Oxidative conversion of α,α-disubstituted acetamides to corresponding one-carbon-shorter ketones using hypervalent iodine (λ5) reagents in combination with tetraethylammonium bromide

Article abstract of DOI:10.1021/jo801580g

(Chemical Equation Presented) α,α-Disubstituted acetamides undergo oxidative dehomologation to give one-carbon-shorter ketones when reacted with a hypervalent iodine (λ⁵) reagent in combination with tetraethylammonium bromide (TEAB) in various solvents. In further studies, one such combination of a hypervalent iodine (λ⁵) reagent, o-iodoxybenzoic acid, and TEAB has been established as a new, mild, efficient, and general method for the transformation.

Full text of DOI:10.1021/jo801580g

Oxidative Conversion of r,r-Disubstituted
Acetamides to Corresponding
One-Carbon-Shorter Ketones Using Hypervalent
Iodine (λ5) Reagents in Combination with
Tetraethylammonium Bromide
The design and development of a simple method for the
transformation of functional groups is one of the most attractive
research themes for organic chemists. Recently, we have
reported oxidative transformation of primary carboxamides to
one-carbon dehomologated nitriles and N,N-disubstituted gly-
cylamides into corresponding cyanamides.3 In continuation of
the studies of the reactions of acetamides with hypervalent iodine
reagents and tetraethylammonium bromide,3 we report, herein
for the first time, a novel conversion of R,R-disubstituted
acetamides, 1, to corresponding one-carbon-shorter ketones, 2
(Scheme 1).
Eknath V. Bellale, Dinesh S. Bhalerao, and
Krishnacharya G. Akamanchi*
Department of Pharmaceutical Sciences & Technology,
Institute of Chemical Technology, Nathalal Parekh Marg,
Matunga, Mumbai 400 019, India
kgap@rediffmail.com
ReceiVed July 31, 2008
SCHEME 1. Oxidative Conversion of r,r-Disubstituted
Acetamides to Ketones
There are no reports on the oxidative dehomologation of R,R-
disubstituted (alkyl/aryl) acetamides forming ketones using
hypervalent iodine reagents. However, there are some reports
in which R,R-disubstituted acetamides with halide or hydroxyl
groups at their R position have been converted into ketones by
sodium hypohalide in low yields.4
R,R-Disubstituted acetamides undergo oxidative dehomolo-
gation to give one-carbon-shorter ketones when reacted with
a hypervalent iodine (λ5) reagent in combination with
tetraethylammonium bromide (TEAB) in various solvents.
In further studies, one such combination of a hypervalent
iodine (λ5) reagent, o-iodoxybenzoic acid, and TEAB has
been established as a new, mild, efficient, and general method
for the transformation.
There are other methods for the dehomologative conversion
of carboxylic acids into ketones.5a These include the reaction
of carboxylic acid with the iron porphyrin-iodosylbenzene
system5b and tetrabutylammonium periodate in refluxing diox-
ane.6 These methods are not convenient due to their long
reaction time and lower yields. The oxidative decarboxylation
of carboxylic acid derivatives via dianion formation, using
lithium diisopropylamide (LDA) and followed by oxygenation,
gives ketone in poor yields and also is an inconvenient method.7
In our preliminary experiments, 1.0 equiv of R,R-dipheny-
lacetamide was treated with 2.5 equiv of IBX in combination
with 2.5 equiv of TEAB in acetonitrile at 60 °C. As expected,
benzophenone, 2a, was obtained in excellent yields in 15 min,
whereas the reaction carried out at room temperature required
a longer reaction time. Studies on optimization of the reaction
were carried out, and the results are summarized in Table 1.
The best yield was obtained with 2.0 equiv of IBX in
Hypervalent iodine (λ5) reagents, mainly o-iodoxybenzoic
acid (IBX) and Dess-Martin periodinane (DMP), have become
alternative oxidizing agents for various metal oxidants. The
versatility of these reagents is becoming firmly established by
the various transformations they cause, like oxidative C-C
coupling, oxidative cyclization, oxidative rearrangements, oxida-
tive deoximation, oxidative ring expansion and contraction,
C-N bond formation, and oxidation of alcohols,1 etc. Because
of their mildness and chemoselectivity, these are the preferred
reagents in the total synthesis of various complex molecules,
including natural products.2
(1) (a) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2002, 102, 2523. (b)
Zhdankin, V. V. Curr. Org. Synth. 2005, 2, 121. (c) Stang, P. J.; Zhdankin,
V. V. Chem. ReV. 1996, 96, 1123. (d) Zhu, J.; Germain, A. R.; Porco, J. A., Jr.
Angew. Chem., Int. Ed. 2004, 43, 1239. (e) Dixon, M. J.; Andersen, O. A.; van
Aalten, D. M. F.; Eggleston, I. M. Eur. J. Org. Chem. 2006, 5002. (f) Nicolaou,
K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y. L. J. Am. Chem. Soc. 2002, 124,
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Finney, N. S. Synlett 2003, 1307. (d) VanderRoest, J. M.; Grieco, P. A. J. Org.
Chem. 1996, 61, 5316. (e) Lach, F.; Moody, C. J. Tetrahedron Lett. 2000, 41,
6893. (f) Bueno, J. M.; Coteron, J. M.; Chiara, J. L.; Fernandez-Mayoralas, A.;
Fiandor, J. M.; Valle, N. Tetrahedron Lett. 2000, 41, 4379. (g) Weigelt, D.;
Krahmer, R.; Bruschke, K.; Hennig, L.; Findeisen, M.; Muller, D.; Welzel, P.
Tetrahedron 1999, 55, 687. (h) Gonzalez, M. A. Tetrahedron 2008, 64, 445.
(3) (a) Bhalerao, D. S.; Mahajan, U. S.; Chaudhari, K. H.; Akamanchi, K. G.
J. Org. Chem. 2007, 72, 662. (b) Chaudhari, K. H.; Mahajan, U. S.; Bhalerao,
D. S.; Akamanchi, K. G. Synlett 2007, (18), 2815.
(4) Wallis, E. S.; Lane, J. F. In Organic Reactions; Adams, R., Ed.; John
Wiley & Sons: New York, 1946; Vol. 3, p 267 and references therein.
(5) (a) Mirkhani, V.; Tangestaninejad, S.; Moghadam, M.; Moghbel, M.
Bioorg. Med. Chem. 2004, 12, 903, and references therein. (b) Komuro, M.;
Nagatsu, Y.; Higuchi, T.; Hirobe, M. Tetrahedron Lett. 1992, 33, 4949.
(6) Santaniello, E.; Ponti, F.; Manzocchi, A. Tetrahedron Lett. 1980, 21, 2655.
(7) (a) Wasserman, H. H.; Lipshutz, B. H. Tetrahedron Lett. 1975, 16, 4611.
(b) Nokami, J.; Kawada, M.; Okawara, R.; Torii, S.; Tanaka, H. Tetrahedron
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3101.
10.1021/jo801580g CCC: $40.75
Published on Web 10/31/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9473–9475 9473

