A general and efficient route to thionoesters via thionoacyl nitrobenzotriazoles

Full text of DOI:10.1021/jo981985u

J . Org. Chem. 1999, 64, 1065-1070
1065
Alternatively, sulfo-hydrolysis of dialkoxycarbonium ions12
has been employed for the synthesis of thionoesters, a
procedure involving treatment of the dialkoxycarbonium
tetrafluoroborate with anhydrous sodium sulfide or so-
dium hydrosulfide in acetonitrile. Mixtures of products
are often obtained which require extensive purification
and ultimately are formed in low yields.13 Alcoholysis of
thioacyl halides14-16 and addition of alcohols to thio-
ketenes17,18 are yet other routes for thionoester formation.
Thioacyl halides are generally very unstable,19 and
aliphatic thioacyl chlorides decompose rapidly even below
-70 °C; only a few thiobenzoyl chlorides continue to find
use.20 Thioketenes are also unstable and can only be
isolated at very low temperatures since they tend to
dimerize readily. An important development has been the
introduction of the phosphetane disulfide reagent21 as a
direct thionating agent for converting the appropriate
esters to thionoesters.22 This procedure, while superior
to previous methods, still suffers from the requirements
of drastic reaction conditions (refluxing xylene or toluene)
and long reaction times that limit its utility with com-
pounds containing sensitive functional groups.23 This
method also provides poor regioselectivity with com-
pounds containing additional ester functionality. Fur-
thermore, esters with conjugated electron-withdrawing
groups3a failed to give reaction with Lawesson’s reagent.21
Thus, the importance of thionoesters for synthetic ap-
plications and the need to overcome the limitations
associated with previous methods for their formation has
led us to develop a new and general method for thiono-
ester formation that proceeds under mild conditions and
in short reaction times.
A Gen er a l a n d Efficien t Rou te to
Th ion oester s via Th ion oa cyl
Nitr oben zotr ia zoles
M. Ashraf Shalaby and Henry Rapoport*
Department of Chemistry, University of California
Berkeley, California 94720
Received October 1, 1998
In tr od u ction
Thionoesters (thiocarboxylic-O-esters), a class of sulfur-
containing compounds of general structure R-C(S)-OR′,
have been a focus of interest due to their altered
reactivity relative to their oxygen analogues.1,2 For
example, thionoesters can be readily desulfurized with
Raney nickel to form the corresponding ethers.3 This
pathway to convert esters to ethers avoids many of the
steric and functional limitations of other methods4 for
ether formation and appears to be general for this
conversion. Thionoesters, unlike their oxoester counter-
parts of lesser electrophilicity of the carbonyl system,
react readily with DAST under mild conditions to provide
cleanly and in good yield the corresponding R,R-difluo-
roethers,5 compounds of current interest. Thionoesters
are also considered as suitable starting materials for the
synthesis of 1,3,4-oxadiazoles6 of considerable activity7,8
as plant cell growth factors, herbicides, and fungicides.
Recently, the influence of thionoesters as effective chain
transfer agents in the polymerization of styrene, methyl
acrylate, and related olefins was reported.9 This activity
was close to the ideal for obtaining narrow molecular-
weight distributions in batch polymerizations. Also, of
potential utility is the anticipated increased acidity of the
R-hydrogens.
Resu lts a n d Discu ssion
In the course of studies on thiopeptide synthesis, we
have demonstrated that R-amino thionoacid derivatives
of nitrobenzotriazole are effective thioacylating agents for
site-specific incorporation of thioamide linkages into a
growing peptide.24 Stimulated by success with these
reagents, we considered applying nitrobenzotriazole as
Several methods exist for the preparation of thiono-
esters. One is the sulfo-hydrolysis of imino esters10 with
hydrogen sulfide in pyridine.11 Thioamides are often a
major side product, and the method is limited in scope.
(1) Nicolaou, K. C.; Sato, M.; Theodorakis, E. A.; Miller, N. D. J .
Chem. Soc., Chem. Commun. 1995, 1583.
(2) Barrett, A. G. M.; Lee, A. C. J . Org. Chem. 1992, 57, 2818.
(3) Baxter, S. L.; Bradshaw, J . S. J . Org. Chem. 1981, 46, 831. (b)
Bradshaw, J . S.; J ones, B. A.; Gebhard, J . S. J . Org. Chem. 1983, 48,
1127. (c) J ones, B. A., Bradshaw, J . S.; Brown, P. R.; Christensen, J .
J .; Izatt, R. M. J . Org. Chem. 1983, 48, 2635.
(4) (a) Baldwin, S. W.; Haut, S. A. J . Org. Chem. 1975, 40, 3885. (b)
Tsurugi, J .; Nakao, R.; Fukumoto, T. J . Am. Chem. Soc. 1969, 91, 4587.
(c) Nagata, Y.; Dohmaru, T.; Tsurugi. J . J . Org. Chem. 1973, 38, 795.
(d) Pettit, G. R.; Piatak, D. M. J . Org. Chem. 1962, 27, 2127. (e) Maione,
A. M.; Torrini, I. Chem. Ind. 1975, 839. (f) Kraus, G. A.; Frazier, K.
A.; Roth, B. D.; Taschner, M. J .; Neuenschwander, K. J . Org. Chem.
1981, 46, 2417.
(12) (a) Hoffmann, R.; Hartke, K. Chem. Ber. 1980, 113, 919. (b)
Kaloustian, M. K.; Nader, R. B. J . Org. Chem. 1981, 46, 5050. (c)
Kantlehner, W.; Haug, E.; Farkas, M. Liebigs Ann. Chem. 1982, 1582.
(d) Nader, R. B.; Kaloustian, M. K. Tetrahedron Lett. 1979, 20, 1477.
(13) Kaloustian, M. K.; Khouri, F. Tetrahedron Lett. 1981, 22, 413.
(14) Hedgley, E. J . Brit. Pat. 1,589,128; 7 May 1981.
(15) Adiwidjaja, G.; Gu¨nther, H.; Voss, J . Angew. Chem., Int. Ed.
Engl. 1980, 19, 563.
(16) Knunyants, I. L.; Lantseva, L. T.; Lure, E. P.; Zeifman, Y. V.
Izv. Akad. Nauk. SSSR, Ser. Khim. 1977, 231.
(17) Bu¨hl, H.; Seitz, B.; Meier, H. Tetrahedron 1977, 33, 449.
(18) Seybold, G.; Heibl, C. Chem. Ber. 1977, 110, 1225.
(19) Scheithauer, S.; Mayer, R. Thio- and Dithiocarboxylic Acids and
Their Derivatives in Topics in Sulfur Chemistry; Senning, A., Ed;
Thieme: Stuttgart, 1979; Vol. 4.
(5) Bunnelle, W. H.; Mckinnis, B. R.; Narayanan, B. A. J . Org. Chem.
1990, 55, 768, and references therein.
(6) Reynaud, P.; El Hamad, Y.; Davrinche, C.; Nguyen-Tri-Xuong,
E.; Tran, G.; Rinjard, P. J . Heterocycl. Chem. 1992, 29, 991.
(7) Kraemer, I.; Schunack, W. Arch. Pharm. (Weinheim, Ger.) 1986,
319, 1091.
(8) Bhattacharya, B. K.; Singh, H. H.; Yadav, L. D. S.; Hoornaert,
G. Acta Chim. Acad. Sci. Hung. 1982, 110, 133.
(20) Lythgoe, B.; Waterhouse, I.; Tetrahedron Lett. 1977, 18, 4223.
