A mild cyclodesulfurization of N-(2-hydroxyethyl)-N′-phenylthioureas to 2-phenylamino-2-oxazolines using TsCl/NaOH

Article abstract of DOI:10.1016/S0040-4020(01)00682-2

An efficient synthesis of 2-phenylamino-2-oxazolines 3 via cyclodesulfurization of N-(2-hydroxyethyl)-N′-phenylthioureas 2 by a one-pot reaction using p-toluenesulfonyl chloride (TsCl) and NaOH in very good yields is described.

Full text of DOI:10.1016/S0040-4020(01)00682-2

TETRAHEDRON
Pergamon
Tetrahedron 57 *2001) 7137±7141
A mild cyclodesulfurization of
N-ꢀ2-hydroxyethyl)-N0-phenylthioureas to
2-phenylamino-2-oxazolines using TsCl/NaOH
Taek Hyeon Kim,a,p Namgun Lee,a Gue-Jae Leea and Jae Nyoung Kimb
aFaculty of Applied Chemistry, College of Engineering, Chonnam National University, Kwangju 500-757, South Korea
bDepartment of Chemistry, College of Natural Science, Chonnam National University, Kwangju 500-757, South Korea
Received 2 May 2001; accepted 22 June 2001
AbstractÐAn ef®cient synthesis of 2-phenylamino-2-oxazolines 3 via cyclodesulfurization of N-*2-hydroxyethyl)-N0-phenylthioureas 2 by
a one-pot reaction using p-toluenesulfonyl chloride *TsCl) and NaOH in very good yields is described. q 2001 Elsevier Science Ltd. All
rights reserved.
1. Introduction
misassigned structures. The cyclization of N-*2-hydroxy-
ethyl)thioamides system with TsCl in the presence of
triethylamine resulted in the formation of thiazolines as
cyclodehydration products.12 In this article, we report that
the cyclization of N-*2-hydoxyethyl)thioureas 2 with TsCl
results in the oxazolines as cyclodesulfurization products as
well as thiazolines depending on N-substituents.
2-Amino-2-oxazolines are of particular interest as bio-
logical active molecules such as a potent adrenoceptor
agonist,1 imidazoline receptor agonist,2 and octopaminergic
agonist.3 This interest has stimulated considerable research
in the preparation of a variety of compounds. 2-Amino-2-
oxazolines are generally prepared by the following
methods: the cyclization of N-*2-haloethyl)ureas1a,4 or
N-*2-hydroxyethyl)guanidine,5 the ring opening of
aziridines with isocyanates,6 the reaction between
2-aminoalcohol and cyano bromide,7 the cyclization of
N-*2-hydroxyethyl)thiopseudoureas with sodium ethoxide
in re¯ux,5a,8 and the cyclodesulfurization of N-*2-hydro-
xyethyl)thioureas with mercuric oxide9 or superoxide
radical anion.10 Each method has its advantages and dis-
advantages in any given situation, therefore, no one reagent
has proven totally general. Thus, the development of other
methods is necessary.
2. Results and discussion
The starting N-*2-hydroxyethyl)thioureas 2 were readily
obtained in high yields from the reaction of the correspond-
ing 1,2-aminoalcohols with phenyl isothiocyanate, which
provided exclusively the desired products under mild con-
ditions, thus avoiding the need for O-protection.11 First
investigations of one-pot reactions of both 2a and 2f by
the combination of TsCl *1.1 equiv.) with various basic
metallic *t-BuOK, NaOH, and NaH) or non-metallic *Et3N
and Et3N/DMAP) reagents were performed in THF *Table
1). Among them, the use of NaOH was found to be most
effective in producing cyclization products *entry 2).
