Preparation of aryl isothiocyanates via protected phenylthiocarbamates and application to the synthesis of caffeic acid (4-isothiocyanato)phenyl ester

Full text of DOI:10.1021/jo000139s

J . Org. Chem. 2000, 65, 6237-6240
6237
Sch em e 1
P r ep a r a tion of Ar yl Isoth iocya n a tes via
P r otected P h en ylth ioca r ba m a tes a n d
Ap p lica tion to th e Syn th esis of Ca ffeic Acid
(4-Isoth iocya n a to)p h en yl Ester
Xuechun Zhang, Young K. Lee,† J ames A. Kelley, and
Terrence R. Burke, J r.*
Laboratory of Medicinal Chemistry, Division of Basic
Sciences, National Cancer Institute, National Institutes of
Health, Bldg 37, Rm 5C06, Bethesda, Maryland 20892-4255
tburke@helix.nih.gov
pyridyl thiocarbonate,23 with product isothiocyanate be-
ing isolated directly from the reaction mixture. A poten-
tial disadvantage of such “direct” approaches is the use
of highly reactive species, which may not be compatible
with functionality found elsewhere in the molecule. One
means of overcoming these difficulties could rely on an
“indirect approach,” whereby latent isothiocyanate func-
tionality could be introduced early in a synthesis and
carried forward through subsequent steps prior to libera-
tion of the isothiocyanate group in a penultimate step.
The advantage of this approach would be that introduc-
tion of the latent isothiocyanate could be achieved either
prior to introduction of contraindicating functionality, or
while such secondary functionality was masked. In this
regard, thiocarbamates could serve as stable, “protected
isothiocyanates” which could be liberated to free isothio-
cyanates when desired. In so doing, side reactions
normally associated with direct isothiocyanate formation
using standard protocols, could be avoided. Accordingly,
we have examined the applicability of this method to the
preparation of isothiocyanates and have taken note of the
recent reports of isocyanates being prepared from car-
bamate intermediates.24 We report herein that this
approach is broadly applicable for the synthesis of a
variety of aryl isothiocyanates and include, as exemplary
of the potential utility of the method, the preparation of
the 4-isothiocyanato derivative of caffeic acid phenethyl
ester (CAPE) as a potential irreversible acylating variant
of this biologically important compound.
Received February 2, 2000
In tr od u ction
Isothiocyanates have been widely used in organic
synthesis, especially in the synthesis of heterocycles,1,2
and they have also been isolated from natural products,
including marine sesquiterpenes.3,4 Additionally, syn-
thetic isothiocyanates have been reported to exhibit
interesting biological effects, among which are antitumor
and antiparasitic activities5,6 and the preparation of
irreversible inhibitors.7 There are currently several meth-
ods of preparing isothiocyanates from amines,8-14 iso-
cyanides,15,16 organic halides,17,18 and olefins.19,20 For
amines, the most widely used methods involve reaction
of the amine with an activated thiocarbonyl species such
as thiophosgene,7,21 thiocarbonyl diimidazole,22 or di-2-
* To whom correspondence should be addressed. Tel: 301-402-1717;
FAX: 301-402-2275.
† Deceased April 29, 1999.
(1) Mukerjee, A. K.; Ashare, R. Chem. Rev. 1991, 91, 1-24.
(2) Sandler, S. R.; Karo, W. Organic Functional Group Preparations,
2nd ed.; Academic Press: New York, 1983; Vol. 12-I.
(3) He, H. Y.; Faulkner, D. J . J . Org. Chem. 1989, 54, 2511-2514.
(4) He, H. Y.; Salva, J .; Catalos, R. F.; Faulkner, D. J . J . Org. Chem.
1992, 57, 3191-3194.
(5) Posner, G. H.; Cho, C. G.; Green, J . V.; Zhang, Y.; Talalay, P. J .
Med. Chem. 1994, 37, 170-176.
(6) Arnold, J . T.; Wilkinson, B. P.; Sharma, S.; Steele, V. E. Cancer
Res. 1995, 55, 537-543.
