Chlorodinitrophenylhydrazine, a useful crystalline agent for absolute configuration determination of various chiral ketones

Article abstract of DOI:10.1016/j.tet.2005.03.037

For the determination of absolute configuration of various chiral ketones, we examined some hydrazines having a heavy atom as crystalline auxiliaries, and found that 2-chloro-4,6-dinitrophenylhydrazine is a useful crystalline agent for carbonyl compounds.

Full text of DOI:10.1016/j.tet.2005.03.037

Tetrahedron 61 (2005) 5049–5055
Chlorodinitrophenylhydrazine, a useful crystalline agent for
absolute configuration determination of various chiral ketones
b
b
Yasushi Kawai,a, Motoko Hayashi and Norihiro Tokitoh
*
aNagahama Institute of Bio-Science and Technology, Nagahama, Shiga 526-0829, Japan
bInstitute for Chemical Research, Kyoto Univeristy, Uji, Kyoto 611-0011, Japan
Received 9 February 2005; revised 9 March 2005; accepted 9 March 2005
Available online 24 March 2005
Abstract—For the determination of absolute configuration of various chiral ketones, we examined some hydrazines having a heavy atom as
crystalline auxiliaries, and found that 2-chloro-4,6-dinitrophenylhydrazine is a useful crystalline agent for carbonyl compounds. Chiral
hydrazones prepared from the hydrazine and various chiral ketones gave suitable single crystals for X-ray crystallographic analysis. The
absolute configurations of the hydrazones were determined by X-ray crystallographic analysis using anomalous dispersion effect of the
chlorine atom. The hydrazine is a useful crystalline agent for absolute configuration determination of various chiral ketones.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
the corresponding enones are oily substances and contain no
heavy atom, so that single crystals must be prepared with a
certain crystalline auxiliary having a heavy atom. Hydra-
zines are well-known to be good crystalline agents for
ketones. It is easy that a halogen atom as a heavy atom is
introduced into a phenyl ring in the phenylhydrazine. Thus,
a phenylhydrazine derivative having (a) halogen atom(s) is
employed as a crystalline agent (Scheme 1). Recently, we
reported some preliminary results on the determination of
absolute configuration of chiral ketones.11 This paper will
describe the details and application of this method.
Optically active a-substituted ketones (a-chiral ketones) are
versatile intermediates for the synthesis of natural products,
especially in pheromone synthesis.1 A number of methods
for the synthesis of a-chiral ketones have been reported, for
example, stereoselective a-alkylation2 and enantioselective
protonation of enolates and enols.3 Enzymatic transform-
ations to obtain a-chiral ketones have also been reported, for
example, hydrolysis of enol esters4 and reduction of a,b-
unsaturated carbonyl compounds (enones).5 The enantio-
selective protonation of enol esters6 and enol ethers7 using a
catalytic antibody has also been reported. We have
developed the method for the asymmetric synthesis of
a-chiral ketones by the reduction of enones with baker’s
yeast8 or a carbon–carbon double bond reductase purified
from baker’s yeast.9 However, few studies are found in the
literature for the direct method to determine the absolute
configurations of these chiral ketones. They have been
determined by derivation to the known compounds2g,6 or
assumed from empirical rules.2f,4c,10
Scheme 1.
2. Results and discussion
X-ray crystallographic analysis is the only method to
determine the absolute configuration of a molecule. The
anomalous dispersion effect of a heavy atom must be used
for the determination of the absolute configuration.
However, in most cases, the chiral ketones reduced from
2.1. Design and synthesis of crystalline agents
At first, commercial 4-bromophenylhydrazine (1) and 2,4-
dichlorophenylhydrazine (2) were used as crystalline
agents, and hydrazones of chiral ketones were prepared
with them under acidic conditions. All chiral ketones here
studied (3a–e) were obtained by baker’s yeast reduction of
enones (Scheme 2).8c The yields of hydrazone (4, 5c,e) are
Keywords: Phenylhydrazine; Chiral ketone; X-ray crystallography; Absol-
ute configuration.
