Oxidative conversion of silyl enol ethers to α,β-unsaturated ketones employing oxoammonium salts

Article abstract of DOI:10.1021/ol2029417

The oxidative conversion of silyl enol ethers to α,β-unsaturated ketones using a less-hindered class of oxoammonium salts (AZADO ⁺BF₄^-) is described. The reaction proceeds via the ene-like addition of oxoammonium salts to silyl enol ethers.

Full text of DOI:10.1021/ol2029417

ORGANIC
LETTERS
2012
Vol. 14, No. 1
154–157
Oxidative Conversion of Silyl Enol Ethers
to r,β-Unsaturated Ketones Employing
Oxoammonium Salts
Masaki Hayashi,‡ Masatoshi Shibuya,† and Yoshiharu Iwabuchi*,†
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku University, 6-3 Aobayama, Sendai 980-8578, Japan, and Process Technology
Research Laboratories, Daiichi Sankyo Co., Ltd., 1-12-1 Shinomiya,
Hiratsuka, Kanagawa 254-0014, Japan
iwabuchi@mail.pharm.tohoku.ac.jp
Received November 1, 2011
ABSTRACT
The oxidative conversion of silyl enol ethers to R,β-unsaturated ketones using a less-hindered class of oxoammonium salts (AZADOþBF4ꢀ) is
described. The reaction proceeds via the ene-like addition of oxoammonium salts to silyl enol ethers.
Oxoammonium salts are attractive oxidants whose use
continuously expands in contemporary organic chemistry.1
They enable efficient alcohol oxidation either catalytically
or stoichiometrically2 and effect particular oxidative trans-
formations such as the R-aminooxylation of ketone and
enol ethers,3 the ene-like addition to alkenes to form allylic
alkoxyl amines,4 the oxidative rearrangement of tertiary
allylic alcohols,5 and others.6ꢀ9
derived from 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)
and the related derivatives in alcohol oxidation10,11
(Figure 1). During our continuous investigation of the
chemistry of oxoammonium salts/nitroxyl radicals, we
encountered an unprecedented reaction of oxoammo-
nium salts with silyl enol ethers.
We have recently disclosed that a less-hindered class of
oxoammonium salts, generated from the corresponding
nitroxyl radicals, namely, 2-azaadamantane N-oxyls (AZADO
and 1-Me-AZADO),10a,f 9-azabicyclo-[3.3.1]nonane N-oxyl
(ABNO),10b and 9-aza-noradamantane N-oxyl (Nor-
AZADO),10g exhibit superior catalytic activity to that
(3) (a) Golubev, V. A.; Miklyush, R. V. J. Org. Chem. USSR Engl.
Transl. 1972, 8, 1376–1377. (b) Hunter, D. H.; Barton, D. H. R.;
Motherwell, W. J. Tetrahedron Lett. 1984, 25, 603–606. (c) Inokuchi,
T.; Nakagawa, K.; Torii, S. Tetrahedron Lett. 1995, 36, 3223–3226. (d)
Ren, T.; Liu, Y.-C.; Guo, Q.-X. Bull. Chem. Soc. Jpn. 1996, 69, 2935–
2941. (e) Liu, Y.-C.; Ren, T.; Guo, Q.-X. Chin. J. Chem. 1996, 14, 252–
€
258. (f) Jahn, U. J. Org. Chem. 1998, 63, 7130–7131. (g) Schamann, M.;
€
€
€
Schafer, H. J. Synlett 2004, 9, 1601–1603. (h) Schamann, M.; Schafer,
H. J. Electrochim. Acta 2005, 50, 4956–4972. (i) Beeson, T. D.
Mastracchio, A.; Hong, J.-B.; Ashton, K.; MacMillan, D. W. C. Science
2007, 316, 582–585. (j) Sibi, M. P.; Hasegawa, M. J. Am. Chem. Soc.
2007, 129, 4124–4125. (k) Koike, T.; Akita, M. Chem. Lett. 2009, 38,
166–167. (l) Bui, N.-N.; Ho, X.-H.; Mho, S.-i.; Jang, H.-Y. Eur. J. Org.
Chem. 2009, 5309–5312. (m) Pouliot, M.; Renaud, P.; Schenk, K.;
Studer, A.; Vogler, T. Angew. Chem., Int. Ed. 2009, 48, 6037–6040. (n)
Kano, T.; Mii, H.; Maruoka, K. Angew. Chem., Int. Ed. 2010, 49, 6638–
6641. (o) Akagawa, K.; Fujiwara, T.; Sakamoto, S.; Kudo, K. Org. Lett.
2010, 12, 1804–1807. (p) Humbeck, J. F. V.; Simonovich, S. P.; Knowles,
R. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10012–10014.
(4) (a) Takata, T.; Tsujino, Y.; Nakanishi, S.; Nakamura, K.; Yoshida,
E.; Endo, T. Chem. Lett. 1999, 937. (b) Church, K. M.; Holloway, L. M.;
Matley, R. C.; Brower, R. J. Nucleosides Nucleotides 2004, 23, 1723–1738.
(c) Pradhan, P. P.; Bobbitt, J. M.; Bailey, W. F. Org. Lett. 2006, 8, 5485–
5487.
‡ Daiichi Sankyo Co., Ltd.
† Tohoku University.
(1) For a comprehensive review, see: Bobbitt, J. M.; Bruckner, C.;
€
Merbouh, N. Org. React. 2009, 74, 103–424.
(2) For reviews on alcohol oxidation, see: (a) Bobbitt, J. M.; Flores,
M. C. L. Heterocycles 1988, 27, 509–533. (b) de Nooy, A. E. J.; Besemer,
A. C.; van Bekkum, H. Synthesis 1996, 1153–1174. (c) Hawker, C. J.;
Bosman, A. W.; Harth, E. Chem. Rev. 2001, 101, 3661–3688. (d)
Sheldon, R. A.; Arends, I. W. C. E. Adv. Synth. Catal. 2004, 346,
€
1051–1071. (e) Merbouh, N.; Bobbitt, J. M.; Bruckner, C. Org. Prep.
Proced. Int. 2004, 36, 1–31. (f) Caron, S.; Dugger, R. W.; Ruggeri, S. G.;
Ragan, J. A.; Ripin, D. H. B. Chem. Rev. 2006, 106, 2943–2989. (g)
Vogler, T.; Studer, A. Synthesis 2008, 1979–1993. (h) Ciriminna, R.;
Pagliaro, M. Org. Process Res. Dev. 2010, 14, 245–251.
r
10.1021/ol2029417
Published on Web 12/19/2011
2011 American Chemical Society