(7) Burke, T. R., J r.; Bajwa, B. S.; J acobson, A. E.; Rice, K. C.;
Streaty, R. A.; Klee, W. A. J . Med. Chem. 1984, 27, 1570-1574.
(8) Habib, N. S.; Rieker, A. Synth. Commun. 1984, 825-827.
(9) Molina, P.; Alajarin, M.; Arques, A. Synthesis 1982, 596-597.
(10) Hodgkins, J . E.; Reeves, W. P. J . Org. Chem. 1964, 29, 3098-
3099.
Resu lts a n d Discu ssion :
Synthesis of aryl isothiocyanates were performed as
shown in Scheme 1. Intermediate N-aryl thiocarbamates
(3) were prepared by reaction of appropriate arylamines
(1) with phenyl chlorothioformate. Subsequent treatment
of resulting N-aryl thiocarbamates (3) with trichloro-
silane in the presence of triethylamine produced the
desired isothiocyanates (4) in moderate to high yield.
Isothiocyanate products (4) were confirmed both on the
basis of NMR, MS, and combustion analysis (or HRMS)
as well as by conversion to their thiourea adducts (5) by
reacting with phenylethylamine.
(11) Pirkle, W. H.; Hoekstra, M. S. J . Org. Chem. 1974, 39, 3904-
3906.
(12) Kim, J . N.; Song, J . H.; Ryu, E. K. Synth. Commun. 1994, 24,
1101-1105.
(13) Kim, J . N.; J ung, K. S.; Lee, H. J .; Son, J . S. Tetrahedron Lett.
1997, 38, 1597-1598.
(14) Sakai, S.; Fujinami, T.; Aizawa, T. Bull. Chem. Soc. J pn. 1975,
48, 2981-2982.
(15) Tanaka, S.; Uemura, S.; Okano, M. Bull. Chem. Soc. J pn. 1977,
50, 2785-2788.
(16) Fujiwara, S.; Shin-Ike, T. Tetrahedron Lett. 1991, 32, 3503-
3506.
(17) Cho, C. G.; Posner, G. H. Tetrahedron Lett. 1992, 33, 3599-
3602.
(18) Kulka, M. Can. J . Chem. 1981, 59, 1557-1559.
(19) Kitamura, T.; Kobayashi, S.; Taniguchi, H. J . Org. Chem. 1990,
55, 1801-1805.
Steric and electrical properties of ancillary aryl sub-
stituents had little effect on either reaction rates or
product yields, as shown in Table 1.
(20) Toshimitsu, A.; Uemura, S.; Okano, M. J . Org. Chem. 1983,
48, 5246-5251.
(21) Haugwitz, R. D.; Angel, R. G.; J acobs, G. A.; Mauer, B. V.;
Narayanan, V. L.; Cruthers, L. R.; Szanto, J . J . Med. Chem. 1982, 25,
969-974.
(23) Kim, S.; Yi, K. Y. Tetrahedron Lett. 1985, 26, 1661-1664.
(24) Chong, P. Y.; J anicki, S. Z.; Petillo, P. A. J . Org. Chem. 1998,
63, 8515-8521.
(22) Sato, M.; Stammer, C. H. J . Med. Chem. 1976, 19, 336-337.
10.1021/jo000139s This article not subject to U.S. Copyright. Published 2000 by the American Chemical Society
Published on Web 08/19/2000

6238 J . Org. Chem., Vol. 65, No. 19, 2000
Ta ble 1. Yield s of Th ioca r ba m a tes 3, Isoth iocya n a tes 4, a n d Th iou r ea s 5
Notes
Appending isothiocyanate functionality onto biologi-
cally active molecules so as to render them as site-
directed acylating agents, has been of demonstrated value
in several instances,25 including the preparation of both
radiolableled26 and unlabeled irreversible opiate ligands7,27
which have proven useful in the isolation of opiate
receptors.28 Caffeic acid phenethyl ester (CAPE) is an
active constituent of “propolis,” derived from honeybee
hives, which has been shown to exhibit a variety of
biological properties, including differential cytotoxicity
against several tumor cell lines.29,30 Interestingly, CAPE
has also been shown to be a moderately potent inhibitor
of HIV-1 integrase31 with its structure being prototypical
example of an entire family of bisaryl catechol-containing
inhibitors of this enzyme.32 To exemplify the application
of our current methodology to the preparation of poten-
tially relevant biological targets, we successfully utilized
this new method for the synthesis of CAPE 4-isothio-
cyanate analogue 9.
