A remarkably simple α-oximation of aldehydes via organo-SOMO catalysis

Article abstract of DOI:10.1039/c2cc31566a

A novel α-oximation reaction of unactivated aldehydes has been achieved in excellent yields by reaction with NaNO₂-FeCl₃ couple and in the presence of pyrrolidine as organocatalyst.

Full text of DOI:10.1039/c2cc31566a

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COMMUNICATION
A remarkably simple a-oximation of aldehydes via organo-SOMO
catalysisw
Patrizia Gentili* and Silvia Pedetti
Received 1st March 2012, Accepted 5th April 2012
DOI: 10.1039/c2cc31566a
A novel a-oximation reaction of unactivated aldehydes has been
achieved in excellent yields by reaction with NaNO2–FeCl3
couple and in the presence of pyrrolidine as organocatalyst.
allows for the selective preparation of 1,2-dione monoximes using
simple acyclic or cyclic ketones as starting materials in the presence
of an excess of concentrated HCl and an equimolar amount of
sodium nitrite in tetrahydrofuran as solvent at 0 1C.7b Alterna-
tively, treating chlorotrimethylsilane with isoamyl nitrite is an
effective method for the in situ generation of NOCl in aprotic
solvent media as well as under solvent-free conditions.7c Rasmussen
and Hassner showed that addition of an excess of NOCl to
trimethylsilyl enol ethers of ketones and esters in dichloro-
methane at À10 1C to À15 1C gives good yields of 2-hydroxyimino
carbonyl derivatives. Unfortunately, in the case of aldehydes, the
initial 2-hydroxyimino carbonyl products are unstable, but might be
trapped by hydroxylamine as glyoxime derivatives.7d Finally,
Sugamoto and colleagues attempted the reduction–nitrosation of
conjugated olefins; a,b-unsaturated ketones, aldehydes and esters
were directly converted to the corresponding a-oximino carbonyl
compounds in good or moderate yields by reduction–nitrosation
with tert-butyl nitrite and triethylsilane in the presence of 5,10,15,20-
tetraphenylporphinatocobalt(II) as catalyst in i-PrOH–CH2Cl2 at
room temperature.7e
As a result of major developments in the field of organocatalysis in
recent years, a new activation methodology termed SOMO (singly
occupied molecular orbital)-enamine activation was developed by
MacMillan et al. in 2007.1 In the same year, Sibi et al. reported that
using a MacMillan organocatalyst and FeCl3 as a single electron-
transfer (SET) catalyst, aldehydes reacted with 2,2,6,6-tetramethyl-
piperidine-1-oxyl (TEMPO) via an electron-deficient enamine
radical intermediate, giving a-oxyamination products of aldehydes
in satisfactory yields with high enantioselectivities.2 In the last four
years, MacMillan’s research group has developed highly stereo-
selective a-allylation1a and intramolecular allylation,3a a-enolation,3b
a-alkylation,3c a-vinylation,3d a-trifluoromethylation,3e a-nitroalkyl-
ation,3f a-arylation3g and a-chlorination3h of aldehydes, and carbon-
oxidation of styrene3i via SOMO enamine of aldehydes. In 2009,
Nicolaou et al. demonstrated that in the presence of a
MacMillan-type catalyst and cerium ammonium nitrate,
aldehydes bearing electron-donating groups on aromatic rings
underwent an intramolecular Friedel–Crafts-type arylation
with excellent enantioselectivities.4
We present here a new and highly efficient a-oximation
reaction with NaNO2 and FeCl3 in dimethylformamide
(DMF) as solvent, using pyrrolidine as organocatalyst. First,
the reaction conditions for the a-functionalisation of aldehydes
were identified (Table 1). Treatment of 3-phenylpropanal 1a for
4.5 h at room temperature with a stoichiometric amount of
NaNO2 and FeCl3 in the presence of 20 mol% of pyrrolidine and
