Direct Hiyama cross-coupling of enaminones with triethoxy(aryl)silanes and dimethylphenylsilanol

Article abstract of DOI:10.1021/ol202202a

2,3-Dihydropyridin-4(1H)-ones undergo direct C-H functionalization at C5 in the palladium(II)-catalyzed Hiyama reaction, using triethoxy(aryl)silanes and dimethylphenylsilanol. The reagent CuF₂ has a dual role in the reactions with triethoxy(ar

Full text of DOI:10.1021/ol202202a

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5413–5415
Direct Hiyama Cross-Coupling of
Enaminones With Triethoxy(aryl)silanes
and Dimethylphenylsilanol
Lei Bi†,‡ and Gunda I. Georg*,‡
Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive,
Lawrence, Kansas 66045, United States, and Department of Medicinal Chemistry
and the Institute for Therapeutics Discovery and Development, University of Minnesota,
717 Delaware Street SE, Minneapolis, Minnesota 55414, United States
georg@umn.edu
Received August 14, 2011
ABSTRACT
2,3-Dihydropyridin-4(1H)-ones undergo direct CÀH functionalization at C5 in the palladium(II)-catalyzed Hiyama reaction, using
triethoxy(aryl)silanes and dimethylphenylsilanol. The reagent CuF2 has a dual role in the reactions with triethoxy(aryl)silanes. It is a source of
fluoride to activate the silane in the Hiyama reaction and also serves as the reoxidant to convert Pd(0) to Pd(II) in the catalytic cycle.
Cross-coupling reactions that directly convert CÀH to
CÀC bonds are valuable atom-efficient chemistry pro-
cesses when compared with conventional cross-coupling
reactions.1,2 A transition metal-catalyzed CÀH functiona-
lization obviates the need for a preactivation step to set up
the substrate for the cross-coupling reaction. As a CÀC
bond-forming strategy, direct arylation of CÀH bonds has
attracted considerable attention.3 However, the majority
of these reactions have been performed employing aro-
matic CÀH bonds and often involve a directing group.4
We have recently shown that enaminones (2,3-dihydropyr-
idin-4(1H)-ones) can be substrates for direct CÀH func-
tionalization in Pd(II)-catalyzed Suzuki-type reactions.5
We have proposed that the innate nucleophilicity of C5 of
enaminones allowsfor the direct reactionwithelectrophilic
Pd(II), which is followed by deprotonation of the palla-
dium intermediate, transmetalation, and reductive elimi-
nation (Figure 1).6 The catalytic cycle is completed by
reoxidation of Pd(0) to Pd(II) with an appropriate oxidant
such as Cu(OAc)2.
† University of Kansas.
‡ University of Minnesota.
(1) (a) Godula, K.; Sames, D. Science 2006, 312, 67. (b) Ellman, J. A.
Science 2007, 316, 1131.
(2) For recent reviews, see:(a) Dyker, G.; Handb., C-H Transform.
2005, 2, 465. (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev.
2007, 107, 465. (c) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem.
Res. 2009, 42, 1074. (d) Chen, X.; Engle, Keary M.; Wang, D.-H.; Yu,
J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (e) Sun, C.-L.; Li, B.-J.; Shi,
Z.-J. Chem. Commun. 2010, 46, 677.
(3) For a recent review, see: Lyons, T. W.; Sanford, M. S. Chem. Rev.
2010, 110, 1147.
(4) For related reactions see: (a) Liu, Y.; Li, D.; Park, C.-M. Angew.
Chem., Int. Ed. 2011, 50, 7333. (b) Bai, Y.-G.; Zeng, J.; Cai, S.-T.; Liu,
X.-W. Org. Lett. 2011, 13, 4394. (c) Cheng, D.; Gallagher, T. Org. Lett.
2009, 11, 2639. (d) Colbon, P.; Ruan, J.; Purdie, M.; Xiao, J. Org. Lett.
2010, 12, 3670. (e) Pelletier, G.; Larivee, A.; Charette, A. B. Org. Lett.
2008, 10, 4791. (f) Ramtohul, Y. K.; Chartrand, A. Org. Lett. 2007, 9,
1029. (g) Sorensen, U. S.; Pombo-Villar, E. Helv. Chim. Acta 2004, 87,
82. (h) Wuertz, S.; Rakshit, S.; Neumann, J. J.; Droege, T.; Glorius, F.
Angew. Chem., Int. Ed. 2008, 47, 7230. (i) Xu, Y.-H.; Lu, J.; Loh, T.-P.
J. Am. Chem. Soc. 2009, 131, 1372. (j) Zhou, H.; Chung, W.-J.; Xu,
Y.-H.; Loh, T.-P. Chem. Commun. 2009, 3472. (k) Zhou, H.; Xu, Y.-H.;
Chung, W.-J.; Loh, T.-P. Angew. Chem., Int. Ed. 2009, 48, 5355. (l) Heck,
R. F. J. Am. Chem. Soc. 1968, 90, 5535.
We have recently demonstrated the utility of this chem-
istry for the concise enantiospecific synthesis of the phe-
nanthropiperidine alkaloids ipalbidine and antofine,7
tylocrebrine,8 and boehmeriasin A.9
(5) Ge, H.; Niphakis, M. J.; Georg, G. I. J. Am. Chem. Soc. 2008, 130,
3708.
(6) Niphakis, M. J.; Turunen, B. J.; Georg, G. I. J. Org. Chem. 2010,
75, 6793.
r
10.1021/ol202202a
2011 American Chemical Society
Published on Web 09/22/2011