Herein, we report a facile and metal-free oxidative
conversion of silyl enol ethers to R,β-unsaturated ketones
employing oxoammonium salts, which can be a useful
alternative to current methods,12ꢀ16 such as the Pd(II)-
based SaegusaꢀIto reaction,12 selenylationꢀselenoxide
elimination method,13 Mukaiyama reaction,14 and a hy-
pervalent-iodine-based method.15
reaction at low temperatures (entries 1, 2). The chemos-
electivity for the R,β-unsaturated ketone was further im-
proved by switching the TMS group to the TBS group
(entries 2, 3).17 We next screened a panel of oxoammonium
salts and found that the chemoselectivity is sensitive to
the structure of the oxoammonium salt (entries 3ꢀ6),
for which the best result was obtained in the case of
AZADOþBF4ꢀ (entry 3). It is interesting to point out that
TEMPOþBF4ꢀ (1) gave the R-aminooxy ketone 7d as the
major product, showing an interesting contrast to less-
hindered oxoammonium salts (entry 6).
Table 1. Optimization of Reaction Conditions for R,β-Unsatu-
rated Ketone 6
Figure 1. Structures of oxoammonium salts.
Oxoammonium salts derived from TEMPO react with
enol ethers to give R-aminooxy ketones.3 Thus, we exam-
ined an R-aminooxylation reaction of silyl enol ether 5
employing the azaadamantane-derived oxoammonium
salts 2ꢀ410 and surprisingly confirmed that R,β-unsatu-
rated ketone 6 was generated along with the anticipated
R-aminooxy ketone 7a (Scheme 1).
Scheme 1. Formation of R,β-Unsaturated Ketone through
Treatment of Silyl Enol Ether with Oxoammonium Salt
To explore the effect of counteranion of oxoammonium
salts, we screened the various salts (Table 2). Although
there were no significant differences in the reactivity,
apparent differences were observed in the chemoselectivity
Prompted by the promising use of the side reaction, we
sought optimal conditions to enhance the yield of the R,β-
unsaturated ketone 6 (Table 1). It was found that the yield
and chemoselectivity were improved by carrying out the
(10) (a) Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. J. Am.
Chem. Soc. 2006, 128, 8412–8413. (b) Shibuya, M.; Tomizawa, M.;
Sasano, Y.; Iwabuchi, Y. J. Org. Chem. 2009, 74, 4619–4622. (c)
Shibuya, M.; Sato, T.; Tomizawa, M.; Iwabuchi, Y. Chem. Commun.
2009, 1739–1741. (d) Tomizawa, M.; Shibuya, M.; Iwabuchi, Y. Org.
Lett. 2009, 11, 1829–1831. (e) Shibuya, M.; Osada, Y.; Sasano, Y.;
Tomizawa, M.; Iwabuchi, Y. J. Am. Chem. Soc. 2011, 133, 6497–6500.
(f) Shibuya, M.; Sasano, Y.; Tomizawa, M.; Hamada, T.; Kozawa, M.;
Nagahama, N.; Iwabuchi, Y. Synthesis 2011, 3418–3425. (g) Hayashi,
