3-Acyl-2-(N-cyanoimino)oxazolidine derivative, a new asymmetric acylating agent for racemic secondary alkyl amines

Article abstract of DOI:10.1016/S0040-4020(01)00933-4

A 3-acyl-2-(N-cyanoimino)oxazolidine derivative was found to serve as an enantioselective acylating agent for sec-alkyl amines. These reagents differentiate the enantiomers of 1-phenylethylamine derivatives up to 85% ee, and the recovered chiral auxiliary is reusable.

Full text of DOI:10.1016/S0040-4020(01)00933-4

TETRAHEDRON
Pergamon
Tetrahedron 57 )2001) 9309±9315
3-Acyl-2-ꢀN-cyanoimino)oxazolidine derivative, a new
asymmetric acylating agent for racemic secondary alkyl amines
Naoyoshi Maezaki,a Akemi Furusawa,a Shuji Uchidab and Tetsuaki Tanakaa,p
aGraduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
bFaculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotogecho, Hirakata, Osaka 573-1041, Japan
Received 29 June 2001; accepted 21 September 2001
AbstractÐA 3-acyl-2-)N-cyanoimino)oxazolidine derivative was found to serve as an enantioselective acylating agent for sec-alkyl amines.
These reagents differentiate the enantiomers of 1-phenylethylamine derivatives up to 85% ee, and the recovered chiral auxiliary is reusable.
q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
3-acyl-4-diphenylmethyl-2-)N-cyanoimino)thiazolidine
)3-acyl-NCTp) recently developed by us is an asymmetric
acylating reagent, which differentiated racemic sec-alkyl
amines with moderate to good selectivity. In this reagent,
the 2-)N-cyanoimino)thiazolidine moiety works not only as
a leaving group but also as a recoverable chiral auxiliary.
The strong electron-withdrawing ability of the N-cyano-
imino group at C-2 activates the N)3)-acyl group transfer
reaction. However, it has not been ascertained whether the
sulfur atom in the thiazolidine ring is essential for the
activation. We were interested in the participation of this
part in achieving the acyl transfer reaction. Furthermore, if
replacement of the sulfur atom with oxygen or nitrogen does
not affect the ability for the acyl transfer reaction, a variety
of chiral amino alcohols and ethylenediamines will serve as
the material of new asymmetric acylating reagents.
Optical resolution of racemic amines is a challenge in the
®eld of recent organic chemistry, since the resulting chiral
amines are useful chiral building blocks for diverse
naturally occurring and synthetic molecules. Although
enzymatic optical resolution has been well established,1
the corresponding non-enzymatic methods regularly
exhibited poor selectivity;2 however a few effective non-
enzymatic methods have been reported very recently.3 In
1998, the ®rst enantioselective acetylation of racemic
amines was reported by Murakami et al., but the selectivity
was less than 50%.3d A high level of enantioselective
acetylation was recently realized by Ie and Fu using an
N-acetylated 4-pyrrolinopyridine derivative, which showed
lower enantioselectivity for transfer of other acyl groups.3b
Two asymmetric benzoylations of racemic amines were
independently reported by Atkinson et al.3c and by us.3a
Atkinson's reagent was the ®rst to differentiate the second-
ary amine with very high enantioselectivity. However, the
application was limited to 2-methylpiperidine. A chiral
In this paper, we describe the development of a new
)N-cyanoimino)oxazolidine-type asymmetric acylating
agent and its application to the kinetic resolution of sec-
alkyl amines )Scheme 1).
Scheme 1.
Keywords: asymmetric reactions; resolution; acylation; amines.
Corresponding author. Tel.: 181-6-6879-8210; fax: 181-6-6879-8214; e-mail: t-tanaka@phs.osaka-u.ac.jp
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020)01)00933-4

9310
N. Maezaki et al. / Tetrahedron 5702001) 9309±9315
Scheme 2.
Scheme 3.
2. Results and discussion
ring structure is resistant to aminolysis by cyclohexylamine
)1.1 equiv.) and the ratio of acylation was obviously
increased comparing with monocyclic 3-benzoyl-NCO 3
)Scheme 4).
2.1. Acyl transfer reaction of 3-benzoyl-2-ꢀN-cyano-
imino)oxazolidine ꢀ3-benzoyl-NCO) and 1,3-dibenzoyl-
2-ꢀN-cyanoimino)imidazolidine ꢀ1,3-dibenzoyl-NCI)
with cyclohexylamine
Next, we examined kinetic resolution of the racemic sec-
alkyl amine using 9a and 10 equiv. of )^)-1-phenylethyl-
amine in MeCN at various temperatures )Table 1). Both the
²
Benzoylation of known 2-)N-cyanoimino)oxazolidine 1
)NCO)4 and 2-)N-cyanoimino)imidazolidine 2 )NCI)5 easily
affords 3-benzoyl-NCO 3 and 1,3-dibenzoyl-NCI 4 in 79
and 65% yields, respectively. Acylation of cyclohexylamine
using 3 and 4 afforded N-cyclohexyl benzamide 56 only in
27 and 15% yields, respectively. A considerable amount of
the ring-aminolysis products 6 )30%) and 7 )24%) was
formed )Scheme 2). This regioselectivity is in sharp contrast
to that of 3-acyl-NCT,7 which reacts at the carbonyl group
exclusively. We assumed that the increased reactivity at the
C2-position of 3 and 4 results from higher electronegativity
of oxygen and nitrogen than that of sulfur. Therefore, we
had to circumvent the instability of the hetrocyclic rings to
amines in order to develop these chiral analogs as acylating
agents.
yield and enantiomeric excess were increased with lowering
Scheme 4.
