and are thus not applicable to the
synthesis of functionalized fluoroaromatics. Indeed, while
(4) For reviews of C-F activation, see: (a) Kiplinger, J. L.; Richmond,
T. G.; Osterberg, C. E. Chem. ReV. 1994, 94, 373-431. (b) Torrens, H.
Coord. Chem. ReV. 2005, 249, 1957-1985.
(5) For C-F bond strengths, see: (a) Smart, B. E. Mol. Struct. Energ.
1986, 3, 141-191. (b) Smart, B. E. In The Chemistry of Functional Groups,
Supplement D; Patai S., Rappoport, Z., Eds.; John Wiley & Sons: New
York, 1983; Chapter 14, pp 603-655.
(6) (a) Kiso, Y.; Tamao, K.; Kumada, M. J. Organomet. Chem. 1973,
50, C12. (b) Bo¨hm, V. P. W.; Gsto¨ttmayr, C. W. K.; Weskamp, T.;
Herrmann, W. A. Angew. Chem., Int. Ed. 2001, 40, 3387-3389. (c) Mongin,
F.; Mojovic, L.; Guillamet, B.; Tre´court, F.; Que´guiner, G. J. Org. Chem.
2002, 67, 8991-8994. (d) Terao, J.; Ikumi, A.; Kuniyasu, H.; Kambe, N.
J. Am. Chem. Soc. 2003, 125, 5646-5647. (e) Ackermann, L.; Born, R.;
Spatz, J. H.; Meyer, D. Angew. Chem., Int. Ed. 2005, 44, 7216-7219. (f)
Dankwardt, J. W. J. Organomet. Chem. 2005, 690, 932-938. (g) Liu, J.;
Robins, M. J. Org. Lett. 2005, 7, 1149-1151.
(1) (a) Hewitt, C. D.; Silvester, M. J. Aldrichimica Acta 1988, 21, 3-10.
(b) Hiyama, T. In Organofluorine Compounds: Chemistry and Applications;
Yamamoto, H., Ed.; Springer: New York, 2000. (c) Mu¨ller, K.; Faeh, C.;
Diederich, F. Science 2007, 317, 1881-1886.
(7) (a) Wilhelm, R.; Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1
2000, 3808-3813. (b) Kim, Y. M.; Yu, S. J. Am. Chem. Soc. 2003, 125,
1696-1697. (c) Mikami, K.; Miyamoto, T.; Hatano, M. Chem. Commun.
2004, 2082-2083.
(8) Guo, H.; Kong, F.; Kanno, K.-i.; He, J.; Nakajima, K.; Takahashi,
T. Organometallics 2006, 25, 2045-2048.
(2) Thayer, A. M. Chem. Eng. News 2006, 84, 15-24.
(3) (a) Gribble, G. W. J. Chem. Educ. 2004, 81, 1441-1449. (b)
Vaillancourt, F. H.; Yeh, E.; Vosburg, D. A.; Garneau-Tsodikova, Walsh,
C. T. Chem. ReV. 2006, 106, 3364-3378.
10.1021/ol702591b CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/30/2007

catalytic defluorination of polyfluoroarenes is well-estab-
lished,9 only a few examples of catalytic C-C bond forma-
tion have been reported.8,10-12 Although these pioneering
studies revealed the feasibility of such a process, the limited
substrate scope in each case indicates that considerable chal-
lenges remain for selective cross-coupling of polyfluoroaro-
matics.
explored a variety of methylmetal reagents (entries 2-7).
To our delight, Me2Zn provided the monomethylated product
(2a) in excellent yield and regioselectivity (entry 3). The
selectivity for monomethylation indicates that C-F activation
is faster for more highly fluorinated imines.14 Importantly,
no reaction occurs in the absence of catalyst (entry 4).
