Solid-phase synthesis of 2-aminothiazoles

Full text of DOI:10.1021/jo971542a

196
J . Org. Chem. 1998, 63, 196-200
Solid -P h a se Syn th esis of 2-Am in oth ia zoles
Patrick C. Kearney, Monica Fernandez, and
J ohn A. Flygare*
Tularik Inc., Two Corporate Drive,
South San Francisco, California 94080
Received August 19, 1997X
The 2-aminothiazole ring system 1 (Figure 1) is a
useful structural element in medicinal chemistry. This
structure has found application in drug development for
the treatment of allergies,1 hypertension,2 inflammation,3
schizophrenia,4 and bacterial5 and HIV6 infections. Given
this proven utility, it seems reasonable that the develop-
ment of libraries of 2-aminothiazoles might provide
additional lead molecules for use in drug discovery.
Solid-phase synthesis plays a central role in the genera-
tion of such small molecule libraries.7 Herein we report
a general, high-yielding solid-phase method for the
synthesis of 2-aminothiazoles.8 Our goal during this
work was to provide a clean, high-yielding, and traceless
synthesis of 2-aminothiazoles. We also desired that the
route would utilize diverse commercially available start-
ing materials and would be simple enough to be used in
conjunction with other synthetic methods.
F igu r e 1.
Two characteristics of 2-aminothiazoles suggested their
amenability to a solid-phase approach. First, the 2-ami-
nothiazole moiety contains an amino group, which could
serve as a convenient, traceless point of attachment to
acid-sensitive resins (Figure 1). Second, it is known that
2-aminothiazoles can be synthesized cleanly and in high
yields from an R-bromo ketone and a thiourea via the
Hantzsch thiazole synthesis (Figure 1).8,9 This route of
synthesis was particularly attractive in light of the large
number of commercially available R-bromo ketones,
which could be used to introduce diversity at the R2 and
R3 positions of the thiazole ring.10 However, our desire
to take advantage of both of these characteristics in a
single synthetic route highlighted a practical problem of
F igu r e 2.
the solid-phase synthesis of 2-aminothiazoles: one must
utilize a resin-bound thiourea.
We decided it was best to produce the thiourea directly
from a resin-bound primary or secondary amine. An
advantage of this approach was that existing proce-
dures7,11 for immobilizing various primary amines to resin
could be used prior to synthesis of the thiourea, thereby
incorporating diversity at the R1 position of the thiazole.
Methods for synthesizing N-substituted thioureas from
primary and secondary amines have been reported in the
literature.12 However, these either proceed in low yields
or require harsh acidic or basic conditions that are
generally incompatible with solid-phase synthesis. There-
fore, a new milder reagent was necessary to perform the
desired chemical transformation.
Compound 2, fluorenylmethyloxycarbonyl isothiocyan-
ate (Fmoc-NCS), was designed to overcome this problem.
We envisioned that this compound would react directly
with resin-bound amines in a low polarity solvent to
produce Fmoc-protected thioureas (Figure 2). Subse-
quent removal of the Fmoc-group under basic conditions
(1) Hargrave, K. D.; Hess, F. K.; Oliver, J . T. J . Med. Chem. 1983,
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Med. Chem. 1990, 33, 1453.
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M., J r.; Nore´en, R.; O¨ berg, B.; Palkowitz, J . A.; Parrish, C. A.; Pranc,
P.; Sahlberg, C.; Ternansky, R. J .; Vasileff, R. T.; Vrang, L.; West, S.
J .; Zhang, H.; Zhou, X.-X. J . Med. Chem. 1995, 38, 4929.
(7) (a) Ellman, J . A. Acc. Chem. Res 1996, 29, 132. (b) Hermkens,
P. H. H.; Ottenheijm, H. C. J .; Rees, D. Tetrahedron 1996, 52, 4527.
(c) Balkenhohl, F.; von dem Bussche-Hu¨nnefeld, C.; Lansky, A.; Zechel,
C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2288.
(8) For a report of the solution-phase preparation of libraries of
2-aminothiazoles see: Bailey, N.; Dean, A. W.; J udd, D. B.; Middlemiss,
D.; Storer, R.; Watson, S. P. Bioorg. Med. Chem. Lett. 1996, 6, 1409.