As shown in Scheme 2, reaction of phenyl chloro-
thionoformate (2) with 2-(4-aminophenyl)ethanol (1e)
resulted in selective acylation of the amino functionality
to provide the phenyl thiocarbamate 3e in 75% yield.
Reaction with TBS-protected caffeoyl chloride33 6 gave
CAPE intermediate 7 bearing the isothiocyanate group
in its latent, “protected” form. It proved advantageous
to liberate the free isothiocyanate group prior to depro-
tection of the catechol functionality. Accordingly, treat-
ment of 7 with trichlorosilane in the presence of NEt3
provided the corresponding isothiocyanate 8 in nearly
quantitative yield. Presumably, the trichlorosilane-
induced cleavage reaction involves initial nitrogen sila-
tion followed by elimination akin to that of the Wittig or
Pederson reactions.34 Subsequent removal of catechol
(25) Newton, D. L.; Burke, T. R., J r.; Rice, K. C.; Klee, C. B.
Biochemistry 1983, 22, 5472-5476.
(26) Burke, T. R., J r.; Rice, K. C.; J acobson, A. E.; Simonds, W. F.;
Klee, W. A. J . Label Comput. Radiopharm. 1984, 21, 693-702.
(27) Rice, K. C.; J acobson, A. E.; Burke, T. R., J r.; Bajwa, B. S.;
Streaty, R. A.; Klee, W. A. Science 1983, 220, 314-316.
(28) Simonds, W. F.; Burke, T. R., J r.; Rice, K. C.; J acobson, A. E.;
Klee, W. A. Proc. Natl. Acad. Sci., U.S.A. 1985, 82, 4974-4978.
(29) Grunberger, D.; Banerjee, R.; Eisinger, K.; Oltz, E. M.; Efros,
L.; Caldwell, M.; Estevez, V.; Nakanishi, K. Experentia 1988, 44, 230-
232.
(32) Neamati, N.; Sunder, S.; Pommier, Y. Drug Discovery Today
1997, 2, 487-498.
(33) Lin, Z. W.; Neamati, N.; Zhao, H.; Kiryu, Y.; Turpin, J . A.;
Aberham, C.; Strebel, K.; Kohn, K.; Witvrouw, M.; Pannecouque, C.;
Debyser, Z.; DeClercq, E.; Rice, W. G.; Pommier, Y.; Burke, T. R., J r.
J . Med. Chem. 1999, 42, 1401-1414.
(30) Su, Z. Z.; Grunberger, D.; Fisher, P. B. Mol. Carcinog. 1991, 4,
231-242.
(31) Fesen, M. R.; Kohn, K. W.; Leteurtre, F.; Pommier, Y. Proc.
Natl. Acad. Sci., U. S.A 1993, 90, 2399-2403.

Notes
J . Org. Chem., Vol. 65, No. 19, 2000 6239
(In d a n -5-yla m in o)p h en oxym et h a n e-1-t h ion e (3b ). 1H
NMR (CDCl3) δ 7.61-7.13 (m, 8H), 2.92 (t, J ) 7 Hz, 4H), 2.12-
Sch em e 2
(m, 2H); FABMS m/z: 270 (MH+, 100). Anal. Calcd for C16H15
-
NOS: C, 71.34; H, 5.61; N, 5.20. Found: C, 71.06; H, 5.93; N,
4.97.
(Na p h th -1-yla m in o)p h en oxym eth a n e-1-th ion e (3c). 1H
NMR (CDCl3) δ 8.31-7.85 (m, 3H), 7.72-7.05 (m, 9H); FABMS
m/z 280 (MH+, 100). Anal. Calcd for C17H13NOS: C, 73.09; H,
4.68; N, 5.01; S, 11.48. Found: C, 73.06; H, 4.78; N, 5.02; S,
11.40.