Furthermore, the reaction can also proceed with a substo-
ichiometric amount of Me2Zn (entry 5), indicating that both
methyl groups can be transferred from zinc. In comparison,
the reaction of 1a with MeLi provides a mixture of products
(<5% of 2a) in the presence and absence of Pt catalyst
(entries 6 and 7).
Inspired by the report from Crespo and Martinez that [Me2-
13
Pt(µ-SMe2)]2 promotes stoichiometric C-F activation of
a series of aryl imines (eq 1),14 we decided to explore the
potential for this reaction to be part of a catalytic process.
We reasoned that the Pt-F species could undergo transmeta-
lation with an appropriate organometallic reagent. Subsequent
reductive elimination would provide the functionalized
product and would regenerate the Pt(II) catalyst.
Table 2. Scope of Pt-Catalyzed Methylation of Fluoroimines
Our study began with trifluoroimine 1a. Attempts to use
phenyl nucleophiles, such as PhSi(OMe)3 (Table 1, entry 1),
Table 1. Optimization of Conditions for Catalytic Methylation
mol %
Pt
entry
R-M (equiv)
solvent
yielda
1
2
3
4
5
6
7
PhSi(OMe)3 (1.2)
MeSi(OMe)3 (1.2)
Me2Zn (1.2)
Me2Zn (1.2)
Me2Zn (0.6)
5
5
5
0
5
5
0
acetone-d6
acetone-d6
acetonitrile-d3
acetonitrile-d3
acetonitrile-d3
THF-d8
4%
10%
88%
0%
>95%
MeLi (1.2)
MeLi (1.2)
complex mixture
complex mixture
THF-d8
a Yields based on 1H NMR spectroscopy using 1,3,5-trimethoxybenzene
as an internal standard.
resulted in exclusive incorporation of methyl, presumably
from the original Pt complex. Upon this discovery, we
(9) (a) Aizenberg, M.; Milstein, D. Science 1994, 265, 359-361. (b)
Aizenberg, M.; Milstein, D. J. Am. Chem. Soc. 1995, 117, 8674-8675. (c)
Kiplinger, J. L.; Richmond, T. G. J. Am. Chem. Soc. 1996, 118, 1805-
1806. (d) Burdeniuc, J.; Crabtree, R. H. J. Am. Chem. Soc. 1996, 118, 2525-
2526. (e) Young, R. J.; Grushin, V. V. Organometallics 1999, 18, 294-
296. (f) Yang, H.; Gao, H.; Angelici, R. J. Organometallics 1999, 18, 2285-
2287. (g) Kraft, B. M.; Lachicotte, R. J.; Jones, W. D. J. Am. Chem. Soc.
2000, 122, 8559-8560. (h) Kuhl, S.; Schneider, R.; Fort, Y. AdV. Synth.
Catal. 2003, 345, 341-344. (i) Vela, J.; Smith, J. M.; Yu, Y.; Ketterer, N.
A.; Flaschenriem, C. J.; Lachicotte, R. J.; Holland, P. L. J. Am. Chem. Soc.
2005, 127, 7857-7870. (j) Scott, V. J.; C¸ elenligil-C¸ etin, R.; Ozerov, O. V.
J. Am. Chem. Soc. 2005, 127, 2852-2853. (k) Peterson, A. A.; McNeill,
K. Organometallics 2006, 25, 4938-4940. (l) Guo, H.; Kong, F.; Kanno,
K.; He, J.; Nakajima, K.; Takahashi, T. Organometallics 2006, 25, 2045-
2048.
a A: 60 °C; B: 80 °C. b Isolated yield, unless otherwise indicated.
1
1
c Conversion based on H NMR spectroscopy. d Yield based on H NMR
spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. e Note:
product 2h is identical to 2g. f 1.2 equiv of Me2Zn used.