TABLE 1. Studies on the Mole Ratio of Substrate IBX:TEABa
TABLE 4. Oxidative Conversion of r,r-Disubstituted Acetamide
to Ketonea b
,
IBX
(equiv)
TEAB
(equiv)
recovered starting
material (%)
entry
yieldb (%)
1
2
3
4
5
6
7
2.5
2.0
1.5
1.0
2.0
2.0
2.0
2.5
2.0
1.5
1.0
0.1
1.0
1.5
98
98
0
0
13
33
85
0
74c
60c
10c
98
98
0
a Reactions were conducted on a 5 mmol scale. b Yield was by gas
chromatography. c No further conversion occurred, even with increased
reaction time.
TABLE 2. Solvent Study for the Conversion of
r,r-Diphenylacetamide 1a to Benzophenone 2aa
sr. no.
solvent
yieldb (%)
1
2
3
4
5
toluene
dioxane
tetrahydrofuran
acetonitrile
chloroform
90
71
65
98
92
a Reactions were conducted on a 5 mmol scale at 60 °C with IBX
(2.0 equiv) and TEAB (1.0 equiv). b Yield was by gas chromatography.
TABLE 3. Reactions with Other Hypervalent Iodine (λ5)
Reagentsa
entry
1
reagent
IBX
temperature
time
8 h
yieldb (%)
rt
92
60 °C
rt
60 °C
rt
15 min
22 h
50 min
24 h
98
90
2
3
DMP
HIO3
90
NRc
NRc
60 °C
24 h
a Reactions were conducted on a 5 mmol scale. b Yield was by gas
chromatography. c No reaction.
combination with 1.0 equiv of TEAB (entry 6). When a catalytic
amount of TEAB was used, the reaction did not proceed to
completion (entry 5).
Reactions were carried out in different solvents, and many
solvents were found to be viable. The best results were obtained
with acetonitrile (Table 2). Also, both DMP and HIO3 were
screened for the reaction. DMP gave a 90% yield in 50 min,
whereas no reaction occurred with HIO3 (Table 3).
To explore the generality of the reaction, a variety of
substrates was reacted with optimized reaction conditions, i.e.,
2.0 equiv of IBX in combination with 1.0 equiv of TEAB at 60
°C in acetonitrile. The results are summarized in Table 4. The
results indicate that acetamides having at least one aromatic
substituent at the R position reacted comparatively faster and
gave relatively higher yields in comparison to the reaction speed
and yields of the dialkyl and cycloalkyl acetamides (entries
7-10). Acetamides containing a heterocyclic substituent also
underwent smooth transformation (entries 11 and 12).
a Reactions were conducted on 5 mmol scale in acetonitrile at 60 °C
with IBX (2.0 equiv) and TEAB (1.0 equiv). b For preparation of
R,R-disubstituted acetamides, see Supporting Information. c Yield after
column chromatography, and the compounds were characterized by IR,
1H NMR, and physical constants. d Numbers in parentheses indicate the
reaction time and the yield for the reaction at rt, respectively.
Some investigations were carried out to study the trans-
formation. During the reaction, in all cases, the formation
of a nonpolar intermediate (as seen with TLC) was observed,
which disappears during the workup to form ketone. In the
9474 J. Org. Chem. Vol. 73, No. 23, 2008