(21) (a) Pederson, B. S.; Scheibye, S.; Nilsson, N. H.; Lawesson, S.-
O. Bull. Soc. Chim. Belg. 1978, 87, 223. (b) Cava, M. P.; Levinson, M.
I. Tetrahedron 1985, 41, 5061 and references therein.
(22) Pederson, B. S.; Scheibye, S.; Clausen, K.; Lawesson, S.-O. Bull.
Soc. Chim. Belg. 1978, 87, 293.
(9) Meijs, G. F.; Rizzardo, E.; Le, T. P. T.; Chen, Y. Makromol. Chem.
1992, 193, 369.
(10) Nielson, D. G. In The Chemistry of Amidines and Imidates;
Patai, S., Ed.; Wiley: New York, 1975; pp 385-489.
(11) Vinkler, P.; Thimm, K.; Voss, J . Liebigs Ann. Chem. 1976, 2083.
(b) Voss, J .; Schmueser, W.; Schlapkohl, K. J . Chem. Res. S (Synopses)
1977, 144. (c) Hartke, K.; Hoffmann, R. Liebigs Ann. Chem. 1980, 483.
(23) Sato, M.; Ban, H.; Uehara, F.; Kaneko, C. Chem. Commun.
1996, 775. (b) Barrett, A. G. M.; Lee, A. C. J . Org. Chem. 1992, 57,
2818. By substituting the Belleau reagent, they have successfully
lowered the temperature to 70-80 °C for some sugar lactones and
sugar esters.
(24) Shalaby, M. A.; Grote, C. W.; Rapoport, H. J . Org. Chem. 1996,
61, 9045.
10.1021/jo981985u CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/09/1999

1066 J . Org. Chem., Vol. 64, No. 3, 1999
Sch em e 1. Gen er a l Rou te to Ben zotr ia zole Th ioa cyla tin g Agen ts a n d Th ion oester s
Notes
a leaving group in thionoester synthesis. The procedure
for the preparation of benzotriazole thioacylating agents
(4a -h ) is illustrated in Scheme 1. Coupling was effected
between 4-nitro-1,2-phenylenediamine and carboxylic
acids 1 in THF at 0 °C using mixed carbonic anhydride
methodology for amide synthesis. After isolation, this
process gave the crystalline anilides 2 in 86-88% yield.
Direct thionation of 2 was achieved with a mixture of
P4S10 and anhydrous Na2CO3 in THF. The reaction
proceeded smoothly for a total of 2 h at 0 °C and room
temperature to afford thioanilides 3 in good yield (78-
82%) with the exception of 2j,k ,l.
Surprisingly, thionation of the cinnamoyl derivative 2j
with P4S10 did not afford the corresponding thioamide but
rather a single cyclization product. Four possible struc-
tures were considered, resulting from addition to the
double bond by (a) the sulfur of the thioamide to give a
four-membered ring, (b) the acylated nitrogen to give a
â-lactam, (c) the ortho amino group to the R-position to
give a six-membered ring, or (d) the ortho amino group
to the â-position to give a 1,5-benzodiazepine. Since
analysis of the NMR spectra was not definitive, an X-ray
crystal structure determination was made, and from it
the structure was established as 8-nitro-5-phenyl-2-
thiono-1,5-benzodiazepine (5j), shown in Figure 1. The
propensity for this Michael addition with the weakly
nucleophilic amine para to the nitro group was surprising
and warranted further investigation. Therefore, three
allylic derivatives were prepared to determine whether
the phenyl group on the cinnamoyl derivative 2j was
influencing the cyclization. The first derivative was the
methyl-substituted acryloyl derivative 2k which readily
underwent cyclization in a manner similar to give the
benzodiazepine 5k in 49% yield. The second was the
nonsubstituted acryloyl derivative 2l which upon thion-
ation with P4S10 did not yield the thioamide but rather
polymerization products which were not further charac-
terized. While cyclization occurred when the â-substitu-
ent was methyl or phenyl, none was observed with the
fumaroyl derivative 2i containing a â-carboxy methyl
ester substituent; the normal thioamide was formed.
Intramolecular cyclization of thioamides 3 using ni-
trous acid generated in situ with NaNO2 in AcOH gave
benzotriazoles 4 in 72-76% yield, with the exception of
F igu r e 1. Structure of 8-nitro-5-phenyl-2-thiono-1,5-benzo-
diazepine (5j) as determined by X-ray crystallography.
3i which failed to yield the corresponding benzotriazole
derivative. These compounds are orange-red solids, stable
to storage, and can be used without further purification.
Our initial attempts at thionoester formation were
made by coupling thioacylating agent 4d with benzyl
alcohol in THF at ambient and elevated temperatures
as well as by catalysis of the reaction with the addition
of base such as Bu3P, Et3N, or DMAP. These attempts
resulted in either no reaction or disappointingly low
yields (24-29%) which required tedious purification by
chromatography. After much experimentation, including
thionoimidazolide formation and methylation to the
imidazolium species25 and use of the alkoxide,26 general
and mild procedures giving high yields were developed.
These involved use of imidazole, pyridine (neat), and
DBU in either CH2Cl2, THF, or DMF. Times varied from
1 to 48 h, and temperatures were generally ambient, as
summarized in Table 1. These relatively mild conditions
should be compatible with numerous functional groups.
Exemplary alcohols, considered reasonably representa-
tive, included primary (benzyl) and secondary (cyclohexyl,
(25) Saha, A. K.; Schultz, P.; Rapoport, H. J . Am. Chem. Soc. 1989,
111, 4856.
(26) Staab, H. A.; Mannschreck, A. Chem. Ber. 1962, 95, 1284.

Notes
J . Org. Chem., Vol. 64, No. 3, 1999 1067
Ta ble 1. Rea ction P a r a m eter s for F or m a tion of Th ion oester s 6-19 fr om Alcoh ols R4OH a n d Th ion oa cylben ztr ia zoles 4
thionoacyl
benztriazole 4, R1
alcohol
R4OH
thionoester
R4O(CdS)R1
time
(h)/temp (°C)
entry
solvent
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
CH3
CH3CH2
C(CH3)3
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
cyclopropyl
succinoyl â-methyl ester
O-acetylmaloyl â-methylester
O-acetylmandeloyl
Bn
Bn
Bn
Bn
6
7
8
CH2Cl2/Im
CH2Cl2/Im
pyridine
THF/DBU
THF/DBU
THF/DBU
DMF/DBU
DMF/DBU
pyridine
THF/DBU
THF/DBU
THF/Im
THF/Im
THF/DBU
48/25
48/25
2/50
81
83
79
89
74
69
74
66
79
67
83
63
53
64
9
1/0-25
2/0-25
3/0-25
2/0-25
2/0-25
24/25
1/0-25
1/0-25
48/25
cyclohexyl
menthyl
N-BOC serinyl methyl ester
N-BOC threoninyl methyl ester
6-â-methhl glucosidyl
3-pyridyl
Bn
Bn
Bn
Bn
10
11
12
13
14
15
16
17
18
19
48/25
2/0
menthyl) alcohols and a number containing other func-
tionalities.
whose structure was verified by comparison with an
authentic sample prepared from maleic anhydride.32
Of major concern was the question of the enantiomeric
integrity of the thionoester components. This was inves-
tigated with the acetyl mandelic acid derivartive 4h ,
considered potentially highly susceptible to epimeriza-
tion. The enantiomeric composition of the thionoester 19
was determined by chiral HPLC using racemic 19 as
control, and the enantomeric ratio (er) was found to be
92/8.