Table 1. Temperature effect on enantioselective benzoylation of )^)-1-
phenylethylamine with 9a
2.2. Asymmetric acylation using chiral 3-acyl-2-
ꢀN-cyanoimino)oxazolidine derivatives
Entry
Temperature )8C)
Time )h)
Yield )%)a
ee )%)b
1
2
3
4
5
rt
0
220
240
270c
0.8
2.5
6.5
21
48
57
65
53
87
38
39
48
59
83
Based on a preliminary experiment, we designed a chiral
2-)N-cyanoimino)oxazolidine derivative )NCOp) 8. We
expected that the oxazolidine ring involved in the fused
ring system should be stabilized toward aminolysis, since
the suitably oriented amino alcohol moiety would suppress
ring-opening by the attack of amines. The chiral NCOp 8
was synthesized from commercially available )1S,2R)-1-
amino-2-indanol and S,S0-dimethyl N-cyanodithioimino-
carbonate in 95% yield. Then, the resulting NCOp 8 was
subjected to benzoylation with BzCl and Et3N in CH2Cl2
to give 9a in 85% yield. In a similar manner, various 3-
acyl-NCOp derivatives 9b±g were synthesized )Scheme 3).
65
All reactions were carried out in MeCN unless otherwise stated.
Isolated yields based on 9a.
a
b
The enantiomeric excess and absolute con®guration of the amide were
determined by comparison of the speci®c rotation with the standard
sample derived from the corresponding optically pure sec-alkyl amine.
A 1:1 mixture of MeCN and CH2Cl2 was used as a solvent.
c
²
In the previous work using 3-acyl-NCTp, we found that MeCN is the best
solvent to achieve high enantioselectivity.3a In addition, this solvent is
suitable to dissolve the polar 3-acyl-NCOp even at low temperature.
As we expected, the oxazolidine ring of 9a having a fused

N. Maezaki et al. / Tetrahedron 5702001) 9309±9315
9311
Table 2. Enantioselective acylation of )^)-1-phenylethylamine with various acylating agents 9a±g
Entry
Reagent
R
Temperature )8C)
Time )h)
Yielda )%)
eeb )%)
Con®guration
1
2
3
4
5
6
7
8
9
10
9a
9b
9c
9d
9a
9e
9f
9g
9g
9g
Ph
270
270
270
270
0
0
0
0
220
240
80
192
192
108
45
48
21
53
40
76
41
87
90
40
43
70
68
85
62
78
74
25
10
17
64
65
±
R
R
R
R
R
S
R
R
R
±
4-MeO±Ph
4-Me±Ph
4-F±Ph
Ph
c-Hex
Et
Me
Me
Me
87
trace
168
All reactions were carried out in a 1:1 mixture of MeCN±THF.
a
Isolated yields based on 3-acyl-NCOp )9).
The enantiomeric excess and absolute con®guration of the amide were determined by comparison of the speci®c rotation with the standard sample derived
from the corresponding optically pure sec-alkyl amine.
b
Table 3. Enantioselective benzoylation of racemic amines with 9a
Entry
R
R0
Temperature )8C)
Time )h)
Yielda )%)
eeb )%)
Con®guration
1
2
3
4
5
6
7
Ph
Me
Me
Me
Me
Et
270
270
270
270
80
140
288
81
216
38
76
55
42
76
67
53
49
85
58c
16c
4
R
R
R
R
R
R
Se
4-MeOPh
2-MePh
c-Hex
Ph
Ph
Ph
270
270 to 240
270 to 240
58c
40
65
Me
CH2OMOM
252
All the reactions were carried out in a 1:1 mixture of MeCN±THF.
Isolated yields based on RCO±NCOp )9).
a
b
The enantiomeric excess and absolute con®guration of the amide were determined by comparison of the speci®c rotation with the standard sample derived
from the corresponding optically pure sec-alkyl amine.
c
The enantiomeric excess and absolute con®guration of the amide were determined by comparison of the speci®c rotation with the reported values.8±10
Change of absolute con®guration stems from the change of the priority substituent at the stereogenic center.
d
the reaction temperature. The selectivity reached 83% ee at
show remarkable effects on either the reactivity or the selec-
tivity )entries 1±4). On the other hand, reactivity of the
3-alkylcarbonyl-NCOps 9e±g was lower than that of the
3-aroyl-NCOps. Therefore, these reactions were conducted
at 08C. The selectivity decreased with the bulkiness of the
alkyl group )entries 5±7). Interestingly, the 3-acetyl-NCOp
9g showed higher selectivity at 08C than that of the
3-benzoyl-NCOp 9a )entry 8).§ However, the selectivity
was not increased by lowering the reaction temperature to
2208C )entry 9), and no reaction was observed at 2408C
)entry 10). In all cases, except cyclohexylcarbonylation
)entry 6), acylation of )R)-1-phenylethylamine proceeded
mainly.
