Direct asymmetric N-specific reaction of nitrosobenzene with aldehydes catalyzed by a chiral primary amine-based organocatalyst

Article abstract of DOI:10.1002/chir.20960

Nitroso compounds have two reactive nitrogen and oxygen atoms. It is interesting and important to perform a nitrogen or oxygen selective reaction with interesting substrates. These atom specific reactions are crucial to specifically synthesis of specific compounds. An enantioselective N-specific reaction of nitrosobenzene with unmodified aldehydes was successfully achieved catalyzed first by a variety of primary amine-based organocatalysts with higher yield and enantioselectivity. The bulkier substituted groups of the organocatalyst and two hydrogen bonds from the organocatalyst and the oxygen atom of nitrosobenzene make the reaction preferentially N-specific and predominantly afford R products.

Full text of DOI:10.1002/chir.20960

CHIRALITY 23:527–533 (2011)
Direct Asymmetric N-Specific Reaction of Nitrosobenzene
with Aldehydes Catalyzed by a Chiral Primary
Amine-Based Organocatalyst
LONG QIN,1 LEI LI,1 LEI YI,1 CHAO-SHAN DA,1,2* AND YI-FENG ZHOU
3
*
1Institute of Biochemistry and Molecular Biology, School of Life Sciences, Lanzhou University, Lanzhou, China
2State Key laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, China
3College of Life Sciences, China Jiliang University, Hangzhou, China
ABSTRACT
Nitroso compounds have two reactive nitrogen and oxygen atoms. It is interest-
ing and important to perform a nitrogen or oxygen selective reaction with interesting substrates.
These atom specific reactions are crucial to specifically synthesis of specific compounds. An
enantioselective N-specific reaction of nitrosobenzene with unmodified aldehydes was success-
fully achieved catalyzed first by a variety of primary amine-based organocatalysts with higher
yield and enantioselectivity. The bulkier substituted groups of the organocatalyst and two
hydrogen bonds from the organocatalyst and the oxygen atom of nitrosobenzene make the reac-
tion preferentially N-specific and predominantly afford R products. Chirality 23:527–533,
C
VV
2011.
2011 Wiley-Liss, Inc.
KEY WORDS: asymmetric catalysis; organocatalysis; direct nitroso-aldol reaction; atom-specific
reaction; nitrosobenzene
INTRODUCTION
nocatalysts were all based on secondary amines, the derivatives
of L-Proline and its similar synthetic molecules. When com-
pared with proline, primary amine-based enantioenriched
amino acids are more common in natural chiral amine pools,
and many natural enzymes in cells are based its catalytic
groups on primary amine amino acids, such as L-Lys locates in
the active center of the aldolase,35–39 whereas L-proline has
rarely been reported to appear as an active component of the
active center of an enzyme. A more abundant chiral primary
than secondary amine pool will conveniently furnish more dif-
ferent and efficient primary amine organocatalysts. Further-
more, primary amine organocatalysts will be greatly beneficial
to reasonably clarify the mechanism of abundant primary-
amine-based natural enzymatic reactions. Undoubtedly, chiral
primary amine organocatalysts will introduce new contents to
amine-catalyzed nitroso aldol reactions. To the best of our
knowledge, there has not been any report on N-specific reac-
tion of nitroso compounds with aldehydes to give a-hydroxya-
minated aldehydes catalyzed by an enantioenriched primary
amine-based organocatalyst to date. This situation makes it
more challenging and interesting to develop a successful pri-
mary amine organocatalyst to promote the preferentially N-
selective Aldol reaction of nitrosobenzene with aldehydes.
Not long ago, our group reported that the direct highly
asymmetric aldol reactions could be catalyzed by an efficient
Atom-specific reaction is very interesting and important for
a compound including variable reactive atoms to prepare dis-
tinct product from each other. Nitroso compounds are such
interesting compounds, they have different highly reactive N
and O atoms toward nucleophiles (for reviews, see: Refs. 1–7)
and are frequently used to prepare nitrogen- or oxygen-contain-
ing molecules. Therefore, various catalytic asymmetric reac-
tions of nitroso compounds such as aminoxylation,8–23 hydrox-
yamination,24–27 and nitroso Diels–Alder reactions28,29 have
recently been developed, which exploited their unique proper-
ties. Because of the high reactivity of the nitroso compounds,
regioselective control of either the nitrogen or oxygen to pref-
erentially react with the nucleophile, i.e., atom-specific reaction,
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 na-
ture of the enolate and the presence or absence of a Lewis acid
catalyst.30–33 Momiyama and Yamamoto reported that pre-
formed enamines reacted with nitrosobenzene in the presence
of the chiral glycolic acid to preferentially give O-nitroso aldol
product, but to result in the N-nitroso product in the presence
of the chiral TADDOL (Fig. 1).34
Organocatalytic asymmetric reactions are current interest-
ing centers because they are metal-free, environmentally
friendly, and easily handled. Therefore, organocatalyzed
reactions of nitrosobenzene in the presence of L-proline and
the similar organocatalysts have also been actively investi-
gated and gave a-oxygenated carbonyl compounds as the
major products.8–23 In comparison with this O-specific reac-
tion, the organocatalytic N-specific adducts were rarely been
disclosed. Recently, three research groups of Gong and co-
workers,24 Maruoka and coworkers,25 and Palomo et al.27
successively reported direct nitroso-aldol reactions of car-
bonyl compounds that occurred preferentially at the nitrogen
of nitrosobenzene with high enantioselectivity. Their used orga-
Additional Supporting Information may be found in the online version of this
article.