((2,6-D i m e t h o p h e n y l)a m i n o )p h e n o x y m e t h a n e -1-
th ion e (3d ). 1H NMR (CDCl3) δ 7.47-7.03 (m, 8H), 2.42 (s, 3H),
2.38 (s, 3H); FABMS m/z 258 (MH+, 100). Anal. Calcd for C15H15
-
NOS: C, 70.00; H, 5.87; N, 5.44; S, 12.46. Found: C, 70.11; H,
5.89; N, 5.45; S, 12.38.
2-(4-((P h en oxyt h ioxom et h yl)a m in o)p h en yl)et h a n -1-ol
1
(3e). H NMR (CDCl3) δ 7.75-7.08 (m, 9H), 3.88 (t, J ) 6.5 Hz,
2H), 2.88 (t, J ) 6.5 Hz, 2H); CI-MS (NH3) m/z 291 (M + NH4
+
98). Anal. Calcd for C15H15NO2S: C, 65.91; H, 5.53; N, 5.12.
Found: C, 65.70; H, 5.68; N, 5.16.
((3-Ch lor o-4-m et h oxyp h en yl)a m in o)p h en oxym et h a n e-
1-th ion e (3f). 1H NMR (CDCl3) δ 7.47-6.87 (m, 8H), 3.92 (s,
3H); FABMS m/z 294 (MH+, 100). Anal. Calcd for C14H12
-
ClNO2S: C, 57.24; H, 4.11; N, 4.76; Cl, 12.06; S, 10.91. Found:
C, 57.02; H, 4.20; N, 4.83; Cl, 12.22; S, 10.77.
((3-Ch lor o-4-m eth ylp h en yl)a m in o)p h en oxym eth a n e-1-
th ion e (3g). 1H NMR (CDCl3) δ 7.47-7.11 (m, 8H), 2.37 (s, 3H);
FABMS m/z 278 (MH+, 100), 110 (63), 95 (46). FABMS (exact
mass) MH+: Calcd m/z 278.0406; Found: 278.0416. Anal. Calcd
for C14H12ClNOS: C, 60.53; H, 4.35; N. 5.04. Found: C, 60.25;
H, 4.36; N, 5.02.
((4-Cya n op h en yl)a m in o)p h en oxym eth a n e-1-th ion e (3h ).
1H NMR (CDCl3) δ 7.70-7.30 (m, 7H), 7.15 (d, J ) 6.8 Hz, 2H);
FABMS m/z 255 (MH+, 100). Anal. Calcd for C14H10N2OS: C,
66.12; H, 3.96; N, 11.01; S, 12.61. Found: C, 66.19; H, 4.10; N,
10.92; S, 12.53.
((3-Cya n op h en yl)a m in o)p h en oxym eth a n e-1-th ion e (3i).
1H NMR (CDCl3) δ 7.52-7.13 (m, 9H); FABMS m/z 255 (MH+,
100), 161 (5), 110 (34), 95 (24), 77 (12). Anal. Calcd for C14H10N2-
OS: C, 66.12; H, 3.96; N, 11.01. Found: C, 66.26; H, 4.11; N,
10.95.
protection (HF in pyridine) gave the desired CAPE
4-isothiocyanate 9 in 75% yield.
In conclusion, we have developed a new procedure for
the synthesis of aryl isothiocyanates under mild condi-
tions. An advantage of this method is its utilization of
stable thiocarbamate intermediates which may be intro-
duced as a protected isothiocyanates early in a synthetic
sequence with subsequent liberation to free isothiocyan-
ates then undertaken in later steps. In this fashion,
potential side reactions normally associated with direct
formation of isothiocyanates using standard protocols
may be avoided.
Gen er a l P r oced u r e for Con ver sion of P h en yl Th ioca r -
ba m a tes to Isoth iocya n a tes.
