Bronsted acid assisted regio- and enantioselective direct o-nitroso aldol reaction catalysed by α,α-diphenylprolinol trimethylsilyl ether

Article abstract of DOI:10.1002/chem.201000376

In the presence of p-nitrobenzoic acid, the O-nitroso aldol reaction of nitrosobenzene with enolisable aldehydes may be promoted by commercially available α,α-diphenylprolinol trimethylsilyl ether. The reaction proceeds with good yields and essentially complete enantioselectivity, with catalyst loadings in the 510 mol % range. The resulting α-oxyaldehyde adducts may be transformed in situ into α-oxyimines, which provide 1,2-amino alcohols upon treatment with Grignard reagents, in good overall yield (45-59%) and with typical diastereomeric ratios ≥ 95:5.

Full text of DOI:10.1002/chem.201000376

DOI: 10.1002/chem.201000376
Brønsted Acid Assisted Regio- and Enantioselective Direct O-Nitroso Aldol
Reaction Catalysed by a,a-Diphenylprolinol Trimethylsilyl Ether
Antonia Mielgo, Irene Velilla, Enrique Gꢀmez-Bengoa, and Claudio Palomo*[a]
Dedicated to Professor Saverio Florio on the occasion of his 70th birthday
Abstract: In the presence of p-nitrobenzoic acid, the O-nitroso aldol reaction of
nitrosobenzene with enolisable aldehydes may be promoted by commercially avail-
able a,a-diphenylprolinol trimethylsilyl ether. The reaction proceeds with good
Keywords: amino alcohols · enam-
yields and essentially complete enantioselectivity, with catalyst loadings in the 5–
ine activation · aldehydes · nitroso
10 mol% range. The resulting a-oxyaldehyde adducts may be transformed in situ
aldol reaction · organocatalysis
into a-oxyimines, which provide 1,2-amino alcohols upon treatment with Grignard
reagents, in good overall yield (45–59%) and with typical diastereomeric ratios
ꢀ95:5.
Introduction
amine by using proline (1) and secondary amines 2–6
(Scheme 1) in sub-stoichiometric quantities.[5] A common
structural feature of all these catalysts is the presence of a
The asymmetric O-nitroso aldol reaction is an important
tool for the preparation of enantioenriched a-hydroxy car-
bonyl compounds.[1] In this reaction two important issues
are the enantioselectivity and regioselectivity—attack
through the nitrogen atom (oxyamination reaction) or
oxygen atom (aminoxylation reaction).[2] First insights by
Yamamoto et al. on the reaction of nitrosobenzene with silyl
or metal enolates revealed that the regioselectivity of the
process is dependent on the nature of the enolate and the
presence or absence of a Lewis acid catalyst.[3] Later, the
same author reported that in the presence of sub-stoichio-
metric amounts of glycolic acid the reaction of nitrosoben-
zene with pre-formed enamines preferentially afforded O-
nitroso aldol products (aminoxylation). Conversely, in the
presence of a,a,a’,a’-tetraaryl-2,2-dimethyl-1,3-dioxolan-4,5-
dimethanol (TADDOL), the a-amino derivatives were ex-
clusively obtained (oxyamination).[4] Some examples of
highly enantioselective nitroso aldol reactions have also
been realised through in situ generation of the reactive en-
Scheme 1. Organocatalysts for the nitroso aldol reaction: A) Catalysts for
aminoxylation, B) Catalysts for oxyamination. TMS=trimethylsilyl,
TBS=tert-butyldimethylsilyl.
[a] Dr. A. Mielgo, I. Velilla, Dr. E. Gꢀmez-Bengoa,+ Prof. Dr. C. Palomo
Departamento de Quꢁmica Orgꢂnica I, Universidad del Paꢁs Vasco
Manuel Lardizabal 3, 20018 San Sebastiꢂn (Spain)
Fax : (+34)943015270
E-mail: claudio.palomo@ehu.es
[+] Computational study.
Brønsted acid functionality as key element for controlling
regioselectivity.[6] Thus, catalysts with strong acidic function-
alities, such as carboxylic acids or sulfonamides (1–4 in
Scheme 1A), predominantly give a-oxygenated products,
whereas those that contain less acidic functionalities,
namely, hydroxy groups (5, 6 in Scheme 1B), afford mainly
a-oxyaminated compounds.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000376.
7496
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Chem. Eur. J. 2010, 16, 7496 – 7502

FULL PAPER
a,a-Diarylprolinol silyl ethers, such as 7, have proven to
be very effective chiral amine catalysts in a number of orga-
nocatalytic transformations.[7,8] In contrast to proline and its
congeners, these catalysts work through steric control[9] and
very high levels of enantioselectivity may be achieved. This
concept has not been applied to the O-nitroso aldol reaction
(Scheme 2) as yet. Herein, we report the first O-nitroso
aldol reaction catalysed by commercially available a,a-di-
phenylprolinol trimethylsilyl ether (7), for the formation of
a-aminoxylated products with extremely high regio- and
enantiocontrol.
with 91–99% enantiomeric excess (ee).[13] We were pleased
to find that in CH2Cl2 at À208C a catalyst loading between
2 and 10 mol% sufficed for the O-nitroso aldol reaction to
proceed with the assistance of a Brønsted acid, without ap-
preciable formation of N-nitroso aldol products (Scheme 3).