(9) (a) Hantzsch, A. R.; Weber, J . H. Ber. 1887, 20, 3118. (b) J oshua,
C. P.; Nambisan, P. N. K. Indian J . Chem. 1973, 11, 118.
(10) A search of the Available Chemicals Directory database indi-
cated over 300 commercially available R-bromo ketones.
(11) (a) Ngu, K.; Patel, D. V. Tetrahedron Lett. 1997, 38, 973. (b)
Szardenings, A. K.; Burkoth, T. S.; Look, G. C.; Campbell, D. A. J .
Org. Chem. 1996, 61, 6720. (c) Boojamra, C. G.; Burow, K. M.;
Thompson, L. A.; Ellman, J . A. J . Org. Chem. 1997, 62, 1240. (d)
Gordon, D. W.; Steele, J . Bioorg. Med. Chem. Lett. 1995, 5, 47.
(12) (a) Nair, G. V. Indian J . Chem. 1966, 4, 516. (b) Rasmussen,
C. R.; Villani, F. J ., J r.; Weaner, L. E.; Reynolds, B. E.; Hood, A. R.;
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T.; Molinari, A. J . Synthesis 1988, 456. (c) Poss, M. A.; Iwanowicz, E.;
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Y.; Adachi, M.; Kawasaki, T.; Kita, Y. Tetrahedron Lett. 1978, 20, 1753.
S0022-3263(97)01542-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/09/1998

Notes
J . Org. Chem., Vol. 63, No. 1, 1998 197
Sch em e 1
in a more polar environment would generate the simple
thioureas needed for the Hantzsch thiazole synthesis.
Given that the reaction of amines with isothiocyanates13
and the cleavage of the Fmoc protecting group14 are clean,
high-yielding reactions, it seemed plausible that the
generation of a thiourea could be achieved with minimal
loss of yield.
It was first necessary to synthesize Fmoc-NCS and test
its ability to generate thioureas. The molecule was
prepared easily through the reaction of Fmoc-chloride
with potassium thiocyanate in anhydrous ethyl acetate.
Solution phase testing was conducted by reacting Fmoc-
NCS with a poor nucleophile (aniline), as well as with a
more basic secondary amine (piperidine). The reaction
of aniline with 1.2 equiv of 2 in methylene chloride,
followed by the addition of a methanolic solution of
piperidine, generated phenylthiourea 3, which was iso-
lated in 88% yield. The addition of piperidine to a
solution of Fmoc-NCS (1.1 equiv) in methylene chloride
formed exclusively the Fmoc-protected thiourea 4; the
the resin maintained a negative response to ninhydrin,
suggesting that carbamate formation did not occur.
Further evaluation of this reagent was conducted in the
context of 2-aminothiazole generation.
Scheme 1 shows our general procedure for synthesizing
2-aminothiazoles. The same procedure was used with
the three different resin types shown. Amine-containing,
acid-sensitive resins were reacted first with Fmoc-NCS
in methylene chloride. A solution of 20% piperidine in
DMF was used to remove the Fmoc-group from the resin-
bound thioureas, and thiazoles were formed by treatment
of the resins with a dioxane solution of an R-bromo ketone
at room temperature. Cleavage of the 2-aminothiazoles
was effected with 95% TFA, 5% H2O.
This synthetic procedure was elucidated with the use
of Rink amide MBHA resin to produce thiazoles that were
unsubstituted at the 2-amino position (R1 ) H, com-
pounds 5-9, Table 1). Purities of the (often crystalline)
cleavage materials obtained with this resin were excel-
lent, as determined by HPLC analysis. Purification by
passage over basic alumina (to remove residual TFA) and
radial centrifugal chromatography (silica gel plates)
resulted in the isolation of 2-aminothiazoles as free bases.
The isolated yields are high (71-96%), reflective of the
high overall efficiency of the reaction scheme.
Thiazoles substituted at the 2-amino position (R1
)
alkyl, compounds 10-13, Table 1) were generated from
ArgoGel-MB-CHO resin that had been reductively ami-
nated via the two-step procedure shown in Scheme 2. In
dibenzofulvene cleavage product was not observed. Also,
there was no evidence of carbamate formation,13 which
might have resulted from a nucleophilic attack on the
carbonyl carbon of 2. Chromatographic workup of this
reaction netted compound 4 in 98% yield. These results
indicated that Fmoc-NCS could be used to produce
thioureas and suggested that favorable transformations
of a wide variety of primary and secondary amines could
be expected.