*
Corresponding author. Tel.: C81 749 64 8116; fax: C81 749 64 8140;
e-mail: y_kawai@nagahama-i-bio.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.037

5050
Y. Kawai et al. / Tetrahedron 61 (2005) 5049–5055
2-Chloro-4,6-dinitrophenylhydrazine (8) having two nitro
groups was designed with the hope of more crystallinity.12
2-Chloro-4,6-dinitroaniline is a weak base because of two
nitro groups and a chlorine atom, so that diazotization does
not occur with a conventional way. Therefore, the aniline
dissolved in hot acetic acid was diazotized with nitrosyl
sulfate prepared from sodium nitrite and sulfuric acid,13 and
iodinated with potassium iodide to afford 1-chloro-2-iodo-
3,5-dinitrobenzene (9). It was stirred with hydrazine
monohydrate in methanol at room temperature to give the
desired hydrazine 8 (Scheme 4).14
2.2. Determination of the absolute configuration of chiral
ketones
Scheme 2.
listed in Table 1. Unfortunately, these hydrazones did not
give suitable single crystals for X-ray crystallographic
analysis.
The reaction of hydrazine 8 with chiral ketones in the
presence of an acid catalyst gave chiral hydrazones 10 in
good yields as shown in Table 1. The ketone 3a and 3b
having a methyl group at the a-position of carbonyl group
were racemized slowly under a strong acidic condition. The
conditions to prevent the racemization were studied and
found that ee of the chiral ketone kept with a catalytic
amount of sulfuric acid. Therefore, syntheses of hydrazone
with chiral ketones 3a and 3b having a methyl group at the
a-position of carbonyl group were carried out under that
condition (condition A). Syntheses with other ketones were
done under a strong acid condition (condition B). Syn-
thesized 2-chloro-4,6-dinitrophenylhydrazone derivatives
(10a–e) were recrystallized from various solvents to obtain
single crystals. Single crystals of the hydrazone were
subjected to X-ray crystallographic analysis in order to
elucidate their absolute configurations using the anomalous
dispersion effect of a chlorine atom. The ORTEP drawings
of 10a–e are shown in Figures 1–5, respectively. Crystal-
lographic data of the above analysis are listed in Table 2.
Table 1. Yields (%) of hydrazone
Ketone
Hydrazine
1
2
6
8
3a
3b
3c
3d
3e
11
12
13
4 (70)
10a (64)
10b (75)
10c (31)
10d (80)
10e (86)
14 (91)
5c (63)
5e (35)
7c (40)
7d (61)
7e (24)
15 (59)
16 (80)
Since, a nitro group is also known to have a good
crystallinity, introduction of a nitro group into the
hydrazone is expected for more crystallinity. Therefore,
2-chloro-4-nitrophenylhydrazine (6) was designed and
synthesized. It has a chlorine atom as a heavy atom and a
nitro group for a crystallinity. Its synthesis was carried out
in the conventional method (Scheme 3). 2-Chloro-4-
nitrophenylhydrazones (7) were prepared from the corre-
sponding hydrazine 6 and various chiral ketones (Table 1),
but they did not give good single crystals as in the cases of 4
and 5.
Except for 10c, the structures of hydrazones exhibit (E)-
forms at the carbon–nitrogen double bond, and the
1
production of single isomer was confirmed by H NMR
experiments. As judged by 1H NMR experiment, hydrazone
10c consisted of two isomers, which should be (E)- and (Z)-
forms. The ratio of isomers was about 1/1 estimated by
Scheme 3.
Scheme 4.

Y. Kawai et al. / Tetrahedron 61 (2005) 5049–5055
5051
Figure 4. The ORTEP drawing of 10d with displacement ellipsoids at 50%
probability level.
Figure 1. The ORTEP drawing of 10a with displacement ellipsoids at 50%
probability level. The asymmetric unit contains two independent molecules
(only one molecule is shown).
Figure 5. The ORTEP drawing of 10e with displacement ellipsoids at 50%
probability level.
1
integral curves in a H NMR spectrum, but all the single
Figure 2. The ORTEP drawing of 10b with displacement ellipsoids at 50%
probability level. The asymmetric unit contains two independent molecules
(only one molecule is shown).
crystals which subjected to X-ray crystallographic analysis
were exhibited to be (Z)-form. The ORTEP drawing of (Z)-
10c illustrated in Figure 3 shows that there exists a hydrogen
bond between N in the pyridine ring and NH in the
˚
hydrazone moiety, the length of which is 2.91 A. Because of
the hydrogen bond, the (Z)-form should be stabilized and
exhibit a good crystallinity. The absolute configurations of
these hydrazones 10a–e were determined to be S by Flack
parameters16 and intensities comparisons of Bijvoet pairs.17
These configurations were determined by the anomalous
dispersion effect of a chlorine atom in the crystalline
auxiliary, 2-chloro-4,6-dinitrophenylhydrazine. Therefore,
the absolute configurations of the chiral ketone obtained by
baker’s yeast reduction 3a–e were determined to be S.