4-Ch lor op h en yl Isoth iocya n a te (4a ). To a stirred solution
of 3a (150 mg, 0.57 mmol) in benzene (5 mL) was added
triethylamine (92 mg, 0.91 mmol) and trichlorosilane (123 mg,
0.91 mmol) and the mixture was stirred at room temperature
(1 h) then filtered through Celite 521. The resulting solution
was evaporated under reduced pressure and purified by silica
gel chromatography [EtOAc: hexane (1:8)] to provide 4-chlo-
robenzoisothiocyanate 4a 35 (77 mg, 80%).1H NMR (CDCl3) δ 7.33
(d, J ) 9 Hz, 2H), 7.16 (9 Hz, 2H).
Exp er im en ta l Section
Gen er a l Met h od s. All commercial reagents were used as
supplied. Products solutions were dried over Na2SO4 prior to
evaporation of the solvent under reduced pressure by using a
rotary evaporator. Column chromatograph was performed on
silica gel 60 (40-60 µm, E. Merck Darmstadt). Combustion
analysis were obtained from Atlantic Microlab Inc., Norcross,
GA. Mass spectra were obtained using fast atom bombardment
ionization with the sample in a 3-nitrobenzyl alcohol matrix,
except where noted.
In d a n -5-yl Isoth iocya n a te (4b). 1H NMR (CDCl3) δ 7.25
(d, J ) 8 Hz, 1H), 7.16 (s, 1H), 7.07 (dd, J ) 8 Hz, 2 Hz,1H),
2.97 (t, J ) 7.4 Hz, 4H), 2.17 (m, 2H); FABMS m/z 175 (MH+,
100).
1-Na p h t h a len yl Isot h iocya n a t e (4c). Previously pre-
pared.23 1H NMR (CDCl3) δ 8.14 (d, J ) 8 Hz, 1H), 7.91-7.87
(m, 1H), 7.82-7.76 (m,1H), 7.67-7.54 (m, 2H), 7.46-7.42 (m,
2H); FABMS m/z 185 (M+, 100).
2,6-Dim eth ylp h en yl Isoth iocya n a te (4d ). Previously re-
ported.36 1H NMR (CDCl3) δ 7.08-7.02 (m, 3H), 2.38 (s, 6H);
EI-MS m/z 163 (M+•, 100).
4-(2-Hyd r oxyeth yl)p h en yl Isoth iocya n a te (4e). 1H NMR
(CDCl3) δ 7.23-7.14 (m, 4H), 3.84 (t, J ) 6.5 Hz, 2H), 2.85 (t, J
) 6.5 Hz, 2H); FABMS m/z 179 (M+, 100). Anal. Calcd for C9H9-
NOS: C, 60.31; H, 5.06; N, 7.81; S, 17.89. Found: C, 60.48; H,
5.22; N, 7.67; S, 17.61.
Gen er a l P r oced u r e for Syn th esis of P h en yl Th ioca r -
ba m a tes fr om Ar yla m in es.
((4-Ch lor oph en yl)am in o)ph en oxym eth an e-1-th ion e (3a).
A mixture of 4-chloroaniline (1a ) (255 mg, 2 mmol) and phenyl
chlorothionoformate (173 mg, 1 mmol) in THF (5 mL) was stirred
at room temperature (30 min), the mixture was filtered through
Celite 521 to remove precipitate, and the resulting solution was
evaporated under reduced pressure. Residue was chromato-
graphed [EtOAc:hexane (1:5)] to afford product thiocarbamate
3a (210 mg, 80%). 1H NMR (CDCl3) δ 7.55-7.34 (m, 7H), 7.24-
7.19 (m, 2H); FABMS m/z 264 (MH+, 100). Anal. Calcd for
3-Ch lor o-4-m eth oxyp h en yl Isoth iocya n a te (4f). Previ-
ously reported.37 1H NMR (CDCl3) δ 7.29-6.85 (m, 3H), 3.91 (s,
3H); FABMS m/z 199 (M+, 100). Anal. Calcd for C8H6ClNOS:
C
13H10ClNOS: C, 59.20; H, 3.82: N, 5.31; Cl, 13.44; s, 12.15.