p-toluenesulfonic acid (p-TsOH) in DMF resulted in a good yield
of 2-hydroxyimino-3-phenylpropanal 2a (Table 1, entry 1). An
excess of NaNO2 and FeCl3 did not increase product yield
(Table 1, entry 2). The reaction carried out in the presence of
30 mol% of iron(III) chloride gave product 2a (yield 68%)
Continuing our studies on aminoxyl radicals (R2NOꢀ),5 we
decided to extend the a-oxyamination reaction of aldehydes to
this class of reactive intermediates other than TEMPO.2 Instead
of the expected a-oxyaminated products, we surprisingly
obtained a-oximinoaldehydes, which are important synthetic
building blocks for many biologically significant compounds
and pharmaceutically useful heterocyclic compounds.6
The direct a-oximation of ketones, esters and aldehydes by
NOCl is well established.7a Generally, it is carried out in
aqueous acid solutions using as nitrosating agent organic
nitrites (isoamyl, isobutyl or tert-butyl nitrite) or inorganic
salts such as NaNO2. In a very interesting article, Ruedi and
colleagues presented a convenient a-oximation method that
together with 15% of (E)-2-benzyl-5-phenyl-2-pentenal
3
(Table 1, entry 3). Accomplishing the reaction in the absence
of FeCl3 only 3 was obtained (yield 60%) and 1a was partially
recovered (Table 1, entry 4). In the absence of pyrrolidine, the
starting aldehyde was completely recovered (Table 1, entry 5).
The reaction under anaerobic conditions gave 2a in quantitative
yield (Table 1, entry 6).
Dipartimento di Chimica and IMC-CNR Sezione Meccanismi di
`
Carrying out the reaction in the presence of NaNO2–
p-TsOH couple, known as a nitrosating system able to produce
the ion NO+,8 the product 2a was obtained in low to moderate
yields even in the presence of an excess of protic acid (Table 1,
entries 7 and 8). When DMSO was employed instead of DMF, the
Reazione, Universita degli Studi La Sapienza, P. le A. Moro 5,
I-00185 Roma, Italy. E-mail: patrizia.gentili@uniroma1.it;
Fax: +39 06 490421; Tel: +39 06 49913082
w Electronic supplementary information (ESI) available: Experimental
details and characterization data for the compounds 2a–g, 4 and 8. See
DOI: 10.1039/c2cc31566a
c
5358 Chem. Commun., 2012, 48, 5358–5360
This journal is The Royal Society of Chemistry 2012

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Table 1 Screening of reaction conditions for a-oximation of 3-phenyl-
propanal 1aa
Yieldsb (%)
Scheme 1 a-Oximation reaction of citronellal 1f.
2a
3
Entry
Solvent
Recovered, 1ab (%)
by the development of red-brown vapours after the introduction
of FeCl3 in the reaction vessel).9
1
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
CH3CN
EtOAc
THF
89
77
68
—
—
98
31
69
58
2
3
—
15
60
4
2c
3d
4e
5f
—
17
22
96
2
67
31
7
82
60
84
Traces
Having identified an appropriate set of conditions, we then
performed reactions with a variety of aldehydes (Table 2). The
experimental results showed that a variety of aliphatic aldehydes
underwent the reaction smoothly, to give the desired a-oximino
product 2b–2g with high yields, regardless of the steric hindrance
of the substituent on Ca (Table 2). When the reaction was carried
out with neral 1h, unfortunately the starting a,b-unsaturated
aldehyde was totally recovered and no trace of g- or a-oximino
aldehyde was present (Table 2, entry 7). Moreover, the reaction
of citronellal 1f with NaNO2–FeCl3 couple gave a-oximino
aldehyde 2f (yield 77%) and 19% of 2-methyl-5-(1-hydroxy-1-
methylethyl)cyclopentanecarbaldehyde 4 as a mixture of the two
diastereomers 4a and 4b in the ratio 2 : 1 (Table 2, entry 5 and
Scheme 1).