Table 1. Reaction Optimization for the Hiyama Coupling
Reaction of Enaminone 1a
yield
(%)b
entrya
1
catalyst
Pd(OAc)2
oxidant/activator
Cu(OAc)2/TBAF
solvent
THF
0c
trace
trace
30
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Cu(OAc)2/KF
Cu(OAc)2/AgF
Cu(OTf)2/AgF
AgF2
dioxane
dioxane
dioxane
dioxane
3
4
5e
0d
Figure 1. Proposed catalytic cycle for the direct arylation of
enaminones 1.
50
62f
40
6
White catalystg AgF2
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxaneh
tBuOH/AcOH
(4:1)i
On the basis of our results with the Suzuki-type reac-
tions, we hypothesized that the palladated enaminone
intermediate could participate in other cross-coupling
reactions, such as the Hiyama coupling. Hiyama reactions
typically take place between organohalides (alkyl, aryl,
and alkenyl) and organosilanes.10 Organosilanes have a
number of advantages that make them desirable organic
reagents for cross-coupling reactions in comparison to
organoboranes or organostannanes. They are stable, rela-
tively nontoxic, and can be easily prepared. Nonetheless,
only a few cases of direct CÀH arylation with organosilane
coupling partners have been reported. Yang et al.11 de-
scribed the direct Hiyama ortho arylation of acetanilides
and Zhou et al.4k described the reaction of cyclic N-acetyl
enamides with arylsilanes. In both cases, the palladation is
believed to be dependent upon neighboring group assis-
tance. To explore whether enaminones could participate
directly in the Hiyama reaction, we selected 1-benzyl-2-
phenyl-2,3-dihydropyridin-4(1H)-one (1a) as the sub-
strate, Pd(OAc)2 as the catalyst, Cu(OAc)2 as the reox-
idant, and TBAF to activate the triethoxy(phenyl)silane
(2a) (Table 1, entry 1). The initial result was quite dis-
couraging because only a trace amount of the desired
reaction product 3a could be identified, accompanied by
the biphenyl homocoupled product. Similar results were
obtained when potassium fluoride was employed (Table 1,
entry 2). Silver(I) fluorideappearedtobe a better activator,
compared to the more commonly used TBAF and KF,
possibly due to the oxidative effect of silver(I) (Table 1,
entry 3).
7
Pd(TFA)2
PdCl2
AgF2
AgF2
AgF2
AgF2
AgF2
CuF2
48
8
trace
0
9
PdI2
10
11
12
NiBr2
0
NiF2
trace
0
Pd(OAc)2
82
13j
14j
Pd(OAc)2
Pd(OAc)2
Cu(OAc)2/TBAF
DMF
80
77
Cu(OAc)2/KOTMS DME
a Reaction conditions unless otherwise specified: enaminone 1a
(0.1 M), siloxane 2a (2 equiv), catalyst (0.3 equiv), oxidant (2 equiv),
activator (2 equiv), 3 h. b Isolated yield. c PhSiMeCl2 was used. d Enam-
inone 1a decomposed. e Typical reaction was completed within 1 h when
AgF2 was used. f Siloxane 2a (3.5 equiv). g 1,2-Bis(phenylsulfinyl)-
ethane palladium(II) acetate. h Enaminone 1a was recovered. i Pd(OAc)2
(0.25 equiv), CuF2 (2.5 equiv), siloxane 2a (2.5 equiv), 65 °C, 3 h.
j PhSiMe2OH (2b) was used instead of 2a.
Since copper and silver are both in group 11 in the
periodic table, we next explored Ag(II) in this reaction
because itisexpected topossess chemical properties similar
to Cu(II). We selected AgF2, which contains two equiva-
lents of fluoride and is also an oxidant to test the proposi-
tion that AgF2 could not only provide the necessary
fluoride atoms for the activation of the silane but also
function as the reoxidant in the palladium catalytic cycle.
Gratifyingly, the Hiyama coupling reaction proceeded
smoothly and with a satisfactory yield (Table 1, entry 5).
When different catalysts were examined in this reaction,
Pd(TFA)2 exhibited comparable activity while other Pd-
(II) or Ni(II) salts showed inferior catalytic capabilities
(Table 1, entries 6À11). The reaction with AgF2, however,
required the use of a large excess of organosilane. There-
fore, we decided to replace AgF2 with CuF2. An initial
attempt with CuF2, using dioxane as the solvent, did not
provide the reaction product (Table 1, entry 12). However,
when the solvent was changed to a 4:1 mixture of tert-butyl
alcohol and acetic acid, the yield of the Hiyama coupling
product increased to 82% (Table 1, entry 12). We also
examined dimethylphenylsilanol (2b), an organosilanol
(7) Niphakis, M. J.; Georg, G. I. J. Org. Chem. 2010, 75, 6019.
(8) Niphakis, M. J.; Georg, G. I. Org. Lett. 2011, 13, 196.
(9) Leighty, M. W.; Georg, G. I. ACS Med. Chem. Lett. 2011, 2, 313.
(10) For recent reviews, see:(a) Hiyama, T.; Shirakawa, E. Handb.
Organopalladium Chem. Org. Synth. 2002, 1, 285. (b) Denmark, S. E.;
Ober, M. H. Aldrichim. Acta 2003, 36, 75. (c) Denmark, S. E.; Sweis,
R. F. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere,
A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004; p 163.
(d) Hiyama, T. Chem. Rec. 2008, 8, 337.
(11) Yang, S.; Li, B.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129,
6066.
5414
Org. Lett., Vol. 13, No. 20, 2011