In order to apply this method to other types of chiral ketone,
hydrazones were synthesized from a chiral alkyl ketone 11,
commercially available (R)-carvone 12, and a chiral
hydroxy ketone 13 (Scheme 5). The alkyl ketone 11 was
supplied by Daicel Chemical Industries, Ltd and the
hydroxy ketone 13 was obtained by baker’s yeast reduction
of the corresponding b-diketone.15 The hydrazones 14–16
also gave single crystals which were subjected to X-ray
crystallographic analysis in order to elucidate their absolute
Figure 3. The ORTEP drawing of 10c with displacement ellipsoids at 50%
probability level.

5052
Y. Kawai et al. / Tetrahedron 61 (2005) 5049–5055
Table 2. Crystallographic data of hydrazone 10a–e
10a
10b
10c
10d
10e
Formula
C16H16ClN5O4
377.79
C16H16ClN5O4
377.79
C17H18ClN5O4
391.81
Orthorhombic
P212121 (#19)
7.508 (4)
C17H18ClN5O4
391.81
C17H18ClN5O4
391.81
Formula weight
Crystal system
Space group
Monoclinic
C2 (#5)
18.456 (10)
9.039 (5)
21.007 (11)
104.183 (6)
3397.6 (27)
8
7616
593
0.050
0.128
Orthorhombic
P21212 (#18)
17.500 (2)
21.236 (2)
9.1634 (9)
Monoclinic
P21 (#4)
7.013 (7)
5.527 (5)
23.38 (2)
93.40 (2)
904.6 (13)
2
3124
316
0.049
0.133
Monoclinic
P21 (#4)
7.010 (4)
5.514 (2)
23.89 (1)
103.031 (5)
899.7 (7)
2
3899
315
0.060
0.168
˚
a (A)
˚
b (A)
14.258 (7)
16.590 (9)
˚
c (A)
b (8)
3
˚
V (A )
3405.4 (5)
8
7788
1776.0 (14)
4
4045
Z value
No. observations
No. variables
R1 (F2O2.0s(F2))
wR2 (all data)
S (all data)
597
316
0.050
0.085
1.01
0.038
0.066
1.00
1.04
K0.03 (7) (S)
1.08
0.0 (1) (S)
1.10
0.0 (1) (S)
Flack parameter
0.05 (5) (S)
0.03 (5) (S)
should be noted that 2-chloro-4,6-dinitrophenylhydrazine
(8) is a useful crystalline agent for this purpose. This method
can be applied to both of aromatic and aliphatic chiral
ketones, and is helpful for the determination of the absolute
configuration of various chiral ketones.
3. Experimental
3.1. General
Scheme 5.
configurations using the anomalous dispersion effect of a
chlorine atom. The ORTEP drawings of 14–16 are
illustrated in Figures 6–8. The crystallographic data of
14–16 are listed in Table 3. The absolute configurations
were successfully determined by Flack parameter16 and
intensities comparison of Bijvoet pairs.17 To improve the
Organic reagents and solvents were purchased from Nacalai
Tesque, Inc., Wako Pure Chemical Ind., Ltd, Tokyo Kasei
Kogyo Co., Ltd, and Aldrich Chemical Co. Optically active
3-methyl-2-pentanone (11) was supplied by Daicel
Chemical Industries, Ltd. 1H NMR spectra (300 MHz)
were recorded on a JEOL AL-300 spectrometer on CDCl3
˚
practical usefulness of this method, Cu Ka (lZ1.5418 A)
radiation was tested as an alternative X-ray source.
Structure determination of hydrazone 15 using Cu Ka
radiation at room temperature also gave satisfactory results
(Flack parameter16Z0.05 (2)).
In conclusion, we have developed a new method for the
determination of the absolute configuration of chiral
ketones. This is the simple and direct method and the
potential of this methodology was clearly demonstrated. It
Figure 6. The ORTEP drawing of 14 with displacement ellipsoids at 50%
probability level. The asymmetric unit contains two independent molecules
(only one molecule is shown).
