Silica nanoparticles as a highly efficient catalyst for the one-pot synthesis of 2-hydroxyacetamide derivatives from isocyanides and electron-poor aromatic aldehydes

Article abstract of DOI:10.1002/hlca.201000280

Reaction of an isocyanide with an electron-poor aromatic aldehyde in the presence of silica nanoparticles (silica NP; ca. 42 nm) proceeds smoothly at room temperature to afford 2-hydroxyacetamide derivatives in high yields (Scheme 1 and Table 1). Copyrigh

Full text of DOI:10.1002/hlca.201000280

Helvetica Chimica Acta – Vol. 94 (2011)
611
Silica Nanoparticles as a Highly Efficient Catalyst for the One-Pot Synthesis of
2-Hydroxyacetamide Derivatives from Isocyanides and Electron-Poor
Aromatic Aldehydes
a
a
b
c
c
´
by Ali Ramazani* ), Amir Mahyari ), Hamed Lashgari ), Katarzyna Slepokura ), and Tadeusz Lis )
a) Chemistry Department, Zanjan University, P.O. Box 45195-313, Zanjan, Iran
(phone: þ 98-241-5152572; fax: þ 98-241-5152477; e-mail: aliramazani@yahoo.com)
b) Chemistry Department, Payame Noor University (PNU), Abhar, Zanjan, Iran
c) Faculty of Chemistry, University of Wrocław, 14 Joliot-Curie St., PL-50-383 Wrocław
Reaction of an isocyanide with an electron-poor aromatic aldehyde in the presence of silica
nanoparticles (silica NP; ca. 42 nm) proceeds smoothly at room temperature to afford 2-hydroxyacet-
amide derivatives in high yields (Scheme 1 and Table 1).
Introduction. – As part of our ongoing program to develop efficient and robust
methods for the preparation of organic compounds [1 – 22], we wish to report now a
simple and practical procedure for the preparation of 2-hydroxyacetamide derivatives
3 through reaction of alkyl isocyanides 1 and electron-poor aromatic aldehydes 2 in the
presence of silica nanoparticles (silica NP; ca. 42 nm) at room temperature for 8 h (cf.
Scheme 1 and Table 1).
Results and Discussion. – Silica NP were prepared by thermal decomposition of rice
hulls [22][23]. The results from XRD showed that the sample was silica NP as indicated
by broadened peaks around 2q ¼ 228 [22]. The morphology and grain size of the silica
NP was investigated by scanning electron microscopy (SEM) [22].
Silica NP were found to catalyze the formation of 2-hydroxyacetamide derivatives
3 from alkyl isocyanides 1 and electron-poor aromatic aldehydes 2 under solvent-free
conditions in high yields (Scheme 1 and Table 1). We also have used silica-gel powder
instead of silica NP in this reaction, but increasing reaction times and decreasing yields
of the 2-hydroxyacetamides were observed (Table 2). The use of just 0.2 g of silica NP
(per mmol of reactants) was sufficient to push the reaction forward. Higher amounts of
silica NP (0.3 g) did not improve the result to a great extent (Table 2).
Scheme 1. Synthesis of 2-Hydroxyacetamide Derivatives 3 in the Presence of Silica Nanoparticles (NP)
(see Table 1)
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 94 (2011)
Table 1. Synthesis of 2-Hydroxyacetamide Derivatives 3 in the Presence of Silica Nanoparticlesa)
R
Ar
Product
Yield [%]b)
91
Cyclohexyl
2-NO2C6H4
Cyclohexyl
4-NO2C6H4
96
Cyclohexyl
Cyclohexyl
Cyclohexyl
3-NO2C6H4
96
90
96
3-HC(O)C6H4
4-HC(O)C6H4
t-Bu
t-Bu
3-NO2C6H4
4-NO2C6H4
95
97
t-Bu
t-Bu
3-HC(O)C6H4
4-HC(O)C6H4
93
97
1,1,3,3-Tetramethylbutyl 2-NO2C6H4
1,1,3,3-Tetramethylbutyl 3-NO2C6H4
87
93

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613
Table 1 (cont.)
R
Ar
Product
Yield [%]b)
95
1,1,3,3-Tetramethylbutyl 4-NO2C6H4
1,1,3,3-Tetramethylbutyl 3-HC(O)C6H4
1,1,3,3-Tetramethylbutyl 4-HC(O)C6H4
88
92
Bn
Bn
3-NO2C6H4
4-NO2C6H4
82
83
a) Cf. Scheme 1; 0.2 g of SiO2 NP/mmol reactants were applied, reaction time 8 h. b) Yield of isolated 3.
Table 2. Synthesis of 2-Hydroxyacetamide 3a from the Reaction of 2-Nitrobenzaldehyde and Cyclohexyl
Isocyanide under Various Conditions
Catalysta)
Temperature
Time [h]
Yield [%]b)
Silica-gel powder (0.2 g)
Silica-gel powder (0.5 g)
Silica-gel powder (1 g)
Silica-gel powder (1.2 g)
SiO2 NP (0.1 g)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
24
24
24
24
8
42
55
71
71
80
91
91
SiO2 NP (0.2 g)
SiO2 NP (0.3 g)
8
8
a) Amount of SiO2 catalyst per mmol of reactants. b) Yields of isolated 3a.
