Synthesis of sterically hindered ketones from aldehydes via O-silyl oximes

Article abstract of DOI:10.1016/j.tetlet.2012.05.005

A mild and efficient method to synthesize sterically hindered ketones from aldehydes via O-silyl oximes was developed. Treatment of O-triphenylsilylated oximes with alkyl iodides in the presence of triethyl borane afforded the corresponding ketones.

Full text of DOI:10.1016/j.tetlet.2012.05.005

Tetrahedron Letters 53 (2012) 3527–3529
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of sterically hindered ketones from aldehydes via O-silyl oximes
Joong-Gon Kim b, Mithilesh Kumar Mishra a, Doo Ok Jang a,
⇑
a Department of Chemistry, Yonsei University, Wonju 220-710, Republic of Korea
b Biotechnology Division, Hanwha Chemical R&D Center, Daejeon 305-345, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and efficient method to synthesize sterically hindered ketones from aldehydes via O-silyl oximes
was developed. Treatment of O-triphenylsilylated oximes with alkyl iodides in the presence of triethyl
borane afforded the corresponding ketones.
Received 14 March 2012
Revised 24 April 2012
Accepted 2 May 2012
Available online 10 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ketone
Aldehyde
Triethyl borane
O-triphenylsilylated oxime
The synthesis of ketones has attracted considerable attention
from the synthetic community due to their great importance as
building blocks for the preparation of pharmaceutically useful com-
pounds.1 Ketones are widely used in the chemical industry as useful
synthetic intermediates for the preparation of fine chemicals in the
fields of pharmaceuticals, fragrances, and agrochemicals.2 They are
also present in a wide range of natural products and are useful as
flavoring agents.3 Consequently, different methodologies have been
developed for the preparation of ketones,4 including a one-pot prep-
aration from aldehydes using N-tert-butylphenylsulfinimidoyl
chloride,4a palladium-catalyzed oxidative coupling of trialkyl-
amines with aryl iodides,4b and (N-heterocyclic carbene)-Pd com-
plex-catalyzed anaerobic oxidation of secondary alcohols.4c
Recently, the sodium nitrite-catalyzed aerobic oxidative deoxima-
tion of ketoximes and aldoximes has also been reported.5 However,
these methods are generally limited to the synthesis of less sterically
hindered ketones. Therefore, there is still a need for synthetic routes,
which can be used to synthesize sterically hindered ketones. Most of
the recently developed methods for the synthesis of sterically hin-
dered ketones have been developed by Lockhart and co-workers6
starting with arylstannanes and aroyl chlorides. Other reported
methods include the rhodium-catalyzed oxidative arylation of alde-
hydes7 and the carbonylative Suzuki–Miyaura cross-coupling of ste-
rically hindered ortho-disubstituted aryl iodides with aryl boronic
acids.8
X
O
Et3B
N
tBu
I
+
Ph
tBu
Ph
2
3
1a: X = OSiPh3
1b:
1c:
X = OSiTBDM
X = OSiMe3
Scheme 1. Synthesis of ketones from O-silylated oximes.
report a method for the preparation of sterically hindered ketones
from aldehydes via O-silyl oximes (Scheme 1).
O-(Triphenylsilyl)benzaldoxime (1a) was synthesized from
benzaldehyde via benzaldoxime using a known protocol.10
A
reaction of 1a was carried out with t-butyl iodide (2.0 equiv) and
triethyl borane (1.0 equiv) in toluene at 90 °C affording the product
3 in poor yield (Table 1, entry 1). During the course of our investi-
gation, a variety of reactions were carried out using different
equivalents of reactants (entries 1–6). After several attempts, the
best result was obtained with 8.0 equiv of t-butyl iodide and
5.0 equiv of triethyl borane in toluene at 90 °C (entry 4). We also
performed the reaction in various solvents. The reaction in benzene
afforded a comparable yield (entry 8). Although the yield of prod-
uct 3 was reduced slightly when the reaction was performed in tol-
uene at reflux (entry 7), the reaction was best performed in toluene
(entry 4). The reaction was very sluggish in dichloromethane or
diethyl ether even after prolonged reaction times (entries 10–12).
The O-silylated benzaldoximes 1b and 1c were also investigated
while maintaining the other optimized conditions, but in both
As a part of our ongoing research, we previously developed a
novel method of synthesizing aryl ketones by means of an
indium-mediated Friedel–Crafts acylation.9 In this Letter, we
⇑
Corresponding author.
E-mail address: dojang@yonsei.ac.kr (D.O. Jang).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.005