Figure 7. The ORTEP drawing of 15 with displacement ellipsoids at 50%
probability level. The asymmetric unit contains two independent molecules
(only one molecule is shown).

Y. Kawai et al. / Tetrahedron 61 (2005) 5049–5055
5053
dropwise to it keeping the temperature below 20 8C. The
solution was stirred at 15–20 8C for 1 h. To the solution,
potassium iodide (2.32 g, 14 mmol) dissolved in 20 mL of
water was added slowly, then heated at 50 8C for 15 min.
The solution was neutralized with aqueous sodium carbon-
ate and the aqueous solution was extracted with ethyl
acetate. The combined extracts were washed with aqueous
sodium hydrogensulfite and brine, and dried over anhydrous
magnesium sulfate. Removal of the solvent gave 1-chloro-
2-iodo-3,5-dinitrobenzene quantitatively. 1H NMR (CDCl3,
TMS) dZ8.35 (1H, d, JZ2.4 Hz), 8.49 (1H, d, JZ2.4 Hz).
IR (KBr) 3082, 1554, 1534, 1364, 1342 cmK1
.
3.2.2. 2-Chloro-4,6-dinitrophenylhydrazine (8). A slight
modification of the reported method was adopted for the
synthesis of this compound.14 1-Chloro-2-iodo-3,5-dinitro-
benzene (9, 3.28 g, 10 mmol) was dissolved in 30 mL of
methanol. To the solution, hydrazine hydrate (1.03 g,
20.6 mmol) in 6 mL of methanol was added dropwise and
stirred at room temperature, yellow precipitate was
generated. After 28 h, the solvent and excess hydrazine
were removed by suction filtration, and the residue was
washed with methanol. The solid was recrystallized from
Figure 8. The ORTEP drawing of 16 with displacement ellipsoids at 50%
probability level.
Table 3. Crystallographic data of hydrazone 14–16
14
15
16
Formula
C12H15ClN4O4
314.73
Monoclinic
P21 (#4)
7.090 (6)
C16H17ClN4O4
364.79
Triclinic
P1 (#1)
8.146 (9)
8.748 (10)
12.388 (14)
97.347 (13)
91.298 (10)
108644 (14)
827.7 (16)
2
5013
456
0.074
0.222
1.24
0.00 (11) (R)
C16H15ClN4O5
378.77
Orthorhombic
P212121 (#19)
7.0719 (5)
Formula weight
Crystal system
Space group
˚
a (A)
˚
b (A)
16.003 (12)
12.855 (10)
13.1074 (11)
17.718 (2)
˚
c (A)
a (8)
b (8)
g (8)
96.229 (11)
3
˚
V (A )
1449.9 (17)
4
1642.3 (2)
4
3736
295
0.028
0.066
1.00
K0.02 (5) (S)
Z value
No. observations
No. variables
R1 (F2O2.0s(F2))
wR2 (all data)
S (all data)
2813a
379
0.074a
0.184a
1.01a
Flack parameter
K0.1 (2) (S)
a F2O3.0s(F2)
with TMS as an internal reference. IR spectra were obtained
on a HORIBA FT-720 spectrophotometer. Elemental
analysis was performed with a Yanaco MT-5 elemental
analyzer.
ethyl acetate, 2-chloro-4,6-dinitrophenylhydrazine was
obtained as yellow needles (1.36 g, 58.4%). 1H NMR
(CDCl3, TMS) d 4.08 (2H, br), 6.91 (1H, br), 8.32 (1H, d,
JZ2.4 Hz), 8.47 (1H, d, JZ2.4 Hz). IR (KBr) 3353, 1654,
1540, 1508, 1324 cmK1. Found: C, 30.76; H, 2.23; N,
23.86%. Calcd for C6H5ClN4O4: C, 30.98; H, 2.17; N,
24.09%.
3.2. Preparation of hydrazine 8
3.2.1. 1-Chloro-2-iodo-3,5-dinitrobenzene (9). A slight
modification of the reported method was adopted for the
synthesis of this compound.13,18 2-Chloro-4,6-dinitroaniline
(2.18 g, 10 mmol) in 27 mL of acetic acid was stirred at
70 8C until the aniline was dissolved. The solution was
rapidly cooled below 20 8C. In another flask, 5.6 mL of
sulfuric acid was cooled and vigorously stirred on an ice
bath, sodium nitrite (0.80 g, 12 mmol) was added slowly.