SCHEME 2. Plausible Mechanism for the Oxidative
Conversion of r,r-Disubstituted Acetamides to Ketones
of bromide ions from reaction medium, explains why the use
of a catalytic amount of TEAB is not feasible.
In order to justify the isocynate inclusion as a possible
intermediate in the mechanism, cyclohexyl isocynate, 1i D, was
reacted with IBX/TEAB and with o-iodosylbenzoic acid (IBA)/
TEAB. Both were found to be very fast reactions, giving
cyclohexanone, 2i, in 85-90% yield (Scheme 3).
In summary, an efficient and mild method for the conversion
of R,R-disubstituted acetamides to the corresponding one-
carbon-shorter ketones with hypervalent iodine (λ5) reagents was
developed, particularly when using IBX in combination with
TEAB.
Experimental Section
General Experimental Procedure for the Preparation of
Ketones. To a stirred suspension of 10 mmol of hypervalent iodine
(λ5) reagent and 30 mL of CH3CN was added 5 mmol of TEAB,
and the mixture was stirred for 5 min. A yellow suspension was
observed to which was added R,R-disubstituted acetamides, 1 (5
mmol), in one portion at rt. The temperature of the reaction mixture
was raised to 60 °C, and the mixture was stirred until complete
consumption of the starting material, as observed with TLC.
Acetonitrile was removed under reduced pressure, and the resultant
residue was suspended in 30 mL of chloroform and filtered. The
organic layer was washed with 30 mL of 10% sodium bisulfite
solution, 30 mL of saturated sodium bicarbonate, and 30 mL of
brine. The organic layer was dried over anhydrous sodium sulfate
and concentrated to give crude ketone. Pure ketones, 2, were isolated
after silica gel column chromatography (EtOAc:hexane ) 5:95).
Benzophenone, 2a. White solid, mp 47-48 °C. 1H NMR (300 MHz,
CDCl3): δ 7.80-7.78 (d, J ) 7.8 Hz, 4H), 7.59-7.54 (t, J ) 7.35
Hz, 2H), 7.49-7.44 (t, J ) 7.5 Hz, 4H). IR (KBr) νmax: 3060, 3030,
SCHEME 3. Reaction of Cyclohexyl Isocynate with
IBX/TEAB
and 1659 cm-1
.
case of R,R-diphenylacetamide, this intermediate, H (Scheme
2), was isolated and characterized by NMR, IR, and MS,
and it was found to be N-bromo-1,1-diphenylmethanimine,
1a H.
It is reported that N-bromoimines are less stable and slowly
hydrolyze to give ketones.8 Because of this observation and on
the basis of our previous investigations,3a a tentative mechanism
is proposed for the transformation (Scheme 2). The formation
of the N-bromoimine intermediate, H, which results into removal
Acknowledgment. E.V.B. thanks the World Bank for finan-
cial assistance under the Technical Education Quality Improve-
ment Program (TEQIP). We are also thankful to M/S Omkar
Chemicals in Badalapur, Thane, India, for their generous gift
of IBX.
Supporting Information Available: General methods and
spectral data of all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(8) Praly, J. P.; Senni, D.; Faure, R.; Descotes, G. Tetrahedron 1995, 51,
1697.
JO801580G
J. Org. Chem. Vol. 73, No. 23, 2008 9475