M.; Sasano, Y.; Nagasawa, S.; Shibuya, M.; Iwabuchi, Y. Chem. Pharm.
Bull. 2011, 59, 1570–1573.
(5) (a) Shibuya, M.; Tomizawa, M.; Iwabuchi, Y. J. Org. Chem. 2008,
73, 4750–4752. (b) Shibuya, M.; Tomizawa, M.; Iwabuchi, Y. Org. Lett.
ꢀ
2008, 73, 4715–4718. (c) Vatele, J.-M. Synlett 2008, 1785–1788. (d)
ꢀ
ꢀ
Vatele, J.-M. Synlett 2009, 2143–2145. (e) Vatele, J.-M. Tetrahedron
2010, 66, 904–912.
(6) For oxidative coupling, see: (a) Kirchberg, S.; Vogler, T.; Studer,
A. Synlett 2008, 2841–2845. (b) Vogler, T.; Studer, A. Org. Lett. 2008,
10, 129–131. (c) Maji, M. S.; Pfeifer, T.; Studer, A. Angew. Chem., Int.
Ed. 2008, 47, 9547–9550. (d) Maji, M. S.; Studer, A. Synthesis 2009, 14,
2467–2470. (e) Maji, M. S.; Murarka, S.; Studer, A. Org. Lett. 2010, 12,
3878–3881. (f) Maji, M. S.; Pfeifer, T.; Studer, A. Chem.;Eur. J. 2010,
16, 5872–5875.
(11) Yamakoshi, H.; Shibuya, M.; Tomizawa, M.; Osada, Y.; Kanoh,
N.; Iwabuchi, Y. Org. Lett. 2010, 12, 980–983.
(12) (a) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–
1013. (b) Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24,
5635–5638. (c) Tsuji, J.; Minami, I.; Shimizu, I.; Kataoka, H. Chem.
Lett. 1984, 1133–1136. (d) Minami, I.; Takahashi, K.; Shimizu, I.;
Kimura, T.; Tsuji, J. Tetrahedron 1986, 42, 2971–2977. (e) Larock,
R. C.; Hightower, T. R. Tetrahedron Lett. 1995, 36, 2423–2426. (f) Yu,
J.-Q.; Wu, H.-C.; Corey, E. J. Org. Lett. 2005, 7, 1415–1417.
(13) Trost, B. M.; Saltzmann, T. N.; Hiroi, K. J. Am. Chem. Soc.
1976, 98, 4887–4902.
(7) For carboaminohydroxylation of olefins, see: (a) Heinrich, M. R.;
Wetzel, A.; Kirschstein, M. Org. Lett. 2007, 9, 3833–3835. (b) Kirchberg,
€
S.; Frohlich, R.; Studer, A. Angew. Chem., Int. Ed. 2009, 48, 4235–4238.
(8) For oxidation at benzylic and allylic positions, see: (a) Breton, T.;
Liaigre, D.; Belgsir, E. M. Tetrahedron Lett. 2005, 46, 2487–2490. (b)
Pradhan, P. P.; Bobbitt, J. M.; Bailey, W. F. J. Org. Chem. 2009, 74,
(14) Mukaiyama, T.; Matsuo, J.; Kitagawa, H. Chem. Lett. 2000, 29,
1250–1251.
~
9524–9527. (c) Richter, H.; Mancheno, O. G. Eur. J. Org. Chem. 2010,
4460–4467.
(15) (a) Magnus, P.; Evans, A.; Lacour, J. Tetrahedron Lett. 1992, 33,
2933–2936. (b) Magnus, P.; Lacour, J. J. Am. Chem. Soc. 1992, 114, 769–
771. (c) Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T.
Angew. Chem., Int. Ed. 2002, 41, 996–1000.
(9) For biomimetic oxidation of aldehydes, see: Guin, J.; Sarkar,
S. D.; Grimme, S.; Studer, A. Angew. Chem., Int. Ed. 2008, 47, 8727–
8730.
Org. Lett., Vol. 14, No. 1, 2012
155