The mixture was heated at 70 8C until the solution was
became clear, then the solution was cooled below 20 8C.
With aniline solution stirring, nitrite solution was added
3.3. Preparation of hydrazones
Method A. Phenylhydrazine derivative (0.43 mmol) was in 5
drops of sulfuric acid and 15 mL of ethanol, and heated on a
boiling water bath until hydrazine was dissolved. After
cooling, chiral ketone (0.43 mmol) in 2 mL of ethanol and
1 mL of water was added to the solution. After appropriate
time, the solution was basified with saturated aqueous
sodium carbonate and the aqueous solution was extracted
with dichloromethane. The combine extracts were dried

5054
Y. Kawai et al. / Tetrahedron 61 (2005) 5049–5055
over anhydrous magnesium sulfate, and the solvent was
removed under reduced pressure. The residue was purified
by column chromatography on silica gel with ethyl acetate
as an eluent to obtain phenylhydrazone derivative. The
hydrazone was recrystallized to generate single crystals for
X-ray crystallographic analysis. The yields of the isolated
products, recrystallization solvents, and their spectra as well
as physical data are listed below.
dissolved in 0.25 mL of sulfuric acid and 0.37 mL of water,
then 1 mL of ethanol were added. To the solution, chiral
ketone (0.23 mmol) in 1 mL of ethanol was added, and
heated on boiling water for 3 min. After appropriate time,
the solution was basified with 2 M sodium hydroxide and
the aqueous solution was extracted with dichloromethane.
The combined extracts were dried over anhydrous mag-
nesium sulfate, and the solvent was removed under reduced
pressure. The residue was purified by column chromato-
graphy on silica gel with ethyl acetate as an eluent to obtain
six chloro-2.4-dinitrophenylhydrazone derivatives. The
hydrazone was recrystallized to generate single crystals
for X-ray crystallographic analysis. The yields of the
isolated products, recrystallization solvents, and their
spectra as well as physical data are listed below.
3.3.1. (E)-3-Methyl-4-(3-pyridyl)-2-butanone 2-chloro-
4,6-dinitrophenylhydrazone (10a). Recrystallized from
dichloromethane/ethyl acetate. Mp 146.5–147.8 8C; 64%
1
yield; H NMR (CDCl3, TMS) d 1.11 (3H, d, JZ6.5 Hz),
1.96 (3H, s), 2.58–2.71 (2H, m), 2.95 (1H, dd, JZ5.6,
13.1 Hz), 7.20–7.25 (1H, m), 7.49–7.51 (1H, m), 8.36–8.47
(4H, m); IR (KBr) 3333, 1598, 1545, 1518, 1327 cmK1
.
Found: C, 50.71; H, 4.29; N, 18.46%. Calcd for
C16H16ClN5O4: C, 50.87; H, 4.27; N, 18.54%.
3.3.6. 3-(2-Pyridylmethyl)-2-pentanone 2-chloro-4,6-
dinitrophenylhydrazone (10c)
3.3.2. (E)-3-Methyl-4-(4-pyridyl)-2-butanone 2-chloro-
4,6-dinitrophenylhydrazone (10b). Recrystallized from
dichloromethane/ethyl acetate. Mp 182.3–183.9 C; 75%
Recrystallized from ethyl acetate. Mp 149.8–155.9 8C (dec);
31% yield; 1H NMR of (E)- and (Z)-forms mixture (CDCl3,
TMS) d 0.89 (3H, t, JZ7.4 Hz), 1.03 (3H, t, JZ7.4 Hz),
1.56–1.73 (2H!2, m), 1.81 (3H, s), 1.93 (3H, s), 2.90–3.02
(2H!2, m), 3.28 (1H, dd, JZ4.2, 17.1 Hz), 3.76–3.88 (1H,
m), 7.07–7.17 (2H!2, m), 7.55–7.64 (1H!2, m), 8.33–
8.57 (3H!2C1H, m), 10.81 (1H, br); IR (KBr) 2959, 1601,
1534, 1517, 1324 cmK1. Found: C, 52.13; H, 4.64; N,
17.75%. Calcd for C17H18ClN5O4: C, 52.11; H, 4.63; N,
17.83%.
