Regio- and enantioselective direct oxyamination reaction of aldehydes catalyzed by α,α-diphenylprolinol trimethylsilyl ether

Article abstract of DOI:10.1002/anie.200703001

(Chemical Equation Presented) Donors not required: External hydrogen-bond donors are not required for a highly regio- and enantioselective oxyamination reaction of aldehydes with nitrosobenzene (see scheme). The reaction proceeds in the presence of the st

Full text of DOI:10.1002/anie.200703001

Communications
DOI: 10.1002/anie.200703001
Organocatalysis
Regio- and Enantioselective Direct Oxyamination Reaction of
Aldehydes Catalyzed by a,a-Diphenylprolinol Trimethylsilyl Ether**
Claudio Palomo,* Silvia Vera, Irene Velilla, Antonia Mielgo, and Enrique Gómez-Bengoa
The nitroso function is recognized as a unique source to
prepare nitrogen- and oxygen-containing molecules, and
various catalytic asymmetric reactions of nitroso com-
pounds[1] such as aminoxylation,[2] oxyamination,[3] and ni-
troso Diels–Alder reactions[4] have recently been developed
which exploit their unique properties. Owing to the high
reactivity of nitroso derivatives toward nucleophiles, control-
ling the regioselectivity of either the nitrogen or oxygen to
preferentially react with the nucleophile is a challenge of
fundamental importance. Investigations of the reaction of
nitrosobenzene with a silyl or metal enolate have revealed
that the O versus N selectivity is dependent on the nature of
the enolate and the presence or absence of a Lewis acid
catalyst.[5] Yamamoto and Momiyama reported the reaction
between preformed enamines and nitrosobenzene in the
presence of catalytic amounts of glycolic acid to preferentially
afford the O-nitroso aldol product, while in the presence of
TADDOL (a,a,a’,a’-tetraaryl-2,2-dimethyl-1,3-dioxolan-4,5-
dimethanol) the a-amino derivatives are exclusively obtained
(Scheme 1).[6]
also been actively investigated.[2d–o,7] In sharp contrast, only
two contributions on organocatalyzed direct nitrosoaldol
reactions of carbonyl compounds that take place preferen-
tially at the nitrogen have been reported.[2a,8] The first by
Maruoka and co-workers[3a] described the asymmetric oxy-
amination reaction of aldehydes with nitrosobenzene cata-
lyzed by the novel binaphthyl-based axially chiral secondary
amine 1 (Figure 1). Although the preparation of the catalyst
Figure 1. Developed organocatalysts for the N-nitroso aldol reaction of
aldehydes (1 and 2) and a complementaryalternative proposal ( 3).
Organocatalyzed reactions of nitrosobenzene and car-
bonyl compounds with proline and its derivatives as catalysts
to give a-oxygenated compounds as the major products have
requires several steps, high yields and excellent enantioselec-
tivities were achieved. The second report implied the direct
nitrosoaldol reaction of a-branched aldehydes in the presence
of the l-prolinamide derivative 2 (Figure 1) as catalyst.[3b] In
this case, the catalyst is structurally simple, but the reported
enantioselectivities were modest. Here, we present our
finding that prolinol ether derivatives are capable of effi-
ciently promoting the oxyamination reaction of aldehydes
with nitrosobenzene.
A structural feature of catalysts 1 and 2 for the direct
oxyamination of aldehydes is the presence of a weak hydro-
gen-bond donor (OH group), which apparently coordinates
the oxygen atom of nitrosobenzene to facilitate the oxy-
amination pathway.[9] We hypothesized that the a-oxyamina-
tion of aldehydes could be promoted by catalysts which lack
hydrogen-bond donors. As the reaction results in the pro-
duction of hydroxylamine, either the product itself or water
generated from formation enamine could activate the oxy-
amination reaction through hydrogen-bond coordination to
the oxygen of nitrosobenzene. In a first instance and owing to
the recent emergence of a,a-diarylprolinol ether derivatives
as fairly general organocatalysts,[10] we considered that
derivative 3[11] (Figure 1) could be a reasonable candidate to
evaluate the above assumption. Concordant with our expect-
ations, product 6b (Table 1, entry 3), obtained from the
reaction of butanal with nitrosobenzene promoted by 3 in
methylene chloride as solvent, was produced after subsequent
reduction of the resulting oxyaminated intermediate, in good
yield and, most remarkably, with essentially perfect regiose-
Scheme 1. Possible products from the nitroso aldol reaction.
[*] Prof. Dr. C. Palomo, S. Vera, I. Velilla, Dr. A. Mielgo,
Dr. E. Gómez-Bengoa
Departamento de Química Orgµnica I
Facultad de Química
Universidad del País Vasco. Apdo. 1072
20080 San Sebastiµn (Spain)
Fax: (+34)943-015-270
E-mail: claudio.palomo@ehu.es
[**] This work was financiallysupported byThe Universityof the Basque
Country(UPV/EHU) and the Ministerio de Educación yCiencia
(MEC, Spain). Predoctoral grants to S.V. (MEC) and to I. Velilla
(UPV/EHU) are also acknowledged. We also thank the SGI/IZO-
SGIker UPV/EHU for allocation of computational resources.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
8054
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Angewandte
Chemie
Table 1: Solvent screening in the oxyamination reaction of butanal with
À208C overnight (Table 2, entries 4–6) in either methylene
nitrosobenzene.[a]
chloride or THF.
The absolute configuration of the resulted adduct in the
reaction of pentanal with nitrosobenzene was determined by
comparison of the value for the optical rotation with that
previously described[3a] and was found to be S. This result is in
accordance with the approach of the nitrosobenzene by the