The structures of compounds 3a – 3p were deduced from their IR and high-field 1H-
and 13C-NMR spectra. For example, the IR spectrum of 3a showed a strong adsorption
at 3386 cmꢀ1 indicating the presence of an amide group (NH), a sharp band at
1644 cmꢀ1 was assigned to the amide C¼O group, and two sharp bands at 1529 and
1359 cmꢀ1 were assigned to the NO2 group. The 1H-NMR spectrum of 3a consisted of
three ms for the cyclohexyl substituent (d(H) 0.99 – 1.92 and 3.67 – 3.78), an OH signal

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Helvetica Chimica Acta – Vol. 94 (2011)
exchangeable by D2O (d(H) 4.70), a CH signal (d(H) 5.23), an amide NH signal (d(H)
6.79) also exchangeable by D2O, and partially overlapping coupling patterns of four
adjacent aromatic H-atoms (d(H) 7.41 – 7.48 (HꢀC(5)), 7.60 – 7.62 (HꢀC(4), HꢀC(6)),
and 7.89 (d, 3J(H,H) ¼ 7.0 Hz, HꢀC(3))). The 1H-decoupled 13C-NMR spectrum of 3a
showed 14 distinct resonances; partial assignment of these resonances is given in the
Exper. Part. The 1H- and 13C-NMR spectra of compounds 3b – 3p were similar to those
of 3a, except for the aromatic moieties and the alkyl groups, which exhibited
characteristic signals with appropriate chemical shifts.
Finally, the structure of 3a was confirmed unambiguously by single-crystal X-ray
analysis (Fig. 1). Enantiomorphic crystals of 3a were formed by slow evaporation from
light petroleum ether/AcOEt 3 :1. The crystal-structure determination was performed
on one of the enantiomers refined in the chiral space group P212121. However, it should
be stressed that the absolute configuration could not be established unambiguously by
anomalous dispersion effects (see Exper. Part), and therefore, Fig. 1 may not show the
real absolute configuration of the molecule. A summary of the conditions for the data
collection and the structure refinement parameters are given in Table 3. The values of
selected bond lengths and valence angles (Table 4) correspond well with those typical
for the respective types of chemical connections [24].
Fig. 1. Molecular structure of compound 3a, showing the X-ray atom-numbering scheme and intra-
molecular NꢀH ··· O H-bond-forming S(5) motif (dashed line). Displacement ellipsoids represent the
50% probability level.
The central part of molecule 3a is the 2-hydroxyacetamide moiety, with atoms C(1),
N(1), H(N1), C(14), O(3), and C(13) lying in one plane and the OH atom O(4) slightly
deviating from this plane by 0.34 ꢂ. As seen from the torsion angles
C(1)ꢀN(1)ꢀC(14)ꢀC(13)/O(3) (ꢀ179.69(7)/1.05(12)8), compound 3a is a trans (Z)
isomer. Synperiplanar orientation of the OH atom O(4) with respect to the amide atom
N(1), reflected in the O(4)ꢀC(13)ꢀC(14)ꢀN(1) torsion angle of 14.57(9)8, is stabilized
by the intramolecular H-bond NꢀH ··· O forming an S(5) motif, as shown in Fig. 2. The
amide moiety is inclined at an angle of ca. 638 with respect to the phenyl ring, as
confirmed by the torsion angle C(8)ꢀC(7)ꢀC(13)ꢀC(14) of 62.63(9)8. The NO2 group
is twisted relative to the phenyl ring by ca. 388, which is reflected in the torsion angle
O(2)ꢀN(2)ꢀC(8)ꢀC(7) of 37.92(10)8. Such a twist of the NO2 group is accompanied by
a weak intramolecular interaction C(13)ꢀH(13) ··· O(2) forming an S(6) motif

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615
Table 3. Crystallographic Data of Compound 3a
Crystallized from
Empirical formula
Mr
Crystal color, habit
Crystal dimensions [mm]
Radiation type, l [ꢂ]
Temperature [K]
Crystal system
Space group
Z
petroleum ether/AcOEt
C14H18N2O4
278.30
colorless, block
0.40 ꢂ 0.32 ꢂ 0.28
MoKa, 0.71073
86(2)
orthorhombic
P212121
4
Scan type
Index range
w and f
ꢀ 17 ꢁ h ꢁ 12,
ꢀ 19 ꢁ k ꢁ 19,
ꢀ 21 ꢁ l ꢁ 19
35165
4375
3863
0.027
99.5%
F2
Measured reflections
Independent reflections
Reflections with I > 2s(I)
Rint
Completeness to q ¼ 308
Refinement on
q Range [8]
Unit cell parameters:
a [ꢂ]
4.27 – 38.43
Data, restraints, parameters
R (Fo2 > 2s(Fo2 ))
4375, 0, 253
R1 ¼ 0.032a),
wR2 ¼ 0.086a)
R1 ¼ 0.037,
wR2 ¼ 0.089
1.00
0.0670/0.0
0.33; ꢀ 0.24
10.132(3)
11.388(4)
12.305(4)
1419.8(8)
1.302
b [ꢂ]
R (all data)
c [ꢂ]
V [ꢂ3]
Goodness-of-fit S
Weighting parameter a/b
D1 (max; min) [e ꢂꢀ3
]
Dx (calc.) [g cmꢀ3
]
m [mmꢀ1
]
0.096
592
F(000) [e]
pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
P
P
P
P
a)R1 ¼ jjFoj ꢀ jFcjj= jFoj; wR2 ¼
½wðFo2 ꢀ Fc2Þ ꢃ= ½wðFo2Þ ꢃ. Weighting scheme: w ¼ 1/
2
2
[s2(Fo2 ) þ (aP)2 þ bP] where P ¼ (Fo2 þ 2 Fc2 )/3.