Sch em e 2
On the solid-phase, the reaction of Fmoc-NCS (5 equiv)
in methylene chloride with the free amino group of Rink
Amide MBHA resin was rapid, reaching completion
within 15 min as indicated by a negative ninhydrin test.
After subsequent treatment with 20% piperidine in DMF,
(13) Drobnica, L.; Krista´n, P.; August´ın, J . In The Chemistry of
Cyanates and Their Thio Derivatives; Patai, S., Ed.; J . Wiley & Sons:
New York, 1977; Part 2, pp 1109-1115.
(14) Greene, T.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J . Wiley & Sons: New York, 1991, and references
therein.
this procedure, the dehydrating agent trimethyl ortho-
formate was used as the solvent to drive imine forma-

198 J . Org. Chem., Vol. 63, No. 1, 1998
Notes
Ta ble 1
Compounds 11, 13, and 14 demonstrate an advantage
of our method over other strategies for producing 2-ami-
nothiazoles. Because Fmoc-NCS is used to transform
primary and secondary amines into thioureas, noncom-
merically available thiourea structures can be incorpo-
rated into our synthesis. As a result, libraries of com-
pounds containing greater diversity at the 2-amino
position are accessible.
Some general notes about the synthetic procedure are
warranted. In the course of our work we did not observe
compound 2 to undergo amine attack at its less electro-
philic carbonyl carbon to form the Fmoc-carbamate. As
such, it was not necessary to iteratively treat the resin
with Fmoc-NCS followed by piperidine deprotection to
drive thiourea formation to completion. Solutions of
Fmoc-NCS in methylene chloride were stable for several
weeks at room temperature. The use of solutions of 2 in
DMF is not recommended, as the reagent can decompose
over the course of a few hours in this solvent. Solvents
other than dioxane could be used for the solid-phase
Hantzsch synthesis. However, we found that using
dioxane eliminated the need for heating, which is re-
quired with the more polar solvent DMF. When the less
polar solvent methylene chloride was used, small amounts
of uncharacterized side products were often generated.
Furthermore, in methylene chloride, the acid produced
during the synthesis caused partial cleavage of the
2-aminothiazole products from the Rink amide MBHA
resin. Usage of dioxane eliminated both of the problems
associated with methylene chloride.
In conclusion, we have demonstrated that 2-ami-
nothiazoles can be produced in good yields and with high
degrees of purity from a primary amine and an R-bromo
ketone. The key to this method is the conversion of a
resin-bound amino group to a thiourea using Fmoc-NCS.
The chemistry involved occurs under mild conditions and
should easily find use in conjunction with other solid- and
solution-phase chemistries. Finally, other chemical ma-
nipulations of thioureas are known. We are presently
investigating solid-phase adaptations of these reactions
and will report in due course.
tion.11b,15 The arylimines were sufficiently stable, and
their reduction could be carried out separately with
sodium borohydride. The resulting resin-bound amines
were then converted to 2-aminothiazoles with the use of
the general procedure described above. Cleavage of the
thiazoles from this resin required longer cleavage times
(4 h) and modest heating (50 °C). In addition, cleavage
efficiency was enhanced when the resins were dried
under vacuum before exposure to the TFA cleavage
solution. The purities of materials generated in this
fashion remained high (94-99%). Compounds 10-13
were purified via reverse phase HPLC followed by
passage over basic alumina. Yields of these materials
were slightly lower than those of 5-9, a result not
unexpected given the additional synthetic steps of the
reductive amination.
Compound 14 (Table 1) was generated from glycine
linked to Rink amide MBHA resin. In this synthesis, the
2-amino group of the thiazole did not serve as the point
of attachment to the resin. Despite the additional step
of coupling the glycine to the resin, the purity and yield
of 14 were comparable to those of compounds 5-9, which
were obtained directly from the amino group of Rink
amide MBHA resin.