Scheme 3. O-Nitroso aldol reaction between aldehydes 10 and nitroso-
benzene (11), catalysed by 7. PNBA= p-nitrobenzoic acid, Boc=tert-bu-
tyloxycarbonyl, Bn=benzyl.
For example, compound 12a, obtained from the reaction of
propanal with nitrosobenzene (11) in the presence of cata-
lyst 7 (2 mol%) and benzoic acid (5 mol%), followed by in
situ reduction with NaBH4, was formed with essentially
complete regio- and enantioselectivity (Table 1, entry 1).
Scheme 2. Catalytic nitroso aldol reaction promoted by secondary amine
catalysts 1–4 and 7.
Table 1. Brønsted acid screening for the O-nitroso aldol reaction of
propanal (10a) with nitrosobenzene (11) promoted by catalysts 7–9.[a]
Entry
Catalyst
Additive
Yield of
ee[c]
[%]
12a[b] [%]
Results and Discussion
1
2
3
4
5
PhCO2H
50
22
81
35
52
>99
>99
>99
>99
>99
Background, catalyst screening and conditions: Previously,
we reported that the reaction of aldehydes with nitrosoben-
zene may be promoted by catalyst 7 to produce a-oxyami-
nated products as single regioisomers.[10] We envisaged that
in the presence of an external Brønsted acid a switch in re-
giocontrol might occur in the above reaction, as a result of a
protonation of the nitrogen atom of nitrosobenzene.[11] The
question was to establish whether O-nitroso aldol adducts
would be produced as sole reaction products to render the
procedure operationally simple and practical. In this way,
generation of both a-amino and a-hydroxy carbonyl com-
pounds from a common chiral source should be made feasi-
ble, which would be useful from a practical viewpoint. The
resulting O-nitroso aldol adducts could be easily trans-
formed in situ into 1,2-diols and related compounds, which
are of considerable interest because these structural moiet-
ies are widely found in biologically active natural products
and synthetic pharmaceuticals.[12]
4-MeOC6H4CO2H
4-NO2C6H4CO2H
CH3CO2H
ClCH2CO2H
6
7
4-NO2C6H4CO2H
4-NO2C6H4CO2H
<5
nd[d]
70
>99
[a] Reactions performed on a 1 mmol scale in CH2Cl2 (2 mL) with cata-
lyst (2 mol%), Brønsted acid (5 mol%) and 10a (3 equiv) at À208C for
16 h. [b] Isolated yield after flash column chromatography. [c] Deter-
mined by HPLC analysis after flash chromatography; see the Supporting
Information for details. [d] Not determind.
From the outset we realised that the search for reaction
conditions under which the oxyamination would be slow or
totally suppressed would be central for the success of this
approach. In our initial studies, it was observed that the re-
action of nitrosobenzene with freshly distilled enolisable al-
dehydes proceeds efficiently in CH2Cl2 at temperatures
ꢀ08C (typically in the range 08C–RT), or in THF at À208C
for long-chain aldehydes. In all cases 20 mol% of catalyst 7
was required for the reaction to proceed and the resulting
N-nitroso aldol products were obtained in 60–75% yield,
When this reaction was conducted in the absence of acid, no
a-oxyaminated nor a-aminoxylated adducts were detected
1
by H NMR spectroscopy. Other Brønsted acids[14] were ex-
amined and it was found that PNBA (Table 1, entry 3) was
superior in terms of both chemical yield and enantioselectiv-
ity, whereas the less acidic p-methoxybenzoic acid (Table 1,
entry 2) provided the product in lower yield. Similarly, the
more acidic chloroacetic acid provided better yield than
acetic acid (Table 1, entries 4 and 5).
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7497

C. Palomo et al.
For comparison, other catalysts that work through steric
control (Table 1, entries 6 and 7) were tested. Catalyst 8,[7a,b]
which has proven to be very effective in diverse enamine-
based reactions,[8,15] did not lead to the expected adducts,
whereas the a,a-dihexylprolinol silyl ether 9[16] behaved sim-
ilarly to the commercially available catalyst 7.
Screening of other solvents for this reaction (Table 2) re-
vealed that CHCl3 and 1,2-dichloroethane were also effec-
tive. Diethyl ether and THF, or more polar solvents such as
methanol and DMF, were not appropriate. In acetonitrile
and toluene the yield was modest but could be improved by
increasing the catalyst loading to 10 mol% (Table 2, en-
tries 1 versus 2 and 9 versus 10).
chloromethane at À208C. The reaction was easily monitored
by complete disappearance of the initial green colour. The
resulting adducts were reduced in situ by treatment with
sodium borohydride in ethanol to afford the aminoxylated
compounds 12 as one regioisomer.[17] Both, short- and long-
chain aldehydes, as well as functionalised aldehydes, are tol-
erated. Even the less reactive isovaleraldehyde was convert-
ed to 12e, although afforded the expected adduct in some-
what lower yield (Table 3, entries 7 and 8). The reactions of
freshly distilled hydrocinnamaldehyde with 11 conducted
under these conditions, but in the absence of PNBA, afford-
ed neither N- nor O-nitroso aldol products.[13] In general, we
have employed 10 mol% of catalyst for the O-nitroso aldol
reaction, although it can be reduced to 5 mol% without det-
riment to the yield or ee value (Table 3, entries 3 and 6).
With the exception of propanal, the use of 2 mol% of cata-
lyst was not effective.