In summary, we provide a general and efficient method
for thionoester synthesis. The simplicity of reagent
preparation and product isolation, high yields, mild
conditions, and enhanced reactivity of the thioacylating
agents should make it widely applicable.
A number of entries in Table 1, as they potentially
extrapolate to ether formation, warrant further comment.
Thus, entry 11 demonstrates the ready formation of a
cyclopropylcarboxylic acid thionester. Coupled with the
known conversion of thionoesters to ethers,3 this offers
an attractive method for preparing cyclopropylmethyl
ethers.27,28 Benzylation of hydroxy amino acids, namely
serine and threonine (entries 7 and 8), is another
potential use of thionoester methodology. Direct benzy-
lation procedures using Williamson ether synthesis lead
to racemization, and the alternative present preparation
of these compounds is quite complex.29 Formation of the
thionoesters 12 and 13 proceeds with no epimerization,
as would also be anticipated for the further conversion
to ethers.3 Two other examples of interest for further
ether formation are the thionoester of 3-pyridol (entry
10) and that of â-methyl glucoside, avoiding any protec-
tion protocol.30
A further demonstration of the versatility of the
present method is its application to mono-thionation of
methyl succinate (entry 12) and the resulting regiospeci-
ficity which is not achievable by literature methodology.
It was interesting to observe that thionation of the amide
derived from methyl succinate 2f smoothly afforded the
corresponding thioamide 3f in 62% yield, while the
analogous amide derived from aspartic acid methyl ester
gave an acylthioimidate derivative as the major prod-
uct.24 To clarify the influence of the NHBOC substituent
on cyclization, other substituted succinates were exam-
ined. Thus the acetoxysuccinic acid â-methyl esters were
prepared.31 Unlike the aspartic acid analogue, R-acetoxy-
succinic acid â-methyl ester derivative 2g did not undergo
cyclization upon treatment with P4S10, thus providing an
example of regiospecific monothionation of a triester
(entry 13). Interestingly, the â-acetoxy derivative did not
give the corresponding amide upon reaction with 4-nitro-
1,2-phenylenediamine but rather underwent elimination
to afford the R,â-unsaturated methyl ester derivative 2i
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. 1H and 13C NMR
spectra were recorded in DMSO unless otherwise stated at 400
and 100.6 MHz, and chemical shifts are reported relative to
either a tetramethylsilane internal standard or the solvent
signals. Chemical shifts (δ) are reported in ppm, and coupling
constants are in hertz. TLC was carried out using precoated
sheets (Merck silica gel 60-F250, layer thickness 0.2 mm) which,
after development, were visualized by UV light (254 nm) and/
or by spraying with 0.3% solution of ninhydrin in tert-BuOH/
AcOH (93/3, v/v) or silver nitrate/ammonium hydroxide-sodium
chloride solutions and heating. Merck silica gel 60 (70-230
mesh) was used for column chromatography. Epimerization
studies were conducted by analytical HPLC on an 0.46 × 25 cm
CHIRALCEL OD column, eluting with hexane/2-propanol (99/
1) and utilizing detection at 254 nm. All reactions were con-
ducted under a nitrogen or argon atmosphere. Solvents were
distilled prior to use (THF over Na/benzophenone; N-methyl-
morpholine and triethylamine over CaH2) and dried over 4 Å
molecular sieves. Organic extracts were dried over anhydrous
MgSO4, filtered, and evaporated under reduced pressure at 30-
40 °C unless otherwise indicated. Microanalysis were performed
by College of Chemistry Micro Analytical Laboratory, University
of California at Berkeley.
Gen er al P r ocedu r e for th e P r epar ation of Acyl 2-Am in o-
5-n itr oa n ilin es 2a -l. Cou p lin g of Ca r boxylic Acid s (1a -
l) w ith 4-Nitr o-1,2-p h en ylen ed ia m in e. N-Methylmorpholine
(2.2 mL, 20 mmol) was added to a solution of carboxylic acid
(1a -l) in THF (100 mL) at -15 °C, followed by dropwise addition
of isobutyl chloroformate (1.3 mL, 10 mmol). The mixture was
stirred for 10 min, and then 4-nitro-1,2-phenylenediamine (1.53
g, 10 mmol) was added and the resulting slurry stirred at -15
°C for 2 h and at room temperature overnight. The mixture was
filtered and the filtrate evaporated to dryness. The residue,
dissolved in EtOAc (250 mL), was washed successively with 1
M NaH2PO4, brine, 5% NaHCO3, and brine and then dried and
(27) (a)Orr, G. F.; Musso, D. L. Synth. Commun. 1996, 26, 179. (b)
Lansbury, P. T.; Pattison, V. A. J . Am. Chem. Soc. 1962, 84, 4295.
(28) Forne Felip, E.; Foquet Ambros, R. Span. Pat. 488,558; 16 Dec
1980.
(29) Nozulak, J .; Scho¨llkopf, U. Synthesis 1982, 866.
(30) (a) Tsuda, Y.; Haque, M. E.; Yoshimoto, K. Chem. Pharm. Bull.
1983, 31, 1612. (b) Weinges, K.; Haremsa, S.; Maurer, W. Carbohydr.
Res. 1987, 164, 453. (c) Ogawa, T.; Matsui, M. Carbohydr. Res. 1977,
56, C1.
(31) Pan, B.-C.; Zhang, H.; Pan, C.-Y., Shu, Y.; Wang, Z.-F.; Gao,
Y.-S. Hua Hsueh Hsueh Pao 1980, 38, 502.
(32) Spatz, S. M.; Stone, H. J . Org. Chem. 1958, 23, 1559.

1068 J . Org. Chem., Vol. 64, No. 3, 1999
Notes
evaporated to dryness. Crystallization of the residue from EtOAc/
hexane afforded pure 2a -l as yellow solids in 86-88% yield.
N-Acetyl-2-a m in o-5-n itr oa n ilin e (2a ):33 mp 202 °C; 1H
NMR δ 9.16 (s, 1H), 8.2 (d, 1H, J ) 2.56), 7.8 (dd, 1H, J ) 2.6,
9), 6.7 (d, 1H, J ) 9), 6.4 (s, 2H), 2.03 (s, 3H); 13C NMR δ 169.4,
149.4, 135.9, 123.1, 122.1, 121.7, 114, 23.9. Anal. Calcd for
C8H9N3O3: C, 49.2; H, 4.7; N, 21.5. Found: C, 49.1; H, 4.6; N,
21.4.
1H, J ) 8.3), 6.8 (m, 1H), 6.4 (s, 2H), 6.2 (d, 1H, J ) 15.27) 1.8
(d, 3H, J ) 1.4); 13C NMR δ 175.5, 169.2, 153.7, 145.4, 140.8,
130.8, 127.7, 126.9, 125.9, 118.9. Anal. Calcd for C10H11N3O3:
C, 54.3; H, 5.0; N, 19.0. Found: C, 54.2; H, 4.5; N, 19.0.
N-Acr yloyl-2-a m in o-5-n itr oa n ilin e (2l): mp 183 °C; 1H
NMR δ 9.3 (s, 1H), 8.3 (d, 1H, J ) 2.4), 7.8 (dd, 1H, J ) 9.8,
2.8), 6.75 (d, 1H, J ) 9), 6.5 (s, 2H), 6.4 (m, 1H), 6.2 (dd, 1H, J
) 17, 2), 5.7 (dd, 1H, J ) 9.8, 1.8); 13C NMR δ 169.0, 153.9, 140.8,
136.7, 132.3, 128.0, 126.5, 126.2, 119.0. Anal. Calcd for
C9H9N3O3: C, 52.2; H, 4.4; N, 20.3. Found: C, 52.0; H, 4.5; N,
20.4.