Exp er im en ta l Section
Gen er a l. Except for compound 2, all reagents used are
available from commercial sources. Reagents were used without
further purification, except for potassium thiocyanate, which was
dried with heating under vacuum at 80 °C before use. Rink
amide MBHA resin was purchased from Novabiochem and had
a loading capacity of 0.55 mmol/g. ArgoGel-MB-CHO resin was
purchased from Argonaut Technologies and had a loading
capacity of 0.41 mmol/g. Compounds 5-14 were produced using
a Rainin Instruments Symphony/Multiplex multiple peptide
synthesizer. All NMR spectra (400 MHz) were recorded on a
Varian Instruments Gemini-400 spectrometer. Radial centrifu-
gal chromatography was carried out with a Chromatotron Model
8924 apparatus (Harrison Research, Palo Alto, CA) with 1 mm
silica gel plates (Analtech). Analytical work employed a Rainin
Microsorb-MV C18 column (water/acetonitrile 9:1 to 2:8 eluant
gradient over 40 min, 1.5 mL/min flow-rate). Preparative HPLC
work utilized a Dynamax-60A C18 column (water/acetonitrile 9:1
to 2:8 eluant gradient over 40 min, 20 mL/min flow-rate). All
HPLC solutions contained 0.1% TFA. Yields of all compounds
reported in Table 1 are of purified material and were based upon
the loading levels of the starting resins. Purities of all com-
pounds were estimated from integrated peak areas of HPLC
chromatographs generated at 254 nm. Mass spectral analysis
was performed by M-Scan, Inc., West Chester, PA. Elemental
analysis was done at Atlantic Microlab, Inc., Norcross, GA.
(15) Look, G. C.; Murphy, M. M.; Campbell, D. A.; Gallop, M. A.
Tetrahedron Lett. 1995, 36, 2937.

Notes
F lu or en ylm eth yloxyca r bon yl Isoth iocya n a te (2). Fluo-
J . Org. Chem., Vol. 63, No. 1, 1998 199
mL, 2 h); this eluate and two subsequent TFA washes (2.5 mL)
were collected and combined, and the solvent was removed with
a Speedvac. This crude material was passed over a short column
of basic alumina with a methanol eluant to isolate the product
as the free base. Purified product was isolated with the use of
a Chromatotron centrifugal radial thin-layer chromatograph (1
mm silica gel plates, CH2Cl2/acetonitrile gradient).
renylmethyloxycarbonyl chloride (2.60 g, 10 mmol) was dissolved
in 10 mL of anhydrous ethyl acetate. This solution was added
dropwise to a suspension of dry potassium thiocyanate (1.07 g,
11 mmol) in 10 mL of anhydrous ethyl acetate at 0 °C under a
nitrogen atmosphere. The solution was allowed to warm to room
temperature over several hours, and the reaction was monitored
by thin-layer chromatography [silica gel plates; eluant solution,
CH2Cl2/hexane (1:3)]. After the reaction with the Fmoc-chloride,
the reaction mixture was passed through a Celite pad to remove
residual salts, and the ethyl acetate was removed by rotary
evaporation. The crude product was purified via flash chroma-
tography [silica gel; eluant solution, CH2Cl2/hexane (2:3)] to give
2.08 g of the Fmoc-isothiocyanate as an off-white solid (74%
yield). 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J ) 7.5 Hz, 2H),
7.58 (d, J ) 7.5 Hz, 2H), 7.43 (t, J ) 7.5 Hz, 2H), 7.32 (t, J ) 7.5
Hz, 2H), 4.45 (d, J ) 7.4 Hz, 2H), 4.25 (t, J ) 7.4 Hz, 1H). 13C
NMR (400 MHz, CDCl3) δ 150.45, 147.43, 142.89, 141.37, 128.21,
127.39, 125.16, 120.31, 70.75, 46.36. IR (polyethylene film) 2917,
2848, 1965 (NdCdS stretch), 1745, 1450, 1242, 1085, 757, 740
2-Am in o-4-(4-(dieth ylam in o)ph en yl)th iazole (5): 1H NMR
(400 MHz, CD3CN) δ 7.61 (d, J ) 9 Hz, 2H), 6.68 (d, J ) 9 Hz,
2H), 6.54 (s, 1H), 5.49 (bs, 2H), 3.38 (q, J ) 7 Hz, 4H), 1.14 (d,
J ) 7 Hz, 6H). HR-MS FAB m/z for C13H17N3S calcd 247.1143
(M+), obsd 247.1156. Anal. Calcd: C, 63.12; H, 6.93; N, 16.99;
S, 12.96. Obsd: C, 63.06; H, 6.88; N, 17.07; S, 12.89.