Contract grant sponsor: National Science Foundation of China; Contract
grant numbers: 20672051, 21072087
Contract grant sponsor: Foundation of Zhejiang Educational Committee;
Contract grant number: Y200702756
*Correspondence to: Dr. Chao-Shan Da, Institute of Biochemistry and Molec-
ular Biology, School of Life Sciences, Lanzhou University, Southern Tianshui
Road 222#, Lanzhou 730000, China. E-mail: dachaoshan@lzu.edu.cn and Dr.
Yi-Feng Zhou, College of life sciences, China Jiliang University, Xueyuan
street, Xiasha, Hangzhou 310018, China. E-mail: zhouyifeng@cjlu.edu.cn
Received for publication 21 May 2010; Accepted 23 February 2011
DOI: 10.1002/chir.20960
Published online 29 April 2011 in Wiley Online Library
(wileyonlinelibrary.com).
C
VV
2011 Wiley-Liss, Inc.

528
QIN ET AL.
Fig. 1. The O- or N-selective reaction of nitrosobenzene.
portions (addition of too much methyl ester hydrochloride in one portion
would make the reaction too violent on account of the rapid reaction of
HCl with PhMgBr). The reaction was then naturally warmed to room
temperature and allowed to stir overnight. When the reaction was com-
pleted checked by TLC, the mixture was slowly poured into 60 ml stir-
ring ice water, then 2 ml (0.25 mmol) concentrated HCl was added. The
mixture was stirred for an hour, filtered, and washed thrice with water to
afford a yellow residue. The yellow residue was introduced with NaOH
(55 ml, 0.25 mmol), stirred for another 30 min, and then extracted thrice
with ether. The ether layers were combined, concentrated in vacuo, and
recrystallized from ethyl acetate or purified by preparative column to
yield the amino alcohols 3a–e.
primary organocatalyst system formed by a primary amine
organocatalyst, which was readily derived from natural pri-
mary amino acids, and an efficient cocatalyst DNP (2,4-dini-
trophenol).40,41 We presumed that the primary amine organo-
catalysts 1a–g (Scheme 1) with an additional cocatalyst DNP
or others might also successfully catalyze the reaction of
unmodified aldehydes with nitrosobenzene to preferentially
result in N-specific aldol products. Herein, we present this
direct asymmetric a-hydroxyamination of aldehydes, which
was first and successfully catalyzed by a primary amine orga-
nocatalyst.
(S)-Diphenyl phenylalanol (3a). White solid; Yield 53%; m.p. 145–
1468C; [a]2D0 5 273 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.59–
7.66 (dd, J 5 8.4 Hz, J 5 8.0 Hz, 4H), 7.28–7.35 (m, 6H), 7.17–7.25 (m,
5H), 4.16–4.20 (dd, J 5 2.6 Hz, J 5 10.6 Hz, 1H), 2.62–2.66 (dd, J 5 2.0
Hz, J 5 14.0 Hz, 1H), 2.4122.47 (dd, J 5 10.8 Hz, J 5 13.6 Hz, 1H).
EXPERIMENTAL
General Methods
All reagents were commercial products. The reactions were monitored
by thin layer chromatography (TLC). The column and preparative TLC
purification were carried out using silica gel. Melting points were meas-
ured on X-4 melting point apparatus without correction. Optical rotations
(S)-Diphenyl leucinol (3b). White solid; Yield 51%; m.p. 12121238C;
[a]2D0 5 296 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.6027.62 (d,
J 5 7.6 Hz, 2H), 7.4727.48 (d, J 5 7.2 Hz, 2H), 7.1427.33 (m, 6H),
3.9723.99 (dd, J 5 2.0 Hz, J 5 10.0 Hz, 2H), 1.5521.62 (m, 1H),
1.2121.30 (m, 2H), 0.8920.90 (d, J 5 6.4 Hz, 3H), 0.8620.87 (d, J 5 6.8
Hz, 3H).
1
were recorded on a polarimeter. H NMR spectra were recorded on 200
MHz and 400 MHz spectrometers. The chemical shifts were reported in
ppm with TMS as an internal standard. Data were reported as follows:
chemical shift, multiplicity (s 5 single, d 5 doublet, t 5 triplet, q 5
quartet, br 5 broad, m 5 multiplet), coupling constants (Hz). 13C NMR
spectra were recorded on 400 MHz. HRMS were measured with ESI
mass spectrometer. IR spectra were obtained by FT-IR. The ee value
determination was carried out using HPLC with chiral OJ-H, AS-H, or
AD-H column. For NMR Spectra and HPLC conditions and spectra, see
the supporting information of this work
(S)-Diethyl phenylalaninol (3c).. Colorless oil; Yield 63%; [a]D20
5
228 (c 1.0, CHCl3); FT-IR 3389, 3026, 2966, 2936, 2881, 1600, 1494, 1457,
1378, 1032, 951, 753, 700 cm21; 1H NMR (200 MHz, CDCl3) d 7.3527.17
(m, 5H), 3.0022.94 (dd, J 5 3.2 Hz, J 5 12.4 Hz, 2H), 2.3722.24 (app t, J
5 12.5 Hz, 1H), 1.7321.41 (m, 4H), 1.00–0.92 (23 t, J 5 7.3 Hz, 6H); 13
C
NMR (50 MHz, CDCl3) d 140.1, 129.1, 126.3, 74.4, 57.3, 38.1, 27.9, 26.6,
7.7. HRMS calcd. for (C13H21NO 1 H)1 208.1696, found 208.1691.
General Procedure for Preparation
of Aminoalcohols (3a–e)
(S)-Di-3,5-bis(trifluoromethyl)phenyl-phenylalaninol (3d). Color-
less oil; Yield 54%; [a]2D0 5 250 (c 1.0, CHCl3); FT-IR 3398, 3092, 2932,
2873, 2461, 1949, 1712, 1623, 1463, 1369, 1284, 1169, 1128, 900, 844, 707
The freshly prepared Grignard reagent RMgBr 60 ml (2.5 M, 150
mmol) in ether was cooled to 08C under an argon atmosphere, and 15
mmol hydrochloride of methyl ester of amino acid 5 was added in 10
cm21 1H NMR (200 MHz, CDCl3): d 8.12 (s, 2H), 8.04 (s, 2H), 7.80 (s,
;
2H), 7.39–7.13 (m, 5H), 5.03 (s, 1H), 4.23 (t, J 5 6.7 Hz, 1H), 2.4822.45
(d, J 5 6.7 Hz, 2H), 1.26–1.17 (br, 2H); 13C NMR (50 MHz, CDCl3) d
2
2
148.4, 145.5, 137.7, 132.5 (q, Jc,f 5 13.5 Hz), 132.7 (q, Jc,f 5 13.5 Hz),
3
3
129.1, 129.0, 127.2, 126.0 (q, Jc,f 5 2.5 Hz), 125.7 (q, Jc,f 5 2.5 Hz),
121.8, 121.6, 120.5, 120.4, 76.4, 58.1, 36.6. HRMS calcd. for
(C25H17F12NO 1 H)1 576.1191, found 576.1180.
(R)-Diphenyl phenylalanol (3e). White solid; Yield 53%; m.p. 125–
1278C; [a]2D0 5 168 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.59–
7.66 (dd, J 5 8.4 Hz, J 5 8.0 Hz, 4H), 7.2827.35 (m, 6H), 7.1727.25 (m,
5H), 4.1624.20 (dd, J 5 2.6 Hz, J 5 10.6 Hz, 1H), 2.6222.66 (dd, J 5 2.0
Hz, J 5 14.0 Hz, 1H), 2.4122.47 (dd, J 5 10.8 Hz, J 5 13.6 Hz, 1H).
General Procedure for Preparation of Catalysts (1a–f)
ClCOOiBu (5.1 mmol, 0.67 ml) was slowly introduced dropwise into a
mixture of 5.1 mmol Boc-protected amino acid 4 and 0.56 ml NMM (5.1
mmol) in 25 ml dry THF under an argon atmosphere at 2158C. Five
minutes later, the amino alcohol 3 in THF (10 ml) was added dropwise
into the mixture. After stirring for 30 min at the same temperature, the
reaction was warmed to room temperature and continued stirring until it
finished. THF was evaporated in vacuo, and the residue was redissolved
with CH2Cl2, washed successively with dilute HCl, water, 10% NaHCO3,
Scheme 1. Synthesis of organocatalysts.
Chirality DOI 10.1002/chir

DIRECT ASYMMETRIC N-SPECIFIC REACTION
529
water and a little brine, dried with anhydrous Na2SO4, and condensed in
vacuo to give the residue. The residue was recrystallized from ethyl ace-
tate and petroleum ether to give a crystal or solid. The solid was redis-
solved with CH2Cl2 and cooled to 08C, then 2 ml TFA in CH2Cl2 (TFA/
CH2Cl2 5 1:1) was added dropwise. The mixture was stirred for 1–2 h
until the reaction finished checked by TLC, and then condensed to dry-
ness in vacuo. The residue was redissolved with CH2Cl2 and NH3ÁH2O
was added to adjust the solution pH to 10.0 or so. The organic layer was
separated, and the aqueous layer was re-extracted thrice with CH2Cl2.
Then the combined organic layers were washed with a little brine, dried
with anhydrous Na2SO4, condensed to dryness in vacuo, and recrystal-
lized from ethyl acetate and petroleum ether to give the catalyst 1a–g.
The configuration was assigned by comparison of the retention time of
the major isomer in HPLC with reported values and by comparison of
the sign of the optical rotation with the reported value.24–27
1135, 1033, 731, 698 cm21; 1H NMR (200 MHz, CDCl3) d 7.23 (d, J 5 8.8
Hz, 1H),7.29–7.11 (m, 4H), 4.16–4.14 (m,1H), 3.10–3.00 (m, 2H), 2.78–
2.65 (dd, J 5 11.8 Hz, J 5 14 Hz, 1H), 2.18–2.02 (m, 1H), 1.76–1.42 (m,
4H), 1.08–1.01 (br, 2H), 1.00–0.90 (23 t, J 5 7.4 Hz, 6H), 0.80–0.77 (d, J
5 7 Hz, 3H), 0.36–0.33 (d, J 5 6.8 Hz, 3H); 13C NMR (50 MHz, CDCl3) d
175.3, 139.1, 129.1, 128.4, 126.3, 76.6, 60.1, 56.9, 35.0, 30.1, 28.5, 27.7,
19.6, 15.4, 7.9, 7.6; HRMS calcd. for (C18H30N2O2 1 H)1 307.2380, found
307.2385.
(S,R)-2-Amino-N-(1-hydroxy-1,1,3-triphenylpropan-2-yl)-4-methyl-
pentanamide (1g). White solid; Yield 45%; m.p. 162–1638C; [a]D20
5
149 (c 1.0, CHCl3); FT-IR 3349, 3061, 2956, 2932, 2868, 1648, 1551, 1495,
1451, 1170, 1163, 747, 700 cm21 1H NMR (200 MHz, CDCl3) d
;
7.6727.01 (m, 15H), 4.90–4.79 (m, 1H), 3.16–2.99 (m, 2H), 2.89–2.81
(dd, J 5 3 Hz, J 5 14.2 Hz, 1H), 1.43–1.22 (m, 4H), 0.9–0.86 (m, 1H),
0.83–0.80 (d, J 5 6.2 Hz, 2H), 0.76–0.73 (d, J 5 6.2 Hz, 2H); 13C NMR
(100 MHz, DMSO-d6) d 175.8, 146.4, 145.0, 139.2, 129.2, 128.4, 128.3,
128.0, 126.8, 126.6, 126.3, 125.7,125.6, 80.8, 60.0, 53.2, 43.5, 34.7, 24.6,
23.1, 21.4; HRMS calcd. for (C27H32N2O2 1 H)1 417.2537, found
417.2538.