Table 4. Selected Interatomic Distances, Valence Angles, and Torsion Angles of 3a
Bond lengths [ꢂ]
O(1)ꢀN(2)
O(2)ꢀN(2)
O(3)ꢀC(14)
1.2317(11)
1.2296(11)
1.2383(10)
O(4)ꢀC(13)
N(1)ꢀC(1)
N(1)ꢀC(14)
1.4116(9)
1.4665(10)
1.3284(10)
Valence angles [8]
C(14)ꢀN(1)ꢀC(1)
O(2)ꢀN(2)ꢀO(1)
O(2)ꢀN(2)ꢀC(8)
O(1)ꢀN(2)ꢀC(8)
123.24(7)
123.92(8)
118.13(7)
117.84(8)
C(9)ꢀC(8)ꢀN(2)
O(3)ꢀC(14)ꢀN(1)
O(3)ꢀC(14)ꢀC(13)
N(1)ꢀC(14)ꢀC(13)
115.73(7)
124.32(7)
119.44(6)
116.24(6)
Torsion angles [8]
C(14)ꢀN(1)ꢀC(1)ꢀC(6)
C(14)ꢀN(1)ꢀC(1)ꢀC(2)
C(1)ꢀN(1)ꢀC(14)ꢀO(3)
C(1)ꢀN(1)ꢀC(14)ꢀC(13)
N(1)ꢀC(1)ꢀC(2)ꢀC(3)
N(1)ꢀC(1)ꢀC(6)ꢀC(5)
C(13)ꢀC(7)ꢀC(8)ꢀC(9)
N(2)ꢀC(8)ꢀC(9)ꢀC(10)
146.99(8)
ꢀ 88.72(9)
1.05(12)
ꢀ 179.69(7)
ꢀ 179.55(7)
ꢀ 179.20(7)
ꢀ 174.09(7)
174.84(8)
O(1)ꢀN(2)ꢀC(8)ꢀC(7)
O(2)ꢀN(2)ꢀC(8)ꢀC(7)
C(8)ꢀC(7)ꢀC(13)ꢀO(4)
C(8)ꢀC(7)ꢀC(13)ꢀC(14)
O(4)ꢀC(13)ꢀC(14)ꢀO(3)
C(7)ꢀC(13)ꢀC(14)ꢀO(3)
O(4)ꢀC(13)ꢀC(14)ꢀN(1)
C(7)ꢀC(13)ꢀC(14)ꢀN(1)
ꢀ145.62(8)
37.92(10)
ꢀ174.59(7)
62.63(9)
ꢀ166.13(7)
ꢀ43.46(9)
14.57(9)
137.24(7)
(Table 5). The cyclohexyl substituent at N(1) adopts a typical chair conformation, the
Cremer and Pople puckering parameters [25] being Q ¼ 0.580(1) ꢂ, V¼ 1.5(1)8, F ¼
107(4)8, and endocyclic torsion angles averaging 56.58.

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Fig. 2. Two ribbons (solid and open lines) joined by weak CꢀH ··· O interactions (dashed lines) and
bifurcated CꢀH ··· p contacts (dotted lines) in the crystal lattice of 3a. Symmetry codes are given in
Table 5.
Table 5. Geometry of Proposed H-Bonds and CꢀH ··· O Close Contacts of 3a
DꢀH ··· A
DꢀH [ꢂ]
H ··· A [ꢂ]
D ··· A [ꢂ]
DꢀH ··· A [8]
O(4)ꢀH(4) ··· O(3)i
N(1)ꢀH(1N) ··· O(4)
N(1)ꢀH(1N) ··· O(1)i
C(1)ꢀH(1) ··· O(3)
0.88(2)
0.85(2)
0.85(2)
0.97(2)
1.02(2)
0.98(2)
0.93(2)
1.74(2)
2.22(2)
2.51(2)
2.49(2)
2.64(2)
2.28(2)
2.39(2)
2.618(1)
2.653(1)
3.235(2)
2.838(2)
3.457(2)
2.700(2)
2.920(2)
172(2)
112(2)
144(2)
101(1)
138(2)
105(1)
116(1)
C(10)ꢀH(10) ··· O(1)ii
C(12)ꢀH(12) ··· O(4)
C(13)ꢀH(13) ··· O(2)
Symmetry codes: i, x þ 1/2, ꢀ y þ 1/2, ꢀ z þ 1; ii, ꢀ x,y ꢀ 1/2, ꢀ z þ 1/2.
The crystal packing in 3a is determined mainly by the H-bonds OꢀH ··· O and NꢀH
··· O involving the 2-hydroxyacetamide moiety and atom O(1) of the NO2 group (see
Fig. 3 and Table 5), and reveals arrangement of the molecules into ribbons running
down the a-axis. The structure of the ribbon is additionally stabilized by weak CꢀH ··· p
contacts (dotted lines in Fig. 2) with a H(3B)i ··· ring-centroid(Ph) distance of ca. 3.2 ꢂ.