3528
J.-G. Kim et al. / Tetrahedron Letters 53 (2012) 3527–3529
Table 1
Synthesis of t-butyl phenyl ketone 3 under various reaction conditions
Entry
tBuI (equiv)
Et3B (equiv)
Solvent
Time (h)
Temp. (°C)
Yielda (%)
1
2
3
4
5
6
7
8
9
2.0
3.0
5.0
1.0
2.0
5.0
5.0
5.0
10.0
5.0
5.0
5.0
5.0
5.0
5.0
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Benzene
THF
12
12
4
3
3
3
3
5
10
24
24
24
90
90
90
90
90
90
110
80
66
40
25
34
28
49
78
85
84
85
83
75
63
39
10
25
8.0
10.0
10.0
8.0
8.0
8.0
8.0
8.0
8.0
10
11
12
CH2Cl2
CH2Cl2
Et2O
a
Isolated yield.
bromide resulted in a drastic drop in yield from 85% to 16% (entry
4). A general trend was observed that aromatic oximes with an elec-
tron-donating group gave higher yields than those with an elec-
Table 2
Synthesis of ketones using O-silylated oximes
tron-withdrawing group (entries 5–7).
A
ortho-substituted
OSiPh3
O
Et3B, toluene
N
aromatic aldehyde also reacted well to produce the corresponding
sterically demanding ketone in high yield (entry 8). The reaction
performed equally well with aliphatic oximes (entries 9–10). The
method was also applicable to highly sterically hindered ketones.
For example, the reaction proceeded efficiently even with the
highly sterically hindered O-(triphenylsilyl) neopentyl oxime and
t-butyl iodide to afford a high yield of the corresponding ketone
(entry 11).
Radical additions to oxime ethers have become important syn-
thetic tools because of their high reactivity and unique properties
that provide selectivity in many organic transformations.11 Natio’s
group has extensively investigated triethyl borane-induced inter-
molecular carbon radical addition to oxime ethers.11a–c Clive has re-
ported an intramolecular radical cyclization of iodo O-trityl oximes
in the presence of diphenyl diselenide and Hunig’s base to produce
cyclic oximes.12 We attempted to determine whether triethyl bor-
ane was acting as a free radical initiator in the present reaction.
Controlled experiments were performed to reveal the mechanism
of the transformation. First, a reaction was carried out in carefully
degassed solvent under argon. Then, the reaction did not proceed
whereas the reaction was well performed under air atmosphere.
Second, a reaction was executed under air atmosphere in the pres-
ence of TEMPO as radical scavenger. In this case, 1.0 equiv of O-silyl
oxime, 8.0 equiv of tBuI and 5.0 equiv of TEMPO were taken and fi-
nally 5.0 equiv of triethyl borane was added. The reaction did not
proceed at all. On the basis of the above observations, it was con-
+
R'
X
o
R
R'
90 C, 3 h
R
Entry
R
R0-X
iPr-I
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
5
5
12
10
3
73
71
45
16
89
85
72
87
69
78
82
Cyclohexyl-I
Adamantyl-I
tBu-Br
tBu-I
p-MeO-Ph
p-Me-Ph
p-F-Ph
o-MeO-Ph
iPr
tBu-I
4
7
3
5
5
4
tBu-I
tBu-I
iPr-I
10
11
iPr
tBu-I
tBu
tBu-I
a
Isolated yield.
cases, the product 3 was obtained in less than 10% yield with
recovering unreacted starting materials.
On the basis of the above observations, various O-(triphenylsi-
lyl)oximes were subjected to the optimized reaction conditions to
determine the scope and limitations of the reaction. The results
are summarized in Table 2. Reactions with secondary iodides affor-
ded good yields, while the reaction with adamantyl iodide gave a
poor yield (entries 1–3). Replacement of t-butyl iodide with t-butyl
O
N
SiPh3
Ph
O
N
SiPh3
tBuI
Ph
tBu
O2
tBu
Et3B
Et
EtI
Ph3SiI
OH
tBu
O
O
N
N
H2O
SiPh3
tBuI
tBu
Ph
Ph
tBu
Ph
Scheme 2. A plausible reaction mechanism for conversion of O-triphenylsilylated oximes with alkyl iodides in the presence of triethyl borane into the corresponding ketones.