2-Am in o-4-(4-m eth oxyp h en yl)th ia zole (6): 1H NMR (400
MHz, DMSO-d6) δ 7.71 (d, J ) 9 Hz, 2H), 6.97 (bs, 2H), 6.90 (d,
J ) 9 Hz, 2H), 6.81 (s, 1H), 3.75 (s, 3H). HR-MS FAB m/z for
C
10H10N2OS calcd 207.0592 (M + H+), obsd 207.0589. Anal.
Calcd: C, 58.23; H, 4.89; N, 13.58; S, 15.54. Obsd: C, 58.34; H,
5.01; N, 13.36; S, 15.39.
2-Am in o-4-(3-n itr op h en yl)th ia zole (7):
1H NMR (400
cm-1
16H11NO2S calcd 281.0510 (M+), obsd 281.0518. Anal. Calcd:
.
FAB-MS m/z 281, 179, 165. HR-MS FAB m/z for
MHz, DMSO-d6) δ 8.59 (d, J ) 2 Hz, 1H), 8.22 (d, J ) 8 Hz,
1H), 8.10 (dd, J ) 8, 2 Hz, 1H), 7.65 (t, J ) 8 Hz, 1H), 7.33 (s,
H), 7.21 (bs, 2H). HR-MS FAB m/z for C9H7N302S calcd 222.0337
(M + H+), obsd 222.0336. Anal. Calcd: C, 48.86; H, 3.19; N,
18.99; S, 14.49. Obsd: C, 49.26; H, 3.33; N, 18.81; S, 14.29.
2-Am in o-4-a d a m a n tylth ia zole (8): 1H NMR (400 MHz,
DMSO-d6) δ 6.74 (bs, 2H), 5.98 (s, 1H), 1.97 (bs, 3H), 1.79 (s,
6H), 1.70 (d, J ) 12 Hz, 3H), 1.65 (d, J ) 12 Hz, 3H). HR-MS
FAB m/z for C10H10N2OS calcd 234.1190 (M+), obsd 234.1174.
Anal. Calcd: C, 66.63; H, 7.74; N, 11.95; S, 13.68. Obsd: C,
66.66; H, 7.78; N, 11.86; S, 13.58.
C
C, 68.31; H, 3.94; N, 4.98; S, 11.40. Obsd: C, 68.33; H, 3.93; N,
4.97; S, 11.46.
P h en ylth iou r ea (3). Compound 2 (392 mg, 1.4 mmol) was
dissolved in 5 mL of methylene chloride in a 25-mL round-bottom
flask. Aniline (109 µL, 1.2 mmol) was added dropwise to this
solution. TLC analysis of the reaction mixture after 30 min
(silica gel plates, CH2Cl2 eluant) indicated complete consumption
of the aniline (Rf ) 0.4) and the clean formation of a new product
(Rf ) 0.7) distinct from 2 (Rf ) 0.9). A solution of 20% piperidine
in methanol (2.5 mL) was added to the flask, and the reaction
was allowed to stir overnight. TLC analysis of the reaction
(silica gel plates, CH2Cl2/acetone 3:2 eluant) indicated the
formation of a product that coeluted with a genuine sample of
phenylthiourea (Rf ) 0.6). Flash chromatography of the reaction
(silica gel, CH2Cl2/acetone 8:1 eluant) resulted in product
isolation of 159 mg, which had clean 1H and 13C NMR spectra
identical with those of a genuine sample of phenylthiourea.
3-(F lu or en ylm et h yloxyca r b on yl)-1-p ip er id in et h ioca r -
boxa m id e (4). In a 50-mL round-bottom flask, Fmoc-NCS (562
mg, 2 mmol) was dissolved in 10 mL of dry methylene chloride.
A solution of piperidine (179 µL, 1.81 mmol) in 2 mL of
methylene chloride was added dropwise to the stirring solution
of Fmoc-NCS over 3 min. TLC (silica gel plates, CH2Cl2 eluant)