2708C, wherein CH2Cl2 was employed as a co-solvent to
prevent the solvent from freezing. At this temperature, the
aminolysis of the oxazolidine ring was not observed.
Then, reaction of various 3-acyl-NCOps 9a±g with )^)-1-
phenylethylamine was examined )Table 2). 5 equiv. of the
racemic amine were used in a mixture of MeCN±THF )1:1),
since these reaction conditions afforded higher recovery of
NCOp than the conditions shown in Table 1 )the racemic
amine )10 equiv.), MeCN±CH2Cl2 )1:1)). In the reaction of
9a with )^)-1-phenylethylamine, asymmetric acylation
proceeds smoothly at 2708C to give the benzoylated
)R)-amine with 85% ee along with the recovered chiral
NCOp 8 )95%), which was easily separated by column
Next, kinetic resolution of other )^)-sec-alkyl amines using
9a was examined )Table 3). The phenyl moiety in the
amines is essential to achieve high selectivity )entries 1
and 2). Replacement of the phenyl group with a non-
aromatic cyclohexyl group caused considerable decrease
of selectivity )entry 4). The ee value was decreased in the
³
chromatography for reuse. Acyl transfer of 3-aroyl-
NCOps 9c±d also proceeded at 2708C, but the yield of 9b
was low, presumably due to low solubility of 9b in the
solvent. The substituent on the phenyl group does not
³
The use of 2.5 equiv. of the racemic amine caused a considerable loss of
the yield )43%) and ee )53% ee).
§
Similar results were obtained in the case of 3-acetyl-NCTp derivative.3a

9312
N. Maezaki et al. / Tetrahedron 5702001) 9309±9315
imino)oxazolidine-type asymmetric acylating agents for
racemic sec-alkyl amines. 3-Benzoyl-NCOp 9a is readily
synthesized from a commercially available amino alcohol
in two steps, and differentiates the enantiomeric isomers of
the 1-phenylethylamine derivatives with considerably good
enantioselectivity )up to 85% ee), and the resulting chiral
auxiliary can be recovered and is reusable. Since the reagent
9a shows opposite selectivity to that of the chiral NCTp,
these reagents can be used complementarily.
4. Experimental
4.1. General
Melting points are uncorrected. Optical rotations were
measured using a JASCO DIP-360 digital polarimeter. H
1
Figure 1. Plausible reaction mechanism of asymmetric benzoylation of
)^)-phenylethylamine.
NMR spectra were recorded in CDCl3 solution at 500 MHz
with a JEOL JNM-GX500 spectrometer. 13C NMR spectra
were recorded in CDCl3 at 67.8 or 75 MHz with a JEOL
JNM-EX270 spectrometer or a JEOL JMN-AL-300, respec-
tively. All signals are expressed as ppm down®eld from
tetramethylsilane used as an internal standard )d value).
IR spectra were measured with a Horiba FT-210 IR spectro-
meter. Mass spectra were taken with a Shimadzu QP-1000
mass spectrometer or a JMS-600 mass spectrometer. High
resolution mass spectra were measured by a JEOL JMS-
600H. Merck Kieselgel 60 was used as an adsorbent for
column chromatography. All air- or moisture-sensitive reac-
tions were carried out in ¯ame-dried glassware under N2
atmosphere. All organic extracts were dried over anhydrous
MgSO4, ®ltered, and concentrated with a rotary evaporator
under reduced pressure.
reaction with 1-)o-tolyl)ethylamine, in which the confor-
mation of the aryl group is affected by the o-methyl group
)entry 3). Replacement of the methyl group with an ethyl
group decreased the reaction rate, but showed comparative
selectivity )entry 5). Reaction of 9a with the phenylglycinol
O-methoxymethyl ether was sluggish at 2708C. However,
the acylation proceeded at 2408C, giving higher ee than that
of 1-phenylethylamine )entries 6 and 7).¶
The selectivity is speculated as follows. Stable confor-
mation of the amide carbonyl group in the 3-benzoyl-
NCOp 9a would be depicted as Fig. 1a,b, in which the car-
bonyl group is oriented opposite to the N-cyanoimino group
so as to minimize unfavorable dipole±dipole interaction and
to avoid steric repulsion with the large indan ring )Y). In this
conformation, the re-face of the carbonyl group is shielded
by the large indan ring )Y). Therefore, approach of the
amine would proceed mainly from the si-face. We have
reported3a that attractive interaction between the benzoyl
group in the acylating agent and the benzylamines seems
to play an important role for differentiation of the enantio-
meric isomers, that is, p±p interaction11 for the chiral
3-aroyl-NCT and CH±p interaction12 for that of the chiral
3-acetyl-NCT, respectively. The results obtained above
indicate that the p±p or CH±p interaction would be
similarly involved in the reaction of the 3-acyl-NCOps as
well as that of 3-acyl-NCTps. That is, the racemic amines
would approach the 3-aroyl-NCOp 9a±d so as to overlap
two phenyl groups by virtue of the p±p interaction )Fig.