Found: C, 58.98; H, 4.00; N, 5.30; Cl, 13.68; S, 12.04.
(35) Commercially available.
(36) Walter, W.; Wohlers, K. Liebigs Ann. Chem. 1971, 752, 115-
(34) Pirkle, W. H.; Hauske, J . R. J . Org. Chem. 1977, 42, 2781-
2782.
135.
(37) Brown, D. W.; Dyson, G. M. J . Chem. Soc. 1931, 3285-3308.

6240 J . Org. Chem., Vol. 65, No. 19, 2000
Notes
C, 48.12; H, 3.03; N, 7.01; Cl, 17.75; S, 16.06. Found: C, 48.17;
H, 3.18; N, 6.97; Cl, 17.86; S, 15.98.
((3-Ch lor o-4-m eth ylp h en yl)a m in o)((2-p h en yleth yl)a m i-
1
n o)m eth a n e-1-th ion e (5g). H NMR (CDCl3) δ 7.33-6.78 (m,
3-Ch lor o-4-m eth ylp h en yl Isoth iocya n a te (4g). Previously
reported.37 1H NMR (CDCl3) δ 7.24-7.18 (m, 2H), 7.05-7.01 (dd,
J ) 8 Hz, 2 Hz, 1H), 2.37 (s, 3H); EI-MS m/z 183 (M+•, 100).
4-Cya n op h en yl Isoth iocya n a te (4h ). 1H NMR (CDCl3) δ
7.67 (d, J ) 8 Hz, 2H), 7.31 (d, J ) 8 Hz, 2H); FABMS m/z 161
(MH+, 100). Anal. Calcd for C8H4N2S: C, 59.98, H, 2.51; N, 17.48;
S, 20.01. Found: C, 59.79; H, 2.60; N, 17.27; S, 19.73.
3-Cya n op h en yl Isot h iocya n a t e (4i). 1H NMR (CDCl3) δ
7.59-7.43 (m, 4H); EI-MS m/z 160 (M+, 100). Anal. Calcd for
C8H4N2S: C, 59.98; H, 2.51; N, 17.48; S, 20.01. Found: C, 60.09;
H, 2.48; N, 17.38; S, 19.97.
8H), 3.89 (t, J ) 6.8 Hz, 2H), 2.93 (t, J ) 6.8 Hz, 2H), 2.35 (s,
3H); FABMS m/z: 305 (MH+, 100). Anal. Calcd for C16H17
-
ClN2S: C, 63.04; H, 5.61; N, 9.18; Cl;, 11.62; S, 10.52. Found:
C, 63.20; H, 5.76; N, 9.05; Cl, 11.60;, S, 10.37.
((4-Cyan oph en yl)am in o)((2-ph en yleth yl)am in o)m eth an e-
1-th ion e (5h ). 1H NMR (CDCl3) δ 7.54 (d, J ) 8 Hz, 2H), 7.34-
7.19 (m, 5H), 7.04 (d, J ) 8 Hz, 2H), 3.94 (t, J ) 6.5 Hz, 2H),
2.99 (t, J ) 6.5 Hz, 2H); FABMS m/z 282 (MH+, 98). Anal. Calcd
for C16H15N3S: C, 68.30; H, 5.37; N, 14.93; S, 11.39. Found: C,
68.48; H, 5.53; N, 14.69; S, 11.26.
((3-Cyan oph en yl)am in o)((2-ph en yleth yl)am in o)m eth an e-
1-th ion e (5i). 1H NMR (CDCl3) δ 7.45-7.15 (m, 9H), 3.86 (m,
2H), 2.94 (t, J ) 7 Hz, 2H); FABMS m/z 282 (MH+, 100). Anal.
Calcd for C16H15N3S: C, 68.30; H, 5.37; N, 14.93. Found: C,
68.42; H, 5.63; N, 14.54.
Gen er a l P r oced u r e for th e Rea ction of Isoth iocya n a tes
w ith P h en yleth yla m in e.