indicated clean transformation of the Fmoc-NCS (Rf ) 0.9) into
4 (Rf ) 0.2). Chromatographic purification (silica gel, CH2Cl2
eluant) netted 649 mg (98% yield) of compound 3. 1H NMR (400
MHz, CDCl3) δ 7.75 (d, J ) 7.5 Hz, 2H), 7.56 (d, J ) 7.5 Hz,
2H), 7.39 (t, J ) 7.5 Hz, 2H), 7.31 (t, J ) 7.5 Hz, 2H), 7.26 (s,
1H), 4.48 (d, J ) 6.6 Hz, 2H), 4.20 (t, J ) 6.6 Hz, 1H), 3.98 (bs,
2H), 3.44 (bs, 2H), 1.65 (bs, 6H). HR-MS FAB m/z for
2-Am in o-4,5-d ip h en ylth ia zole (9). 1H NMR (400 MHz,
DMSO-d6) δ 7.36 (m, 2H), 7.30-7.18 (m, 8H), 7.11 (bs, 2H). HR-
MS FAB m/z for C15H12N2S calcd 253.0799 (M + H+), obsd
253.0800. Anal. Calcd: C, 71.40; H, 4.79; N, 11.10; S, 12.71.
Obsd: C, 71.31; H, 4.82; N, 11.10; S, 12.65.
Gen er a l P r oced u r e for th e N-Su bstitu ted Th ia zoles 10-
13. Argogel-MB-CHO resin (366 mg, 0.41 mmol/g substitution)
was placed into an Ace pressure tube. Trimethyl orthoformate
(TMOF, 5 mL) was added to the flask along with 10 equiv of
primary amine. The tube was capped and heated for 2 h at 70
°C in an oil bath. The tube was swirled periodically during
heating. After cooling and removal of the TMOF solution with
the use of a filtration cannula, the entire process was repeated
a second time. The resin was then washed once with TMOF (5
mL) and three times with anhydrous methanol (5 mL.) Anhy-
drous methanol (5 mL) was then added to the resin, followed by
the addition of 133 mg (20 equiv) of sodium borohydride. After
vigorous gas evolution had ceased, the tube was capped and
agitated for 8 h at room temperature. The resin was then
transferred to a polypropylene reaction vessel and washed with
methanol (5 mL, 3×), methanol:water (1:1, 5 mL, 3×), DMF:
water (1:1, 5 mL, 3×), DMF (5 mL, 3×), and methylene chloride
(5 mL, 3×). The reaction vessel was transferred to the Symphony/
Multiplex multiple peptide synthesizer, and a modified version
of the above-described program for 2-aminothiazole synthesis
was executed. In this version, the initial exposure to 20%
piperidine was eliminated, and all delivered volumes were
reduced to 3.75 mL. After completion of the program, the resin
was transferred to a Whatman polypropylene syringe-type
reaction vessel (12-mL) and dried under vacuum. A solution of
95:5 TFA:water (5 mL) was added, and the tube was heated at
50 °C for 4 h. The cleavage solution and two subsequent rinses
of the resin (one of 5 mL of 95% TFA and one of 5 mL of MeOH)
were combined and evaporated to dryness with a Speedvac. The
desired compound was purified via preparative HPLC and then
passed over a column of basic alumina with acetonitrile as the
eluant to afford the free base of the pure compound.
C
21H22N2O2S calcd 367.1480 (M + H+), obsd 367.1486. Anal.
Calcd: C, 68.83; H, 6.05; N, 7.64; S, 8.75. Obsd: C, 68.65; H,
6.08; N, 7.62; S, 8.67.
Gen er a l Syn th esis of Un su bstitu ted 2-Am in oth ia zoles
5-9. Rink amide MBHA resin (364 mg, 0.55 mmol/g substitu-
tion) was placed into a polypropylene reaction vessel. The
synthesis was carried out automatically in
a Symphony/
Multiplex multiple peptide synthesizer. The resin was swollen
through the addition of DMF (5 mL, 5 min, 3×). The resin was
then treated with a solution of 20% piperidine in DMF (5 mL,
2.5 min, 3×) to remove the Fmoc protecting group from the resin.
After washing with DMF (5 mL, 30 s, 3×) and methylene
chloride (5 mL, 30 s, 5×), a 0.2 M solution of 2 in methylene
chloride was applied to the resin (5 mL, 20 min, 1×). The resin
was washed with methylene chloride (5 mL, 30 s, 3×) and DMF
(5 mL, 30 s, 3×) and subsequently reacted with 20% piperidine
in DMF (5 mL, 2.5 min, 3×) to produce the resin-bound thiourea.