Gen er a l P r oced u r e for th e P r ep a r a tion of Th ioa n ilid es
(3a -i). Under a flow of argon, purified P4S10 (1.1 g, 2.47 mmol)
was mixed with Na2CO3 (0.27 g, 2.5 mmol) in THF (100 mL).
The mixture was stirred for 1 h at 25 °C and then cooled to 0
°C. To this clear solution was added anilides 2a -i (5 mmol, 200
mol %), and the reaction was stirred at this temperature for 30
min and then at room temperature for 2.5 h. The solution was
filtered through Celite, and the filtrate was evaporated to
dryness. The residue was dissolved in EtOAc/heptane (2/1, v/v,
75 mL) and washed with 5% NaHCO3 (2 × 30 mL), and the
aqueous layers were back extracted with EtOAc/heptane (75
mL). The combined organic layer was washed with brine, dried,
and evaporated. The resulting yellow solid was crystallized from
ethyl acetate/hexane in yields of 78-82%.
N-Th ioa cetyl-2-a m in o-5-n itr oa n ilin e (3a ): mp 184 °C; 1H
NMR δ 9.56 (s, 1H), 7.9 (m, 2H), 6.7 (d, 1H, J ) 9.0), 6.56 (s,
2H), 2.59 (s, 3H); 13C NMR δ 216.3, 151.5, 151.3, 135.6, 123.2,
114.8, 114.5, 34.1. Anal. Calcd for C8H9N3O2S: C, 45.5; H, 4.3;
N, 19.9. Found: C, 45.6; H, 4.3; N, 19.8.
N-Th iop r op ion yl-2-a m in o-5-n itr oa n ilin e (3b): mp 168 °C;
1H NMR δ 10.59 (s, 1H), 7.9 (s, 1H), 7.7 (d, 1H, J ) 6.5), 6.8 (d,
1H, J ) 9.1), 6.59 (s, 2H), 2.7 (m, 2H), 1.4 (m, 3H); 13C NMR δ
213.9, 156.0, 140.3, 130.3, 129.9, 127.9, 119.2, 18.9. Anal. Calcd
for C9H11N3O2S: C, 48.0; H, 4.9; N, 18.7. Found: C, 47.8; H,
4.6; N, 18.4.
N-P r op ion yl-2-a m in o-5-n itr oa n ilin e (2b):34 mp 190-191
°C; 1H NMR δ 9.0 (s, 1H), 8.2 (s, 1H), 7.7 (d, 1H, J ) 8.95), 6.7
(d, 1H, J ) 8.95), 6.4(s, 2H), 2.3 (m, 2H), 1.1 (m, 3H); 13C NMR
δ 177.8, 154.1, 140.7, 127.8, 126.9, 126.4, 118.8, 34.2, 14.7. Anal.
Calcd for C9H11N3O3: C, 51.7; H, 5.3; N, 20.1. Found: C, 51.7;
H, 5.6; N, 19.8.
N-P iva loyl-2-a m in o-5-n itr oa n ilin e (2c): mp 177 °C; 1H
NMR δ 8.8 (s, 1H), 7.9 (d, 1H, J ) 2.35), 7.8 (dd, 1H, J ) 2.3,
8.9), 6.7 (d, 1H, J ) 9.0), 6.2 (s, 2H), 1.21 (s, 9H); 13C NMR δ
182.6, 155.8, 140.7, 128.9, 128.5, 127.0, 119.1, 32.5. Anal. Calcd
for C11H15N3O3: C, 55.7; H, 6.4; N, 17.7. Found: C, 55.7; H, 6.4;
N, 17.6.
N-Ben zoyl-2-a m in o-5-n itr oa n ilin e (2d ): mp 214 °C; 1H
NMR δ 9.74 (s, 1H), 8.1 (dd, 2H, J ) 7.2, 2.27), 7.9 (dd, 2H, J )
9.0, 2.5), 7.5 (m, 3H), 6.8 (d, 1H, J ) 9.0), 6.5 (s, 2H); 13C NMR
δ 171.3, 155.9, 140.6, 139.5, 136.9, 133.5, 133.2, 128.8, 126.5,
119.1. Anal. Calcd for C13H11N3O3: C, 60.7; H, 4.3; N, 16.3.
Found: C, 60.7; H, 4.3; N, 16.3.
N-(Cyclopr opylcar bon yl)-2-am in o-5-n itr oan ilin e (2e): mp
1
183 °C; H NMR (DMSO) δ 9.41 (s, 1H), 8.32 (s, 1H), 7.79 (dd,
1H, J ) 2.37, 6.58), 6.72 (d, 1H, J ) 9), 1.82 (s, 2H), 1.94 (S,
1H), 0.8 (m, 4H); 13C NMR δ 177.5, 153.4, 140.8, 127.5, 127.1,
125.7, 118.9, 25.9, 12.6. Anal. Calcd for C10H11N3O3: C, 54.3;
H, 5.0; N, 19.0. Found: C, 54.2; H, 5.1 N, 19.3.
N -(â-(Me t h oxyca r b on yl)p r op ion yl)-2-a m in o-5-n it r o-
a n ilin e (2f): mp 168 °C; 1H NMR δ 9.25 (s, 1H), 8.17 (d, 1H, J
) 2.53), 7.8 (dd, 1H, J ) 9, 2.5), 6.7 (d, 1H, J ) 9), 6.4 (s, 2H),
3.5 (s, 3H), 2.6 (m, 4H); 13C NMR δ 178.2, 175.8, 154.2, 140.7,
128, 126.7, 126.5, 118.7, 35.6, 33.8. Anal. Calcd for C11H13N3O5:
C, 49.4; H, 4.9; N, 15.7. Found: C, 49.9; H, 4.8; N, 16.1.
N-(R-Acetoxy-â-(m eth oxyca r bon yl)p r op ion yl)-2-a m in o-
5-n itr oa n ilin e (2g) was prepared from methyl 3-acetoxysucci-
nate according to the general procedure described above: mp
166 °C; 1H NMR δ 9.55 (s, 1H), 8.18 (d, 1H, J ) 2.6), 7.8 (dd,
1H, J ) 9, 2.6), 6.7 (d, 1H, J ) 9), 6.4 (s, 2H), 5.3 (m, 1H), 3.6
(s, 3H), 2.8 (m, 2H), 2.07 (s, 3H); 13C NMR δ 175.3, 175.2, 173.0,
155.2, 140.6, 128.9, 127.9, 125.5, 118.9, 75.2, 57.0, 41.1, 25.8.
Anal. Calcd for C13H15N3O7: C, 48.0; H, 4.7; N, 12.9. Found: C,
47.9; H, 4.6; N, 13.2.
N-Th iop iva loyl-2-a m in o-5-n itr oa n ilin e (3c): mp 203 °C;
1H NMR δ 10.36 (s, 1H), 7.9 (d, 1H, J ) 9.0), 7.74 (s, 1H), 6.7 (d,
1H, J ) 9.1), 6.2 (s, 2H), 1.3 (s, 9H); 13C NMR δ 220.6, 156.2,
140.6, 130.7, 129.9, 129.1, 119.4, 35.2. Anal. Calcd for
C11H15N3O2S: C, 52.2; H, 6.0; N, 16.6. Found: C, 52.4; H, 6.1;
N, 16.7.