Table 2. Solvent screening for the aminoxylation reaction of propanal
(10a) with nitrosobenzene (11) promoted by catalyst 7.[a]
Entry
Solvent
Yield of 12a[b] [%]
ee[c] [%]
The absolute configuration of the adduct 12b from the re-
action of 10b with 11 was determined by comparison of the
value of the optical rotation of the free diol with that previ-
ously described and was found to be S.[5f] This approach pro-
vides (S)-aminoxylated aldehydes from the S-prolinol silyl
ether 7, thus complements the results obtained with S-pro-
line and its congeners, which afford the R enantiomer.[18]
1
2
3
4
5
6
7
8
toluene
toluene
Et2O
THF
CHCl3
CH2Cl2
ClCH2CH2Cl
MeOH
CH3CN
CH3CN
DMF
22
67[d]
10
<10
71
>99
>99
nd[e]
nd[e]
>99
>99
>99
nd[e]
>99
>99
nd[e]
80
71
<10
41
9
10
11
53[d]
<10
Synthetic applications: The a-oxyaldehyde adducts are gen-
erally unstable and must be isolated as the corresponding al-
cohols. Nonetheless, they may undergo reactions typical of
aldehydes,[12] such as Grignard additions to produce 1,2-dis-
ubstituted diols with remarkably high diastereoselectivity.[12a]
We now show that 1,2-aminoalcohols, common structural
motifs in naturally occurring and synthetic molecules,[19] may
also be produced with equal efficiency by Grignard addition
to the corresponding imines.
[a] Reactions conducted with 10a (3 equiv), 7 (2 mol%) and PNBA
(5 mol%) at À208C for 16 h. [b] Isolated yield after column chromatog-
raphy. [c] Determined by HPLC analysis; see the Supporting Information
for further details. [d] Reactions conducted with catalyst 7 (10 mol%)
and PNBA (10 mol%). [e] Not determined.
Results obtained from the reaction of 11 with other alde-
hydes are shown in Table 3. The reactions were carried out
by addition of the aldehyde 10a–h (3 equiv) to a solution of
the catalyst (10 mol%), PNBA (10 mol%) and 11 in di-
As illustrated in Scheme 4, the nitroso aldol reaction from
hydrocinnamaldehyde (10d) with catalyst 7 provided the
corresponding aldehyde adduct 12d, which could be trans-
formed in situ to the imine 13. At this stage, Grignard addi-
tion[20] afforded the expected adducts with concomitant par-
tial cleavage of the phenylaminoxy group.[12a] Subsequent
hydrogenation provided the expected (S,S)-amino alcohols
14 and 15 in good yields over four steps and, most remarka-
bly, with essentially perfect diastereocontrol.[21] As predict-
ed, the same sequence of reactions and the use of l-proline
for the nitroso aldol addition[5b] led to the production of
(R,R)-amino alcohol 16. N-Aryl imines[22] can also be
formed and treated with Grignard reagents. For instance,
following the same sequence, the aldehyde adduct from the
reaction of propanal with 11 afforded imine 17 after treat-
ment with p-anisidine. Subsequent reaction with Grignard
reagents provided adducts 18 and 19 in good overall yields
and with diastereomeric ratios of 95:5.[23] In this case, com-
plete deprotection of the phenylaminoxy group occurred
during the Grignard addition, thus the final hydrogenation
was no longer necessary and, as a result, the protocol was
rendered compatible with aryl Grignard reagents. The sim-
plified model A explains the observed stereochemical out-
Table 3. Catalytic asymmetric O-nitroso aldol reactions of aldehydes 10
with nitrosobenzene (11) promoted by catalyst 7.[a]
Entry
R
Product
t [h]
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
9
Me
nPr
nPr
nBu
12a
12b
12b
12c
12d
12d
12e
12e
12 f
12g
16
2
16
2
5
16
2
3
16
3
80[d]
78
>99
>99
>99
>99
>99
>99
>99
>99
95
71[e]
81
CH2Ph
CH2Ph
iPr
68
68[e]
55
iPr
59[f]
45
BnOCH2
10
BocHN
N
88
>99
11
12h
4
66
>99
[a] Reactions performed on a 1 mmol scale in CH2Cl2 (2 mL) at À208C
with 7 (10 mol%), PNBA (10 mol%) and 10 (3 equiv). [b] Isolated yield
after flash column chromatography. [c] Determined by HPLC analysis
after flash chromatography; see the Supporting Information for details.
[d] Reaction performed with catalyst 3 (2 mol%) and PNBA (5 mol%).
[e] Reaction conducted with catalyst 7 (5 mol%). [f] Reaction performed
with catalyst 7 (20 mol%) and PNBA (20 mol%).
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Chem. Eur. J. 2010, 16, 7496 – 7502

Regio- and Enantioselective O-Nitroso Aldol Reaction
FULL PAPER
of the weak hydrogen-bond-donor water, is reversed to a
clear O-selective addition for the acid species (benzoic acid
and PNBA), see Figure 1.
Figure 1. N- and O-selective transition states calculated at the B3LYP/6-
311++G**//B3LYP/6-31G* level of theory in the gas phase.
Scheme 4. 1,2-Amino alcohols from a nitroso aldol reaction, imine forma-
tion and Grignard addition sequence.
Conclusion
come of the Grignard addition,
although a five-membered-che-
late model should not be ex-
cluded.[20]
We have demonstrated that commercially available a,a-di-
phenylprolinol trimethylsilyl ether (7) in the presence of a
Brønsted acid is a very effective and general catalyst for the
reaction of aldehydes with nitrosobenzene to afford O-ni-
troso aldol adducts with both high enantio- and regioselec-
tivity. Because S enantiomers are produced, this procedure
complements the (S)-proline (1)-catalysed reaction, in which
R enantiomers are formed, and provides a new entry to
enantiomerically pure (S,S)- and (R,R)-1,2-aminoalcohols.