Each ribbon is further linked with four adjacent ones via interactions C(10)ꢀH(10) ···
O(1)ii in a manner shown in Fig. 2 (symmetry code in Table 5) giving rise to the three-
dimensional network. Additional stabilization of the crystal structure comes from
bifurcated CꢀH ··· p contacts formed between the adjacent ribbons, with H(5A) ··· ring-
centroid(Ph)iii and H(5B) ··· ring-centroid(Ph)iii distances of ca. 3.1 and 3.2 ꢂ,
respectively (dotted lines in Fig. 2; iii: ꢀ x, y þ 1/2, ꢀ z þ 3/2).
Although we have not established the mechanism of the reaction in an
experimental manner, a plausible reaction sequence that accounts for the formation

Helvetica Chimica Acta – Vol. 94 (2011)
617
Fig. 3. The arrangement of 3a molecules within the ribbons running down the a-axis. Intra- and
intermolecular H-bonds are shown with dashed lines, CꢀH ··· p contacts with dotted lines. The symmetry
code is given in Table 5.
of 3 is shown in Scheme 2. Thus, intermediate 4 was produced by nucleophilic reaction
of alkyl isocyanide 1 and electron-poor aromatic aldehyde 2, followed by nucleophilic
attack of H2O on the nitrilium moiety and production of compound 5. Finally,
tautomerization of 5 leads to the 2-hydroxyacetamide derivatives 3 (Scheme 2).
Scheme 2. Proposed Mechanism for the Preparation of 2-Hydroxyacetamide Derivatives 3 in the
Presence of Silica Nanoparticles
The recycling potential of the silica-NP catalyst was studied by coupling cyclohexyl
isocyanide and 2-nitrobenzaldehyde in five consecutive cycles. The silica NP could be
recycled and reused by separating them from the reaction mixture through
centrifugation, frequent washing with EtOH, and drying under vacuum to remove
the residual solvent. The results show that the yield of product, after five runs, was only
slightly reduced (Fig. 4).

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Fig. 4. Recycle of the catalyst
Conclusions. – We have developed an efficient route for the one-pot synthesis of 2-
hydroxyacetamide derivatives 3 from simple and readily available alkyl isocyanides 1
and electron-poor aromatic aldehydes 2 in the presence of silica NP (Scheme 1 and
Table 1). The ease of workup and high yields of products make this procedure a useful
addition to modern synthetic methods. Furthermore, this solvent-free reaction has
many advantages: reduced pollution, low costs, and simplicity in process and handling.
These factors may be important, especially in industry.
This research was supported by the Zanjan University.
Experimental Part
General. Freshly distilled solvents were used throughout, and anh. solvents were dried according to
Perrin and Armarego [26]. The silica-NP samples were characterized with a scanning electron microscope
(SEM) (Philips XL 30) with gold coating. M.p.: Electrothermal-9100 apparatus; uncorrected. X-Ray
powder diffraction (XRD) measurements: Xꢀpert diffractometer of Philips company with monochrom-
atized CuKa radiation. IR Spectra: Jasco-6300 FT-IR spectrometer; ˜n in cmꢀ1. 1H- and 13C-NMR Spectra:
Bruker-DRX-250-Avance spectrometer at 250.0 and 62.5 MHz, resp.; CDCl3 or (D6)DMSO soln.; d in
ppm rel. to Me4Si as internal standard, J in Hz. Elemental analyses: Heraeus-CHN-O-Rapid analyzer.
General Procedure. Silica NP (0.2 g) were added to a mixture of an electron-poor aromatic aldehyde
(1 mmol) and an isocyanide (1 mmol) at r.t., followed by 8 h of stirring. After completion of the reaction,

Helvetica Chimica Acta – Vol. 94 (2011)
619
flash column chromatography (silica gel (powder), petroleum ether/AcOEt 5 :2) of the residue gave the
2-hydroxyacetamide derivative.
N-Cyclohexyl-2-hydroxy-2-(2-nitrophenyl)acetamide (3a): Colorless crystals. M.p. 132 – 1348. IR:
3388, 3256, 2937, 2858, 1647, 1534, 1449, 1361. 1H-NMR (CDCl3): 0.99 – 1.92 (2m, 5 CH2 of Chx); 3.67 –
3.78 (m, CHꢀN of Chx); 4.70 (s, OH); 5.53 (s, CH); 6.79 (d, 3J(NH,CH) ¼ 6.8, NH); 7.41 – 7.48 (m,
3
HꢀC(5) of C6H4); 7.60 – 7.62 (m, HꢀC(4), HꢀC(6) of C6H4); 7.89 (d, J(H,H) ¼ 7.0, HꢀC(3) of C6H4).
13C-NMR (CDCl3): 24.47, 24.50 (2 CH2(b) of Chx); 25.35 (CH2(g) of Chx); 32.53, 32.70 (2 CH2(a) of
Chx); 48.64 (CHꢀN of Chx); 68.53 (CH); 124.52, 128.98, 129.33, 133.84 (4 CH of C6H4); 135.46, 148.68
(2 C of C6H4); 169.73 (CONH). Anal. calc. for C14H18N2O4: C 60.42, H 6.52, N 10.07; found: C 60.39, H
6.48, N 10.04.