Si face of the enamine as shown in Figure 2.
EntrySolvent
6b/7b
Yield [%][b]
ee [%][c]
1
2
3
4
5
toluene
THF
CH2Cl2
CH3CN
H2O
>99:1
>99:1
>99:1
>99:1
>99:1
21
40
65
n.d.[d]
90
90
85
90
50
25[e]
[a] Reactions were conducted with aldehyde (3 equiv) at 08C, with
addition of the catalyst to a solution of the aldehyde and nitrosobenzene.
[b] Isolated yield of product 6b after column chromatography. [c] Deter-
mined byHPLC analysis. See Supporting Information for further details.
[d] Not determined. [e] Nitrosobenzene shows poor solubilityin water.
Figure 2. The approach of nitrosobenzene from the Si face of the
enamine.
lectivity and very high enantioselectivity. Screening of other
solvents for this reaction revealed that THF and acetonitrile
are also efficient, although methylene chloride is somewhat
superior.
To gain more insight into our assumption, we computed by
density functional theory (DFT) the different transition states
À
À
Results with other aldehydes are shown in Table 2. The
reactions were carried out by dropwise addition of catalyst 3
to a greenish solution of nitrosobenzene and the aldehyde in
methylene chloride at 08C or room temperature, whereby an
almost instantaneous decoloration was observed after the
addition (Table 2, entries 1–3, 7–10). In general, the oxy-
amination reaction proceeded fast and the subsequent
reduction with sodium borohydride provided the correspond-
ing N-hydroxy b-aminoalcohols 6 in good yields over the two
steps and with excellent enantioselectivities. Long-chain
aldehydes afford at room temperature the expected adducts
in somewhat lower yields (Table 2, entry 7). In these cases, the
best results are obtained by carrying out the reaction at
for the formation of the C N and C O bonds in the reaction
between propionaldehyde and nitrosobenzene in the absence
of any added hydrogen-bonding source (non-functionalized
pyrrolidine catalyst) and in the presence of water or N,N-
dimethylhydroxylamine (8; mimicking product 6 or its
precursor).[12] We found that the free activation energy DG°
for the non-catalyzed oxyamination is 25.6 kcalmolÀ1 (Fig-
ure 3A). Water or N,N-dimethylhydroxylamine (8) catalyze
the reaction with similar efficiency, reducing the activation
barrier to 20.9 kcalmolÀ1 for water (Figure 3B) and 20.3 kcal
molÀ1 for 8 (Figure 3C).
In agreement with the experimentally encountered regio-
selectivity of over 99:1 in favor of the formation of 6, the
computed DG° values for the non-
catalyzed and catalyzed aminoxyla-
Table 2: Enantioselective oxyamination of various aldehydes with nitrosobenzene.[a]
tion are in all cases over 3.0 kcal
molÀ1 higher than those of the oxy-
amination.
In summary, we have demon-
strated that the direct and regiose-
lective oxyamination reaction of
aldehydes with nitrosobenzene can
be successfully achieved in the pres-
ence of a structurally simple and
readily accessible organocatalyst
such as a,a-diphenylprolinol trime-
thylsilyl ether to afford the oxy-
aminated compounds in good yields
and with excellent regio- and enan-
tioselectivities.
Entry
6,7
R
Solvent
t [min]
T [8C]
6/7[b]
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
9
a
b
c
c
d
e
e
f
Me
Et
nPr
nPr
n-Pent
n-Hex
n-Hex
Bn
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
5
5
RT
0
0
À20
À20
À20
RT
0
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
70
65
60
66
74
75
42
70
40
60
94
99
96
98
10
30
16 h
16 h
5
5
5
30
98[e]
98[e]
n.d.[f]
94
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
g
h
2-MeOC6H4CH2
iPr
RT
0
91
99
10
[a] Reactions were conducted with aldehyde (3 equiv) at 08C or RT, with addition of the catalyst to a
solution of the aldehyde and nitrosobenzene. See Experimental Section for the experimental procedure
at À208C. [b] Determined by 1H NMR spectroscopic analysis of the crude mixture. [c] Isolated yield of
Experimental Section
product 6 after column chromatography. [d] Determined by HPLC analysis. See Supporting Information General procedure for the oxyamination
for further details. [e] Determined by HPLC analysis of the benzoyl and naphthoyl derivatives. See of aldehydes with nitrosobenzene: The
Supporting Information for further details. [f] Not determined.
catalyst (0.4 mmol, 20 mol%) was added
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Communications
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to a solution of the aldehyde (6 mmol, 3 equiv) in THF (1 mL) at
À208C. A solution of nitrosobenzene (2 mmol, 1 equiv) in THF
(1 mL) was then added dropwise to the reaction mixture, and the
resulting solution was stirred at À208C for 16 h. EtOH (2 mL) and
NaBH4 (8 mmol) were successively added at the same temperature,
and after stirring for 30 min the reaction was quenched with saturated
NaCl (3 mL) and allowed to reach room temperature. After
extraction with CH2Cl2 (3 ” 4 mL), the combined organic phases
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chromatography to afford the expected adducts.
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Received: July 5, 2007
Revised: July 18, 2007
Published online: September 12, 2007
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[12] All the calculations were performed at the standard 6-31G* basis
set (see Supporting Information for details). Further studies at
higher level involving the actual catalyst 3, as suggested by one
referee, are currently underway.
Keywords: aldehydes · enantioselectivity · organocatalysis ·
.
oxyamination · regioselectivity
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