((4-Ch lor oph en yl)am in o)((2-ph en yleth yl)am in o)m eth an e-
1-th ion e (5a ). To a solution of 4-chlorophenyl isothiocyanate
(4a ) (21 mg, 0.124 mmol) in THF (5 mL) was added phenylethy-
lamine (16.5 mg, 0.136 mmol), and the mixture was stirred at
room temperature (1 h). Solvent was evaporated under reduced
pressure, and the residue was purified by silica gel flash
chromatography [EtOAc:hexanes (1:2]) to provide product 5a (31
mg, 86%).1H NMR (CDCl3) δ 7.28-7.13 (m, 7H), 6.91 (d, J ) 8
Hz, 2H), 3.89 (t, J ) 6.6 Hz, 2H), 2.93 (t, J ) 6.6 Hz, 2H); FABMS
m/z 291 (MH+, 100). Anal. Calcd for C15H15ClN2S: C, 61.95; H,
5.20; N, 9.63; S, 11.02. Found: C, 62.06; H, 5.32; N, 9.45; S, 10.92
(In d a n -5-yla m in o)((2-p h e n yle t h yl)a m in o)m e t h a n e -1-
th ion e (5b). 1H NMR (CDCl3) δ 7.26-6.74 (m, 8H), 3.88 (m,
2H), 2.87 (m, 6H), 2.08 (m, 2H); FABMS m/z 297 (MH+, 100),
263 (8), 176 (5), 105 (57). Anal. Calcd for C18H20N2S‚1/5H2O: C,
72.06; H, 6.85; N, 9.34; S, 10.69. Found: C, 72.39; H, 6.97; N,
9.13; S, 10.42. FABMS (exact mass) MH+: Calcd for C18H21N2S;
297.1425. Found 297.1408.
(Na p h t h -1-yla m in o)((2-p h en ylet h yl)a m in o)m et h a n e-1-
th ion e (5c). 1H NMR (CDCl3) δ 8.10-7.82 (m, 3H), 7.58-7.54
(m, 2H), 7.43-7.37 (t, J ) 8 Hz, 1H), 7.26-7.21 (m, 1H), 7.10-
7.08 (m, 3H), 6.92-6.90 (m, 2H), 3.82 (t, J ) 6.6 Hz, 2H), 2.78
(t, J ) 6.6 Hz, 2H); FABMS m/z 307 (MH+, 100). Anal. Calcd
for C19H18N2S: C, 74.47; H, 5.91; N, 9.14. Found: C, 73.98; H,
6.06; N, 8.90. HR-FABMS Calcd for C18H21N2S; 307.1269.
Found 307.1237.
((2,6-Dim et h ylp h en yl)a m in o)((2-p h en ylet h yl)a m in o)-
m eth a n e-1-th ion e (5d ). 1H NMR (CDCl3) δ 7.71-7.08 (m, 8H),
3.87 (m, 2H), 2.90 (t, J ) 7 Hz, 2H), 2.21 (s, 6H); FABMS m/z
285 (MH+, 100). Anal. Calcd for C17H20N2S: C, 71.79; H, 7.08;
N, 9.84; S, 11.27. Found: C, 71.85; H, 7.12; N, 9.68; S, 11.11
2-(4-((((2-P h e n yle t h yl)a m in o)t h ioxom e t h yl)a m in o)-
p h en yl)eth a n -1-ol (5e). 1H NMR (CDCl3) δ 7.51-7.12 (m, 7H),
7.0 (d, J ) 8 Hz, 2H), 3.93 (m, 4H), 3.01-2.89 (m, 4H); FABMS
m/z 301 (MH+, 49). Anal. Calcd for C17H20N2OS: C, 67.97; H,
6.71; N, 9.32; S, 10.67. Found: C, 67.75; H, 6.69; N, 9.15; S,
10.43.