Table 2. Optimization of Reaction Conditions: Effect of
Counteranion of Oxoammonium Salts
Table 3. Scope of the Reactiona
a Product ratio was determined by 1H NMR of the crude product.
Scheme 2. Isolation of Mixed Acetal Intermediates and Their
Conversion to R,β-Unsaturated Ketone
a All reactions were carried out using 1 equiv of AZADOþBF4 in
CH2Cl2 at ꢀ78 °C for 1 h, followed by treatment with sat. aqueous
NaHCO3 at rt. b The corresponding R-aminooxylated ketone was
obtained in 80% yield.
ꢀ
depending on the type of counteranion, in which the best
result was obtained in the case of BF4 salt (entry 1).
During the experiments, we observed a transient intermedi-
ate on analytical TLC, which was ultimately isolated upon
careful quench/workup of the reaction and determined to be
the mixed acetal 9 or 10 (Scheme 2) (see Supporting Informa-
tion, SI). The treatment of 9 with 0.1 M HCl in CH2Cl2
afforded the R,β-unsaturated ketone 6 and AZADOH.
Figure 2. Plausible reaction pathway.
156
Org. Lett., Vol. 14, No. 1, 2012

The plausible reaction pathway of this novel transfor-
mation is shown in Figure 2. The mixed acetal intermediate
(9, 10) may be formed through the ene-like addition4c of
the oxoammonium salt onto the carbonꢀcarbon π-bond
ofthe silyl enol ether, the hydrolysisof whichintheworkup
leads to the R,β-unsaturated ketone 6. The difference in
steric hindrance between TEMPO and AZADO provides a
reasonable rationale for the selectivity of these radicals: the
NdO double bond of less-hindered AZADOþ can ap-
proach and attack the CdC;C;H moiety of the silyl
enol ether, whichinduces anene-like reaction. On the other
hand, a similar approach by TEMPOþ is disfavored owing
to the steric hindrance of four bulky methyl groups. As a
result, TEMPO-derived oxoammonium ion attacks the π-
electrons of silyl enol ether to give an R-aminooxy ketone.3
The scope and limitations of this reaction are demon-
strated in Table 3.18 Six- and five-membered ring sub-
strates, which have aryl, alkyl, and alkenyl substituents,
were smoothly converted to the corresponding products in
high yield (entries 1ꢀ11). Unfortunately, a seven-mem-
bered substrate, namely, 3-phenylcyclohept-1-enyl
tert-butyldimethylsilyl ether, only gave the R-aminooxy-
lated ketone (see SI). The reaction of tetrasubstituted
acyclic silyl enol ethers proceeded in moderate to high
yield except 24a having an electron-withdrawing group on
the aromatic ring (entries 12ꢀ15), which were converted to
R,β-unsaturated ketones stereoselectively. E isomers were
obtained as a single isomer (entries 12ꢀ14). Meanwhile,
the trisubstituted acyclic substrate (26a) resulted in low
yields because of predominant R-aminooxylation
(entry 16). It should be stressed that AZADOH is
facilely recovered after conventional workup and sim-
ple recrystallization and used to regenerate AZADOþBF4
ꢀ
(see SI).
In summary, we disclose a oxidative conversion of silyl
enol ethers to R,β-unsaturated ketones by employing a
less-hindered class of oxoammonium salts, the operational
simplicity of which offers a useful option for the synthesis
of R,β-unsaturated ketones from ketones. This study high-
lights the critical difference in chemoselectivity between
less-hindered oxoammonium ions and TEMPO-derived
ones, which should inspire the development of useful
chemistry based on oxoammonium salts.
(16) For other reported methods for the synthesis of R,β-unsaturated
ketones from silyl enol ethers, see: (a) Evans, P. A.; Longmire, J. M.;
Modi, D. P. Tetrahedron Lett. 1995, 36, 3985–3988. (b) Friedrich, E.;
Lutz, W. Angew. Chem., Int. Ed. 1977, 16, 413–415. (c) Jung, M. E.; Pan,
Y.-G.; Rathke, M. W.; Sullivan, D. F.; Woodbury, R. P. J. Org. Chem.
1977, 42, 3961–3963. (d) Ryu, I.; Murai, S.; Hatayama, Y.; Sonoda, N.
Tetrahedron Lett. 1978, 19, 3455–3458. (e) Magnus, P.; Lacour, J.;
Evans, P. A.; Rigollier, P.; Tobler, H. J. Am. Chem. Soc. 1998, 120,
12486–12499.
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research (B) (No. 17390002)
and a Grant-in-Aid for Young Scientists (A) (No.
23689001) from the Japan Society for the Promotion of
Science (JSPS).
(17) We also attempted a reaction of lithium enolate, 28, which is
prepared in situ from 5, although a trace amount of R,β-unsaturated
ketone 6 was observed because of predominant R-aminooxylation.
Supporting Information Available. Experimental pro-
cedures, characterization data, and copy of NMR spec-
tra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) The silyl enol ether substrates (11aꢀ13a and 15aꢀ21a) were
prepared by conjugate cuprate addition or conjugate reduction of R,β-
unsaturated ketones followed by quenching with TBSCl. The substrates
(14a and 22aꢀ26a) were prepared by silyl enolization of ketones (see SI).
Org. Lett., Vol. 14, No. 1, 2012
157