1
yield; H NMR (CDCl3, TMS) d 1.11 (3H, d, JZ6.9 Hz),
1.96 (3H, s), 2.60 (1H, dd, JZ8.4, 13.7 Hz), 2.67–2.79 (1H,
m), 2.95 (1H, dd, JZ6.0, 13.7 Hz), 7.10 7.12 (2H, m), 8.36–
8.38 (2H, m), 8.46–8.51 (2H, m); IR (KBr) 3350, 1601,
1543, 1521, 1328 cmK1. Found: C, 50.88; H, 4.40; N,
18.50%. Calcd for C16H16ClN5O4: C, 50.87; H, 4.27; N,
18.54%.
3.3.3. (E)-3-Methyl-2-pentanone 2-chloro-4,6-dinitro-
phenylhydrazone (14). Recrystallized from anisole/
hexane. mp 61.2–63.3 8C; 91% yield; H NMR (CDCl3,
3.3.7. (E)-3-(3-Pyridylmethyl)-2-pentanone 2-chloro-4,6-
dinitrophenylhydrazone (10d)
1
TMS) d 0.88 (3H, t, JZ7.4 Hz), 1.08 (3H, d, JZ6.8 Hz),
1.33–1.48 (1H, m), 1.52–1.66 (1H, m), 1.95 (3H, s), 2.34
(1H, sextet, JZ6.8 Hz), 8.36 (1H, d, JZ2.5 Hz), 8.40 (1H,
br), 8.47 (1H, d, JZ2.5 Hz); IR (KBr) 3347, 1602, 1542,
1521, 1333 cmK1; HRMS m/z found: 314.0782. Calcd for
C12H15ClN4O4: 314.0782.
Recrystallized from hexane/ethyl acetate. Mp 108.5–
110.0 8C; 80% yield; H NMR (CDCl3, TMS) d 0.89 (3H,
1
t, JZ7.5 Hz), 1.54–1.63 (2H, m), 1.88 (3H, s), 2.54–2.63
(1H, m), 2.77–2.82 (2H, m), 7.19–7.24 (1H, m), 7.48–7.52
(1H, m), 8.35–8.47 (5H, m); IR (KBr) 3342, 1603, 1539,
1517, 1341 cmK1. Found: C, 52.05; H, 4.57; N, 17.96%.
Calcd for C17H18ClN5O4: C, 52.11; H, 4.63; N, 17.83%.
3.3.4. (R)-Carvone 2-chloro-4,6-dinitrophenylhydrazone
(15). Recrystallized from dichlorometane/ethanol. Mp
189.5–190.2 8C; 59% yield; 1H NMR (CDCl3, TMS) d;
1.56 (3H, s), 1.81 (3H, s), 2.14–2.26 (2H, m), 2.33–2.39
(1H, m), 2.50–2.57 (1H, m), 2.75 (1H, dd, JZ3.9, 15.3 Hz),
4.83 (1H, br), 4.88 (1H, br), 6.19 (1H, br), 8.37 (1H, d, JZ
2.5 Hz), 8.47 (1H, d, JZ2.5 Hz), 8.69 (1H, br); IR (KBr)
3348, 1600, 1550, 1517, 1323 cmK1. Found: C, 52.41; H,
4.70; N, 15.20%. Calcd for C16H17ClN4O4: C, 52.68; H,
4.70; N, 15.36%.
3.3.8. (E)-3-(4-Pyridylmethyl)-2-pentanone 2-chloro-4,6-
dinitrophenylhydrazone (10e)
Recrystallized from methanol/chloroform/ethyl acetate. Mp
129.7–129.9 8C; 86% yield; 1H NMR (CDCl3, TMS) d 0.89
(3H, t, JZ7.4 Hz), 1.53–1.60 (2H, m), 1.88 (3H, s),
2.60–2.67 (1H, m), 2.72–2.86 (2H, m), 7.09–7.12 (2H, m),
8.35–8.47 (5H, m); IR (KBr) 3342, 1603, 1539, 1517,
1340 cmK1; HRMS m/z found: 391.1035. Calcd for
C17H18ClN5O4: 391.1047.