1c,d). For the 3-acetyl-NCOp 9g, CH±p interaction would
attract the acetyl group and the phenyl group instead of the
p±p interaction. Since the approach of the )S)-isomer
suffers from larger steric repulsion between the R0 )Me, Et
or CH2OMOM) group and the 2-)N-cyanoimino)oxazo-
lidine ring )Fig. 1d), the reaction of the )R)-isomer would
be faster than that of the )S)-isomer.
4.1.1. 3-Benzoyl-2-ꢀN-cyanoimino)oxazolidine ꢀ3). Benz-
oyl chloride )0.14 ml, 1.20 mmol) was added to a mixture of
1 )111 mg, 1.00 mmol) and Et3N )0.16 ml, 1.24 mmol) in
CH2Cl2 )3 ml) with stirring at 08C under N2. The stirring
was continued at rt for 13 h. The reaction was quenched
with 10% HCl. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2. The combined
organic layers were washed with brine prior to drying and
solvent evaporation. The residue was recrystallized with
AcOEt to give 3 )169 mg, 79%) as a colorless powder.
Mp 179.5±180.08C )AcOEt). 1H NMR d: 4.17 )t, Jˆ
7.9 Hz, 2H, CH2N), 4.49 )t, Jˆ7.9 Hz, 2H, CH2O), 7.42±
7.69 )m, 5H, Ar±H). 13C NMR )d6-DMSO) d: 46.4, 67.9,
112.8, 127.9 )2C), 128.8 )2C), 132.3, 133.0, 161.9, 167.9.
IR )KBr) 2200 )CN), 1670 )CvO) cm21. MS m/z )%): 215
)M1, 19.4), 105 )100). HRMS )EI) Calcd for C11H9N3O2
)M1): 215.0695. Found: 215.0693.
4.1.2. 1,3-Dibenzoyl-2-ꢀN-cyanoimino)imidazolidine ꢀ4).
Benzoyl chloride )0.22 ml, 2.00 mmol) was added to a
mixture of
2 )110 mg, 1.00 mmol), Et3N )0.26 ml,
2.00 mmol), DMAP )122 ml, 1.00 mmol) in CH2Cl2 )2 ml)
with stirring at 08C under N2. The stirring was continued at
rt for 1 d. The reaction was quenched with 10% HCl. The
organic layer was separated and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were
washed with brine prior to drying and solvent evaporation.
The residual solid was washed with MeOH to give 4
)206 mg, 65%) as a colorless powder. Mp 170.0±170.58C
3. Conclusion
In conclusion, we have developed new 2-)N-cyano-
¶
Kinetic resolution of 2-methylpiperidine was attempted, but failed due to
low reactivity of 9a with the sec-amine even at rt.

N. Maezaki et al. / Tetrahedron 5702001) 9309±9315
9313
)AcOEt). 1H NMR d: 4.12 )s, 4H, CH2N£2), 7.45±7.72 )m,
10H, Ar±H). 13C NMR d: 46.0 )2C), 111.2, 128.5 )4C),
129.1 )4C), 132.4 )2C), 133.2 )2C), 154.5, 168.7 )2C). IR
)KBr) 2186 )CN), 1689 )CvO) cm21. MS m/z )%): 318
)M1, 25.1), 105 )100). HRMS )EI) Calcd for C18H14N4O2
)M1): 318.1116. Found: 318.1116.
C11H9N3O: C, 66.32; H, 4.55; N, 21.09. Found: C, 66.26; H,
4.68; N, 20.99.
4.2. General procedure of acylation of 8
Benzoyl chloride )0.060 ml, 0.55 mmol) was added to a
mixture of 8 )100 mg, 0.50 mmol) and Et3N )0.070 ml,
0.55 mmol) in CH2Cl2 )1 ml) with stirring at 08C under
N2. The stirring was continued at rt for 2 d. The reaction
was quenched with 10% HCl. The organic layer was
separated and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were washed with
brine prior to drying and solvent evaporation. The residue
was chromatographed on silica gel.
4.1.3. N-[2-[ꢀN-Cyanoimino)ꢀcyclohexylamino)methoxy]-
ethyl]benzamide ꢀ6). A mixture of 3 )108 mg, 0.50 mmol)
and cyclohexylamine )0.050 ml, 0.55 mmol) in CH2Cl2
)3 ml) was stirred at rt for 5 d. The resulting precipitate
was ®ltered off and the ®ltrate was washed with 1N
NaOH, 5% HCl, and brine prior to drying and solvent
evaporation. The residue was chromatographed on silica
gel )CHCl3±MeOHˆ50:1) to give 5 )28 mg, 27%) along
with 6 )48 mg, 30%) each as a colorless powder. The data
of 56 is comparable to that reported. 6: mp 164.5±165.08C
)AcOEt). 1H NMR d: 1.12±1.60 )m, 10H, cyclohexyl), 3.49
)d, Jˆ7.9 Hz, 2H, CH2N), 3.87 )d, Jˆ7.9 Hz, 2H, CH2O),
4.09 )m, 1H, cyclohexyl), 7.29±7.55 )m, 6H, CONH and
Ar±H), 9.06 )d, Jˆ7.9 Hz, 1H, cyclohexyl-NH). 13C NMR
d: 24.6 )2C), 25.0 )2C), 39.1, 51.8 )2C), 67.5, 115.7, 126.9
)2C), 128.5 )2C), 131.7, 133.9, 167.6, 165.5. IR )KBr) 3317
)NH), 3284 )NH), 2200 )CN), 1641 )CvO) cm21. MS m/z
)%): 314 )M1, 0.5), 147 )100). HRMS )EI) Calcd for
C17H22N4O2 )M1): 314.1742. Found: 314.1743.