(S,S)-2-Amino-N-(1-hydroxy-1,1,3-triphenylpropan-2-yl)-4-methyl-
pentanamide (1a). White solid; Yield 41%; m.p. 16721688C; [a]D20
5
1
230 (c 1.0, DMSO); H NMR (400 MHz, DMSO-d6) d 7.7627.78 (d, J 5
9.6 Hz, 1H), 7.5927.51 (d, J 5 7.6 Hz, 2H), 7.3027.34 (t, J 5 7.6 Hz,
2H), 7.0327.18 (m, 8H), 6.19 (s, 1H), 5.0525.09 (t, J 5 9.6 Hz, J 5 8.0
Hz, 1H), 2.7422.78 (dd, J 5 19.4 Hz, J 5 5.6 Hz, J 5 8.4 Hz, 1H),
2.5722.70 (m, 2H), 1.26 (br, 1H), 1.1521.22 (m, 1H), 0.7920.86 (m,
1H), 0.6520.69 (m, 1H), 0.6220.64 (d, J 5 7.2 Hz, 3H), 0.5920.60 (d, J
5 5.6 Hz, 3H).
(S,S)-2-Amino-N-(1-hydroxy-4-methyl-1,1-diphenylpentan-2-
yl)propanamide (1h). White solid; Yield 53%; m.p. 165–1678C; [a]D20
5 222 (c 1.0, CHCl3); FT-IR 3306, 3027, 2956, 2930, 2871,1963, 1645,
1525, 1448, 1366, 1139, 1060, 750, 702 cm21; 1H NMR (200 MHz, CDCl3)
d 7.57–7.52 (m, 3H), 7.39–7.09 (m, 7H), 4.91–4.81 (m, 1H), 3.29–3.19
(dd, J 5 6.8 Hz, J 5 13.8 Hz, 1H), 1.70–1.57 (m, 2H), 1.29–1.17 (m, 1H),
0.99–0.95 (d, J 5 6.8 Hz, 6H), 0.87–0.84 (d, J 5 6.4 Hz, 3H); 13C NMR
(50 MHz, CDCl3) d 175.9, 145.9, 145.0, 128.2, 127.9, 126.8, 126.6, 125.7,
125.6, 81.1, 54.9, 50.7, 38.7, 25.1, 23.9, 21.6, 21.2; HRMS calcd. for
(C21H28N2O2 1 Na)1 363.2043, found 363.2048.
(S,S)-2-Amino-N-(1-hydroxy-4-methyl-1,1-diphenylpentan-2-yl)-4-
methylpentan-amide (1b). White solid; Yield 54%; m.p. 18021828C;
[a]2D0 5 244 (c 1.0, DMSO); 1H NMR (400 MHz, DMSO-d6) d 7.5427.56
(q, J 5 7.8 Hz, J 5 8.0 Hz, 4H), 7.4027.43 (d, J 5 8.8 Hz, 1H), 7.1327.35
(m, 5H), 4.7824.84 (t, J 5 9.6 Hz, 1H), 1.7523.18 (dd, J 5 4.2 Hz, J 5
10.2 Hz, 1H), 1.5621.63 (m, 1H), 1.4421.49 (m, 1H), 1.2121.33 (m, 4H),
0.9720.98 (d, J 5 6.8 Hz, 3H), 0.8520.86 (d, J 5 6.4 Hz, 3H), 0.8420.85
(d, J 5 6.4 Hz, 3H), 0.8020.82 (d, J 5 6.8 Hz, 3H).
(S,S)-2-Amino-N-(1-hydroxy-1,1,3-triphenylpropan-2-yl)-3-phenyl-
propanamide (1i). White solid; Yield 46%; m.p. 17221738C; [a]D20
5
2125 (c 1.0, CHCl3); FT-IR 3312, 3026, 2923, 2856,1952, 1647, 1531,
1446, 1349, 1164, 1060, 750, 697 cm21 1H NMR (200 MHz, CDCl3) d
(S,S)-2-Amino-N-(1,1-bis(3,5-bis(trifluoromethyl)phenyl)-1-hydroxy-3-
phenylpropan-2-yl)-4-methylpentanamide (1c). White solid; Yield
42%; m.p. 169–1718C; [a]2D0 5 275 (c 1.0, CHCl3); FT-IR 3315, 3094,
2960, 2874, 1711, 1643, 1527, 1369, 1280, 1172, 1135, 900, 843, 707, 682
;
7.70–7.57 (m, 5H), 7.40–7.07 (m, 13H), 6.70–6.95 (m, 2H), 5.61 (br, 1H),
4.82–4.73 (t, J 5 8.6 Hz, 1H), 3.35–3.28 (m, 1H), 3.19–3.07 (m, 1H), 2.90–
2.78 (m, 2H), 1.82–1.70 (m, 1H), 1.00 (br, 2H); 13C NMR (50 MHz,
CDCl3) d 175.2, 146.2, 145.0, 139.3, 137.8, 129.2, 129.0, 128.6, 128.4,
128.3, 128.0, 126.8, 126.7, 126.3, 125.8, 125.6, 80.5, 60.3, 56.3, 40.2, 34.8;
HRMS calcd. for (C30H30N2O2 1 Na)1 473.2199, found 473.2185.