Compound 2f due to a gem-dimethyl effect cyclized quickly
offering 3f in high yields.13 With 2a, the cyclization did not
occur in some conditions *entries 3±6) yielding the
tosylated product. The structure of 2-oxazoline 3f was
wrongly proposed to S-cyclization product such as 2-thiazo-
line in our previous report, assigning the peak at d 4.02 to
the ±NvCZSCH2± proton in NMR.11
Recently we reported that 2-phenylamino-2-thiazolines 4
were synthesized by the selective S-cyclization of N-*2-
hydroxyethyl)-N0-phenythioureas
2
using TsCl and
NaOH.11a During the course of our development of a new
chiral auxiliary using a chiral 2-phenylamino-2-thiazoline
prepared according to this procedure *TsCl/NaOH), we
found that this compound contained no sulfur atom in
elemental analysis. Thus, the previous report has the
wrongly proposed structure,11 prompting us to embark on
the detailed cyclization reaction of N-*2-hydoxyethyl)-N0-
phenylthioureas 2 under TsCl/NaOH and corrections of
The cyclization of various substrates 2a±2i using 1.1 equiv.
of TsCl and 2.5 equiv. of NaOH was performed at room
temperature and the results are shown in Table 2. With
thiourea 2a±2f prepared from N-unsubstituted amino-
alcohols *R3ˆH), 2-phenylamino-2-oxazolines 3a±3f
Keywords: cyclization; oxazoline; p-toulenesulfonyl chloride.
Corresponding author. Tel.: 182-62-530-1891; fax: 182-62-530-1889;
e-mail: thkim@chonnam.chonnam.ac.kr
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020*01)00682-2

7138
T. H. Kim et al. / Tetrahedron 57 (2001) 7137±7141
Table 1. Effect of base in one-pot reaction of 2a and 2f
Entry
Base
Time, temperature
Yield %a,b of 3a
Yield %a,b of 3f
1
2
3
4
5
t-BuOK *2.5 equiv.)
NaOH *2.5 equiv.)
NaH *2.5 equiv.)
Et3N *5.0 equiv.)
Et3N/DMAP *5.0/0.5 equiv.)
30 min, 08C
30 min, rt
30 min, rt
17 h, re¯ux
17 h, re¯ux
37 *13)
64 *6)
± *11)
± *44)
± *33)
78
94
62 *10)
62
c
a
Isolated yields by column chromatography.
Parenthesis is the isolated tosylate yield and the position of tosylation was not determined.
Not tested.
b
c
and the comparison of authentic sample data.4,5a In contrast,
the thioureas 2g±2i prepared from N-substituted amino-
alchols *R3ˆMe, Et, Bn) gave a cyclodehydrated mixture
of 2-iminothiazolines *S-cyclization products) 4g±4i and 2-
imidazolidinethiones *N-cyclization products) 5g±5h with-
out the 2-oxazolines *entries 7±9).14,15 It is noteworthy in
the above reactions to note that the ring closure of the
substrates 2a±2f having N-unsubstituents using TsCl/
NaOH proceeded through the cyclodesulfurization to
provide regiocontrolled 2-phenylamino-2-oxazolines.16
Table 2. Cyclization of N-*2-hydroxyethyl)-N-phenylthioureas 2
Entry
Substrate
R1
R2
R3
Product Yield %a
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
Me
Et
*S)-PhCH2
*S)-i-Pr
Me
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
4g/5g
4h/5h
64
77
78
90
85
94
Me
Et
29/54b
27/65b
18/50b
H
H
PhCH2 4i/5i
a
Next, we were interested to see if the related selective trans-
formation could be effected on a variety of thioureas derived
from the alkyl isothiocyanate and benzoyl isothiocyanate to
®gure out the scope and limitations of this synthetic
methodology *Scheme 2). Thus, cyclization of the
N-methylthioureas such as 6f and 6i was performed to
produce along with a mixture of the S- and N-cyclization
in the proton NMR ratios of 92/8 and 70/30, respectively.
Isolated yields by column chromatography.
The ratio of the crude mixtures determined by 1H NMR was as follows:
43/57 in 4g/5g, 30/70 in 4h/5h, and 31/69 in 4i/5i.
b
through O-cyclization were regioselectively obtained
*entires 1±6) and only 2a gave the tosylated products in
6% yield as a by-product *Scheme 1). All 2-oxazolines
were identi®ed with spectroscopic data, elemental analysis,
Scheme 1.
Scheme 2.

T. H. Kim et al. / Tetrahedron 57 (2001) 7137±7141
7139
Compared to 2f, the cyclization of 6f yielded the mixture
of S- and N-alkylation products without the oxazoline.