Silyl-P r otected CAP E Th ioca r ba m a te (7). To a stirred
solution of freshly prepared TBS-protected caffeoyl chloride (6)
(0.807 mmol) in toluene (8 mL) were added 3e (221 mg, 0.807
mmol) and pyridine (1.2 mL), and the mixture was stirred at
room temperature (overnight) and then filtered through Celite
521 and solvent removed under reduced pressure. The residue
was chromatographed [EtOAc:hexane (1:4)] to afford 7 (256 mg,
48%). 1H NMR (CDCl3) δ 7.56 (d, J ) 16 Hz, 1H), 7.46-6.80 (m,
12H), 6.23 (d, J ) 16 Hz, 1H), 4.41 (t, J ) 7.3 Hz, 2H), 3.02 (t,
J ) 7.3 Hz, 2H), 0.99 (s, 18H), 0.22 (s,12H); CI-MS (NH3) m/z
665 (MH+, 100). Anal. Calcd for C36H49NO5SSi2: C, 65.11; H,
7.43; N, 2.10. Found: C, 65.05; H, 7.45; N, 2.08.
Silyl-P r otected CAP E 4-Isoth iocya n a te (8). To a stirred
solution of silyl-protected CAPE thiocarbamate 7 (80 mg, 0.12
mmol) in benzene (5 mL) was added triethylamine (19 mg, 0.19
mmol) followed by trichlorosilane (26 mg, 0.19 mmol), and the
mixture was stirred at room temperature (1 h) and then filtered
through Celite 521. The resulting solution was evaporated under
reduced pressure and purified by silica gel chromatography
[EtOAc:hexane (1:10)] to provide 8 (69 mg, 98%). 1H NMR
(CDCl3) δ 7.57 (d, J ) 16 Hz, 1H), 7.29-7.19 (m, 4H), 7.05-
7.02 (m, 2H), 6.85 (d, J ) 8.8 Hz, 1H), 6.23 (d, J ) 16 Hz, 1H),
4.42 (t, J ) 6.8 Hz, 2H), 3.04 (t, J ) 6.8 Hz, 2H), 1.02 (s, 18H),
0.25 (s, 12 H). FABMS m/z 570 (MH+, 2). Anal. Calcd for C30H43
-
NO4SSi: C, 63.22; H, 7.60; N, 2.45. Found: C, 63.13; H, 7.63;
N, 2.43.
CAP E 4-Isoth iocya n a te (9). To a stirred solution of silyl-
protected CAPE 4-isothiocyanate 8 (72 mg, 0.126 mmol) in THF
(3 mL) was added pyridinium hydrogen fluoride (0.1 mL), and
the mixture was stirred at room temperature (4h) then filtered
through Celite 521. The resulting solution was evaporated under
reduced pressure and purified by silica gel chromatography
[EtOAc: Hexane (1:2)] to give the desired CAPE 4-isothiocyanate
9 (34 mg, 75%). 1H NMR (CD3OD) δ 7.50 (d, J ) 16 Hz, 1H),
7.34-7.20 (m, 4H), 7.01-6.90 (m, 2H), 6.77 (d, J ) 7 Hz, 1H),
6.21 (d, J ) 16 Hz, 1H), 4.36 (t, J ) 6.5 Hz, 2H), 3.01 (t, J ) 6.5
((3-Ch lor o-4-m et h oxyp h en yl)a m in o)((2-p h en ylet h yl)-
1
a m in o)m eth a n e-1-th ion e (5f). H NMR (CDCl3) δ 7.28-6.85
(m, 8H), 3.90 (m, 5H), 2.91 (m, 2H); FABMS m/z 321 (MH+, 100).
Anal. Calcd for C16H17ClN2OS: C, 59.90; H, 5.33; N, 8.73; Cl,
11.04. Found: C, 59.62; H, 5.55; N, 8.23; Cl, 10.92. FABMS
(exact mass) MH+: Calcd for C16H17ClN2OS; 321.0828. Found
321.0776.
Hz, 2H); FABMS m/z 342 (MH+, 100). Anal. Calcd for C18H15
-
NO4S: C, 63.33; H, 4.42; N, 4.10; S, 9.39. Found: C, 63.50; H,
4.56; N, 4.16; S, 9.28.
J O000139S