cm21 1H NMR (200 MHz, CDCl3) d 8.17–7.82 (m, 6H), 7.35–6.99 (m,
;
5H), 4.42–4.32 (m, 1H), 3.39–3.27 (dd, J 5 11.2 Hz, J 5 14.2 Hz, 1H),
3.28–3.21 (dd, J 5 4 Hz, J 5 9.6 Hz, 1H), 2.71–2.63 (app t, J 5 4 Hz, 1H),
1.32–1.17 (m, 3H), 1.14–1.08 (br, 1H), 0.73–0.69 (23 d, J 5 6.4 Hz, 6H);
13C NMR (100 MHz, CDCl3) d 178.5, 148.5, 146.5, 138.4, 132.1, 131.7,
129.0, 128.8, 127.0, 126.2, 125.9, 124.5, 121.7, 121.2, 79.0, 83.9, 53.1, 43,5,
33.3, 24.6, 22.8, 21.2; HRMS calcd. for (C31H28F12N2O2 1 H)1 689.2032,
found 689.2037.
(S,S)-2-amino-N-(1-hydroxy-4-methyl-1,1-diphenylpentan-2-yl)-3-phe-
nylpropanamide (1j). White solid; Yield 48%; m.p. 152–1538C; [a]D20
5
242 (c 1.0, CHCl3); FT-IR 3318, 3026, 2953, 2926,,2868,1950, 1644, 1515,
1448, 1366, 1164, 1062, 746, 700 cm21 1H NMR (200 MHz, CDCl3) d
;
7.57–7.47 (m, 5H), 7.36–7.06 (m, 10H), 4.92–4.81 (m, 1H), 3.36–3.30 (m,
1H), 3.03–2.94 (m, 1H), 2.31–2.20 (m, 1H), 1.72–1.51 (m, 2H), 1.30–1.17
(S,S)-2-Amino-N-(1-hydroxy-1,1,3-triphenylpropan-2-yl)-3-methyl-
butanamide (1d). White solid; Yield 58%; m.p. 160–1628C; [a]D20
5
(m, 2H), 0.99–0.96 (d, J 5 6.6 Hz, 3H), 0.86–0.83 (d, J 5 6.4 Hz, 3H); 13
C
289 (c 1.0, CHCl3); FT-IR 3326, 3027, 2958, 2927, 2869, 1952, 1710, 1638,
1525, 1448, 1365, 1170, 1063, 750, 700 cm21; 1H NMR (200 MHz, CDCl3)
d 7.71–7.55 (m, 5H), 7.38–7.06 (m, 10H), 6.29 (br, 1H), 4.76–4.65 (m,
1H), 3.23–3.11 (dd, J 5 11.2 Hz, J 5 14.2 Hz, 1H), 2.96 (d, J 5 4 Hz, 1H),
2.87–2.78 (dd, J 5 2.8 Hz, J 5 14.2 Hz, 1H), 1.97–1.87 (m, 1H), 0.92 (br,
1H), 0.67–0.63 (d, J 5 7 Hz, 3H), 0.19–0.16 (d, J 5 7 Hz, 3H); 13C NMR
(50 MHz, CDCl3) d 175.6, 146.6, 145.2, 139.7, 129.1, 128.3, 128.0, 126.7,
126.5, 126.3, 125.8, 125.6, 80.2, 61.9, 60.0, 34.1, 30.3, 19.4, 15.2; HRMS
calcd. for (C26H30N2O2 1 H)1 403.2380, found 403.2375.
NMR (50 MHz, CDCl3) d 174.5, 145.9, 144.9, 137.8, 129.1, 129.1, 128.6,
128.3, 128.2, 128.0, 127.9, 126.8, 126.7, 126.6, 125.8, 125.7, 125.6, 81.1,
56.4, 54.9, 40.6, 38.6, 25.1, 23.9, 21.6; HRMS calcd. for (C27H32N2O2
Na)1 439.2356, found 439.2343.
1
General Procedure for the Hydroxyamination
of Aldehydes with Nitrosobenzene
The solid of catalyst 1 (0.2 mmol, 20 mol %) was added to a solu-
tion of the aldehyde (3.0 mmol, 3.0 equiv) in CH2Cl2 (1.0 ml) at
2208C. A solution of nitrosobenzene (1.0 mmol, 1.0 equiv) in CH2Cl2
(1.0 ml) was then added dropwise to the reaction mixture, and the
resulting mixture was stirred at 2208C for 3–5 days. EtOH (2.0 ml)
and NaBH4 (4.0 mmol) were successively added at the same tempera-
ture. After 30 min, the reaction was quenched with saturated brine
(2.0 ml), extracted with CH2Cl2 (33 2.0 ml), dried over anhydrous
Na2SO4, and concentrated under a reduced pressure. The residue was
purified over silica gel by the flash column chromatography to afford
the hydroxyamination adducts. The enantiomeric excess was deter-
mined by chiral HPLC.