Cyclization of 7i derived from benzoyl isothiocyanate led
to the mixture of the O-*60%) and N-cyclized product *15%)
with trace amount of S-cyclized product *5%). Benzoyl
substituted 7i having N-substituted benzyl group, compared
to 2i, provided the oxazoline as a main product to be consid-
ered to proceed via S-tosylation. That is, 6f and 7i gave
totally different mixtures from N-phenylthiourea 3. Thus,
we abandoned any further efforts to establish the generality
of this transformation.
rated, and puri®ed by ¯ash column chromatography to
give the cyclized product.
3.2.1. 4,5-Dihydro-N-phenyl-2-oxazolamine ꢀ3a). White
solid, mp 121±1238C *lit.5a mp 119±1208C); Rfˆ0.2
1
*ethyl acetate); H NMR *CDCI3) d 7.24±7.26 *4H, m),
6.94±7.00 *1H, m), 4.36 *2H, t, Jˆ8.2 Hz), 3.81 *2H, t,
Jˆ8.2 Hz); 13C NMR *CDCl3) d 157.9, 141.4, 128.9,
122.2, 119.7, 67.4, 49.8. Anal. Calcd for C9H10N2O: C,
66.65; H, 6.21; N, 17.27. Found: C, 67.10; H, 6.39; N, 17.75.
3.2.2. 4,5-Dihydro-4-methyl-N-phenyl-2-oxazolamine ꢀ3b).
White solid, mp 108±1108C *lit.4 mp 1118C); Rfˆ0.3*ethyl
acetate); IR *CDCl3, cm21) 1687; 1H NMR *CDCl3) d 7.20±
7.28 *4H, m), 6.94±7.00 *1H, m), 4.43 *1H,t, Jˆ8.0 Hz),
4.10±4.17 *1H, M), 3.87 *1H,t, Jˆ7.5 Hz), 1.27 *3H, d,
Jˆ6.3 Hz); 13C NMR *CDCl3) d 156.8, 142.8, 128.8,
122.2, 120.4, 73.6, 55.3, 21.2. Anal. Calcd for C10H12N2O:
C, 68.16; H, 6.86; N, 15.90. Found: C, 68.35; H, 6.67; N,
16.41.
The exact mechanistic explanation of this study remains
unclear at the present time. The ratio, however, of O-, N-,
and S-cyclized products seems to depend on the acidity of
the thiourea moiety and steric hindrance around the sulfur
atom. The substrate having more acidic thiourea moiety
*PhCONH.PhNH.MeNH) and the less hindered sulfur
atom *N-unsubstituted.N-substituted) tends to undergo
O-cyclization rather than N- and S-cyclization via S-tosyl-
ation, giving the 2-oxazoline derivative mainly.
3.2.3. 4,5-Dihydro-4-ethyl-N-phenyl-2-oxazolamine ꢀ3c).
White solid, mp 100±1028C *lit. 5a mp 100±1018C); Rfˆ0.2
*ethyl acetate); IR *CDCl3, cm21) 1703; 1H NMR *CDCl3) d
7.13±7.29 *4H, m), 6.94±7.03 *1H, m), 4.37±4.43 *1H, m),
3.88±3.99 *2H, m), 1.49±1.67 *2H, m), 0.93 *3H, t.
Jˆ7.4 Hz); 13C NMR *CDCl3) d 156.8, 143.1, 128.7,
122.1, 120.6, 71.9, 60.8, 28.5, 9.7. Anal. Calcd for
C11H14N2O: C, 69.45; H, 7.42; N, 14.73. Found: C, 69.82;
H, 7.75; N, 15.16.