Mechanistic insights: To firmly
establish the origin of regio-
and enantioselectivity in the
present catalytic system, we
computed the different transi-
À
À
tion states for the formation of the C N and C O bonds in
the reaction between propionaldehyde and nitrosobenzene,
promoted by catalyst 7 in the presence of hydrogen-bond
donors, by density functional theory (DFT). On the basis of
evidence for enamine formation,[24] we assumed that the re-
action proceeds through an enamine mechanism[6,9] (rather
than via an enol intermediate)[25] and that the activation of
the oxygen and nitrogen atoms of 11 takes place by hydro-
gen bonding, with participation of two molecules of acid.[26]
In each case, the activation energies were computed by the
difference between the transition-state energy and the
energy of the corresponding pre-transition-state complexes.
After an extensive conformational search, we found that the
lowest-energy transition states (TS-N and TS-O) involve the
attack of 11 from the opposite face to the bulky
Experimental Section
General methods: All reactions were carried out under a nitrogen atmos-
phere in flame-dried glassware, with efficient magnetic stirring. CH2Cl2
was distilled from CaH2. Toluene, THF and Et2O were dried in the pres-
ence of sodium metal. Reagent grade methanol, ethyl acetate and DMF
were used. Purification of reaction products was carried out by flash
column chromatography on silica gel 60 (0.040–0.063 mm, 230–400
mesh). Analytical TLC was performed on 0.25 mm silica gel 60-F plates.
Visualisation was accomplished with UV light and by dipping the devel-
oped plate into a solution of cerium ammonium molybdate (ammonium
molybdate (21 g), cerium sulfate (1 g), concentrated sulfuric acid
(31 mL), water (470 mL)), followed by heating. Melting points were mea-
sured with a Bꢄchi SMP-20 melting point apparatus and are uncorrected.
1H and 13C NMR spectra were recorded on a Bruker Advance-500 (or
300) spectrometer and chemical shifts (d) are reported in ppm relative to
internal tetramethylsilane (TMS). Analytical HPLC was performed on
Waters-600E, Waters-2996 and Hewlett–Packard series 1050 chromato-
graphs equipped with diode array UV detectors and Daicel Chiralpak
AD-H and OD-H columns. Optical rotations were recorded on a Jasco
P-2000 polarimeter. MS spectra were recorded on an ESI ion-trap mass
spectrometer (Agilent 1100 series LC/MSD, SL model). Prolinol trime-
thylsilyl ether catalysts 7 and 8 were purchased from Aldrich and used
without further purification. Catalyst 9 was prepared by a previously de-
scribed procedure.[15]
À
C(Ph)2OSiMe3 directing group (in accordance with previ-
ous observations on related enamine-based reactions).[9]
Also the enamine double bond is in the E configuration and
anti to the silyl group. The energy data clearly point to a hy-
drogen-bond reduction of the Gibbs free energy of activa-
tion (DG°) in the presence of PNBA, from 21.4 (absence of
catalyst) to 1.3 kcalmolÀ1. More interestingly, the N-selectiv-
ity computed in the absence of catalyst, or in the presence
Chem. Eur. J. 2010, 16, 7496 – 7502
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C. Palomo et al.
General procedure for the aminoxylation reaction: Nitrosobenzene
(S)-tert-Butyl-6-hydroxy-5-(phenylaminooxy)hexylcarbamate (12g): Pre-
pared according to the general procedure from 6-(tert-butoxycarbonyla-
mino)-1-hexanal (645 mg, 3 mmol). The crude material was purified by
column chromatography on silica gel (hexane/ethyl acetate 60:40) to give
12g as an orange oil (88%, 306 mg). Spectroscopic data are in agreement
with published data for the R enantiomer.[28] The enantiomeric excess
(1 mmol, 1 equiv) and the freshly distilled aldehyde[27] (3 mmol, 3 equiv)
were successively added to
a solution of the catalyst (0.1 mmol,
10 mol%) and PNBA (0.1 mmol, 10 mol%) in CH2Cl2 (2 mL) at À208C.
The resulting green solution was stirred at À208C until the colour turned
yellow. EtOH (2 mL) and NaBH4 (8 mmol) were added successively at
À208C. After stirring for 30 min, the reaction was quenched with a satu-
rated aqueous solution of NaCl (3 mL) and allowed to reach room tem-
perature. After extraction with CH2Cl2 (3ꢅ4 mL), the combined organic
phases were dried over anhydrous MgSO4, concentrated under reduced
pressure and purified by flash column chromatography on silica gel to
afford the expected adducts. The regioselectivity of the process was de-
termined by 1H NMR spectroscopy analysis of the crude products and
was found to be >99:1 in all cases.
AHCTUNGTREG(NNUN >99%) was determined by HPLC analysis (Daicel Chiralpak OD-H,
hexane/isopropanol 92:8, flow rate=1 mLminÀ1
;
retention times:
26.5 min (minor) and 30.3 min (major)). [a]2D5 =À8.4 (c=1, CHCl3).