N-Cyclohexyl-2-hydroxy-2-(4-nitrophenyl)acetamide (3b): Yellow crystals. M.p. 145 – 1478. IR: 3367,
3278, 2931, 2857, 1638, 1519, 1451, 1349. 1H-NMR (CDCl3): 0.88 – 1.82 (2m, 5 CH2 of Chx); 3.64 – 3.73 (m,
CHꢀN of Chx); 3.87 (s, OH); 5.13 (s, CH); 6.27 (d, 3J(NH,CH) ¼ 6.8, NH); 7.63 (d, 3J(H,H) ¼ 8.3,
3
HꢀC(2,6) of C6H4); 8.20 (d, J(H,H) ¼ 8.3, HꢀC(3,5) of C6H4). 13C-NMR (CDCl3): 24.65 (2 CH2(b) of
Chx); 25.31 (CH2(g) of Chx); 32.81 (2 CH2(a) of Chx); 48.52 (CHꢀN of Chx); 73.13 (CH); 123.78, 127.35
(4 CH of C6H4); 135.40, 148.27 (C of C6H4); 169.67 (CONH). Anal. calc. for C14H18N2O4: C 60.42, H 6.52,
N 10.07; found: C 60.38, H 6.47, N 10.03.
N-Cyclohexyl-2-hydroxy-2-(3-nitrophenyl)acetamide (3c): Yellow crystals. M.p. 143 – 1458. IR: 3351,
3322, 2938, 2857, 1646, 1525, 1452, 1350. 1H-NMR (CDCl3): 1.12 – 1.81 (m, 5 CH2 of Chx); 3.64 – 3.73 (m,
CHꢀN of Chx); 3.80 (s, OH); 5.12 (s, CH); 6.47 (s, NH); 7.52 – 7.59 (m, HꢀC(5) of C6H4); 7.77 (s, HꢀC(6)
of C6H4); 8.14 (s, HꢀC(4) of C6H4); 8.30 (s, HꢀC(2) of C6H4). 13C-NMR (CDCl3): 24.67 (2 CH2(b) of
Chx); 25.31 (CH2(g) of Chx); 32.79 (2 CH2(a) of Chx); 48.48 (CHꢀN of Chx); 72.92 (CH); 121.42,
123.25, 129.55, 132.78 (4 CH of C6H4); 141.74, 148.27 (2 C of C6H4); 169.98 (CONH). Anal. calc. for
C14H18N2O4: C 60.42, H 6.52, N 10.07; found: C 60.37, H 6.49, N 10.02.
N-Cyclohexyl-2-(3-formylphenyl)-2-hydroxyacetamide (3d): White oil. IR: 3348, 2931, 2855, 1699,
1653, 1532, 1451. 1H-NMR (CDCl3): 1.13 – 1.81 (m, 5 CH2 of Chx); 3.59 – 3.78 (m, CHꢀN of Chx); 4.09 (s,
OH); 5.07 (s, CH); 6.33 (s, NH); 7.52 (t, 3J(H,H) ¼ 7.5, HꢀC(5) of C6H4); 7.69 (d, 3J(H,H) ¼ 7.8, HꢀC(6)
3
of C6H4); 7.8 (d, J(H,H) ¼ 7.3, HꢀC(4) of C6H4); 7.92 (s, HꢀC(2) of C6H4); 9.98 (s, CH¼O). 13C-NMR
(CDCl3): 24.68 (2 CH2(b) of Chx); 25.35 (CH2(g) of Chx); 32.80 (2 CH2(a) of Chx); 48.42 (CHꢀN of
Chx); 73.37 (CH); 127.63, 129.40, 129.78, 132.71 (4 CH of C6H4); 136.61, 140.41 (2 C of C6H4); 170.51
(CONH); 192.11 (CH¼O). Anal. calc. for C15H19NO3: C 68.94, H 7.33, N 5.36; found: C 68.88, H 7.38, N
5.32.
N-Cyclohexyl-2-(4-formylphenyl)-2-hydroxyacetamide (3e): White crystals. M.p. 99 – 1018. IR: 3363,
2933, 2855, 1699, 1632, 1536, 1450. 1H-NMR ((D6)DMSO): 1.13 – 1.62 (m, 5 CH2 of Chx); 3.80 – 3.86 (m,
CHꢀN of Chx); 4.99 (s, OH); 6.36 (s, CH); 7.92 (s, NH); 7.61 (d, 3J(H,H) ¼ 8.0, HꢀC(2,6) of C6H4); 7.84
(d, 3J(H,H) ¼ 8.0, HꢀC(3,5) of C6H4); 9.96 (s, CH¼O). 13C-NMR ((D6)DMSO): 25.06 (2 CH2(b) of
Chx); 25.52 (CH2(g) of Chx); 32.60 (2 CH2(a) of Chx); 47.81 (CHꢀN of Chx); 73.43 (CH); 127.49, 129.67
(4 CH of C6H4); 135.79, 148.61 (2 C of C6H4); 170.77 (CONH); 193.28 (CH¼O). Anal. calc. for
C15H19NO3: C 68.94, H 7.33, N 5.36; found: C 68.90, H 7.28, N 5.33.