—
6g
7e,h
8e,i
9
Traces
—
—
12
10
11
12
13
Traces
7
—
5
8
CH2Cl2
66j
—
a
The reaction of 1a (1.0 mmol), pyrrolidine (0.2 mmol), p-TsOH
(0.2 mmol), H2O (2.0 mmol), NaNO2 (1.0 mmol) and FeCl3 (1.0 mmol) in
1.5 mL of anhydrous solvent was performed for 4.5 h at room temperature.
b
Determined by GC with an internal standard method versus initial moles
d
of 1a. c 1.5 mmol NaNO2 and 1.5 mmol FeCl3 were employed. 0.3 mmol
g
FeCl3 was used. e There is not FeCl3. f There is not pyrrolidine. Under
This latter result provides circumstantial evidence for the
generation and participation of a radical-cation species given
the propensity of these radicals to undergo cyclization with
unactivated olefins,1a,3a,10 thus suggesting the plausible mechanism
depicted in Scheme 2 for the direct a-oximation of aldehydes.
In the presence of p-TsOH, pyrrolidine as an organocatalyst
initially reacts with aldehyde 1a–1g to form the corresponding
enamine 5, followed by oxidation with SET reagent Fe3+ to
generate the three-p-electron SOMO-activated intermediate 6
and Fe2+.2 This transient aminyl radical-cation 6 according to
the persistent radical effect (PRE)11 undergoes highly selective
cross-coupling with the persistent NO. radical (probably formed
by reaction of Fe2+ with nitrite in the presence of H+)12 to give
the cationic imine 7. The nitroso-imine cation 7 tautomerises and
hydrolyses to ultimately form 2-hydroxyimino-aldehyde 2a–2g.
We undertook studies to investigate more precisely the
participation of the putative radical-cation intermediate 6 in
h
an argon atmosphere. 2.2 mmol p-TsOH was used. 3.7 mmol p-TsOH
i
was used. j As PhCH2CH2CO2H and isolated yield.
product 2a was obtained but in moderate yield (Table 1, entry 9).
In other solvents (CH3CN, EtOAc and THF), the reaction barely
occurred (Table 1, entries 10–12).
In CH2Cl2, the isolated product was 3-phenylpropionic acid
instead of 2a (Table 1, entry 13), probably formed by oxidation
of aldehyde 1a by nitrogen oxides (their formation was indicated
Table 2 a-Oximation of aldehydes by the NaNO2–FeCl3 systema
Yieldb (%),
2-hydroxy-
imino-aldehyde (%)
Recovered,
aldehydeb
Entry Aldehyde, R
1
2
3
4
5
C6H5–
1b 2b 95
5
7
4
7
—
C8H17
(CH3)3CCH2CH(CH3)–
–
1c 2c 84
1d 2d 96
1e 2e 93
C6H11
–
(CH3)2CQCHCH2CH2CH(CH3)– 1f 2f 77
19
(CH3)3C–
4
1g 2g 98
6
7
Trace
99
1h — —
a
The reaction of aldehyde 1b–h (1.0 mmol), pyrrolidine (0.2 mmol),
p-TsOH (0.20 mmol), H2O (2.0 mmol), NaNO2 (1.0 mmol) and FeCl3
(1.0 mmol) in 1.5 mL of anhydrous DMF was performed for 3–4.5 h at
b
room temperature. Determined by GC with an internal standard
method versus initial moles of aldehyde.
Scheme 2 Plausible mechanism for the direct a-oximation of
aldehydes.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5358–5360 5359

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Table 3 Oxidation of citronellal 1f with metallic oxidantsa
route for the synthesis of a large variety of natural products
and drugs. In particular, the nitroso function is recognised as a
unique source to prepare nitrogen- and oxygen-containing
molecules. Hence, the methodology reported here adds to
the repertoire of organocatalytic direct a-heteroatom functio-
nalisation of aldehydes and ketones.14
Notes and references
1 (a) T. D. Beeson, A. Mastracchio, J.-B. Hong, K. Ashton and D. W. C.
MacMillan, Science, 2007, 316, 582; (b) S. Bertelsen, M. Nielsen and
K. A. Jørgesen, Angew. Chem., Int. Ed., 2007, 46, 7356.
2 (a) M. P. Sibi and M. Hasegawa, J. Am. Chem. Soc., 2007,
129, 4124; (b) J. F. Van Humbeck, S. P. Simonovich,
R. R. Knowles and D. W. C. MacMillan, J. Am. Chem. Soc.,
2010, 132, 10012.