(S)-2-(Phenylaminooxy)hex-5-en-1-ol (12h): Prepared according to the
general procedure from hexen-5-al (294 mg, 3 mmol). The crude material
was purified by column chromatography on silica gel (hexane/ethyl ace-
tate 80:20) to give 12h as a yellow oil (66%, 134 mg). Spectroscopic data
are in agreement with published data for the R enantiomer.[28] The enan-
tiomeric excess (>99%) was determined by HPLC analysis (Daicel Chir-
alpak AD-H, hexane/isopropanol 94:6, flow rate=1 mLminÀ1; retention
times: 15.8 min (major) and 19.5 min (minor)). [a]2D5 =À1.4 (c=1,
CHCl3).
(S)-2-(Phenylaminooxy)propan-1-ol (12a): Prepared according to the
general procedure from propanal (0.22 mL, 3 mmol). The crude material
was purified by column chromatography on silica gel (hexane/ethyl ace-
tate 80:20) to give 12a as a yellow oil (80%, 133 mg). Spectroscopic data
are in agreement with published data for the R enantiomer.[5a] The enan-
tiomeric excess (>99%) was determined by HPLC analysis (Daicel Chir-
alpak AD-H, hexane/ethanol 90:10, flow rate=1 mLminÀ1; retention
times: 14.5 min (major), 20.1 min (minor)). [a]2D5 =À1.1 (c=1, CHCl3).
(S)-2-(Phenylaminooxy)pentan-1-ol (12b): Prepared according to the
general procedure from pentanal (0.32 mL, 3 mmol). The crude material
was purified by column chromatography on silica gel (hexane/ethyl ace-
tate 85:15) to give 12b as a yellow oil (78%, 152 mg). Spectroscopic data
are in agreement with published data for the R enantiomer.[5a] The enan-
tiomeric excess (>99%) was determined by HPLC analysis (Daicel Chir-
alpak AD-H, hexane/isopropanol 95:5, flow rate=0.8 mLminÀ1; reten-
tion times: 20.5 min (major), 24.5 min (minor)). [a]2D5 =À24.8 (c=0.9,
CHCl3).
General procedure for the preparation of 1,2-amino alcohols: Method A:
Nitrosobenzene (1 mmol, 1 equiv) and aldehyde (3 mmol, 3 equiv) were
added successively to a solution of the catalyst (0.1 mmol, 10 mol%) and
PNBA (0.1 mmol, 10 mol%) in CH2Cl2 (2 mL) at À208C. The resulting
green solution was stirred at À208C until the colour turned yellow. Anhy-
drous MgSO4 (0.250 g) and benzhydryl amine (3 mmol, 3 equiv) were
added to this solution. The reaction was allowed to reach 08C and the
mixture was stirred at this temperature for 2 h before the solution was fil-
tered and the solvent evaporated. The residue was dissolved in THF
(2 mL) and the solution was cooled to À608C. The corresponding
Grignard reagent (3m in diethyl ether, 15 mmol, 15 equiv) was added
dropwise at this temperature; the mixture was allowed to reach room
temperature and was stirred overnight. The reaction was quenched with
a saturated aqueous solution of NH4Cl (10 mL), extracted with ethyl ace-
tate (2ꢅ15 mL), washed with brine, dried over anhydrous MgSO4 and
evaporated. The residue was purified by flash column chromatography
on silica gel and then hydrogenated in EtOH (2 mLmmolÀ1) over Pd/C
(20%w/w) for 48 h at atmospheric pressure. The mixture was filtered
through Celite, evaporated and purified by an acid–base workup. This
yielded the expected 1,2-aminoalcohols as almost single diastereomers.
(S)-2-(Phenylaminooxy)hexan-1-ol (12c): Prepared according to the gen-
eral procedure from hexanal (0.36 mL, 3 mmol). The crude material was
purified by column chromatography on silica gel (hexane/ethyl acetate
85:15) to give 12c as a yellow oil (81%, 169 mg). Spectroscopic data are
in agreement with published data for the R enantiomer.[5a] The enantio-
meric excess (>99%) was determined by HPLC analysis (Daicel Chiral-
pak AD-H, hexane/ethanol 95:5, flow rate=0.8 mLminÀ1
; retention
General method B: Nitrosobenzene (1 mmol, 1 equiv) and aldehyde
(3 mmol, 3 equiv) were added successively to l-proline (0.1 mmol,
10 mol%) in CHCl3 (1 mL) at 08C and the resulting green solution was
stirred at 08C until the colour turned yellow. The solution was then con-
centrated and CH2Cl2 (2 mL), anhydrous MgSO4 (0.250 g) and benzhy-
dryl amine (3 mmol, 3 equiv) were added. The reaction was stirred at
08C for 2 h before the solution was filtered and evaporated. The residue
was dissolved in THF (2 mL) and cooled to À608C. The corresponding
Grignard reagent (3m in diethyl ether, 15 mmol, 15 equiv) was added
dropwise at this temperature, the mixture was allowed to reach room
temperature and was stirred overnight. The reaction was quenched with
a saturated aqueous solution of NH4Cl (10 mL), extracted with ethyl ace-
tate (2ꢅ15 mL), washed with brine, dried over anhydrous MgSO4 and
evaporated. The residue was purified by flash column chromatography
on silica gel and then hydrogenated in EtOH (2 mLmmolÀ1) over Pd/C
(20%w/w) for 48 h at atmospheric pressure. The mixture was filtered
through Celite, evaporated and purified by an acid–base workup. This
yielded the expected 1,2-aminoalcohols as almost single diastereomers.
times: 19.3 min (major) and 24.6 min (minor)). [a]2D5 =À21.1 (c=1,
CHCl3).