N-Th ioben zoyl-2-a m in o-5-n itr oa n ilin e (3d ): mp 210 °C;
1H NMR δ 10.25 (s, 1H), 8.0 (d, 1H, J ) 2.5), 7.9 (m, 3H), 7.53
(s, 1H,), 7.50 (d, 1H, J ) 9.0), 7.44 (d, 1H, J ) 7.7), 6.8 (d, 1H,
J ) 9.12), 6.6 (s, 2H); 13C NMR δ 204.0, 156.2, 146.2, 140.5,
136.3, 133.2, 133.0, 130.7, 130.0, 128.5, 119.5. Anal. Calcd for
C13H11N3O2S: C, 57.1; H, 4.1; N, 15.4. Found: C, 57.0; H, 4.1;
N, 15.1.
N-(O-Acet yl-D-m a n d eloyl)-2-a m in o-5-n it r oa n ilin e (2h ):
1
mp 160 °C; H NMR δ 9.7 (s, 1H), 8.1 (d, 1H, J ) 2.4), 7.8 (dd,
N-(Cyclop r op ylt h ioca r b on yl)-2-a m in o-5-n it r oa n ilin e
1H, J ) 6.55, 2.49), 7.5 (m, 2H), 7.3 (m, 3H), 6.7 (d, 1H, J )
9.0), 6.4 (s, 2H), 6.0 (s, 1H), 2.14 (s, 3H); 13C NMR δ 175.5, 172.9,
154.4, 140.9, 140.4, 134.1, 133.9, 132.7, 128.6, 126.8, 125.7, 119.1,
118.8, 80.5, 25.9. Anal. Calcd for C16H15N3O5: C, 58.4; H, 4.6;
N, 12.8. Found: C, 58.1; H, 4.3; N, 12.4.
1
(3e): mp 184 °C; H NMR δ 10.37 (s, 1H), 7.9 (s, 1H), 7.8 (dd,
1H, J ) 9, 2.7), 6.7 (d, 1H, J ) 9), 6.55 (s, 2H), 2.29 (m, 1H),
1.15 (m, 2H), 0.9 (m, 2H);); 13C NMR δ 213.8, 155.9, 140.4, 130.4,
129.7, 127.9, 119.4, 28.7, 17.5. Anal. Calcd for C10H11N3O2S: C,
50.6; H, 4.7; N, 17.7. Found: C, 50.4; H, 4.6; N, 17.5.
N -(â-(Me t h o x y c a r b o n y l)a c r y lo y l)-2-a m in o -5-n it r o -
a n ilin e (2i): mp 201 °C; 1H NMR δ 9.75 (s, 1H), 8.36 (d, 1H, J
) 2.5), 7.8 (dd, 1H, J ) 8.9, 2.5), 7.24 (d, 1H, J ) 15.4), 6.75 (s,
2H), 6.75 (d, 1H, J ) 2.3), 6.7 (d, 1H, J ) 9), 3.7 (s, 3H); 13C
NMR δ 170.7, 167.2, 154.0, 142.8, 140.7, 134.2, 128.4, 126.3,
125.9, 119.0, 57.3. Anal. Calcd for C11H11N3O5: C, 49.8; H, 4.2;
N, 15.8. Found: C, 49.7; H, 3.9; N, 15.5.
N-Th io(â-(m et h oxyca r b on yl)p r op ion yl)-2-a m in o-5-n i-
tr oa n ilin e (3f): mp 174 °C; 1H NMR δ 10.38 (s, 1H), 7.9 (d,
1H, 8.9), 7.8 (s, 1H), 6.8 (d, 1H, J ) 9), 6.5 (s, 2H), 3.5 (s, 3H),
2.8 (m, 4H), 13C NMR δ 210.7, 178.1, 156, 140.4, 130.2, 130.1,
127.7, 119.2, 56.7, 37.8. Anal. Calcd for C11H13N3O4S: C, 46.6;
H, 4.6; N, 14.8. Found: C, 46.7; H, 4.4; N, 14.9.
N -Th io(R-a ce t oxy-â-(m e t h oxyca r b on yl)p r op ion yl)-2-
a m in o-5-n itr oa n ilin e (3g): mp 144 °C; 1H NMR δ 10.23 (s,
1H), 7.96 (d, 1H, J ) 9), 7.8 (s, 1H), 6.79 (d, 1H, J ) 9.1), 6.3 (s,
2H), 5.6 (m, 1H), 3.6 (s, 3H), 3.12 (m, 2H), 2.09 (s, 3H); 13C NMR
δ 206.2, 175.4, 175.3, 155.9, 140.6, 130.4, 130.2, 127.0, 119.3,
80.8, 57.1, 26.1. Anal. Calcd for C13H15N3O6S: C, 45.7; H, 4.4;
N, 12.3. Found: C, 46.0; H, 4.6; N, 12.3.
N-Cin n a m oyl-2-a m in o-5-n itr oa n ilin e (2j): mp 223 °C; 1H
NMR δ 9.43 (s, 1H), 8.4 (s, 1H), 7.8 (d, 1H, J ) 6.58), 7.6 (s,
1H), 7.5 (m, 2H), 7.4 (m, 3H), 6.55 (s, 2H), 6.74 (d, 1H, J ) 9),
6.87 (d, 1H, J ) 15.7); 13C NMR δ 169.3, 153.8, 145.6, 140.8,
139.9, 135.0, 134.2, 133.0, 127.9, 127.1, 126.8, 125.9, 119.0. Anal.
Calcd for C15H13N3O3: C, 63.6; H, 4.6; N, 14.8. Found: C, 63.6;
H, 4.5; N, 14.6.
N-Th io(O-a cet yl)-D-m a n d eloyl-2-a m in o-5-n it r oa n ilin e
N-Cr oton oyl-2-a m in o-5-n itr oa n ilin e (2k ): mp 178 °C; 1H
NMR δ 9.1 (s, 1H), 8.36 (s, 1H), 7.79 (dd, 1H, J ) 9, 2.6), 6.7 (d,
1
(3h ): mp 137 °C; H NMR δ 9.9 (s, 1H), 7.9 (dd, 1H, J ) 6.54,
2.58), 7.7 (d, 1H, J ) 2.49), 7.6 (m, 2H), 7.4 (m, 3H), 6.8 (d, 1H,
J ) 9.1), 6.5 (s, 1H), 6.2 (s, 2H), 2.15 (s, 3H); 13C NMR δ 206.3,
175.6, 155.7, 141.9, 140.8, 134.0, 133.7, 132.6, 130.4, 129.9, 126.9,
119.5, 85.8, 26.3. Anal. Calcd for C16H15N3O4S: C, 55.6.; H, 4.4;
N, 12.2. Found: C, 55.8; H, 4.3; N, 12.5.
(33) Phillips, M. A. J . Chem. Soc. 1930, 1409. (b) Mysyk, D. D.;
Maksimenko, N. N. J . Org. Chem. USSR 1974, 10, 1916. (c) Mysyk,
D. D.; Burmistrov, S. I.; Yakovets, A. A. J . Org. Chem. USSR 1973, 9,
1477.
(34) Yang, R.; Chen, J .; Zhang, H. Fuzhou Daxue, Xuebao, Ziran
Kexueban 1997, 25, 95; Chem. Abstr. 1998, 128, 250295.