In conclusion, the right closure of N-*2-hydroxyethyl)-N0-
phenylthioureas 2 is proven to furnish 2-pheylamino-2-
oxazolines 3 as well as 2-phenylamino-2-thiazolines 4 and
2-imidazolidinethiones 5 depending on the substituent of
thioureas. We have found a new entry to the synthesis of
2-phenylamino-2-oxazolines by a mild one-pot cyclization
of N-*2-hydroxyethyl)-N0-phenylthioureas prepared from
N-unsubstituted 1,2-aminoalcohols and phenyl isothio-
cyanate. We believe that this methodology will be applic-
able to the combinatorial approach to 2-arylamino-2-
oxazolines, which is expected to have biological activities
as mentioned above. Additionally, chiral 2-phenylamino-2-
oxazoline like 3d and 3e may be applicable to chiral
auxiliaries as an Evans-type of 2-oxazolidione.17
3.2.4. ꢀ4S)-4,5-Dihydro-N-phenyl-4-phenylmethyl-2-oxa-
zolamine ꢀ3d). Colorless oil, Rfˆ0.3 *ethyl acetate/hexane
1:1); [a]20 ˆ13.6 *CHCl3, cˆ0.7); IR *CDCl3, cm21) 1687
D
1H NMR *CDCl3) d 7.19±7.33 *9H, m), 6.95±6.99 *1H, m),
4.25±4.30 *2H, m), 4.13±4.04 *1H, m), 3.00 *1H, dd, Jˆ5.2,
13.5 Hz), 2.73 *1H, dd, Jˆ7.4, 13.5 Hz); 13C NMR *CDCl3)
d 157.8, 143.1, 138.5, 130.1, 129.7, 129.5, 127.5 123.2,
120.9, 72.4, 63.0, 42.9. Anal. Calcd for C16H16N2O: C,
76.16; H, 6.39; N, 11.10. Found: C, 76.35; H, 6.74; N, 11.40.
3. Experimental
3.1. General
3.2.5. ꢀ4S)-4,5-Dihydro-4-ꢀ1-methylethyl)-N-phenyl-2-
oxazolamine ꢀ3e). White solid, mp 65±678C; Rfˆ0.3
IR *CDCl3, cm21) 1680; H NMR *CDCl3) d 7.19±7.27
1H- and 13C NMR spectra were recorded using 300 and
75 MHz NMR spectrometer; chemical shifts are reported
in ppm using TMS as an internal standard. Melting points
*ethyl acetate/hexane 1:1) [a]20 ˆ13.1 *CHCl3, cˆ0.8);
D
1
were measured in
a glass capillary apparatus and
*4H, m), 6.94±6.99 *1H, m), 4.28 *1H, dd, Jˆ8.2, 8.2 Hz),
3.99 *1H, dd, Jˆ6.6, 8.2 Hz), 3.64±3.71 *1H, m) 1.60±1.71
*1H, m), 0.88 *3H, d, Jˆ6.7 Hz), 0.81 *3H, d, Jˆ6.8 Hz);
13C NMR *CDCl3) d 156.9, 143.3, 128.8, 122.2, 120.8, 70.3,
65.1, 33.1, 18.7, 18.0. Anal. Calcd for C12H16N2O: C, 70.56;
H, 7.90; N, 13.71. Found: C, 71.01; H, 7.45; N, 13.52.
uncorrected. Mass spectra were recorded on a HP 5983B
GC/Mass spectrometer. Elemental analysis was performed
in the Korea Basic Science Institute, Kwangju, Korea.
Analytical TLC was performed on 0.25 mm precoated silica
gel plates. Flash chromatography was carried out with
230±400 mesh silica gel.
3.2.6. 4,5-Dihydro-4,4-dimethyl-N-phenyl-2-oxazolamine
ꢀ3f). White solid, mp 115±1168C *lit.5a mp 114±1168C);
3.2. Cyclization of N-ꢀ2-hydroxyethyl)thioureas
1
Rfˆ0.3 *ethyl acetate); IR *CDCl3, cm21) 1687; H NMR
*CDCl3) d 7.14±7.27 *4H, m), 6.93±7.00 *1H, m), 4.02 *2H,
s), 1.33 *6H, s); 13C NMR *CDCl3) d 157.7, 142.4, 128.8,
122.1, 120.4, 78.6, 61.9, 28.0. Anal. Calcd for C11H14N2O:
C, 69.45; H, 7.42; N, 14.73. Found: C, 69.80; H, 7.72; N,
15.04.
To a stirred solution of thiourea *0.88 mmol) in THF
*10 mL) under nitrogen at room temperature was added a
solution of NaOH *88 mg, 2.2 mmol, 250 M%) in water
*3 mL) and TsCl *0.18 g, 0.97 mmol, 110 M%) in THF
*5 mL) dropwise for 5 min with a syringe. The reaction
mixture was stirred for 30 min at room temperature,
quenched with water *30 mL), and extracted with ether
*50 mL£3). The organic layer was dried, ®ltered, evapo-
3.2.7. 3-Methyl-2-phenyliminothiazolidine ꢀ4g). White
solid, mp 88±898C *lit.9a mp 898C); Rfˆ0.4 *ethyl acetate/

7140
T. H. Kim et al. / Tetrahedron 57 (2001) 7137±7141
hexane/dichloromethane 1:1:1); IR *CDCl3, cm21) 1616,
1H NMR *300 MHz, CDCl3) 3.26 *2H, s), 2.94 *3H, s), 1.42
*6H, s); 13C NMR *75 MHz, CDCl3) 28.28, 31.38, 46.16,
73.11, 159.43; Anal. Calcd for C6H12N2S: C, 49.96; H, 8.39;
N, 19.42; S, 22.23. Found: C, 51.22; H, 8.51; N, 19.00; S,
21.85.