(S,S)-2-Amino-N-(1-hydroxy-4-methyl-1,1-diphenylpentan-2-yl)-3-
methylbutanamide (1e). White solid; Yield 51%; m.p. 17721788C;
[a]2D0 5 249 (c 1.0, DMSO); 1H NMR (400 MHz, DMSO-d6) d 7.6427.66
(d, J 5 9.6 Hz, 1H), 7.4627.50 (t, J 5 8.0 Hz, J 5 8.4 Hz, 4H), 7.0227.27
(m, 5H), 5.92 (s, 1H), 4.9024.96 (t, J 5 10.2 Hz, 1H), 2.6822.69 (d, J 5
4.4 Hz, 1H), 1.6421.68 (m, 1H), 1.4521.51 (m, 4H), 0.7620.78 (d, J 5
7.2 Hz, 3H), 0.7220.73 (d, J 5 6.0 Hz, 3H).
(S,S)-2-Amino-N-(3-ethyl-3-hydroxy-1-phenylpentan-2-yl)-3-methylbu-
tanamide (1f). White solid; Yield 65%; m.p. 106–1078C; [a]2D0 5 273 (c
1.0, CHCl3); FT-IR 3335, 3027, 2962, 2931, 2878, 1644, 1521, 1457, 1383,
Chirality DOI 10.1002/chir

530
QIN ET AL.
(R)-2-(N-Phenylhydroxyamino)propanol (6a). Pale yellow oil; Yield
TABLE 1. Solvent screening in the hydroxyamination reaction
of 3-methylbutanal with nitrosobenzenea
49%; [a]2D0 5 212.8 (c 1.0, CHCl3), Ref. 27 [a]24 5 8.0 (c 1.0, CHCl3); 1H
D
NMR (200 MHz, CD3OD) d 7.26–7.08 (m, 4H), 6.90–6.82 (app t, J 5 7.2
Hz, 1H), 3.84–3.65 (m, 2H), 3.58–3.53 (m, 1H), 1.02–0.98 (d, J 5 6.2 Hz,
3H). ee 5 51%, determined by chiral HPLC. The enantiomeric excess
was determined by HPLC with an AD-H column (hexane/ethanol 5 90/
10), 1.0 ml/min; t 5 9.2 min (major), t 5 13.4 min (minor).
(R)-2-(N-Phenylhydroxyamino)propanol (6b). Pale yellow oil; Yield
51%; [a]2D0 5 23.2 (c 1.0, CHCl3), Ref. 27 [a]2D5 5 22.5 (c 1.0, CH2Cl2);
1H NMR (200 MHz, CD3OD) d 7.24–7.07 (m, 4H), 6.86–6.77 (app t, J 5
7.2 Hz, 1H), 3.77–3.56 (m, 2H), 3.52–3.29 (m, 1H), 1.70–1.55 (m, 2H),
0.97–0.89 (t, J 5 7.4 Hz, 3H). ee 5 54%, determined by chiral HPLC. The
enantiomeric excess was determined by HPLC with an AD-H column
(hexane/ethanol 5 90/10), 1.0 ml/min; t 5 7.9 min (major), t 5 10.4
min (minor).
Entry
Solvent
CH2Cl2
THF
CHCl3
(CH2)2Cl2
EtOAc
EtOH
TBME
DMF
PhCH3
DMB
CH2Cl2/MeOH (9:1)
CH2Cl2
CH2Cl2
Time (day)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
3
4
3
3
4
2
5
5
4
4
2
2
1
62
NDd
56
60
45
24
35
12
55
65
NDd
33
41
27
21
45
15
37
43
51
36
21
(R)-2-(Hydroxy(phenyl)amino)pentan-1-ol (6c). Pale yellow oil;
Yield 54%; [a]2D0 5 212.4 (c 1.0, CHCl3), Ref. 25 [a]2D4 5 8.6 (c 0.9,
CHCl3); 1H NMR (200 MHz, CD3OD) d 7.25–7.06 (m, 4H), 6.86–6.78
(app t, J 5 7.0 Hz, 1H), 3.74–3.55 (m, 3H), 1.48–1.30 (m, 4H), 0.96–0.89
(t, J 5 7.2 Hz, 3H). ee 5 60%, determined by chiral HPLC. The enantio-
meric excess was determined by HPLC with an AD-H column (hexane/
ethanol 5 95/5), 1.0 ml/min; t 5 10.4 min (major), t 5 13.2 min
(minor).
9
10
11
12f
13g
58
62e
56
58
aReactions were conducted with 3.0 equiv 3-methylbutanal, 0.2 equiv catalyst,
and 1.0 equiv nitrosobenzene at 2208C.
(R)-2-(N-Phenylhydroxyamino)-3-methylbutanol (6d). Pale yellow oil;
Yield 63%; [a]2D0 5 26.4 (c 1.0, CHCl3), Ref. 25 [a]2D0 5 11.6 (c 1.0,
CHCl3); 1H NMR (200 MHz, CD3OD) d 7.22–7.15 (app t, J 5 7.0 Hz,
2H), 7.07–7.03 (d, J 5 7.6 Hz, 2H), 6.81–6.74 (app t, J 5 7.1 Hz, 1H),
3.80–3.76 (m, 2H), 3.28–3.18 (m, 2H), 2.20–2.09 (m, 1H), 1.05–1.00 (23
d, J 5 6.8 Hz, 6H). ee 5 65%, determined by chiral HPLC. The enantio-
meric excess was determined by HPLC with an OJ-H column (hexane/
ethanol 5 96/4), 1.0 ml/min; t 5 12.7 min (major), t 5 18.0 min
(minor).
bIsolated yield.
cDetermined by chiral HPLC analysis (Chiralcel OJ-H). The configuration
was assigned by comparison of the retention time of the major isomer in
HPLC with reported values and by comparison of the sign of the optical rota-
tion with the reported value.24–27
dNot determined.
eA little O-nitroso aldol product was observed.
fThe reaction was carried out at 08C.
gThe reaction was carried out at room temperature.
(R)-2-(N-Phenylhydroxyamino)-3-phenylpropanol (6e). Pale yellow oil;
Yield 60%; [a]2D0 5 127 (c 1.0, CHCl3), Ref. 25 [a]2D0 5 299.3 (c 0.8,
CHCl3); H NMR (200 MHz, CD3OD) d 7.27–7.08 (m, 9H), 6.85 (app t, J
meric excess was determined by HPLC with an AS-H column (hexane/i-
PrOH 5 98/2), 1.0 ml/min; t 5 16.1 min (minor), t 5 17.3 min (major).