N-(tert-Butyl)-2-hydroxy-2-(3-nitrophenyl)acetamide (3f): Yellow crystals. M.p. 96 – 988. IR: 3383,
3118, 2973, 2859, 1648, 1532, 1457, 1349. 1H-NMR ((D6)DMSO): 1.21 (s, Me3C); 4.98 (d, 3J(OH,CH) ¼
5.3, OH); 6.57 (d, 3J(CH,OH) ¼ 5.5, CH); 7.44 (s, NH); 7.60 (t, 3J(H,H) ¼ 8.0, HꢀC(5) of C6H4); 7.82 (d,
3
3J(H,H) ¼ 7.5, HꢀC(6) of C6H4); 8.10 (d, J(H,H) ¼ 8.0, HꢀC(4) of C6H4); 8.22 (s, HꢀC(2) of C6H4).
13C-NMR ((D6)DMSO): 28.67 (Me3C); 50.71 (Me3CNH); 72.64 (CH); 121.27, 122.79, 130.05, 136.53
(4 CH of C6H4); 143.87, 147.92 (2 C of C6H4); 171.04 (CONH). Anal. calc. for C12H16N2O4: C 57.13, H
6.39, N 11.10; found: C 57.08, H 6.33, N 11.07.
N-(tert-Butyl)-2-hydroxy-2-(4-nitrophenyl)acetamide (3g): Yellow crystals. M.p. 115 – 1178. IR:
3390, 3324, 2928, 2859, 1648, 1525, 1458, 1349. 1H-NMR ((D6)DMSO): 1.22 (s, Me3C); 4.99 (s, OH); 6.43
3
3
(s, CH); 7.41 (s, NH); 7.66 (d, J(H,H) ¼ 8.0, HꢀC(2,6) of C6H4); 8.18 (d, J(H,H) ¼ 8.0, HꢀC(3,5) of
C6H4). 13C-NMR ((D6)DMSO): 28.76 (Me3C); 50.61 (Me3CNH); 73.05 (CH); 123.54, 127.94 (4 CH of
C6H4); 147.21, 149.49 (2 C of C6H4); 170.66 (CONH). Anal. calc. for C12H16N2O4: C 57.13, H 6.39, N 11.10;
found: C 57.10, H 6.34, N 11.05.

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Helvetica Chimica Acta – Vol. 94 (2011)
N-(tert-Butyl)-2-(3-formylphenyl)-2-hydroxyacetamide (3h): White oil. IR: 3380, 3226, 2969, 1703,
1
1650, 1540, 1457. H-NMR (CDCl3): 1.32 (s, Me3C); 3.88 (s, OH); 4.99 (s, CH); 6.11 (s, NH); 7.53 (t,
3J(H,H) ¼ 7.5, HꢀC(5) of C6H4); 7.68 (d, 3J(H,H) ¼ 7.8, HꢀC(6) of C6H4); 7.84 (d, 3J(H,H) ¼ 7.3, HꢀC(4)
of C6H4); 7.92 (s, HꢀC(2) of C6H4); 10.00 (s, CH¼O). 13C-NMR (CDCl3): 28.62 (Me3C); 51.60
(Me3CNH); 73.59 (CH); 127.64, 129.49, 129.81, 132.70 (4 CH of C6H4); 136.70, 141.16 (2 C of C6H4);
170.44 (CONH); 192.05 (CH¼O). Anal. calc. for C13H17NO3: C 66.36, H 7.28, N 5.95; found: C 66.40, H
7.22, N 5.93.
N-(tert-Butyl)-2-(4-formylphenyl)-2-hydroxyacetamide (3i): White crystals. M.p. 139 – 1418. IR:
3363, 3263, 2974, 1703, 1649, 1536, 1460. 1H-NMR (CDCl3): 1.31 (s, Me3C); 3.84 (s, OH); 4.99 (s, CH);
6.00 (s, NH); 7.57 (d, 3J(H,H) ¼ 8.0, HꢀC(2,6) of C6H4); 7.88 (d, 3J(H,H) ¼ 8.0, HꢀC(3,5) of C6H4); 10.01
(s, CH¼O). 13C-NMR (CDCl3): 28.59 (Me3C); 51.68 (Me3CNH); 73.77 (CH); 127.22, 130.16 (4 CH of
C6H4); 136.29, 146.40 (2 C of C6H4); 170.10 (CONH); 191.84 (CH¼O). IR: 3359, 3259, 2926, 1698, 1648,
1533, 1447, 1209. Anal. calc. for C13H17NO3: C 66.36, H 7.28, N 5.95, found: C 66.31, H 7.25, N 5.92.