1
1576; H NMR *CDCl3) d 6.92±7.29 *5H, m), 3.56 *2H, t,
Jˆ6.8 Hz), 3.13 *2H, t, Jˆ6.8 Hz), 3.03 *3H, s); 13C NMR
*CDCl3) d 159.4, 152.4, 128.8, 123.0, 122.1, 53.0, 33.8,
26.8; EIMS m/z 57 *55), 71 *25), 149 *100), 167 *46), 192
*M, 32). Anal. Calcd for C10H12N2S: C, 62.46; H, 6.29; N,
14.57; S, 16.68. Found: C, 62.90 H, 6.23; N, 14.99; S, 16.35.
3.2.14. 3-Phenylmethyl-2-methyliminothiazolidine ꢀ8i).
1
Yield 35%; colorless oil, Rfˆ0.5 *ethyl acetate); H NMR
*CDCl3) d 7.32±7.25 *m, 5H), 4.50 *s, 2H), 3.34±3.29 *m,
2H), 3.12±3.07 *m, 2H), 3.10 *s, 3H); 13C NMR *CDCl3) d
160.2, 137.7, 128.5, 128.0, 127.2, 50.3, 50.2, 41.4, 26.7;
EIMS m/z 43.2 *74.5), 74.9 *100), 90.9 *89.9), 177.9
*43.5), 206.0 *58.7, M). Anal. Calcd for C11H14N2S: C,
64.04; H, 6.84; N, 13.58; S, 15.54. Found: C, 63.83; H,
6.68; N, 13.42; S, 15.12.
3.2.8. 1-Methyl-3-phenyl-2-imidazolidinethione ꢀ5g). White
solid, mp 90±928C; Rfˆ0.6 *ethyl acetate/hexane/dichloro-
methane 1:1:1) IR *CDCl3, cm21) 1336; 1H NMR *CDCl3) d
7.21±7.54 *5H, m), 4.01 *2H, t), 3.73 *2H, t), 3.24 *3H, s);
13C NMR *CDCl3) d 182.0, 141.0, 128.7, 126.1, 124.8, 48.7,
48.5, 35.2; EIMS m/z 51 *54), 57 *60), 77 *100), 91 *38), 192
*M, 11). Anal. Calcd for C10H12N2S: C, 62.46; H, 6.29; N,
14.57; S, 16.68. Found: C, 62.69; H, 6.64; N, 15.01; S,
17.01.
3.2.15. 1-Methyl-3-phenylmethyl-2-imidazolidinethione
ꢀ9i). Yield 18%; pale yellow solid, mp 109±1118C; Rfˆ
1
0.8 *ethyl acetate); H NMR *CDCl3) d 7.34±7.27 *m, 5H),
3.2.9. 3-Ethyl-2-phenyliminothiazolidine ꢀ4h). Pale
yellow oil, Rfˆ0.5 *ethyl acetate/hexane 3:7); IR *CDCl3,
cm21) 1624, 1585; 1H NMR *CDCl3) d 6.91±7.28 *5H, m),
3.58 *2H, t, Jˆ6.9 Hz), 3.57 *2H, q, Jˆ7.2 Hz), 3.10 *2H, t,
Jˆ6.9 Hz), 1.22 *3H, Jˆ7.2 Hz); 13C NMR *CDCl3) d
158.4, 152.4, 128.7, 122.8, 126.0, 124.9, 50.2, 41.1, 26.7,
11.9; EIMS m/z 51 *45), 56 *57), 77 *100), 206 *M, 1). Anal.
Calcd for C11H14N2S: C, 64.04; H, 6.84; N, 13.58; S, 15.54.