4.2.1. [ꢀ3aS,8aR)-3-Benzoyl-3,3a,8,8a-tetrahydro-2H-in-
deno[1,2-d][1,3]oxazol-2-ylidene]cyanamide ꢀ9a). Pale
yellow powder )85%). Mp 206.0±207.08C )AcOEt).
27
1
[a]D ˆ215.0 )c 1.00, CHCl3). H NMR d: 3.53 )dd, Jˆ
6.1, 5.4 Hz, 1H, CH2), 3.59 )d, Jˆ6.1 Hz, 1H, CH2), 5.66
)td, Jˆ7.3, 1.8 Hz, 1H, CHO), 6.27 )d, Jˆ6.7 Hz, 1H,
CHN), 7.32±7.76 )m, 9H, Ar±H). 13C NMR d: 37.5, 66.5,
83.8, 112.1, 125.4, 126.9, 128.0 )2C), 128.5 )2C), 128.8,
130.5, 132.2, 132.7, 137.3, 139.1, 160.1, 168.4. IR )KBr)
2195 )CN), 1659 )CvO) cm21. MS m/z )%): 303 )M1, 3.6),
105 )100). Anal. Calcd for C18H13N3O2: C, 71.28; H, 4.32;
N, 13.85. Found: C, 71.30; H, 4.49; N, 13.81.
4.1.4.
N,N0-Dibenzoyl-N-[ꢀN-cyanoimino)ꢀcyclohexyl-
amino)methyl]ethylenediamine ꢀ7). A mixture of 4
)95 mg, 0.30 mmol) and cyclohexylamine )0.030 ml,
0.33 mmol) in CH2Cl2 )3 ml) was stirred at rt for 5 d. The
resulting precipitate was ®ltered off and the ®ltrate was
washed with 1N NaOH, 5% HCl, and brine prior to drying
and solvent evaporation. The residue was chromatographed
on silica gel )AcOEt) to give 5 )9 mg, 15%) along with 7
)30 mg, 24%) each as a colorless powder. 7: mp 195.0±
4.2.2. [ꢀ3aS,8aR)-3-ꢀ4-Methoxybenzoyl)-3,3a,8,8a-tetra-
hydro-2H-indeno[1,2-d][1,3]oxazol-2-ylidene]cyanamide
ꢀ9b). Colorless powder )80%). Mp 195.0±196.08C )AcOEt).
27
1
[a]D ˆ212.2 )c 0.50, CHCl3). H NMR d: 3.53 )dd, Jˆ
6.1, 5.5 Hz, 1H, CH2), 3.59 )d, Jˆ6.1 Hz, 1H, CH2), 3.87 )s,
3H, OCH3), 5.64 )td, Jˆ7.9, 1.8 Hz, 1H, CHO), 6.25 )d, Jˆ
7.3 Hz, 1H, CHN), 6.89±7.66 )m, 8H, Ar±H). 13C NMR d:
37.8, 55.6, 66.6, 83.6, 113.4, 123.8, 125.4 )2C), 126.8,
128.4, 130.4 )2C), 131.8, 137.3 )2C), 139.0, 163.6 )3C).
IR )KBr) 2208 )CN), 1647 )CvO) cm21. MS m/z )%):
333 )M1, 2.2), 135 )100). Anal. Calcd for C19H15N3O3: C,
68.46; H, 4.54; N, 12.61. Found: C, 68.27; H, 4.72; N, 12.46.
1
196.08C )AcOEt). H NMR d: 1.13±1.70 )m, 10H, cyclo-
hexyl), 3.48 )dd, Jˆ7.9 Hz, 2H, CH2NH), 3.75 )m, 2H,
CH2N), 4.09 )m, 1H, cyclohexyl), 7.24±7.73 )m, 11H,
CONH and Ar±H), 9.06 )d, Jˆ7.9 Hz, 1H, cyclohexyl-
NH). 13C NMR d: 24.1 )2C), 25.0, 30.8, 39.1, 45.6, 52.2,
115.5, 126.8 )2C), 127.0 )2C), 128.3 )2C), 128.4 )2C),
131.2, 131.7 )2C), 133.1, 134.3, 159.1, 169.7, 169.9. IR
)KBr) 3203 )NH), 2183 )CN), 1676 )CvO), 1599
)CvO) cm21. MS m/z )%): 303 )M1, 5.5), 105 )100).
HRMS )EI) Calcd for C25H29N5O2 )M1): 431.2321.
Found: 431.2320.
4.2.3. [ꢀ3aS,8aR)-3-ꢀ4-Methylbenzoyl)-3,3a,8,8a-tetra-
hydro-2H-indeno[1,2-d][1,3]oxazol-2-ylidene]cyanamide
ꢀ9c). Colorless powder )78%). Mp 216.5±217.08C )AcOEt).