3 (a) P. V. Pham, K. Ashton and D. W. C. MacMillan, Chem. Sci.,
2011, 2, 1470; (b) H.-Y. Yang, J.-B. Hong and D. W.
C. MacMillan, J. Am. Chem. Soc., 2007, 129, 7004;
(c) D. A. Nicewicz and D. W. C. MacMillan, Science, 2008,
322, 77; (d) H. Kim and D. W. C. MacMillan, J. Am. Chem.
Soc., 2008, 130, 398; (e) D. A. Nagib, M. E. Scott and D. W. C.
MacMillan, J. Am. Chem. Soc., 2009, 131, 10875; (f) J. E. Wilson,
A. D. Casarez and D. W. C. MacMillan, J. Am. Chem. Soc., 2009,
131, 11332; (g) J. C. Conrad, J. Kong, B. N. Laforteza and
D. W. C. MacMillan, J. Am. Chem. Soc., 2009, 131, 11640;
(h) M. Amatore, T. D. Beeson, S. P. Brown and
D. W. C. MacMillan, Angew. Chem., Int. Ed., 2009, 48, 5121;
(i) T. H. Graham, C. M. Jones, N. T. Jui and D. W. C. MacMillan,
J. Am. Chem. Soc., 2008, 130, 16494.
Yieldb (%)
Recovered, 1fb (%)
4 (dr)c 8 (dr)c,d
Entry Oxidant
T/1C
1
2
3
4
Cu(OAc)2
Cu(OAc)2
Mn(OAc)3
80
25
25
—
38e
—
73
33
73g
8 (4)
7 (4)
3 (2)
6 (4)
f
NaNO2–FeCl3 25
13 (0.4) 3 (2)
a
The reaction of 1f (0.33 mmol), pyrrolidine (0.065 mmol), p-TsOH
(0065 mmol) and oxidant (0.65 mmol) in 0.5 mL of anhydrous DMF
b
was performed for 24 h. Determined by GC with an internal standard
method versus initial moles of 1f. c Diastereomeric ratio (dr) was deter-
mined by 1H NMR analysis. Diastereomeric ratio 8a :8c (only 8a and 8c
d
were formed). e Diastereomeric ratio 8a :8b :8c :8d= 29:5:1:1. f NaNO2
g
0.065 mmol and FeCl3 0.065 mmol; reaction time 4.5 h. Product 2f was
present (yield 3%).
this catalytic process. Specifically, aldehyde activation–addition
experiments were performed with Cu(OAc)2 and Mn(OAc)3,
established metallic oxidants used in oxidative free-radical
cyclizations.10
4 K. C. Nicolaou, R. Reingruber, D. Sarlah and B. Stefan, J. Am.
Chem. Soc., 2009, 131, 2086.
5 C. Galli, P. Gentili and O. Lanzalunga, Angew. Chem., Int. Ed.,
2008, 47, 4790.
6 (a) E. Abele and E. Lukevics, in The Chemistry of Hydroxylamines,
Oximes and Hydroxamic Acids, ed. Z. Rappoport and
J. F. Liebman, John Wiley & Sons Ltd, England, 2009, part 1,
ch. 7, pp. 233–302; (b) Y. Ashani and I. Silman, in The Chemistry
of Hydroxylamines, Oximes and Hydroxamic Acids, ed.
Z. Rappoport and J. F. Liebman, John Wiley & Sons Ltd,
England, 2009, part 2, ch. 13, pp. 609–651.
7 (a) O. Touster, Org. React., 1953, 7, 327; (b) G. Ruedi,
M. A. Oberli, M. Nagel, C. Weymuth and H.-J. Hansen, Synlett,
2004, 2315; (c) H. A. M. Abdulkarim and N. Gopalpur, Tetrahedron
Lett., 2003, 44, 2753; (d) J. K. Rasmussen and A. Hassner, J. Org.