Found: C, 63.54; H, 6.74; N, 13.20; S, 15.01.
4.84 *s, 2H), 3.57±3.50 *m, 2H), 3.43±3.37 *m, 2H), 3.19 *s,
3H); 13C NMR *CDCl3) d 183.2, 136.5, 128.6, 128.2, 127.6,
51.8, 48.3, 45.4, 35.1; EIMS m/z 44.2 *88.7), 65.1 *73.2), 91.0
*100), 115.0 *34.6), 145.1 *30.1), 206.1 *74.3, M). Anal.
Calcd for C11H14N2S: C, 64.04; H, 6.84; N, 13.58; S, 15.54.
Found: C, 63.90; H, 6.79; N, 13.10; S, 15.20.
3.2.16. 3-Phenylmethyl-2-benzoyliminooxazolidine ꢀ10i).
Yield 60%; white solid, mp 83±848C; Rfˆ0.1 *ethyl acetate/
hexane 1:1); 1H NMR *CDCl3) d 8.25±8.22 *m, 2H), 7.47±
7.32 *m, 8H), 4.68 *s, 2H), 4.55±4.49 *m, 2H), 3.50±3.45
*m, 2H); 13C NMR *CDCl3) d 175.0, 159.7, 137.2, 135.3,
131.6, 129.7, 128.9, 128.3, 128.2, 127.9, 65.8, 49.1, 44.3;
EIMS m/z 77.1 *75.7), 91.1 *100), 105.1 *73.0), 132.1
*25.5), 175.2 *17.9), 280.3 *13.9, M). Anal. Calcd for
C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.83;
H, 5.63; N, 9.66.
3.2.10. 1-Ethyl-3-phenyl-2-imidazolidinethione ꢀ5h).
White solid, mp 65±678C *lit.19 mp 698C); Rfˆ0.4 *ethyl
acetate/hexane 3:7); IR *CDCl3, cm21) 1346; 1H NMR
*CDCl3) d 7.19±7.55 *5H, m), 3.94±4.00 *2H, m), 3.78
*2H, q, Jˆ7.2 Hz), 3.65±3.72*2H, m), 1.23 *3H, t,
Jˆ7.2 Hz); 13C NMR *CDCl3) d 181.1, 140.9, 128.6,
126.0, 124.9, 48.8, 45.5, 42.4, 11.8; EIMS m/z 51 *45), 77
*100), 106 *97), 206 *M, 91). HRMS *EI) Calcd for
C11H14N2S 206.0878, Found 206.0875.
3.2.17. 3-Phenylmethyl-2-benzoyliminothiazolidine ꢀ11i).
Yield 5%; white solid, mp 122±1248C; Rfˆ0.5 *ethyl
3.2.11. 3-Phenylmethyl-2-phenyliminothiazolidine ꢀ4i).
1
acetate/hexane 1:1); H NMR *CDCl3) d 8.33±8.30 *m,
White solid, mp 93±958C *lit.14 mp 92±948C); Rfˆ0.8
1
*ethyl acetate/hexane 1:1); H NMR *CDCl3) d 7.36±7.24
2H), 7.50±7.34 *m, 8H), 5.00 *s, 2H), 3.62±3.57 *m, 2H),
3.18±3.12 *m, 2H); 13C NMR *CDCl3) d 175.9, 172.2,
136.7, 135.8, 131.9, 129.7, 128.9, 128.2, 128.0, 51.2, 48.8,
26.9; EIMS m/z 77.1 *100), 91.1 *62.1), 105.1 *75.1), 191.2
*17.9), 296.4 *8.1, M). Anal. Calcd for C17H16N2OS: C,
68.89; H, 5.44; N, 9.45; S, 10.82. Found: C, 68.47; H,
5.47; N, 9.2; S, 10.48.
*m, 7H), 7.04±6.97 *m, 3H), 4.71 *s, 2H), 3.49±3.44 *m,
2H), 3.10±3.06 *m, 2H); 13C NMR *CDCl3) d 159.0, 152.2,
137.2, 128.8, 128.6, 128.2, 127.4, 123.0, 122.0, 50.2, 50.1,
26.8; EIMS m/z 77.1 *57.6), 91.1 *100), 207.2 *32.7), 268.3
*44.7, M). Anal. Calcd for C16H16N2S: C, 71.60; H, 6.01; N,
10.44; S, 11.95. Found: C, 71.26; H, 5.88; N, 10.34; S,
11.74.
