Chemistry Letters 2000
41
These isothiocyanates could react effectively to amines in
various nonpolar, polar, or protic solvents involving n-hexane,
chloroform, methanol, DMSO, or water. Since the reaction
proceeded smoothly at room temperature, addition of the isoth-
iocyanate reagents to the amines in various NMR solvents
directly provided the samples for the NMR analysis.
In summary, we have demonstrated that phenyl and naph-
thyl isothiocyanates, which can be readily obtained from com-
mercially available amines by one step and are easy for han-
dling due to their insensitivity to the moisture and thermal sta-
bility, are useful as new chirality recognizing reagents for the
determination of enantiomeric purity of the chiral amines by
NMR. Although the magnitude of the nonequivalence are
insufficient in some cases, the splitting is generally large
enough to determine enantiomeric purity of the versatile
amines.
(S)-1-Phenylethyl isothiocyanate (2a) reacted either with
(R)-, or (S)-1-phenylethylamine to give the corresponding opti-
cally pure thiourea derivatives (3a). As shown in Table 1, the
thiourea derivative (S,S)-3a from the (S)-1-phenylethylamine
1
shows a doublet at 1.477 ppm in H NMR and the signal at
22.994 ppm in 13C NMR pertaining to the methyl protons and
the carbon, respectively, while in the (S,R)-3a, the correspon-
ding doublet at 1.329 ppm in 1H NMR and the signal at 22.531
ppm in 13C NMR were observed. With other primary and sec-
ondary amines, the corresponding thioureas (3b and 3c)
obtained also quantitatively from the reaction of the
phenylethyl isothiocyanate, and discernible nonequivalences of
the two methyl protons between the diastereomers in 3b and 3c
were found in both 1H and 13C NMR spectra. (R)-1-
Naphthylethyl isothiocyanate was also proved to be a useful
chiral derivatizing reagent with primary and secondary amine
(Entry 4~11 in Table 1). The thiourea (R,S)-3d from the (R)-1-
phenylethylamine showed two doublet at 1.403 and 1.657 ppm,
pertaining to the methyl protons a and b, respectively, while in
the (R,S)-3d, the corresponding doublet at 1.288 ppm in a and
1.485 ppm in b are observed in 1H NMR.
References and Notes
1
2
For a review, D. Parker, Chem. Rev., 91, 1441 (1991).
W. H. Pirkle and J. R. Hauske, J. Org. Chem., 42, 1839
(1977).
3
4
A. Nabeya and T. Endo, J. Org. Chem., 53, 3358 (1988).
Typical Procedure: To a thiophosgene (5.7 g, 49 mmol)
solution in a mixture of dichloromethane (50 ml) and
water (30 ml) was added slowly (S)-1-methylbenzylamine
(5 g, 41 mmol) solution in dichloromethane (10 ml) and
then added sodium bicarbonate (4.2 g, 49 mmol). The
reaction mixture was stirred at room temperature for 5h.
The usual work up followed by column chromatography
afforded (S)-1-phenylethyl isothiocyanate (6.0 g, 89%).
Spectroscopic data of (S)-1-phenylethyl isothiocyanate
1
(2a): H NMR (CDCl3, 200 MHz) δ 7.44 – 7.26 (5H, m,
Ar), 4.93 (1H, q, J=6.8 Hz), 1.68 (3H, d, J=6.8 Hz) ); IR
(NaCl): 2089 cm-1 ; MS (m/z): 163 (M+); [α]D25 +7.42 (c =
0.3, acetone); HRMS found 163.0454, calcd for C9H9NS
163.0456. (R)-1-Naphthylethyl isothiocyanate (2b): yield:
Since it is generally known that the Z-configuration of the
Z- and E-forms in a thioamide like an amide is more stable,5
the Z-configuration in a thiourea is expected to be more favor-
able, therefore, two methyl proton’s peaks of (S,S)-3a and the
methyl protons a and b of (R,R)-3d should exist at the same
side of the aromatic group. In this case ordinarily, two methyl
proton’s peaks of (S,S)-3a and the methyl protons a and b of
(R,R)-3d should be observed at more upfield than those of
(S,R)-3a and (R,S)-3d by the effect of diamagnetic anisotropy
of the phenyl group at the same side.6,7 However, two methyl
proton’s peaks of (S,S)-3a and the methyl protons a and b of
(R,R)-3d were observed at more downfield than those of (S,R)-
1
88 %; H NMR (CDCl3, 200 MHz) δ 7.96 – 7.47 (7H, m,
Ar), 5.71 (1H, q, J=6.8 Hz), 1.85 (3H, d, J=6.8 Hz); IR
(KBr): 2127 cm-1; MS (m/z): 213 (M+); [α]D25 –130.9 (c =
0.1, acetone); HRMS, found 213.0611, calcd for C13H11NS
213.0611.
5
6
7
8
W. Walter and H. Huhnerfuss, Tetrahedron Lett., 22, 2147
(1981).
S. D. Munari, G. Marazzi, A. Forgione, A. Longo, and P.
Lombardi, Tetrahedron Lett., 21, 2273 (1980).
S. K. Latypov, J. M. Seco, E. Quinoa, and R. Riguera, J.
Org. Chem., 60, 1538 (1995).
N. A. Nedolya, V. P. Zinoveva, V. I. Komel’Kova, and B.
A. Trofimove, Zh. Org. Khim., 30, 1173 (1994). [CA, 121:
229961d]
1
3a and (R,S)-3d in both H and 13C NMR. Further confirma-
tion of these observation remains to solve in the future.
With 1-phenylethanol, (S)-1-phenylethyl isothiocyanate
(2a) and (R)-1-naphthylethyl isothiocyanate (2b) failed to react
under the basic conditions including triethylamine,8 sodium
hydride,9 and potassium hydroxide, but under Lewis acid cat-
alytic conditions such as dibutyltin diacetate and titanium(IV)
ethoxide,10 the corresponding thiourethanes were obtained in
good yields. However, since these thiourethanes exist in two
tautomeric forms at the usual NMR conditions,11,12 we
observed that these isothiocyanates could not be applicable as
chiral derivatizing reagents to alcohols due to the complexity
of the NMR peaks.
9
M. Oba and K. Nishiyama, Tetrahedron Lett., 50, 10193
(1994).
10 G. Purnima and S. Roy, Indian J. Chem. Sec. B., 33, 291
(1994).
11 C. N. R. Rao and R. Venkataraghavan, Tetrahedron, 18,
531 (1962).
12 W. H Pirkle, K. A. Simmons, and C. W. Boeder, J. Org.
Chem., 44, 4891 (1979).