N-Th io(â-(m eth oxyca r bon yl)a cr yloyl)-2-a m in o-5-n itr o-
a n ilin e(3i) was prepared from methyl hydrogen fumarate

Notes
J . Org. Chem., Vol. 64, No. 3, 1999 1069
according to the general procedure described above. It was
purified by column chromatography, eluting with hexane/ethyl
acetate (1/1): yield 41%; mp 158 °C (dec); 1H NMR δ 10.0 (s,
1H), 8.05 (s, 1H), 7.9 (d, 1H, J ) 7.37), 7.5 (d, 1H, J ) 15.24),
6.8 (d, 1H, J ) 15.2), 6.75 (d, 1H, J ) 9.15), 6.7 (s, 2H), 3.6 (s,
3H); 13C NMR δ 197.8, 170.8, 155.8, 147.5, 140.2, 133.3, 130.2,
130.0, 126.9, 119.4, 57.3. Anal. Calcd for C11H11N3O4S: C, 47.0;
H, 3.9; N, 15.0. Found: C, 47.2; H, 3.9; N, 14.7.
4-P h en yl-2-th ion o-1,5-ben zod ia zep in e (5j) was prepared
by treating 2j with P4S10 according to the general procedure
described above. It was purified by column chromatography,
eluting with hexane/ethyl acetate (1/1) and then crystallized from
THF/hexane: yield 53%; mp 227 °C; 1H NMR δ 9.5 (s, 1H), 8.02
(d, 1H, J ) 2.5), 7.8 (dd, 1H, J ) 17.1, 2.5), 7.75 (s, 1H), 7.3 (m,
5H), 7.0 (s, 1H), 4.9 (d, 1H, J ) 8.05), 3.4 (m, 1H), 3.2 (m, 1H);
13C NMR δ 205.9, 151.3, 141.6, 141.8, 133.7, 132.9, 131.7, 128.5,
127.2, 124.9, 123.7, 65.3, 60.1. Anal. Calcd for C15H13N3O2S: C,
60.2; H, 4.4; N, 14.0. Found: C, 60.1; H, 4.4; N, 14.2.
4-Meth yl-2-th ion o-1,4-ben zod ia zep in e (5k ) was prepared
by treating 2k with P4S10 according to the general procedure
described above. It was purified by column chromatography,
eluting with hexane/ethyl acetate (2/1): yield 49%; mp 222 °C;
1H NMR δ 9.65 (s, 1H), 7.9 (s, 1H), 7.7 (d, 1H, J ) 8.5), 7.5 (s,
1H), 6.8 (d, 1H, J ) 9), 3.8 (s, 1s), 3.0 (m, 2H), 1.25 (d, 3H, J )
6.3); 13C NMR δ 206.8, 151.1, 141.2, 127.8, 127.1, 125.0, 123.2,
57.2, 57.0, 28.2. Anal. Calcd for C10H11N3O2S: C, 50.6; H, 4.7;
N, 17.7. Found: C, 50.6; H, 4.7; N, 17.6.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ben zotr ia z-
ole Th ioa cyla tin g Rea gen ts (4a -h ). To a solution of thioa-
nilides 3a -h (2 mmol) dissolved by gentle warming at 40 °C
and then cooling to 0-5 °C in 70% acetic acid (15 mL) was added
NaNO2 (0.21 g, 3 mmol, 150 mol %) in small portions with
stirring. After 30 min, ice-water (100 mL) was added, and the
precipitate was filtered off, washed with water, and dried in
vacuo to afford benzotriazoles 4a -h as orange solids of sufficient
purity for further use without additional purification. For
elemental analyses the benzotriazoles were crystallized from
CH2Cl2 in yields of 72-76%.
169.7, 168.9, 146.5, 146.4, 135, 126.4, 116.5, 112.6, 74.7, 52.3,
38.9, 20.8. Anal. Calcd for C13H12N4O6S: C, 44.3; H, 3.4; N, 15.9.
Found: C, 44.2; H, 3.3; N, 15.6.
1-Th io-(O-acetyl)-D-m an deloyl-6-n itr oben zotr iazole (4h ):
mp 136 °C; 1H NMR (CDCl3) δ 9.5 (d, 1H, J ) 1.95), 8.4 (dd, 1H,
J ) 8.9, 1.93), 8.2 (d, 1H, J ) 8.9), 7.8 (s, 1H), 7.7 (m, 2H), 7.3
(m, 3H), 2.25 (s, 3H); 13C NMR δ 202.2, 170.2, 149.6, 148.8, 134.4,
131.9, 129.6, 128.9, 128.5, 122.3, 121.5, 112.7, 79.8, 21.1. Anal.
Calcd for C16H12N4O4S: C, 53.9; H, 3.3; N, 15.7. Found: C, 54.1;
H, 3.0; N, 15.9.
Ben zyl Th ion oa ceta te (6). A mixture of benzotriazole 4a
(0.44 g, 2 mmol, 100% mol), benzyl alcohol (0.32 g, 3 mmol, 150%
mol), and imidazole (0.16, 2.4 mmol, 120% mol) in anhydrous
CH2Cl2 (20 mL) was stirred at room temperature for 48 h. The
solvent was removed in vacuo, and the residue was digested with
hexane (2 × 40 mL). The insoluble material was removed by
filtration and after solvent evaporation, the residue was chro-
matographed on a short column of silica gel, eluting with hexane,
to afford pure 6 in 81% yield: 1H NMR (CDCl3) δ 7.4 (s, 5H),
5.48 (s, 2H), 2.65 (s, 3H); 13C NMR δ 219.6, 135.1, 128.7, 128.6,
74.2, 34.5. Anal. Calcd for C9H10OS: C, 65.0; H, 6.1. Found: C,
65.3; H, 6.2.
Ben zyl th ion op r op ion a te (7) was prepared from 4b ac-
cording to the procedure described for the preparation of 6: yield
83%; 1H NMR (CDCl3) δ 7.3 (s, 5H), 5.49 (s, 2H), 2.8 (m, 2H),
1.28 (m, 3H); 13C NMR δ 225.1,135.1, 128.6, 128.4, 73.9, 40.1,
12.9. Anal. Calcd for C10H12OS: C, 66.6; H, 6.7. Found: C, 66.3;
H, 6.9.
Ben zyl Th ion op iva la te (8). A mixture of benzotriazole 4c
(0.53 g, 2 mmol, 100% mol) and benzyl alcohol (0.32 g, 3 mmol,
150% mol) in anhydrous pyridine (10 mL) was heated with
stirring at 50 °C for 1.5 h. The solution was cooled to room
temperature, diluted with H2O (40 mL), and extracted with ether
(2 × 40). The combined ether layer was washed with H2O, dried,
and evaporated. The residue was purified by column chroma-
tography, eluting with hexane: yield 79%; 1H NMR (CDCl3) δ
7.4 (s, 5H), 5.5 (s, 2H), 1.36 (s, 9H); 13C NMR δ 231, 135.6, 128.6,
128.3, 127.9, 127.9, 73.9, 47.4, 30.0. Anal. Calcd for C12H16OS:
C, 69.2; H, 7.8. Found: C, 68.9; H, 7.9.
Ben zyl Th ion oben zoa te (9). To a cooled solution (0 °C) of
benzotriazole 4d (0.57 g, 2 mmol, 100% mol) and benzyl alcohol
(0.32 g, 3 mmol, 150%) in THF (20 mL) was added DBU (0.3 g,
2 mmol, 100% mol) in THF (10 mL) in small intervals over a
period of 20 min. The progress of the reaction was followed by
TLC, and after complete disappearance of the starting material,
the solvent was evaporated and the residue digested with hexane
and filtered. The filtrate was concentrated and chromato-
graphed, eluting with hexane, to give thionoester 9 in 89% yield.