23
1
[a]D ˆ215.2 )c 0.93, CHCl3). H NMR d: 2.42 )s, 3H,
CH3), 3.48 )dd, Jˆ6.1, 5.5 Hz, 1H, CH2), 3.55 )d, Jˆ
6.1 Hz, 1H, CH2), 5.63 )td, Jˆ7.9, 1.8 Hz, 1H, CHO),
6.25 )d, Jˆ7.3 Hz, 1H, CHN), 6.89±7.66 )m, 8H, Ar±H).
13C NMR d: 21.7, 37.6, 66.6, 83.7, 112.1, 125.3, 126.8,
128.4, 128.6 )2C), 129.1 )2C), 130.3 )2C), 137.3, 139.0,
143.7, 160.0, 168.1. IR )KBr) 2219 )CN), 1652
)CvO) cm21. MS m/z )%): 317 )M1, 30.4), 119 )100).
Anal. Calcd for C19H15N3O2: C, 71.91; H, 4.76; N, 13.24.
Found: C, 71.65; H, 4.98; N, 13.17.
4.1.5. [ꢀ3aS,8aR)-3,3a,8,8a-Tetrahydro-2H-indeno[1,2-d]-
[1,3]oxazol-2-ylidene]cyanamide ꢀ8). A solution of S,S0-
dimethyl N-cyanodithioiminocarbonate )2.92 g, 20.0
mmol) in EtOH )60 ml) was added to a solution of
)1S,2R)-cis-1-amino-2-indanol )3.28 g, 22.0 mmol) in
EtOH )40 ml) with stirring at rt and the whole was re¯uxed
over night. The solvent was evaporated and the residual
solid was washed with EtOH and dried to give 8 as a pale
yellow powder )3.78 g, 95%). Mp 212.0±213.08C )EtOH).
4.2.4.
[ꢀ3aS,8aR)-3-ꢀ4-Fluorobenzoyl)-3,3a,8,8a-tetra-
hydro-2H-indeno[1,2-d][1,3]oxazol-2-ylidene]cyanamide
ꢀ9d). Colorless powder )78%). Mp 146.0±147.08C )AcOEt).
27
1
[a]D ˆ2190.2 )c 1.00, CHCl3). H NMR d: 3.45 )d, Jˆ
5.5 Hz, 2H, CH2), 5.42 )d, Jˆ7.3 Hz, 1H, CHN), 5.63 )t,
Jˆ4.9 Hz, 1H, CHO), 7.28±7.47 )m, 5H, NH and Ar±H).
13C NMR d: 37.7, 63.2, 85.5, 115.5, 125.1, 125.5, 127.7,
129.3, 139.6, 139.9, 164.9. IR )KBr) 3138 )NH), 2193
)CN) cm21. MS m/z )%): 199 )M1, 100). Anal. Calcd for
22
1
[a]D ˆ24.15 )c 1.25, CHCl3). H NMR d: 3.53 )dd, Jˆ
6.7, 4.9 Hz, 1H, CH2), 3.59 )d, Jˆ6.7 Hz, 1H, CH2), 5.65
)td, Jˆ7.9, 2.4 Hz, 1H, CHO), 6.27 )d, Jˆ6.7 Hz, 1H,
CHN), 6.89±7.66 )m, 8H, Ar±H). 13C NMR d: 37.6, 66.5,
83.9, 111.9, 115.4, 125.4 )2C), 126.8, 128.4, 130.4 )2C),

9314
N. Maezaki et al. / Tetrahedron 5702001) 9309±9315
131.8 )2C), 137.3, 139.0, 163.3, 167.0, 167.1. IR )KBr)
2208 )CN), 1645 )CvO) cm21. MS m/z )%): 321 )M1,
3.0), 123 )100). HRMS )EI) Calcd for C18H12N3O2F )M1):
321.0913. Found: 321.0914.
ArCH2), 5.49 )d, Jˆ6.7 Hz, 1H, cyclohexyl-NH), 5.69 )m,
1H, CHN), 5.86 )t, Jˆ5.5 Hz, 1H, CHO), 6.33 )m, 1H,
CONH), 7.29±7.95 )m, 9H, Ar±H). 13C NMR d: 24.4
)2C), 24.8 )2C), 32.7, 37.5, 51.6, 55.8, 80.2, 115.6, 124.1,
125.2, 126.9 )2C), 127.6, 128.7 )2C), 128.9, 132.0, 133.6,
139.1, 139.6, 162.6, 167.1. IR )KBr) 3365 )NH), 3265 )NH),
2202 )CN), 1643 )CvO) cm21. MS m/z )%): 402 )M1, 0.8),
235 )100). HRMS )EI) Calcd for C24H26N4O2 )M1):
402.2055. Found: 402.2054.
4.2.5. ꢀ3aS,8aR)-3-Cyclohexylcarbonyl-3,3a,8,8a-tetra-
hydro-2H-indeno[1,2-d][1,3]oxazol-2-ylidene]cyanamide
ꢀ9e). Colorless powder )83%). Mp 161.5±162.58C )AcOEt).