(S)-3-Phenyl-2-(phenylaminooxy)propan-1-ol (12d): Prepared according
to the general procedure from hydrocinnamaldehyde (0.39 mL, 3 mmol).
The crude material was purified by column chromatography on silica gel
(hexane/ethyl acetate 85:15) to give 12d as an orange oil (68%, 164 mg).
Spectroscopic data are in agreement with published data for the R enan-
tiomer.[5a] The enantiomeric excess (>99%) was determined by HPLC
analysis (Daicel Chiralpak AD-H, hexane/isopropanol 95:5, flow rate=
0.8 mLminÀ1; retention times: 40.1 min (major) and 54.8 min (minor)).
[a]2D5 =À43.1 (c=1, CHCl3).
(S)-3-Methyl-2-(phenylaminooxy)butan-1-ol (12e): Prepared according to
the general procedure from isovaleraldehyde (0.32 mL, 3 mmol). The
crude material was purified by column chromatography on silica gel
(hexane/ethyl acetate 85:15) to give 12e as a yellow oil (56%, 109 mg).
Spectroscopic data are in agreement with published data for the R enan-
tiomer.[5a] The enantiomeric excess (>99%) was determined by HPLC
analysis (Daicel Chiralpak AD-H, hexane/ethanol 95:5, flow rate=
0.8 mLminÀ1; retention times: 13.9 min (major) and 16.1 min (minor)).
[a]2D5 =À32.6 (c=1, CHCl3).
General method C: Nitrosobenzene (1 mmol, 1 equiv) and aldehyde
(3 mmol, 3 equiv) were added successively to a solution of the catalyst
(0.1 mmol, 10 mol%) and PNBA (0.1 mmol, 10 mol%) in CH2Cl2 (2 mL)
at À208C and the resulting green solution was stirred at À208C until the
colour turned yellow. Anhydrous MgSO4 (0.250 g) and p-anisidine
(3 mmol, 3 equiv) were added to this solution. The reaction was allowed
to reach 08C and the mixture was stirred at this temperature for 2 h
before the solution was filtered and evaporated. The residue was dis-
solved in THF (2 mL) and cooled to À608C. The corresponding Grignard
reagent (3m in diethyl ether, 15 mmol, 15 equiv) was added dropwise at
this temperature and the solution was allowed to reach room tempera-
ture and stirred overnight. The reaction was quenched with a saturated
(R)-3-(Benzyloxy)-2-(phenylaminooxy)propan-1-ol (12 f): Prepared ac-
cording to the general procedure from 3-(benzyloxy)propanal (0.48 mL,
3 mmol). The crude material was purified by column chromatography on
silica gel (hexane/ethyl acetate 80:20) to give 12 f as an orange oil (45%,
122 mg). Spectroscopic data are in agreement with published data for the
R enantiomer.[5a] The enantiomeric excess (95%) was determined by
HPLC analysis (Daicel Chiralpak AD-H, hexane/ethanol 95:5, flow
rate=1 mLminÀ1
(minor)). [a]2D5 =+7.2 (c=1, CHCl3).
; retention times: 55.8 min (major) and 64.0 min
7500
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Chem. Eur. J. 2010, 16, 7496 – 7502

Regio- and Enantioselective O-Nitroso Aldol Reaction
FULL PAPER
aqueous solution of NH4Cl (10 mL), extracted with ethyl acetate (2ꢅ
15 mL), washed with brine, dried over anhydrous MgSO4 and evaporated.
The residue was purified by flash column chromatography on silica gel.
Yamamoto, Org. Lett. 2002, 4, 3579–3582; c) N. Momiyama, H. Ya-
mamoto, J. Am. Chem. Soc. 2003, 125, 6038–6039.
[4] N. Momiyama, H. Yamamoto, J. Am. Chem. Soc. 2005, 127, 1080–
1081.
ACHTUNGTRENNUNG(2S, 3S)-3-Amino-1-phenylbutan-2-ol (14): Prepared according to the
[5] For examples of l-proline (1) as a catalyst, see: a) Z. Zhong, Angew.
Chem. 2003, 115, 4379–4382; Angew. Chem. Int. Ed. 2003, 42, 4247–
4250; b) S. P. Brown, M. P. Brochu, C. J. Sinz, D. W. C. MacMillan, J.
Am. Chem. Soc. 2003, 125, 10808–10809; c) Y. Hayashi, J. Yamagu-
chi, K. Hibino, M. Shoji, Tetrahedron Lett. 2003, 44, 8293–8296;
d) Y. Hayashi, J. Yamaguchi, T. Sumiya, K. Hibino, M. J. Shoji, J.
Org. Chem. 2004, 69, 5966–5973; e) Y. Hayashi, J. Yamaguchi, T.
Sumiya, M. Shoji, Angew. Chem. 2004, 116, 1132–1135; Angew.
Chem. Int. Ed. 2004, 43, 1112–1115; f) A. Cꢀrdova, H. Sundꢆn, A.
Bøgevig, M. Johansson, F. Hilmo, Chem. Eur. J. 2004, 10, 3673–
3684; g) S.-G. Kim, T.-H. Park, Tetrahedron Lett. 2006, 47, 9067–
9071; h) K. Huang, Z.-Z. Huang, Y.-L. Li, J. Org. Chem. 2006, 71,
8320–8323. For 2 as catalyst, see: i) N. Momiyama, H. Torii, S. Saito,
H. Yamamoto, Proc. Natl. Acad. Sci. USA 2004, 101, 5374–5378;
j) S. Kumarn, D. M. Shaw, D. A. Longbottom, S. V. Ley, Org. Lett.