Similar results were obtained when the reaction was carried out
in pyridine at room temperature for 8 h: 1H NMR (CDCl3) δ 8.3
(d, 2H, J ) 7.36), 7.6-7.4 (m, 8H), 5.7 (s, 2H); 13C NMR δ 211.0,
138.4, 135.5, 133.0, 129.1, 128.8, 128.7, 128.6, 128.5, 128.3, 74.2.
Anal. Calcd for C14H12OS: C, 73.6; H, 5.3. Found: C, 73.3; H,
5.5.
1-Th ioa cetyl-6-n itr oben zotr ia zole (4a ): mp 108 °C; 1H
NMR (CDCl3) δ 9.6 (d, 1H, J ) 2.1), 8.4 (dd, 1H, J ) 2.0, 8.9),
8.2 (d, 1H, J ) 8.9), 3.4 (s, 3H); 13C NMR δ 205.4, 149.5, 149.2,
131.6, 121.9, 121.3, 113.0, 36.5. Anal. Calcd for C8H6N4O2S: C,
43.2; H, 2.7; N, 25.2. Found: C, 43.3; H, 2.7; N, 25.1.
1-Th iop r op ion yl-6-n itr oben zotr ia zole (4b): mp 94-95 °C;
1H NMR (CDCl3) δ 9.58 (d, 1H, J ) 1.7), 8.3 (dd, 1H, J ) 8.9,
1.8), 8.2 (d, 1H, J ) 9), 3.7 (m, 2H), 1.47 (m, 3H); 13C NMR δ
211.6, 149.4, 149.0, 131.7, 121.7, 113.0, 40.5, 13.3. Anal. Calcd
for C9H6N4O2S: C, 45.7; H, 3.4; N, 23.7. Found: C, 45.2; H, 3.3;
N, 23.4.
1-Th iop iva loyl-6-n itr oben zotr ia zole (4c): mp 79 °C; 1H
NMR (CDCl3) δ 9.47 (s, 1H), 8.37 (dd, 1H, J ) 2, 9.1), 8.2 (dd,
1H, J ) 0.6, 8.9), 1.6 (s, 9H); 13C NMR δ 219.2, 149.2, 147.9,
133.0, 121.5, 120.9, 113.4, 51.1, 31.2. Anal. Calcd for
C11H12N4O2S: C, 50.0; H, 4.6; N, 21.2. Found: C, 50.1; H, 4.7;
N, 21.2.
Cycloh exyl th ion oben zoa te (10) was prepared from 4d
according to the procedure described for the preparation of 9:
yield 74%;1H NMR (CDCl3) δ 8.2 (dd, 2H, J ) 1.05, 7.22), 7.5
(dd, 1H, J ) 7.3, 13.53), 7.38 (dd, 2H, J ) 7.9, 13.8), 5.7 (m,
1H), 2.05 (dd, 2H, J ) 3.8, 9.89), 1.8-1.7 (m, 4H), 1.6-1.3 (m,
4H); 13C NMR δ 210.6, 139.1, 132.5, 128.8, 128.0, 80.1, 30.8, 25.5,
23.6. Anal. Calcd for C13H16OS: C, 70.9; H, 7.3. Found: C, 71.0;
H, 7.5.
1
1-Th ioben zoyl-6-n itr oben zotr ia zole (4d ): mp 158 °C; H
NMR (CDCl3) δ 9.4 (s, 1H), 8.4 (d, 1H, J ) 8.9), 8.3 (d, 1H, J )
8.9), 7.7 (d, 2H, J ) 8.2), 7.6 (t, 1, J ) 7.0), 7.4 (t, 2H, J ) 7.5);
13C NMR δ 201.2, 149.0, 142.0, 133.4, 133.0, 130.8, 128.3, 121.8,
121.3, 112.2. Anal. Calcd for C13 H8N4O2S: C, 54.9; H, 2.8; N,
19.7. Found: C, 55.0; H, 2.9; N, 19.6.
1-(Cyclop r op ylth ioca r bon yl)-6-n itr oben zotr ia zole (4e):
1
mp 137 °C; H NMR (CDCl3) δ 9.69 (d, 1H, J ) 1.67), 8.37 (dd,
Men th yl th ion oben zoa te (11) was prepared from 4d ac-
cording to the procedure described for the preparation of 9: yield
1H, J ) 8.9, 2.05), 8.2 (d, 1H, J ) 8.9), 4.1 (m, 1H), 1.8 (m, 2H),
1.46 (m, 2H);13C NMR δ 211, 149.2, 149.1, 131.8, 121.6, 121.6,
121.1, 113.2, 26.9, 19.5. Anal. Calcd for C10H8N4O2S: C, 48.4;
H, 3.3; N, 22.6. Found: C, 48.5; H, 3.4; N, 22.7.
1
69%; H NMR (CDCl3) δ 8.18 (d, 2H, J ) 7.25), 7.5 (t, 3H, J )
7.3), 7.3 (t, 2H, J ) 7.84), 5.66-5.62 (m, 1H), 2.3 (d, 1H, J )
11.5), 1.95 (dd, 1H, J ) 4.56, 6.87), 1.7 (m, 2H), 1.59 (m, 1H),
1.24-1.07 (m, 3H), 1.04-0.92 (m, 5H), 0.81-0.79 (d, 2H, J )
6.93); 13C NMR δ 210.7, 138.9, 132.5, 128.9, 128.0, 82.2, 47.5,
39.4, 34.4. Anal. Calcd for C17H24OS: C, 73.9; H, 8.8. Found: C,
73.9; H, 8.9.
1-Th io-(â-(m et h oxyca r b on yl)p r op ion yl)-6-n it r ob en zo-
tr ia zole (4f): mp 92 °C; 1H NMR (CDCl3) δ 9.6 (s, 1H), 8.4 (dd,
1H, J ) 8.9, 1.8), 8.2 (d, 1H, J ) 9), 4.0 (m, 2H), 3.78 (s, 3H), 3.1
(m, 2H); 13C NMR δ 207.2, 172.2, 149.5, 149.1, 131.8, 121.9,
121.4, 112.9, 52.1, 40.8, 31.9. Anal. Calcd for C11H10N4O4S: C,
44.9; H, 3.4; N, 19.0. Found: C, 44.9; H, 3.4; N, 19.2.
N-BOC-(O-th ion oben zoyl)-L-ser in e Meth yl Ester (12). To
a cooled solution (0 °C) of N-(tert-butoxycarbonyl)-L-serine methyl
ester (0.45 g, 2 mmol, 100 mol %) and benzotriazole 4d (0.57 g,
2 mmol, 100 mol %) in dry DMF (10 mL) was added DBU (0.3
g, 2 mmol, 100% mol) in small intervals over a period of 20 min.
The solution was stirred at 0 °C and room temperature for 2 h
1-Th io-(R-a cetoxy-â-(m eth oxyca r bon yl)p r op ion yl)-6-n i-
1
tr oben zotr ia zole (4g): mp 98 °C; H NMR (CDCl3) δ 9.03 (d,
1H, J ) 1.9), 8.8 (d, 1H, J ) 9.2), 8.5 (dd, 1H, J ) 9.1, 1.9), 7.0
(m, 1H), 3.7 (s, 3H), 3.1 (m, 2H), 2.1 (s, 3H); 13C NMR δ 202.4,

1070 J . Org. Chem., Vol. 64, No. 3, 1999
Notes
1
when TLC indicated the disappearance of starting material; it
was then diluted with H2O (40 mL) and extracted with ether (2
× 40), and the combined ether layer was washed with H2O and
dried. Evaporation of the solvent left a brown oil that was
purified by chromatography (hexane/ethyl acetate, 3/1) to afford
12 as a yellow oil in 74% yield: 1H NMR (CDCl3) δ 8.1(d, 2H, J
) 7.3), 7.5(t, 1H, J ) 7.4, 7.3), 7.37 (t, 2H, J ) 8.1, 7.4), 5.4 (d,
1H, J ) 7.4), 4.8 (m, 3H), 3.7 (S, 3H), 1.4 (S, 9H); 13C NMR
(CDCl3) δ 210.5, 170.3, 155.1, 137.7, 133.1, 128.8, 128.2, 80.5,
72.1, 52.9, 52.8, 28.3. Anal. Calcd for C16H21NO5S: C, 56.6; H,
6.2; N, 4.1. Found: C, 56.7; H, 6.2; N, 4.2.