27
[a]D ˆ147.1 )c 0.71, CHCl3). 1H NMR d: 1.23±1.89 )m,
11H, cyclohexyl), 3.41 )dd, Jˆ6.1, 5.5 Hz, 1H, ArCH2),
3.51 )d, Jˆ6.1 Hz, 1H, ArCH2), 5.49 )t, Jˆ6.7 Hz, 1H,
CHO), 6.14 )d, Jˆ6.7 Hz, 1H, CHN), 7.28±7.51 )m, 4H,
Ar±H). 13C NMR d: 25.2, 25.6, 28.6, 29.2, 37.4, 42.5, 65.8,
83.3, 112.4, 123.8, 125.4, 126.7, 128.6, 130.4, 137.9, 138.9,
158.5, 175.8. IR )KBr) 2208 )CN), 1635 )CvO) cm21. MS
m/z )%): 309 )M1, 4.2), 83 )100). Anal. Calcd for
C18H19N3O2: C, 69.88; H, 6.19; N, 13.58. Found: C,
69.83; H, 6.26; N, 13.50.
References
1. )a) Takayama, S.; Lee, S. T.; Hung, S.-C.; Wong, C.-H. Chem.
Â
Commun. 1999, 127±128. )b) Iglesias, L. E.; Sanchez, V. M.;
Rebolledo, F.; Gotor, V. Tetrahedron: Asymmetry 1997, 8,
2675±2677. )c) Takayama, S.; Moree, W. J.; Wong, C.-H.
Tetrahedron Lett. 1996, 37, 6287±6290. )d) Roberts, S. M.
Chimica 1993, 47, 85±92. )e) Asensio, G.; Andreu, C.; Marco,
J . A.Tetrahedron Lett. 1991, 32, 4197±4198. )f) Kitaguchi,
H.; Fitzpatrick, P. A.; Huber, J. E.; Klibanov, A. M. Acc.
Chem. Res. 1990, 23, 114±120. )g) Chen, C.-S.; Sih, C. J.
Angew. Chem., Int. Ed. Engl. 1989, 28, 695±707 and
references cited therein.
4.2.6. ꢀ3aS,8aR)-3-Propionyl-3,3a,8,8a-tetrahydro-2H-
indeno[1,2-d][1,3]oxazol-2-ylidene]cyanamide ꢀ9f). Color-
26
less powder )78%). Mp 179.0±180.08C )AcOEt). [a]D
ˆ
115.2 )c 0.91, CHCl3). 1H NMR d: 1.20 )t, Jˆ7.3 Hz, 3H,
CH2CH3), 2.94 )q, Jˆ7.3 Hz, 2H, CH2CH3), 3.42 )dd, Jˆ
6.1, 5.5 Hz, 1H, ArCH2), 3.51 )d, Jˆ6.1 Hz, 1H, ArCH2),
5.53 )t, Jˆ6.1 Hz, 1H, CHO), 6.14 )d, Jˆ6.7 Hz, 1H, CHN),
7.27±7.59 )m, 4H, Ar±H). 13C NMR d: 8.2, 30.2, 37.4, 65.7,
83.6, 112.2, 125.3, 126.9, 128.4, 130.3, 137.7, 138.9, 160.1,
173.3. IR )KBr) 2212 )CN), 1713 )CvO) cm21. MS m/z
)%): 255 )M1, 32.7), 115 )100). HRMS )EI) Calcd for
C14H13N3O2 )M1): 255.1008. Found: 255.1006.
2. For the diastereoselective acylation of racemic amines, see:
)a) Atkinson, R. S.; Baker, E.; Edwards, P. J.; Thomson, G. A.
J. Chem. Soc., Perkin Trans. 1 1996, 1047±1055. )b) Wang,
M.; Liu, S.; Biu, J.; Hu, B. F. Chem. Lett. 1995, 959±961.
)c) Atkinson, R. S.; Barker, E.; Price, C. J.; Russell, D. R.
J. Chem. Soc., Chem. Commun. 1994, 1159±1160. )d) Hiraki,
Y.; Tai, A. Chem. Lett. 1982, 341±344. )e) Bell, K. H. Aust. J.
Chem. 1981, 34, 665±670. )f) Kolomiets, V. F.; Gracheva,
R. A.; Potapov, V. M. Zh. Org. Khim. 1980, 16, 322±324
)Chem. Abstr. 1980, 93, 7553). )g) Bell, K. H. Aust. J.
Chem. 1979, 32, 2625±2629. )h) Mukaiyama, T.; Onaka,
M.; Shiono, M. Chem. Lett. 1977, 651±654. )i) Cevinka, O.;
Fusek, J. Collect. Czech. Chem. Commun. 1973, 38, 441±446.
)j) Cevinka, O.; Kroupova, E.; Belousk, O. Collect. Czech.
Chem. Commun. 1968, 33, 3551±3557. )k) Okamoto, K.;
Minami, E.; Shingu, H. Bull. Chem. Soc. Jpn 1968, 41,
1426±1432. )l) Herlinger, H.; Kleimann, H.; Ugi, I. Liebigs
Ann. Chem. 1967, 706, 37±46 and references cited therein.