2-Hydroxy-2-(2-nitrophenyl)-N-(1,1,3,3-tetramethylbutyl)acetamide (3j): Yellow crystals. M.p. 132 –
1348. IR: 3369, 3163, 2927, 2871, 1654, 1540, 1477, 1347. 1H-NMR (CDCl3): 0.82 (s, Me3C); 1.36, 1.39 (2s,
Me2CNH); 1.62 (s, Me3CCH2); 4.75 (d, 3J(OH,CH) ¼ 5.3, OH); 5.43 (d, 3J(CH,OH) ¼ 5.0, CH); 6.76 (s,
NH); 7.42 – 7.66 (m, 3 CH of C6H4); 7.90 (d, 3J(H,H) ¼ 8.0, HꢀC(3) of C6H4). 13C-NMR (CDCl3): 28.87,
29.04 (Me2CNH); 31.10 (Me3C); 31.42 (Me3C); 51.69 (Me3CCH2); 55.76 (Me2CNH); 67.84 (CH); 124.31,
128.89, 129.32, 134.00 (4 CH of C6H4); 135.90, 148.63 (2 C of C6H4); 168.93 (CONH). Anal. calc. for
C16H24N2O4: C 62.32, H 7.84, N 9.08; found: C 62.23, H 7.87, N 9.12.
2-Hydroxy-2-(3-nitrophenyl)-N-(1,1,3,3-tetramethylbutyl)acetamide (3k): Yellow crystals. M.p. 109 –
1118. IR: 3379, 3247, 2952, 2867, 1654, 1528, 1347. 1H-NMR ((D6)DMSO): 0.83 (s, Me3C); 1.27 (s,
3
3
Me2CNH); 1.63 (s, Me3CCH2); 5.00 (d, J(OH,CH) ¼ 5, OH); 6.49 (d, J(CH,OH) ¼ 4.8, CH); 7.32 (s,
3
3
NH); 7.57 – 7.63 (m, HꢀC(5) of C6H4); 7.84 (d, J(H,H) ¼ 7.8, HꢀC(6) of C6H4); 8.11 (d, J(H,H) ¼ 7.0,
HꢀC(4) of C6H4); 8.26 (s, HꢀC(2) of C6H4). 13C-NMR ((D6)DMSO): 29.38 (Me2CNH); 31.53 (Me3C);
31.67 (Me3C); 50.93 (Me3CCH2); 54.44 (Me2CNH); 72.70 (CH); 121.41, 122.63, 129.84, 133.59 (4 CH of
C6H4); 144.00, 147.83 (2 C of C6H4); 170.28 (CONH). Anal. calc. for C16H24N2O4: C 62.32, H 7.84, N 9.08;
found: C 62.26, H 7.80, N 9.04.
2-Hydroxy-2-(4-nitrophenyl)-N-(1,1,3,3-tetramethylbutyl)acetamide (3l): Yellow crystals. M.p. 111 –
1138. IR: 3356, 3245, 2943, 2866, 1657, 1523, 1344. 1H-NMR ((D6)DMSO): 0.84 (s, Me3C); 1.28 (s,
Me2CNH); 1.64 (s, Me3CCH2); 4.99 (d, 3J(OH,CH) ¼ 5.3, OH); 6.50 (d, 3J(CH,OH) ¼ 5.3, CH); 7.28 (s,
3
3
NH); 7.67 (d, J(H,H) ¼ 8.8, HꢀC(2,6) of C6H4); 8.75 (d, J(H,H) ¼ 8.0, HꢀC(3,5) of C6H4). 13C-NMR
((D6)DMSO): 29.32 (Me2CNH); 31.58 (Me3C); 31.69 (Me3C); 51.11 (Me3CCH2); 54.45 (Me2CNH);
73.12 (CH); 123.42, 128.03 (4 CH of C6H4); 147.21, 149.34 (2 C of C6H4); 170.05 (CONH). Anal. calc. for
C16H24N2O4: C 62.32, H 7.84, N 9.08; found: C 62.27, H 7.81, N 9.02.
2-(3-Formylphenyl)-2-hydroxy-N-(1,1,3,3-tetramethylbutyl)acetamide (3m): White oil. IR: 3388,
1
2956, 2874, 1702, 1660, 1532, 1479, 1366. H-NMR (CDCl3): 0.88 (s, Me3C); 1.37 (s, Me2CNH); 1.65 (s,
3
Me3CCH2); 3.91 (s, OH); 4.98 (s, CH); 6.08 (s, NH); 7.53 (t, J(H,H) ¼ 7.5, HꢀC(5) of C6H4); 7.68 (d,
3J(H,H) ¼ 7.8, HꢀC(6) of C6H4); 7.83 (d, 3J(H,H) ¼ 7.5, HꢀC(4) of C6H4); 7.92 (s, HꢀC(2) of C6H4); 10.01
(s, CH¼O). 13C-NMR (CDCl3): 28.70, 29.00 (Me2CNH); 31.31 (Me3C); 31.53 (Me3C); 52.17 (Me3CCH2);
55.59 (Me2CNH); 73.67 (CH); 127.67, 129.45, 129.76, 132.68 (4 CH of C6H4); 136.65, 140.94 (2 C of
C6H4); 169.89 (CONH); 192.00 (CH¼O). Anal. calc. for C16H24N2O4: C 70.07, H 8.65, N 4.81; found: C
7.02, H 8.61, N 4.82.