N-BOC-(O-th ion oben zoyl)-L-th r eon in e m eth yl ester (13)
was prepared according to the procedures described for the
preparation of 12: yield 66%; mp 93 °C; 1H NMR (CDCl3) δ 8.04
(d, 2H, J ) 7.2), 7.55 (m, 1H), 7.35 (m, 2H), 6.2 (m, 1H), 4.68
(m, 1H), 3.6 (S, 3H), 1.46 (S, 9H), 1.48 (m, 3H); 13C NMR (CDCl3)
δ 210, 170.5, 155.8, 138.5, 133.2, 132.9, 129.7, 128.4, 80.5, 57.4,
52.7, 28.3, 17.0. Anal. Calcd for C17H23NO5S: C, 57.8; H, 6.6; N,
4.0. Found: C, 58.2; H, 6.5; N, 4.1.
the procedure described for the preparation of 9: yield 67%; H
NMR (CDCl3) δ 8.5 (dd, 1H, J ) 4.6, 1.3), 8.44 (d, 1H, J ) 2.4),
8.34 (d, 1H, J ) 1.3), 8.32 (d, 1H, J ) 1.3), 7.6 (m, 1H), 7.4 (m,
4H); 13C NMR (CDCl3) δ 210.5, 151.4, 147.4, 144.1, 138, 134.1,
133.8, 130.3, 129.5, 128.4, 127.6. Anal. Calcd for C12H9NOS: C,
67.0; H, 4.2; N, 6.5. Found: C, 66.9; H,4.3; N, 6.8.
Ben zyl th ion ocyclop r op yla te (16) was prepared according
to the procedure described for the preparation of 9: yield 83%;
1H NMR (CDCl3) δ 7.4 (s, 5H), 5.53 (s, 2H), 2.37 (m, 1H), 1.5
(m, 2H), 1.0 (m, 2H); 13C NMR (CDCl3) δ 224.7, 135.3, 128.7,
128.6, 128.5, 128.4, 73.6, 30.4, 26.4, 14.4. Anal. Calcd for C11H12
OS: C, 68.7; H, 6.3. Found: C, 68.8; H, 6.4.
-
Ben zyl 1-th io-â-(m eth oxyca r bon yl)p r op ion a te (17) was
prepared according to the procedure described for the prepara-
tion of 6: yield 63%; 1H NMR (CDCl3) δ 7.37 (s, 5H), 5.4 (s, 2H),
3.64 (s, 3H), 3.03 (t, 2H, J ) 14.0, 6.9), 2.8 (t, 2H, J ) 14.0, 6.9);
13C NMR (CDCl3) δ 221, 172.6, 134.9, 128.9, 128.6, 128.6, 128.5,
74.0, 51.8, 40.7, 32.1. Anal. Calcd for C12H14O3S: C, 60.5; H,
5.9. Found: C, 60.4; H, 5.9.
Met h yl 2,3,4-Tr i-O-a cet yl-6-O-t h ion ob en zoyl-R-D-glu -
cop yr a n osid e (14). To a cooled (0 °C) solution of methyl R-D-
glucopyranoside (0.426 g, 2 mmol, 110 mol %) in dry pyridine
was added benzotriazole 4d (0.57 g, 2 mmol, 100 mol %). The
reaction mixture was kept at this temperature overnight, and
after addition of AcOH (0.5 mL), the solvent was evaporated at
40 °C. The residue was partitioned between phosphate buffer
(pH 7, 30 mL) and EtOAc/n-butanol (4/1, v/v, 30 mL). The
aqueous phase was extracted twice with the same mixed solvent
(2 × 20 mL), and the combined organic layer was washed with
H2O and dried. The solvent was evaporated and the residue was
chromatographed on silica gel, eluting with ethyl acetate/hexane,
4/1, to give the corresponding thionoester as an amorphous
yellow solid. It was characterized as its triacetyl derivative (from
pyridine/acetic anhydride at 0 °C following the usual literature
procedures) which was crystallized from ethanol in 79% overall
yield: mp 95 °C; 1H NMR (CDCl3) δ 8.11 (d, 2H, J ) 7.2), 7.5 (t,
1H, J ) 7.3, 7.4), 7.3 (m, 2H), 5.8 (m, 1H), 5.5 (t, 1H, J ) 9.8,
9.5), 5.2 (m, 2H), 4.8 (m, 1H), 4.2 (m, 1H), 3.37 (s, 3H), 2.1 (S,
3H), 2.04 (S, 3H), 1.91 (S, 3H); 13C NMR (CDCl3) δ 211, 170.7,
170.2, 169.6, 138.1, 137.7, 133.3, 128.3, 96.8, 95.9, 70.2, 69.9,
68.5, 66.9, 20.8. Anal. Calcd for C20H24O9S: C, 54.5; H, 5.5.
Found: C, 54.5; H,5.6.
Ben zyl 1-th io-R-(acetoxy-â-(m eth oxycar bon yl)pr opion ate
(18) was prepared according to the procedure described for the
preparation of 6: yield 53%; 1H NMR (CDCl3) δ 7.34 (s, 5H),
5.48 (m, 1H), 5.15 (s, 2H), 3.94 (s, 3H), 2.9 (m, 2H), 2.08 (s, 3H);
13C NMR (CDCl3) δ 221, 215.6, 170.9, 159.0, 136.0, 128.7, 128.6,
128.4, 128.2, 66.3, 54.0, 52.1, 38.5, 21.8. Anal. Calcd for
C14H16O5S: C, 56.7; H, 5.5. Found: C, 56.3; H, 5.7.
Ben zyl 1-th io-(O-a cetyl)-D-m a n d ela te (19) was prepared
according to the procedure described for the preparation of 6:
yield 64%; 1H NMR (CDCl3) δ 7.5 (m, 2H), 7.37 (m, 6H), 7.25
(m, 2H), 6.4 (s, 1H), 5.4 (m, 2H), 2.2 (s, 3H); 13C NMR (CDCl3)
δ 215.5, 170.1, 135.6, 135.0, 134.6, 130.1, 129.1, 128.7, 128.5,
128, 127.6, 81.3, 74.0, 21.1. Anal. Calcd for C17H16O3S: C, 68.0;
H, 5.4. Found: C, 68.2; H, 5.5. To determine the enantiomeric
integrity of the product, a crude sample of 19 was analyzed by
chiral HPLC, and the results were compared with those obtained
from a sample prepared by coupling racemic benzotriazole 4h
with benzyl alcohol: mobile phase, hexane/IPA, 99.1, flow rate
0.5 mL/min, tR 18.2 min for benzyl 1-thio-(O-acetyl)-D-mandelate;
tR 19.7 min for benzyl 1-thio-(O-acetyl)-L-mandelate; er for 19,
92/8.
3-P yr id yl th ion oben zoa te (15) was prepared according to
J O981985U