3. For the enantioselective acylation of racemic amines, see:
)a) Tanaka, T.; Fang, X.; Azuma, T.; Uchida, S.; Ishida, T.;
In, Y.; Iwata, C.; Maezaki, N. J. Chin. Chem. Soc. 2000, 47,
865±868 )Chem. Abstr. 2001, 134, 222653). )b) Ie, Y.; Fu,
G. C. Chem. Commun. 2000, 119±120. )c) Al-Sehemi, A. G.;
Atkinson, R. S.; Fawcett, J.; Russell, D. R. Tetrahedron Lett.
2000, 41, 2239±2242. )d) Kondo, K.; Kurosaki, T.;
Murakami, Y. Synlett 1998, 725±726 and references cited
therein.
4.2.7. [ꢀ3aS,8aR)-3-Acetyl-3,3a,8,8a-tetrahydro-2H-in-
deno[1,2-d][1,3]oxazol-2-ylidene]cyanamide ꢀ9g). Color-
27
less powder )83%). Mp 207.0±208.08C )AcOEt). [a]D
ˆ
148.5 )c 0.97, CHCl3). 1H NMR d: 2.60 )s, 3H, CH3), 3.43
)dd, Jˆ6.1, 5.5 Hz, 1H, CH2), 3.52 )d, Jˆ6.1 Hz, 1H, CH2),
5.53 )t, Jˆ6.7 Hz, 1H, CHO), 6.13 )d, Jˆ6.7 Hz, 1H, CHN),
7.27±7.60 )m, 4H, Ar±H). 13C NMR d: 24.8, 37.4, 65.6,
83.6, 112.0, 125.1, 126.8, 128.2, 130.1, 137.5, 138.8, 160.1,
169.0. IR )KBr) 2190 )CN), 1635 )CvO) cm21. MS m/z
)%): 241 )M1, 10.2), 199 )100). Anal. Calcd for
C13H11N3O2: C, 64.72; H, 4.60; N, 17.42. Found: C,
64.57; H, 4.66; N, 17.32.
4.3. General procedure for asymmetric acylation of
racemic sec-alkyl amines with the 3-acyl-NCOp 9a±e
A mixture of 9a )60.0 mg, 0.20 mmol) and )^)-1-phenyl-
ethylamine )0.12 ml, 1.0 mmol) in a 1:1 mixture of MeCN±
THF )2 ml) was stirred at 2708C for 80 h under N2. The
mixture was diluted with AcOEt and washed 10% HCl and
brine prior to drying and solvent evaporation. The residue
was chromatographed on silica gel )hexane±AcOEtˆ1:1) to
give N-)1-phenylethyl)benzamide )35 mg, 76%, 85% ee)
along with 8 )38 mg, 95%) each as a colorless powder.
4. Zmitek, J.; Jenko, B.; Kosak, A.; Milivojevic, D. Org. Prep.
Proc. Int. 1985, 17, 256±261.
5. Baltzer, C. M.; McCarty, C. G. J. Org. Chem. 1973, 38, 155±
156.
6. Kunishima, M.; Kawach, C.; Morita, J.; Terao, K.; Iwasaki, F.;
Tani, S. Tetrahedron 1999, 55, 13159±13170.
4.3.1. ꢀ1S,2R)-1-Benzoylamino-2-[ꢀcyanoimino)ꢀcyclo-
hexylamino)methoxy]-2,3-dihydro-1H-indene ꢀ10). Color-
7. Tanaka, T.; Iwata, C. J. Synth. Org. Chem. Jpn 1998, 56, 182±
191.
24
less powder )6%). Mp 212.0±213.08C )AcOEt). [a]D
ˆ
8. Huisgen, R.; RuÈchardt, C. Justus Liebigs Ann. Chem. 1956,
601, 21±39.
1
2108.9 )c 0.40, CHCl3). H NMR d: 0.88±1.67 )m, 10H,
cyclohexyl), 3.18 )dd, Jˆ12.2, 2.4 Hz, 1H, ArCH2), 3.36
)m, 1H, cyclohexyl), 3.38 )dd, Jˆ12.2, 5.5 Hz, 1H,
9. Bringmann, G.; Geisler, J.-P.; Geuder, T.; KuÈnkel, G.;
Kinzinger, L. Liebigs Ann. Chem. 1990, 8, 795±805.

N. Maezaki et al. / Tetrahedron 5702001) 9309±9315
9315
10. Katritzky, A. R.; Harris, P. A. Tetrahedron: Asymmetry 1992,
3, 437±442.
Perkin Trans. 1 1993, 3127±3137. )b) Sigel, H.; Fischer,
B. E.; Farkas, E. Inorg. Chem. 1983, 22, 925±934.
Â
)c) Capillon, J.; Guette, J.-P. Tetrahedron 1979, 35, 1817±
11. Janaik, C. Dalton 2000, 3885±3896. )b) Claessens, C. G.;
Stoddart, J. F. J. Phys. Org. Chem. 1997, 10, 254±272.
)c) Jones, G. B.; Chapman, B. J. Synthesis 1995, 475±497.
12. )a) Yamato, T.; Miyazawa, A.; Tashiro, M. J. Chem. Soc.,
1820. )d) Kobuke, Y.; Fueno, T.; Furukawa, J. J. Am. Chem.
Soc. 1970, 82, 6548±6553.