2-(4-Formylphenyl)-2-hydroxy-N-(1,1,3,3-tetramethylbutyl)acetamide (3n): White oil. IR: 3361,
1
3279, 2957, 2857, 1702, 1640, 1530, 1366. H-NMR (CDCl3): 0.88 (s, Me3C); 1.36 (s, Me2CNH); 1.72 (s,
Me3CCH2); 4.25 (s, OH); 4.61 (s, CH); 6.17 (s, NH); 7.54 (d, 3J(H,H) ¼ 8.3, HꢀC(2,6) of C6H4); 7.85 (d,
3J(H,H) ¼ 8.0, HꢀC(3,5) of C6H4); 9.99 (s, CH¼O). 13C-NMR (CDCl3): 28.92 (Me2CNH); 31.32 (Me3C);
31.53 (Me3C); 52.12 (Me3CH2); 55.52 (Me2CNH); 73.47 (CH); 127.16, 130.00 (4 CH of C6H4); 136.12,
146.41 (2 C of C6H4); 169.85 (CONH); 191.92 (CH¼O). Anal. calc. for C17H25NO3: C 70.07, H 8.65, N
4.81; found: C 7.10, H 8.60, N 4.77.
N-Benzyl-2-hydroxy-2-(3-nitrophenyl)acetamide (3o): Yellow oil. IR: 3405, 3262, 2925, 2854, 1648,
1513, 1347. 1H-NMR ((D6)DMSO): 4.24 (d, 3J(H,H) ¼ 6.3, PhCH2); 5.14 (d, 3J(OH,CH) ¼ 4.8, OH); 6.71
(d, 3J(CH,OH) ¼ 5, CH); 7.21 (s, NH); 7.14 – 7.22, 8.69 – 8.74 (2m, 5 CH of C6H5); 7.57 – 7.63 (m, HꢀC(5)

Helvetica Chimica Acta – Vol. 94 (2011)
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of C6H4); 7.85 (d, 3J(H,H) ¼ 7.8, HꢀC(6) of C6H4); 8.10 – 8.13 (d, 3J(H,H) ¼ 7.3, HꢀC(4) of C6H4); 8.26 (s,
HꢀC(2) of C6H4). 13C-NMR ((D6)DMSO): 42.24 (PhCH2); 72.75 (CH); 121.23, 122.90, 130.08, 133.61
(4 CH of C6H4); 127.25, 127.48, 128.66 (5 CH of C6H5); 139.56 (C of C6H5); 143.87, 147.92 (2 C of C6H4);
172.11 (CONH). IR: 3371, 3275, 2919, 1653, 1527, 1348. Anal. calc. for C15H14N2O4: C 62.93, H 4.93, N
9.70; found: C 62.88, H 4.90, N 9.73.
N-Benzyl-2-hydroxy-2-(4-nitrophenyl)acetamide (3p): Yellow oil. IR: 3401, 2930, 2860, 1657, 1530,
1351. 1H-NMR ((D6)DMSO): 4.22 (d, 3J(H,H) ¼ 6.3, PhCH2); 5.12 (s, OH); 6.56 (s, CH); 7.13 (s, NH);
7.15 – 7.25, 8.63 – 8.71 (2m, 5 CH of C6H5); 7.67 (d, 3J(H,H) ¼ 8.8, HꢀC(2,6) of C6H4); 8.16 (d, 3J(H,H) ¼
8.8, HꢀC(3,5) of C6H4). 13C-NMR ((D6)DMSO): 42.30 (PhCH2); 73.14 (CH); 123.57, 127.98 (4 CH of
C6H4); 127.15, 127.56, 128.63 (5 CH of C6H5); 139.79 (C of C6H5); 147.01, 149.22 (2 C of C6H4); 171.60
(CONH). Anal. calc. for C15H14N2O4: C 62.93, H 4.93, N 9.79; found: C 62.88, H 4.91, N 9.75.
X-Ray Crystal-Structure Determination of 3a (Table 3 and Fig. 1)1). Colorless single crystals of 3a
were obtained from its light petroleum ether/AcOEt 3 :1 soln. by slow evaporation at 208 over 2 d. The
colorless single crystals were filtered, washed with cold light petroleum ether/AcOEt 3 :1, and dried at r.t.
(m.p. 132.0 – 134.08). The crystallographic measurement was performed on a k-geometry Xcalibur-PX
automated four-circle diffractometer with graphite-monochromatized MoKa radiation (l 0.71073 ꢂ).
The data for the crystal were collected at 86(2) K by using an Oxford-Cryosystems cooler. Data
collection, cell refinement, and data reduction and analysis were carried out with the Xcalibur-PX
software (Oxford Diffraction Ltd.): CrysAlis CCD and CrysAlis RED, resp. [27]. The data were
corrected for Lorentz and polarization effects. The structure was solved by direct methods with the
SHELXS-97 program [28], and refined by a full-matrix least-squares technique by using SHELXL-97
[28] with anisotropic thermal parameters for all non-H atoms. All H-atoms were found in difference
Fourier maps and were refined isotropically. The absolute configuration could not be established
unambiguously by anomalous dispersion effects (the anomalous scattering power was too small, as the
heaviest atom is O-atom). Therefore, the choice of enantiomer was made relying on the lower Flack
parameter (close to 0), and then, in the final refinement cycles, the Friedel pairs were averaged by using
the MERG 4 instruction. All figures were made with the XP program [29]. Cremer and Pople puckering
parameters [25] were calculated with the PLATON program [30]. A summary of the conditions for the
data collection and the structure refinement parameters are given in Table 3.
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1
)
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Helvetica Chimica Acta – Vol. 94 (2011)
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Received July 27, 2010