with this reactant. The clean, complete conversion clearly
demonstrated the utility of these reagents as alternative
coupling partners. To the best of our knowledge, this is the
first case where an organosilanol has been used in a direct
CÀH cross-coupling reaction.
Table 2. Substrate Scope of Hiyama Coupling Reactions
The optimized reaction conditions from Table 1, entry
12, were next used to examine the scope of the reaction with
different enaminones and substituted triethoxy(aryl)silanes
(Table 2). The Hiyama coupling reactions of enaminone 1a
worked well with substituted triethoxy(phenyl)silanes that
carry a 4-methyl group (Table 2, entry 1), the electron-
withdrawing 4-trifluoromethyl group (Table 2, entry 2),
and the electron-donating 4-methoxy group (Table 2, entry 3).
The sterically hindered R-naphthyltrimethoxysilane was
also a suitable coupling partner (Table 2, entry 6).
Both monocyclic and bicyclic enaminones were suffi-
ciently active in the direct coupling reactions (Table 2, entries
7, 8 and 11). TBAF, often used in Hiyama coupling reactions
to activate the organosilicon reagent, also deprotects silyl
protecting groups and thus presents a limitation of this
method. It is of note that the TBS group was stable in the
presence of CuF2 (Table 2, entry 9). We observed that
halides on both the enaminone and organosiloxane re-
mained intact, presenting positions for further derivatization
(Table 2, entries 4, 5 and 10). Steric (Table 2, entry 12) or
electronic factors (Table 2, entry 13) are presumably respon-
sible for the lack of reactivity of enaminones 1g and 1h.
In summary, effective protocols for the Hiyama cou-
pling reaction with enaminones have been developed. In
the case of triethoxy(aryl)silanes as the coupling partner,
AgF2 and CuF2 were employed for the first time as
bifunctional activator/reoxidants. Dimethylphenylsilanol
was successfully used as well, without fluoride activation.
All reactions took place in open air. To the best of our
knowledge, this is the first direct Hiyama coupling reaction
to take place without neighboring group assistance and
with an organosilanol. The reaction conditions are com-
patible with the TBS protecting groups and, thus, could
find utility in multistep organic syntheses.
a Reaction conditions: enaminone (0.1 M), Pd(OAc)2 (0.25 equiv),
CuF2 (2.5 equiv), ArSi(OEt)3 (2.5 equiv) in tBuOH/AcOH (4:1), 65 °C, 3
h. b Isolated yield. c R-Naphthyltrimethoxysilane was used. d Starting
material recovered.
Acknowledgment. This work was supported by NIH
grant GM081267 and by the University of Minnesota
through the Vince and McKnight Endowed Chairs. We
thank Dr. Haibo Ge for some initial efforts with this
chemistry and Yiyun Yu for the resynthesis of two
compounds.
introduced by Denmark, as a potential coupling partner.12
Both fluoride-containing (Table 1, entry 13) and fluoride-
free (Table 1, entry 14) conditions gave excellent results
Supporting Information Available. Representative ex-
perimental procedures, characterization data and spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) For recent reviews, see: (a) Denmark, S. E.; Sweis, R. F. Acc.
Chem. Res. 2002, 35, 835. (b) Denmark, S. E.; Baird, J. D. Chem.;Eur.
J. 2006, 12, 4954. (c) Denmark, S. E.; Regens, C. S. Acc. Chem. Res. 2008,
41, 1486. (d) Denmark, S. E. J. Org. Chem. 2009, 74, 2915.
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