3.2.18. 1-Benzoyl-3-phenylmethyl-2-imidazolidinethione
ꢀ12i). Yield 14%; white solid, mp 113±1148C; Rfˆ0.8
3.2.12. 1-Phenyl-3-phenylmethyl-2-imidazolidinethione
1
*ethyl acetate/hexane 1:1); H NMR *CDCl3) d 8.19±8.16
ꢀ5i). White solid, mp 119±1218C *lit.14 mp 125±1268C);
1
*m, 2H), 7.50±7.35 *m, 8H), 5.22 *s, 2H), 4.15±4.12 *m,
2H), 3.60±3.57 *m, 2H); 13C NMR *CDCl3) d 178.2, 177.4,
135.8, 134.2, 132.1, 129.6, 128.9, 128.2, 65.8, 57.5, 47.9;
EIMS m/z 77.0 *100), 91.5 *77.4), 105.0 *85.2), 191.1
*28.2), 267.1 *21.8), 296.2 *25.9, M). Anal. Calcd for
C17H16N2OS: C, 68.89; H, 5.44; N, 9.45; S, 10.82. Found:
C, 68.45; H, 5.12; N, 9.69; S, 10.40.
Rfˆ0.7 *ethyl acetate/hexane 1:1); H NMR *CDCl3) d
7.56±7.53 *m, 2H), 7.43±7.25 *m, 8H), 4.95 *s, 2H),
4.00±3.94 *m, 2H), 3.59±3.53 *m, 2H); 13C NMR
*CDCl3) d 181.7, 140.9, 136.2, 129.0, 128.3, 127.6, 126.2,
124.9, 51.7, 48.8, 45.6; EIMS m/z 77.1 *51.4), 91.1 *100),
136.0 *32.1), 148.0 *34.9), 182.1 *14.2), 239.2 *9.8), 268.2
*29.4, M). Anal. Calcd for C16H16N2S: C, 71.60; H, 6.01; N,
10.44; S, 11.95. Found: C, 71.15; H, 5.90; N, 10.06; S,
11.50.
Acknowledgements
3.2.13.
4,5-Dihydro-4,4-dimethyl-N-methyl-2-thiazol-
amine ꢀ8f). Yield 90%; colorless oil, Rfˆ0.2 *ethyl acetate);
This work was supported by the grant No. *2000-1-12300-

T. H. Kim et al. / Tetrahedron 57 (2001) 7137±7141
7141
47, 1981±1989. *b) Jen, T.; Hoeven, H. V.; Groves, W.;
McLean, R. A.; Love, B. J. Med. Chem. 1975, 18, 90±99.
10. Kim, Y. I.; Kim, Y. H. Synlett 1997, 1324±1326.
11. *a) Kim, T. H.; Min, J. K.; Lee, G.-J. Tetrahedron Lett. 1999,
40, 8201±8204. *b) Kim, T. H.; Min, J. K.; Lee, G.-J. Bull.
Korean Chem. Soc. 2000, 21, 919±922. *c) Kim, T. H.; Min,
J. K.; Lee, G.-J. Tetrahedron Lett. 2001, 42, 2413.
004-1) from the Basic Research Program of the Korea
Science and Engineering Foundation and by the grant
from the Brain Korea 21 program of the Ministry of
Education.
References
12. Wipf, P.; Fritch, P. C. Tetrahedron Lett. 1994, 35, 5397±5400.
13. Jung, M. E. Synlett 1990, 186±190.
1. *a) Wong, W. C.; Wang, D.; Forray, C.; Vaysse, P. J.-J.;
Branchek, T. A.; Gluchowski, C. Bioorg. Med. Chem. Lett.
1994, 4, 2317±2322. *b) Wong, W. C.; Sun, W.; Cui, W.;
Chen, Y.; Forray, C.; Vaysse, P. J.-J.; Branchek, T. A.;
Gluchowski, C. J. Med. Chem. 2000, 43, 1699±1704.
2. Bricca, G.; Dontenwill, M.; Molines, A.; Feldman, J.; Tibirica,
E.; Belcourt, A.; Bousquet, P. Eur. J. Pharmacol. 1989, 163,
373±377.