1
5 7.3 Hz, 1H), 3.83–3.73 (m, 3H), 2.91–2.82 (dd, J 5 5.0 Hz, J 5 14.0 Hz,
1H), 2.79–2.75 (dd, J 5 7.8 Hz, J 5 13.8 Hz, 1H). ee 5 61%, determined
by chiral HPLC. The enantiomeric excess was determined by HPLC
with an AD-H column (hexane/ethanol 5 90/10), 1.0 ml/min; t 5 9.6
min (major), t 5 13.5 min (minor).
RESULTS AND DISCUSSION
The seven organocatalysts 1a–g were readily prepared by
using the routine mixed anhydride method to combine the
Boc-protected amino acids 4 with the amino alcohols 3a–e
from natural amino primary amino acids, and successively
remove the Boc group with TFA (Scheme 1).40,41 When L-
phenylalanine was replaced by D-phenylalanine, 1g, the dia-
stereomeric isomer of 1a, was afforded.
In initial experiments, a model reaction of 3-methylbutanal
and nitrosobenzene was investigated by using 20 mol % orga-
nocatalyst 1a in a variety of solvents at 2208C without any
additive (Table 1, entries 1–11).* As expected, N-specific ni-
troso-aldol adduct, which was then reduced in situ into
amino alcohol with NaBH4, was fortunately obtained as the
only product. The results showed that dichloromethane was
the optimal solvent that exclusively gave the N-selective
product with the highest yield and enantioselectivity (Table
1, entry 1). A portion of MeOH in DCM accelerated the reac-
tion but decreased in its enantioselectivity and generated a
little O-selective aminoxylated side product (Table 1, entry
11). The other solvents were found to be less satisfactory in
terms of the chemical yield, reaction rate and enantioselectiv-
ity. Accordingly, CH2Cl2 was selected to be the optimal sol-
(R)-3-(4-tert-butylphenyl)-2-(hydroxy(phenyl)amino)propan-1-ol
(6f). Pale yellow oil; Yield 70%; [a]2D0 5 116 (c 1.0, CHCl3); FT-IR
3320, 3058, 2960, 2868, 1708, 1596, 1488, 1362, 1221, 1026, 832, 760, 695,
568 cm21 1H NMR (200 MHz, CD3OD) d 7.26–7.01 (m, 8H), 6.89–6.81
;
(app t, J 5 7.6 Hz, 1H), 3.87–3.75 (m, 2H), 3.53–3.42 (dd, J 5 7.1 Hz,
1H), 2.87–2.78 (dd, J 5 4.8 Hz, J 5 13.8 Hz, 2H), 2.74–2.63 (dd, J 5 7.7
Hz, J 5 14.2 Hz, 2H), 1.28 (s, 9H); 13C NMR (50 MHz, CD3OD): d 154.1,
149.8, 138.0, 129.8, 129.6, 126.2, 121.7, 117.2, 71.0, 62.2, 35.1, 33.1, 31.9,
31.8. HRMS calcd. for (C19H25NO2 1 H)1: 300.1958, found 300.1962. ee
5 37%, determined by chiral HPLC. The enantiomeric excess was deter-
mined by HPLC with an AD-H column (hexane/ethanol 5 90/10), 1.0
ml/min; t 5 6.8 min (major), t 5 8.0 min (minor).
(R)-2-(Hydroxy-phenyl-amino)-2-methyl-butan-1-ol (6g). Color-
less oil; Yield 68%; [a]D20 5 25.8 (c 1.0, CHCl3); 1H-NMR (200 MHz,
CDCl3) d 7.26–7.09 (m, 5H), 3.69 (d, J 5 11.4 Hz, 1H), 3.53 (d, J 5 11.4
Hz, 1H), 1.79–1.68 (m, 1H), 1.30–1.16 (m, 1H), 0.94 (s, 3H), 0.81 (t, J 5
7.5Hz, 3H); Ref. 26. ee 5 31%, determined by chiral HPLC. The enantio-
meric excess was determined by HPLC with an AD-H column (hexane/
ethanol 5 95/5), 1.0 ml/min; t 5 12.7 min (major), t 5 15.2 min
(minor).
(R)-2-(Hydroxy-phenyl-amino)-2-methyl-pentan-1-ol (6h). Color-
less oil; Yield 73%; [a]D20 5 28 (c 1.0, CHCl3); 1H-NMR (200 MHz,
CDCl3) d 7.26–7.11 (m, 5H), 3.67 (d, J 5 11.4 Hz, 1H), 3.57 (d, J 5 11.4
Hz, 1H), 1.67–1.60 (m, 1H), 1.29–1.11 (m, 4H), 0.95 (s, 3H), 0.82 (t, J 5
6.8 Hz, 3H); Ref. 24. ee 5 35%, determined by chiral HPLC. The enantio-
*Because nitrosobenzene is very reactive and unstable, we used threefold
aldehyde to nitrobenzene to make the reaction complete more quickly and
get higher yield in agreement with the reported procedures.24–27 The self-
aldol reaction of the aldehyde was not observed in this reaction.
Chirality DOI 10.1002/chir

DIRECT ASYMMETRIC N-SPECIFIC REACTION
531
TABLE 2. Catalysts screening in the hydroxyamination
reaction of 3-methylbutanal with nitrosobenzenea
We then investigated the effects of these different catalysts
on the reaction. As showed in Table 2, 1a, 1d, 1e, 1f, and 1i
showed higher enantioselectivity (ꢀ60%) than other catalysts
(Table 2, entries 1, 4, 5, and 6). 1c, which had a stronger
acidic hydroxyl and bulky diaryl groups, gave the fastest
reaction with a very low enantioselectivity (Table 2, entry 3).