Chem., 1974, 39, 2558; (e) K. Sugamoto, Y. Hamasuna,
Y. Matsushita and T. Matsui, Synlett, 1998, 1270.
8 P. B. Sanjay and P. Vincent, Synth. Commun., 2010, 40, 654.
9 (a) Y. Matsumura, Y. Yamamoto, M. Moriyama, S. Furukubo,
F. Iwasaki and O. Onomura, Tetrahedron Lett., 2004, 45, 8221;
(b) Y. Peng, D. Fu, R. Liu, F. Zhang and X. Liang, Chemosphere,
2008, 71, 990.
10 (a) J. Cossy, A. Bouzide and C. Leblanc, Synlett, 1993, 202;
(b) J. Cossy and A. Bouzide, J. Chem. Soc., Chem. Commun.,
1993, 1218; (c) K. Narasaka, T. Okauchi, K. Tanaka and
M. Murakami, Chem. Lett., 1992, 2099.
For instance, oxidation of citronellal 1f with 2 equivalents
of Cu(OAc)2 in the presence of 20 mol% of pyrrolidine and
p-TsOH in DMF at 80 1C for 24 h (Table 3, entry 1) afforded a
yield of 38% containing a 29 : 5 : 1 : 1 mixture of the 2-methyl-
5-(prop-1-en-2-yl)cyclopentanecarbaldehydes 8a, photocitral
A (8b), 8c and epiphotocitral A (8d).3a,13 The same reaction
carried out at room temperature gave 8% of 4 and 3% of 8
(Table 3, entry 2). Similar results were obtained when the
oxidation was performed with Mn(OAc)3 (Table 3, entry 3).
Finally, the reaction of citronellal 1f under the experimental
conditions for a-oximation, but in the presence of only
20 mol% of both NaNO2 and FeCl3 (Table 3, entry 4), gave
principally products 4 and 8 (13% and 3%, respectively), and
only 3% of 2-hydroxyimino-aldehyde 2f. These experimental
results showed that cyclization of 1f could be accomplished
using Cu(OAc)2 and Mn(OAc)3 as oxidants for bona fide
free-radical cyclizations (Table 3, entries 1–3). Moreover, in
the presence of a low concentration of NaNO2–FeCl3 couple,
unsaturated aldehyde 1f gave principally the cyclization
products 4 and 8 (Table 3, entry 4), thus confirming that the
radical-cation 6 is the key intermediate of the a-oximation
mechanism (Scheme 2).
11 (a) D. H. R. Barton, R. P. Budhiraja and J. F. McGhie, J. Chem.
Soc. C, 1969, 336; (b) A. Studer, Angew. Chem., Int. Ed., 2000,
39, 1108; (c) A. Studer, Chem.–Eur. J., 2001, 7, 1159; (d) A. Studer,
Chem. Soc. Rev., 2004, 33, 267; (e) A. Studer and T. Schulte, Chem.
Rec., 2005, 5, 27.
12 I. R. Epstein, K. Kustin and L. Joyce Warshaw, J. Am. Chem.
Soc., 1980, 102, 3751.
In conclusion, we have developed an efficient radical
a-oximation reaction of aldehydes using NaNO2–FeCl3 couple
and pyrrolidine as organocatalyst. The reactions proceed with
good to excellent yields. The introduction of a nitrogen atom
at the a-position of a carbonyl compound provides a valuable
13 B. B. Snider and E. Y. Kiselgof, Tetrahedron, 1996, 52, 6073.
14 (a) T. Vilaivan and W. Bhanthumnavin, Molecules, 2010, 15, 917;
(b) M. Marigo and K. A. Jørgesen, in Enantioselective Organocatalysis,
ed. P. I. Dalko, Wiley-VCH Verlag GmBH & CoKGaA, 2007, ch. 2,
pp. 56–76; (c) M. Marigo and K. A. Jørgesen, Chem. Commun., 2006,
2001.
c
5360 Chem. Commun., 2012, 48, 5358–5360
This journal is The Royal Society of Chemistry 2012