2005, 7, 4189–4191; k) Y. Yamamoto, N. Momiyama, H. Yamamoto,
J. Am. Chem. Soc. 2004, 126, 5962–5963. For catalyst 3, see: l) W.
Wang, J. Wang, H. Li, L. Liao, Tetrahedron Lett. 2004, 45, 7235–
7238. For catalyst 4, see: m) Y. Hayashi, J. Yamaguchi, K. Hibino, T.
Sumiya, T. Urushima, M. Shoji, D. Hashizume, H. Koshino, Adv.
Synth. Catal. 2004, 346, 1435–1439. For a polymer-supported pro-
line-derivative, see: n) D. Font, A. Bastero, S. Salayero, C. Jimeno,
M. A. Pericꢇs, Org. Lett. 2007, 9, 1943–1946. For catalyst 5, see:
o) H.-M. Guo, L. Cheng, L.-F. Cun, L.-Z. Ghong, A.-Q. Mi, Y.-Z.
Jiang, Chem. Commun. 2006, 429–431. For catalyst 6, see: p) T.
Kano, M. Ueda, J. Takai, K. Maruoka, J. Am. Chem. Soc. 2006, 128,
6046–6047.
general method A from hydrocinnamaldehyde (0.39 mL, 3 mmol) and
methyl magnesium bromide. Compound 14 was obtained as an orange oil
(60%, 90 mg). Spectroscopic data are in agreement with published
data.[28] [a]2D5 =À17.8 (c=0.5, CH2Cl2).
ACHTUNGTRENNUNG(2S, 3S)-3-Amino-1-phenylpentan-2-ol (15): Prepared according to the
general method A from hydrocinnamaldehyde (0.39 mL, 3 mmol) and
ethyl magnesium bromide. Compound 15 was isolated as an orange oil
(45%, 74 mg). [a]2D5 =À20.6 (c=0.5, CH2Cl2); 1H NMR (300 MHz,
CDCl3): d=0.91 (t, J=7.5 Hz, 3H), 1.72–1.40 (m, 2H), 1.72–1.56 (m,
1H), 2.71–2.60 (m, 1H), 2.91–2.75 (m, 2H), 3.74–3.62 (m, 1H), 4.99 (s,
2H), 7.37–7.16 ppm (m, 5H); 13C NMR (125 MHz, CDCl3): d=10.0, 24.5,
40.2, 57.2, 73.3, 126.4, 128.4, 129.5, 138.2 ppm.
ACHTUNGTRENNUNG(2R, 3R)-3-Amino-1-phenylbutan-2-ol (16): Prepared according to the
general method B from hydrocinnamaldehyde (0.39 mL, 3 mmol) and
methyl magnesium bromide. Compound 16 was isolated as an orange oil
(51%, 77 mg). Spectroscopic data are in agreement with published
data.[28] [a]2D5 =+20.0 (c=0.5, CH2Cl2).
ACHTUNGTRENNUNG(2S, 3S)-3-(4-Methoxyphenylamino)octan-2-ol (18): Prepared according
to the general method C from propionaldehyde (0.22 mL, 3 mmol) and
pentyl magnesium bromide. Compound 18 was obtained as an orange oil
(55%, syn/anti 95:5, 155 mg). [a]2D5 (95:5 syn/anti non-separable mix-
ture)=+6.8 (c=1, CH2Cl2); 1H NMR (300 MHz, CDCl3, major syn dia-
stereomer): d=0.93–0.80 (m, 5H), 1.49–1.74 (m, 10H), 3.15–4.04 (m,
1H), 3.76–3.65 (m, 2H), 3.78 (s, 3H), 6.67 (d, J=9.0 Hz, 2H), 6.80 ppm
(d, J=9.0 Hz, 2H); 13C NMR (125 MHz, CDCl3, major syn diastereo-
mer): d=14.0, 19.9, 22.5, 25.6, 32.0, 32.3, 55.8, 61.8, 69.7, 115.0, 115.3,
128.7, 142.8, 152.6 ppm.
[6] For DFT studies on the enamine-based nitroso aldol reaction cata-
lysed by chiral Brønsted acids, see: a) M. Akakura, M. Kawasaki, H.
Yamamoto, Eur. J. Org. Chem. 2008, 4245–4249; catalysed by pro-
line (1): b) P. H.-Y. Cheong, K. N. Houk, J. Am. Chem. Soc. 2004,
126, 13912–13913.
[7] For the first reports describing these catalysts, see: a) M. Marigo,
T. C. Wabnitz, D. Fielenbach, K. A. Jørgensen, Angew. Chem. 2005,
117, 804–807; Angew. Chem. Int. Ed. 2005, 44, 794–797; b) J. Fran-
zꢆn, M. Marigo, D. Fielenbach, T. C. Wabnitz, A. Kjærsgaard, K. A.
Jørgensen, J. Am. Chem. Soc. 2005, 127, 18296–18304; c) Y. Haya-
shi, H. Gotoh, T. Hayashi, M. Shoji, Angew. Chem. 2005, 117, 4284–
4287; Angew. Chem. Int. Ed. 2005, 44, 4212–4215.