3.3.5. (S)-3-Hydroxy-1-phenylbutan-1-one 2-chloro-4,6-
dinitrophenylhydrazone (16). Recrystallized from
dichlorometane/ethanol. Mp 204.5–205.8 8C; 80% yield;
1H NMR (CDCl3, TMS) d; 1.47 (3H, d, JZ6.1 Hz), 2.30
(1H, br), 3.00 (1H, d, JZ14.5 Hz), 3.09 (1H, dd, JZ9.2,
14.5 Hz), 4.41–4.45 (1H, m), 7.39–7.42 (3H, m), 7.64–7.66
(2H, m), 8.34 (1H, d, JZ2.4 Hz), 8.44 (1H, d, JZ2.4 Hz),
3.4. Crystallographic studies
A prismatic single crystal was mounted on a glass fiber. The
lattice parameters and intensity data were measured on a
Rigaku R-CCD/III diffractometer and radiation was Mo Ka
10.59 (1H, br); IR (KBr) 3519, 1598, 1539, 1507, 1319 cmK1
.
(lZ0.71070 A). The data were collected at a temperature of
˚
Found: C, 50.51; H, 3.70; N, 14.60%. Calcd for
C16H15ClN4O5: C, 50.74; H, 3.99; N, 14.79%.
K180 8C using the u scan technique to a maximum 2q
value of 55.0 degree. A total of 1200 oscillation images
were collected. All the structures were solved by direct
method SIR9719 and expanded Fourier techniques.20 All
Method B. Phenylhydrazine derivative (0.23 mmol) was

Y. Kawai et al. / Tetrahedron 61 (2005) 5049–5055
5055
Schubert, H.; Kremer, K. A. M. Tetrahedron 1984, 40,
1345–1359.
non-hydrogen atoms were refined anisotropically and
hydrogen atoms were refined isotropically by full-matrix
least square method. All calculations were performed using
CrystalClear software package of Rigaku Corporation.21,22
The ORTEP drawings are presented in Figures 1–8, and the
crystallographic parameters are listed in Tables 2 and 3.
3. Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566–2587.
4. (a) Ohta, H.; Matsumoto, K.; Tsutsumi, S.; Ihori, T. J. Chem.
Soc., Chem. Commun. 1989, 485–486. (b) Matsumoto, K.;
Tsutsumi, S.; Ihori, T.; Ohta, H. J. Am. Chem. Soc. 1990, 112,
9614–9619. (c) Kume, Y.; Ohta, H. Tetrahedron Lett. 1992,
33, 6367–6370. (d) Sakai, T.; Matsuda, A.; Tanaka, Y.;
Korenaga, T.; Ema, T. Tetrahedron: Asymmetry 2004, 15,
1929–1932.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposit with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 172429 for 10a, CCDC 172430
for 10b, CCDC 172427 for 10c, CCDC 172428 for 10d,
CCDC 172432 for 10e, CCDC 172431 for 14, CCDC
262899 for 15, CCDC 262900 for 16. Copies of the data can
be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: C44-(0)1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk].
5. (a) Leuenberger, H. G. W.; Boguth, W.; Widmer, E.; Zell, R.
Helv. Chim. Acta 1976, 59, 1832–1849. (b) Kergomard, A.;
Renard, M. F.; Veschambre, H. Tetrahedron Lett. 1978, 52,
5197–5200. (c) Utaka, M.; Konishi, S.; Takeda, A. Tetra-
hedron Lett. 1986, 27, 4737–4740. (d) Sakai, T.; Matsumoto,
S.; Hidaka, S.; Imajo, N.; Tsuboi, S.; Utaka, M. Bull. Chem.
Soc. Jpn. 1991, 64, 3473–3475.
6. Fujii, I.; Lerner, R. A.; Janda, K. D. J. Am. Chem. Soc. 1991,
113, 8528–8529.
7. Sinha, S. C.; Keinan, E. J. Am. Chem. Soc. 1995, 117,
3653–3654.
Acknowledgements
8. (a) Kawai, Y.; Saitou, K.; Hida, K.; Ohno, A. Tetrahedron:
Asymmetry 1995, 6, 2143–2144. (b) Kawai, Y.; Saitou, K.;
Hida, K.; Dao, D. H.; Ohno, A. Bull. Chem. Soc. Jpn. 1996, 69,
2633–2638. (c) Kawai, Y.; Hayashi, M.; Tokitoh, N.
Tetrahedron: Asymmetry 2001, 12, 3007–3013.
9. Kawai, Y.; Hayashi, M.; Inaba, Y.; Saitou, K.; Ohno, A.
Tetrahedron Lett. 1998, 39, 5225–5228.