14. Thioureas 2 under hydrochloric acidic conditions were usually
converted into the S-cyclized product9a and treatment of 2i
with phosphorus hexaethyl triamide produced along with the
mixture of S-cyclized iminothiazolidine and N-cyclized
imidazolidinethione in the yield of 36 and 26%, respectively,
see: Mizrakh, L. I.; Polonskaya, L. Yu.; Gvozdetskii, A. N.;
Berdyugin, V. V.; Vasil'ev, A. M.; Ivanova, T. M. J. Gen.
Chem. USSR (Engl. Transl.), 1989, 59, 1058±1059; Zh.
Obshch. Khim, 1989, 59, 1195±1196; Chem. Abstr., 1990,
112, 55701.
3. *a) Hirashima, A.; Pan, C.; Katafuchi, Y.; Taniguchi, E.; Eto,
M. J. Pesticide Sci. 1996, 21, 419±424. *b) Hirashima, A.;
Tomita, J.; Pan, C.; Taniguchi, E.; Eto, M. Bioorg. Med.
Chem. 1997, 5, 2121±2128. *c) Hirashima, A.; Pan, C.;
Tomita, J.; Kuwano, E.; Taniguchi, E.; Eto, M. Pestic.
Biochem. Physiol. 1997, 58, 219±228.
15. All reaction conditions surveyed in Table 1 was applied to 2h,
which gave the mixture of 4h and 5h with the following ratios:
t-BuOK *49/22), NaH *57/38), Et3N *0/72), and DMAP *0/50).
It is noteworthy that the use of triethylamine and DMAP gave
the regiospeci®c S-cyclized product without N-cyclization.
16. For a regiocontrolled N-cyclization reaction of N-*2-hydroxy-
ethyl)ureas using TsCl and t-BuOK, see: Kim, T. H.; Lee,
G.-J. J. Org. Chem. 1999, 64, 2941±2943.
4. Najer, H.; Chabrier, P.; Giudielli, R. Bull. Soc. Chim. Fr.
1959, 1611±1617; Chem. Abstr., 1960, 54, 9889.
5. *a) Adcock, B.; Lawson, A.; Miles, D. H. J. Chem. Soc. 1961,
5120±5127. *b) Fishbein, L.; Gallaghan, J. A. J. Org. Chem.
1956, 21, 434±435.
6. *a) Heine, H. W.; Kenyon, W. G.; Johnson, E. M. J. Am.
Chem. Soc. 1961, 83, 2570±2574. *b) Pfeil, E.; Milzner, K.
Angew. Chem., Int. Ed. Engl. 1996, 5, 667. *c) Heine, H. W.;
Kaplan, M. S. J. Org. Chem. 1967, 32, 3069±3073.
7. *a) Wittekind, R. R.; Rosenau, J. D.; Poos, G. I. J. Org. Chem.
1961, 26, 444±446. *b) Poos, G. I.; Carson, J. R.; Rosenau,
J. D.; Roszkowski, A. P.; Kalley, N. M.; McGowin, J. J. Med.
Chem. 1963, 6, 266±272.
17. Chiral 2-alkyl or aryl-2-oxazolines have been extensively used
in asymmetric synthesis as both ligands and auxiliaries.18 Aza-
bis*oxazolines) as a ligand was attached to a soluble support
and successfully applied in asymmetric catalysis, see: Glos,
M.; Reiser, O. Org. Lett., 2000, 2, 2045±2048. So far chiral 3d
and 3e were not reported as chiral auxiliaries and we will
publish its result in another paper.
18. Reviews: *a) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50,
2297±2360. *b) Ghosh, A. K.; Mathivanan, P.; Cappiello, J.
Tetrahedron: Asymmetry 1998, 9, 1±45.
8. Klayman, D. L.; Shine, R. J.; Murray Jr., A. E. J. Pharm. Sci.
1970, 59, 1515±1518.
9. *a) Dains, F. B.; Brewster, R. Q.; Malm, I. L.; Miller, A. W.;
Maneval, R. V.; Sultzaberger, J. A. J. Am. Chem. Soc. 1925,
19. Timmler, F. *Farbenfabriken Bayer, A.-G.) Ger. 1,126,392,
Mar. 29, 1962; Chem. Abstr., 1962, 57, 9859.