J.-G. Kim et al. / Tetrahedron Letters 53 (2012) 3527–3529
3529
cluded that the reaction proceeds via a radical pathway. This radical
References and notes
reaction proceeds in the presence of triethyl borane/oxygen gener-
ates a tBu radical, which attacks the electrophilic C@N to yield the
corresponding a nitrogen-centered radical. The N-centered radical
undergoes b-silyl fragmentation to yield the corresponding nitroso
compound and a silyl radical. The nitroso compound isomerizes to
the oxime which is hydrolyzed to produce the corresponding ke-
tone during workup (Scheme 2).
In summary, we have developed a method for the synthesis of
ketones including sterically hindered ketones under neutral condi-
tions. The present method provides an easy access to sterically hin-
dered ketones and can be applied to a wide variety of ketone
syntheses.
1. (a) Krause, S.; Schaaf, O.; Nicolau, C.; Eliseev, A. V. J. Med. Chem. 2003, 46, 356;
(b) Tolstoluzhsky, N. V.; Gorobets, N. Y.; Kolos, N. N.; Desenko, S. M. J. Comb.
Chem. 2008, 10, 893; (c) Baskakis, C.; Magrioti, V.; Cotton, C.; Stephens, D.;
Kokotou, V.; Dennis, E. A.; Kokotos, G. J. Med. Chem. 2008, 51, 8027; (d) Kokotos,
G.; Hsu, Y. H.; Burke, J. H.; Baskakis, C.; Kokotos, C. G.; Victoria, M.; Dennis, E. A.
J. Med. Chem. 2010, 53, 3602.
2. (a) Franck, H. G.; Stadelhofer, J. W. Industrial Aromatic Chemistry; Springer-
Verlag: Berlin, 1988; (b) Concise Encyclopedia of Chemistry; McGraw-Hill: New
York, 2004; (c)Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim,
2000; (d) Larock, R. C. Comprehensive Organic Transformations; Wiley-VCH: New
York, 1989.
3. (a) Fronza, G.; Fuganti, C. J. Agric. Food Chem. 1998, 46, 248; (b) Fronza, G.;
Fuganti, C.; Pedrocchi-Fantoni, G.; Serra, S.; Zucchi, G.; Fauhl, C.; Guillou, C.;
Reniero, F. J. Agric. Food Chem. 1999, 47, 1150; (c) Surburg, H.; Panten, J.
Common Fragrance and Flavor Materials, 5th ed.; Wiley-VCH: Weinheim, 2006.
4. (a) Crawford, J. J.; Henderson, K. W.; Kerr, W. J. Org. Lett. 2006, 8, 5073. and
references cited therein; (b) Liu, Y.; Yao, B.; Deng, C.; Tang, R.-Y.; Zhang, X.-G.;
Li, J.-H. Org. Lett. 2011, 13, 2184; (c) Landers, B.; Berini, C.; Wang, C.; Navarro, O.
J. Org. Chem. 2011, 76, 1390; (d) Alonso, F.; Lorenzo, E.; Yus, M. J. Org. Chem.
1996, 61, 6058; (e) Lo Fiego, M. J.; Lockhart, M. T.; Chopa, A. B. J. Organometal.
Chem. 2009, 694, 3674.
5. Zhang, G.; Wen, X.; Wang, Y.; Mo, W.; Ding, C. J. Org. Chem. 2011, 76, 4665.
6. LoFiego,M. J.;Silbestri, G. F.;Chopa, A. B.;Lockhart, M. T. J. Org.Chem. 2011, 76, 1707.
7. Chuzel, O.; Roesch, A.; Genet, J.-P.; Darses, S. J. Org. Chem. 2008, 73, 7800.
8. (a) O’Keefe, B. M.; Simmons, N.; Martin, S. Org. Lett. 2008, 10, 5301; (b) O’Keefe,
B. M.; Simmons, N.; Martin, S. Tetrahedron 2011, 67, 4344.
9. Jang, D. O.; Moon, K. S.; Cho, D. H.; Kim, J. G. Tetrahedron Lett. 2006, 47, 6063.
10. (a) Ortiz-Marciales, M.; De Jesus, M.; Figueroa, D.; Hernandez, J.; Vazquez, L.;
Vega, R.; Morales, E. M.; Lopez, J. A. Synth. Commun. 2003, 33, 311; (b) Ortiz, M.;
Cordero, J. F.; Pinto, S.; Alverio, I. Synth. Commun. 1994, 24, 409.
11. (a) Miyabe, H.; Fujii, K.; Naito, T. Org. Lett. 1999, 1, 569; (b) Miyabe, H.; Ushiro,
C.; Ueda, M.; Yamakawa, K.; Naito, T. J. Org. Chem. 2000, 65, 176; (c) Naito, T.
Chem. Pharm. Bull. 2008, 56, 1367; (d) Kim, S.; Lee, Y.; Yoon, J.-Y.; Oh, D. H. J.
Am. Chem. Soc. 1996, 118, 5138; (e) Kim, S. Adv. Synth. Catal. 2004, 346, 19; (f)
Friestad, G. K. Tetrahedron 2001, 57, 5461; (g) Miyabe, H.; Yoshioka, E.; Kohtani,
S. Curr. Org. Chem. 2010, 14, 1254; (h) Yoshimi, Y.; Kobayashi, K.; Kamakura, H.;
Nishikawa, K.; Haga, Y.; Maeda, K.; Morita, T.; Itou, T.; Okada, Y.; Hatanaka, M.
Tetrahedron Lett. 2010, 51, 2332.
Typical procedure for ketone synthesis
To a stirred solution of O-triphenylsilyl oxime (0.25 mmol) and
t-butyl iodide (368 mg, 2.0 mmol) in toluene at 90 °C was added
triethyl borane (1.25 mL, 1.0 M solution in hexane, 1.25 mmol) un-
der air atmosphere. The resulting mixture was stirred until the
starting material was consumed. The reaction mixture was washed
with saturated sodium bicarbonate solution, and the product was
extracted into ethyl acetate. The organic layer was dried over
MgSO4 and was evaporated under reduced pressure to afford a res-
idue, which was purified by silica gel column chromatography.
Acknowledgments
This work was supported by the Yonsei University. MKM is
grateful for a research fellowship from the Yonsei University.
12. Clive, D. L. J.; Pham, M. P.; Subedi, R. J. Am. Chem. Soc. 2007, 129, 2713.