In comparison with 1a, 1g which is the diastereomeric iso-
mer of 1a with a D-Phe instead of L-Phe only lowered the
enantioselectivity with no influence on the configuration of
the product (Table 2, entries 1 and 8). In terms of yield and
enantioselectivity, 1a could be considered as the optimal cat-
alyst.
With the optimized reaction conditions in hand, the scope
of this reaction for various aldehydes with nitrosobenzene
was next investigated, and the results are shown in Table 3.
Generally, all the reactions proceeded smoothly and gave the
N-specific product b-amino alcohols. And it is noteworthy
that no O-selective aminoxylated product was detected. This
result indicated that this primary amine-based organocatalyst
is efficient to the atom specific reaction. As shown in Table
3, a bulkier group in b-carbon is helpful to afford higher
yields and enantioselctivity (Table 3, entry 1–5), and b-
methyl butyraldehyde afforded the highest 65% enantioselec-
tivity and higher yield. An exceptional case was 3-(4-tert-
butylphenyl)propanal, it resulted in a low enantioselectivity
but a higher 70% yield. Maybe the great steric hindrance is
disadvantageous to the enantioselctivity, however, the a-
branched aldehydes achieved lowered enantioselectivity with
higher yields. Among the series aldehydes, 3-methylbutanal
got the highest 65% enantioselectivity while (Table 3, entry
4) while 2-methylvaleraldehyde harvested the highest 73%
yield (Table 3, entry 8).
Entry Catalyst Additive (20%) Time (day) Yield (%)b ee (%)c
1
2
3
4
1a
1b
1c
1d
1e
1f
–
–
–
–
–
–
–
–
–
–
–
–
–
3
2
8 h
3
3
3
1
4
2
3
3
3.5
3
2
1
2.5
3
4
62
45
58
51
47
34
42
35
37
48
41
46
60
58
64
56
15
13
65 (R)
41 (R)
12 (R)
61 (R)
62 (R)
61 (R)
3 (R)
32 (R)
38 (R)
60 (R)
32 (R)
56 (R)
55 (R)
59 (R)
11 (R)
51 (R)
27 (R)
61 (R)
5
6
7d
8
1f
1g
1h
1i
9
10
11
12e
13f
14g
15
16
17
18
1j
1a
1a
1a
1a
1a
1a
1a
–
DNP
Phenol
Et3N
˚
4 A MS
aReactions were conducted with 3.0 equiv 3-methylbutanal, 0.2 equiv catalyst,
and 1.0 equiv nitrosobenzene at 2208C.
bIsolated yield.
cDetermined by chiral HPLC analysis (Chiralcel OJ-H). The configuration
was assigned by comparison of the retention time of the major isomer in
HPLC with reported values and by comparison of the sign of the optical rota-
tion with the reported value.24–27
dThe catalyst is in the form of hydrochloride.
eThe reaction was carried out in the presence of 15 mol % catalyst.
fThe reaction was carried out in the presence of 25 mol % equiv catalyst.
gThe reaction was carried out in the presence of 30 mol % catalyst.
TABLE 3. Enantioselective hydroxyamination
reaction of various aldehydes with nitrosobenzene
catalyzed by 1aa
vent. Raising temperature did not lead to a higher yield but
lowered the enantioselectivity (Table 1, entries 12 and 13).
The effects of the catalyst loading and additive on the cata-
lytic efficiency of 1a were then tested (Table 2, entries 9–
16). Changing the loading of the catalyst had no significant
improvement in enantioselectivity but only accelerated the
reaction (Table 2, entries 9–11). We wished to find some
effective additive to raise the enantioselectivity and yield.
Unexpectedly, however, DNP sharply reduced the enantiose-
lectivity although it significantly accelerated the reaction (Ta-
ble 2, entry 12). Similarly, the lower acidity phenol slightly
decreased the enantiomeric excess (Table 2, entry 13). A ba-
sic additive triethylamine was also observed but it also
sharply reduced the enantioselectivity (Table 2, entry 14).
Entry
Aldehyde
Time (day)
Yield (%)b
ee (%)c
1
2
3
5
5
4
49
51
54
51 (R)
54 (R)
60 (R)
4
5
3
4
62
60
65 (R)
61 (R)
2
4
3
70
68
73
37 (R)
31 (R)
35 (R)
6d
7d
8d
˚
Although 4 A molecular sieves as another additive were
tested, it only made the reaction very slow with no increase
in the enantioselectivity (Table 2, entries 15).27 DNP itself
can not catalyze this reaction. As we know, an acid will
quicken the formation of enamine from an amine group with
carbonyl group of the aldehyde or ketone. We speculate that
DNP might serve an acid to make the enamine quick forma-
tion from the organocalyst with the aldehyde. This quick
enamine might contribute to the accelerated reaction. With
regard to the decreased ee value, it is very unclear here in
combination with the behavior of the basic and molecular
sieves additives.
aReactions were conducted with 3.0 equiv aldehyde, 0.2 equiv catalyst, and
1.0 equiv nitrosobenzene at 2208C.
bIsolated yield.
cDetermined by chiral HPLC analysis. The configuration was assigned by
comparison of the retention time of the major isomer in HPLC with reported
value and by comparison of the sign of the optical rotation with the reported
value.24–27
dThe reaction was carried out at 08C.
Chirality DOI 10.1002/chir

532
QIN ET AL.
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Chirality DOI 10.1002/chir