ACHTUNGTRENNUNG(1S,2S)-1-(4-Methoxyphenylamino)-1-phenylpropan-2-ol (19): Prepared
according to the general method C from propionaldehyde (0.22 mL,
3 mmol) and phenyl magnesium bromide. Compound 19 was obtained as
an orange oil (52%, syn/anti 94:6, 134 mg). [a]2D5(94:6 syn/anti non-sepa-
rable mixture)=+8.2 (c=1, CH2Cl2); 1H NMR (300 MHz, CDCl3, major
syn diastereomer): d=1.25 (d, J=6.3 Hz, 3H), 3.73 (s, 3H), 3.99 (m,
1H), 4.14 (d, J=6.3 Hz, 1H), 6.59 (d, J=8.9 Hz, 2H), 6.74 (d, J=8.9 Hz,
2H), 7.40–7.26 ppm (m, 5H); 13C NMR (125 MHz, CDCl3, major syn dia-
stereomer): d=20.0, 55.7, 66.1, 71.7, 114.8, 115.6, 127.1, 127.5, 128.7,
141.3, 141.5, 152.5 ppm.
[8] For reviews, see: a) C. Palomo, A. Mielgo, Angew. Chem. 2006, 118,
8042–8046; Angew. Chem. Int. Ed. 2006, 45, 7876–7880; b) A.
Mielgo, C. Palomo, Chem. Asian J. 2008, 3, 922–948.
[9] For the mechanism of a-heterofunctionalisation of aldehydes pro-
moted by 7 via enamine, see: P. Dinꢆr, A. Kærsgaard, M. A. Lie,
K. A. Jørgensen, Chem. Eur. J. 2008, 14, 122–127.
[10] C. Palomo, S. Vera, I. Velilla, A. Mielgo, E. Gꢀmez-Bengoa, Angew.
Chem. 2007, 119, 8200–8202; Angew. Chem. Int. Ed. 2007, 46, 8054–
8056.
[11] For a chiral Brønsted acid catalysed direct reaction of nitrosoben-
zene with b-dicarbonyl compounds, see: M. Lu, D. Zhu, Y. Lu, X.
Zeng, B. Tan, Z. Xu, G. Zhong, J. Am. Chem. Soc. 2009, 131, 4562–
4563.
[12] For recent representative examples, see: a) P. Jiao, M. Kawasaki, H.
Yamamoto, Angew. Chem. 2009, 121, 3383–3386; Angew. Chem. Int.
Ed. 2009, 48, 3333–3336; b) L. Yang, R.-H. Liu, B. Wang, L. L.
Weng, H. Zheng, Tetrahedron Lett. 2009, 50, 2628–2631; c) T. M.
Shaikh, A. Sudalai, Tetrahedron: Asymmetry 2009, 20, 2287–2292;
d) N. B. Kondekar, P. Kumar, Org. Lett. 2009, 11, 2611–2614; e) G.
Zhong, Y. Yu, Org. Lett. 2004, 6, 1637–1639; f) M. Lu, D. Zhu, Y.
Lu, Y. Hou, B. Tan, G. Zhong, Angew. Chem. 2008, 120, 10341–
10345; Angew. Chem. Int. Ed. 2008, 47, 10187–10191; g) S. Kumarn,
A. J. Oelke, D. M. Shaw, D. A. Longbottom, S. V. Ley, Org. Biomol.
Chem. 2007, 5, 2678–2689.
Acknowledgements
This work was financially supported by The University of the Basque
Country (UPV/EHU), Basque Government (SAIOTEK s-pe09un40) and
Ministerio de Ciencia e Innovaciꢀn (MICIN, Grant CTQ2007-68095-C02,
Spain). A predoctoral grant to I.V. (from UPV/EHU) is also acknowl-
edged. We also thank SGIker (UPV/EHU) for NMR, HRMS and com-
putational facilities.
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Chem. Eur. J. 2010, 16, 7496 – 7502
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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C. Palomo et al.
[14] pKa values (water) for the employed Brønsted acids: 4-methoxyben-
zoic acid, 4.47; benzoic acid, 4.19; 4-nitrobenzoic acid, 3.44; acetic
acid, 4.76; chloroacetic acid, 2.87; see: B. G. Tehan, E. J. Lloyd,
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[17] The absence of N-nitroso aldol products is easily established by
300 MHz NMR spectroscopy because, for each aldehyde, the signals
corresponding to CHN(OH)Ph appear further upfield than those of
CHONHPh. For more details see reference [10] and the Supporting
Information.
ChÞnevert, M. Dickman, Tetrahedron: Asymmetry 1994, 5, 1727–
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[26] The results from one molecule of acid did not fit well with the ex-
perimental observations. For details, see the Supporting Information.
Also see reference [6a].
[18] For an enantioselective switch in the nitroso aldol reaction by using
binaphthyl-based chiral secondary amines with identical axial chiral-
ity, see: a) T. Kano, A. Yamamoto, K. Maruoka, Tetrahedron Lett.
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[19] S. C. Bergmeier, Tetrahedron 2000, 56, 2561–2576.
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[27] No traces of any acid should be present in the reaction to avoid the
O-nitroso aldol reaction completely.
[28] R. Besse, H. Veschambre, Tetrahedron: Asymmetry 1994, 5, 1727–
1744.
[21] The configuration of aminoalcohols 14 and 15 was established by
comparison with reported data; see: P. Besse, H. Veschambre, R.
Received: February 11, 2010
Published online: April 30, 2010
7502
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ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7496 – 7502