We thank Dr. Yamamoto and Mr. Kimoto (Daicel Chemical
Industries, Ltd.) for providing a chiral alkyl ketone 11. This
work was supported by a Grant-in Aid for Scientific
Research No. 15550033 from the Ministry of Education,
Culture, Sports, Science and Technology, Japan and the
SUNBOR Grant from Suntory Institute for Bioorganic
Research.
10. Hirata, T.; Shimoda, K.; Kawano, T. Tetrahedron: Asymmetry
2000, 11, 1063–1066.
11. Kawai, Y.; Hayashi, M.; Tokitoh, N. Tetrahedron Lett. 2002,
43, 465–467.
References and notes
12. Kawai, Y.; Hayashi, M.; Tokitoh, N. Acta Crystallogr. Sect. E
2002, 58, o1098–o1099.
1. (a) Riley, R. G.; Silverstein, R. M.; Moser, J. C. Science 1974,
183, 760–762. (b) Mori, K.; Masuda, S.; Suguro, T.
Tetrahedron 1981, 37, 1329–1340. (c) Mori, K.; Nomi, H.;
Chuman, T.; Kohno, M.; Kato, K.; Noguchi, M. Tetrahedron
1982, 38, 3705–3711. (d) Mori, K.; Ebata, T. Tetrahedron
1986, 42, 4421–4426. (e) Ebata, T.; Mori, K. Agric. Biol.
Chem. 1987, 51, 2925–2928.
13. Hodgson, H. H.; Walker, J. J. Chem. Soc. 1933, 1620–1621.
14. Borsche, W. Ber.D. Chem. Gesellschaft 1921, 54, 669–684.
15. Ohta, H.; Ozaki, K.; Tsuchihashi, G. Agric. Biol. Chem. 1986,
50, 2499–2502.
16. Flack, H. D. Acta Crystallogr. Sect. A 1983, 39, 876–881.
17. (a) Peerdeman, A. F.; Bijvoet, J. M. Acta Crystallogr. 1956, 9,
1012–1015. (b) Ibers, J. A.; Hamilton, W. C. Acta Crystallogr.
1964, 17, 781–782.
2. (a) Yamashita, T.; Mitsui, H.; Watanabe, H.; Nakamura, N.
Bull. Chem. Soc. Jpn. 1982, 55, 961–962. (b) Murakata, M.;
Nakajima, M.; Koga, K. J. Chem. Soc., Chem. Commun. 1990,
1657–1658. (c) Sonnet, P. E.; Heath, R. R. J. Org. Chem. 1980,
45, 3137–3139. (d) Evans, D. A.; Takacs, J. M. Tetrahedron
Lett. 1980, 21, 4233–4236. (e) Helmchen, G.; Weirchowski, R.
Angew. Chem., Int. Ed. Engl. 1984, 23, 60–61. (f) Mayers,
A. I.; Williams, D. R.; Erickson, G. W.; White, S.; Druelinger,
M. J. Am. Chem. Soc. 1981, 103, 3081–3087. (g) Mayers, A. I.;
Williams, D. R.; White, S.; Erickson, G. W. J. Am. Chem. Soc.
1981, 103, 3088–3093. (h) Tomioka, K.; Ando, K.; Takemasa,
Y.; Koga, K. J. Am. Chem. Soc. 1984, 106, 2718–2719.
(i) Enders, D.; Eicheauer, H. Angew. Chem., Int. Ed. Engl.
1976, 15, 549–551. (j) Enders, D.; Eichenauer, H.; Baus, U.;
18. Sandin, R. B.; Cairns, T. L. In Organic Syntheses; Wiley:
New York, 1943; Collect. Vol. II, pp 604–605.
19. Altomare, A. M. B.; Camalli, M.; Cascarano, G.; Giacovazzo,
C.; Guagliardi, A.; Moliterni, A.; Polidori, G.; Spagna, R.
J. Appl. Crystallogr. 1999, 32, 115–119.
20. Beurskens, P. T.; Admiraal, G.; Beurskens, G.; Bosman, W. P.;
Gelder, R. D.; Israel, R.; Smits, J.M.M. The DIRDIF-99
program system, Technical Report of the Crystallography
Laboratory.
21. Rigaku Corporation 1999, CrystalClear Software User’s
Guide, Molecular Structure Corporation.
22. Pflugrath, J. W. Acta Crystallogr. Sect. D 1999, D55,
1718–1725.