5630
Org. Lett., Vol. 9, No. 26, 2007

Inspired by this initial success, we sought to explore the
ability of a series of polyfluoroaryl imines to undergo
selective C-F cross-coupling with Me2Zn. Of particular
significance, 1b reacts exclusively at the 2-position (Table
2, entry 2), an indication that the directing group permits
the cleavage of the strong C-F bond in the presence of a
considerably weaker C-Br bond. The desired product, 2b,
is formed in 85% isolated yield and is amenable to further
functionalization at the aryl C-Br bond. Likewise, a cyano-
substituted substrate (1c) reacts efficiently; no addition to
the cyano group is observed (entry 3). In comparison, a
difluoroimine (1d) without an additional electron-withdraw-
ing group reacts sluggishly (entry 4).14 Modification of the
imine substituent is well-tolerated, as both aryl (entry 5) and
aliphatic imines (entries 1 and 6) react uneventfully. As with
1b, the bromine substituent within substrate 1f is left
untouched. Imine 1g reacts exclusively at the more hindered
site ortho to the imine (entry 7), consistent with the
stoichiometric results.14 This preference has been attributed
to an electronic effect of the adjacent fluorine atom. Likewise,
1h (entry 8) reacts at the more hindered site. In this case,
however, the selectivity could also arise from preferential
activation of the weaker C-Cl bond. Both the tetrafluoro
substrate (1i) and pentafluoro substrate (1j) provide the
corresponding monomethylated products 2i and 2j, respec-
tively. Pentafluoroimine 1j can undergo dimethylation with
excess Me2Zn.15 These results clearly indicate the exceptional
selectivity of this process.
The products are amenable to a wide range of further
functionalization. For example, the imines are readily
hydrolyzed to the corresponding aldehydes, which in turn
can be converted to a broad range of functional groups.
Furthermore, directed metalation of the methyl group of
ortho-tolualdehydes and imines, followed by trapping with
alkyl halides16 and CO2,17 has been reported.
In summary, we have demonstrated the first examples of
Pt-catalyzed C-F cross-coupling. A series of polyfluoroaryl
imines react with Me2Zn to generate functionalized fluoro-
arenes. The reaction is selective for ortho C-F activation in
the presence of weaker aryl C-Br bonds. Outstanding
selectivity is also achieved because the substrates are more
reactive toward methylation than the products. Efforts to
expand the substrate scope, as well as detailed mechanistic
studies, are underway.
(10) Zr: (a) Edelbach, B. L.; Kraft, B. M.; Jones, W. D. J. Am. Chem.
Soc. 1999, 121, 10327-10331. Ni: (b) Braun, T.; Perutz, R. N.; Sladek,
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(11) For a related example of stoichiometric C-C bond formation, see:
(a) Hughes, R. P.; Zhang, D.; Zakharov, L. N.; Rheingold, A. L.
Organometallics 2002, 21, 4902-4904.
Acknowledgment. We thank the University of British
Columbia, NSERC (Discovery Grant, Research Tools, and
Instrumentation Grants), Merck Frosst, the Canada Founda-
tion for Innovation, and the British Columbia Knowledge
Development Fund for support of this research.
(12) For a related example of catalytic C-Si bond formation, see: Ishii,
Y.; Chatani, N.; Yorimitsu, S.; Murai, S. Chem. Lett. 1998, 157-158.
(13) Hill, G. S.; Irwin, M. J.; Levy, C. J.; Rendina, L. M.; Puddephatt,
R. J.; Andersen, R. A.; McLean, L. Inorg. Synth. 1998, 32, 149-151.
(14) Crespo, M.; Martinez, M.; Sales, J. Organometallics 1993, 12,
4297-4304.
(15) The dimethylated product can also be obtained by treating 2j with
Me2Zn.
Supporting Information Available: Complete experi-
mental details for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) (a) Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078-
1083. (b) Forth, M. A.; Mitchell, M. B.; Smith, S. A. C.; Gombatz, K.;
Snyder, L. J. Org. Chem. 1994, 59, 2616-2619.
(17) Flippin, L. A.; Muchowski, J. M.; Carter, D. S. J. Org. Chem. 1993,
58, 2463-2467.
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