The resin was then washed with DMF (5 mL, 30 s, 3×) and
dioxane (5 mL, 30 s, 3×). The desired R-bromo ketone (0.2 M
in dioxane) was added (5 mL, 1 h), and the resin was washed
with dioxane (5 mL, 30 s, 3×). The R-bromo ketone addition
and subsequent wash were repeated two more times. The resin
was then washed with methylene chloride (5 mL, 30 s, 5×) and
dried briefly (10 min) under a stream of nitrogen. The reaction
products were cleaved with a solution of aqueous TFA (95%, 5
2-(Bu tyla m in o)-4-(4-n itr op h en yl)th ia zole (10): 1H NMR
(400 MHz, CDCl3) δ 11.56 (bs, 1H), 8.20 (d, J ) 9 Hz, 2H), 7.90
(d, J ) 9 Hz, 2H), 6.87 (s, 1H), 5.96 (bs, 1H), 3.29 (m, 2H), 1.65
(m, 2H), 1.41 (m, 2H), 0.94 (t, J ) 7 Hz, 3H). HR-MS FAB m/z
for C13H15N3O2S calcd 278.0963 (M + H+), obsd 278.0969. Anal.
Calcd: C, 56.30; H, 5.45; N, 15.15; S, 11.56. Obsd: C, 56.43; H,
5.58; N, 14.89; S, 11.33.
2-((2-(4-Me t h oxyp h e n yl)e t h yl)a m in o)-4-(4-m e t h oxy-
p h en yl)th ia zole (11): 1H NMR (400 MHz, CDCl3) δ 8.95 (bs,

200 J . Org. Chem., Vol. 63, No. 1, 1998
Notes
1H), 7.64 (d, J ) 8 Hz, 2H), 7.14 (d, J ) 8 Hz, 2H), 6.92 (d, J )
8 Hz, 2H), 6.84 (d, J ) 8 Hz, 2H), 6.42 (s, 1H), 3.82 (s, 3H), 3.77
(s, 3H), 3.47 (m, 2H), 2.95 (t, J ) 7 Hz, 2H). HR-MS FAB m/z
for C19H20N2O2S calcd 341.1324 (M + H+), obsd 341.1310. Anal.
Calcd: C, 67.03; H, 5.92; N, 8.23; S, 9.42. Obsd: C, 67.03; H,
6.01; N, 8.21; S, 9.51.
2-((2-Met h oxyet h yl)a m in o)-4-(4-ch lor op h en yl)t h ia zole
(12): 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J ) 9 Hz, 2H), 7.32
(d, J ) 9 Hz, 2H), 6.66 (s, 1H), 5.38 (bt, 1H), 3.60 (t, J ) 5 Hz,
min, 3×). After washing again with DMF (5 mL, 30 s, 5×), the
resin was treated for 2 h with a 0.4 M Fmoc-glycine-OH solution
in DMF (2.5 mL) and a 0.4 M solution of diisopropylcarbodiimide
in DMF (2.5 mL). The resin was then washed with DMF (5 mL,
30 s, 3×). The coupling reaction and the subsequent wash were
repeated two more times. A negative ninhydrin test at this point
indicated completion of the coupling reaction. The 2-aminothia-
zole was then constructed with the use of 4-fluorophenyacyl
bromide and the general procedure described above. The desired
compound was purified via preparative HPLC ansd passed over
a column of basic alumina (MeOH eluant) to afford the free base
of the pure compound. 1H NMR (400 MHz, DMSO-d6) δ 7.84
(dd, J ) 9, 6 Hz, 2H), 7.80 (bt, J ) 6 Hz, 1H), 7.41 (bs, 1H), 7.18
(t, J ) 9 Hz, 2H), 7.06 (bs, 1H), 7.04 (s, 1H), 3.88 (d, J ) 6 Hz,
2H). HR-MS FAB m/z for C11H10FN3OS calcd 252.0606 (M +
H+), obsd 252.0594. Anal. Calcd: C, 52.58; H, 4.01; N, 16.72;
S, 12.76. Obsd: C, 52.33; H, 4.02; N, 16.57; S, 12.71.
2H), 3.51 (m, 2H), 3.38 (s, 3H). HR-MS FAB m/z for C12H13
-
ClN2OS calcd 269.0515 (M + H+), obsd 269.0503. Anal. Calcd:
C, 53.56; H, 4.88; N, 10.42; S, 11.93. Obsd: C, 53.74; H, 4.85;
N, 10.34; S, 11.83.
2-(Cyclop en tyla m in o)-4-(4-ch lor op h en yl)-5-p h en ylth ia -
zole (13): 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J ) 9 Hz, 2H),
7.26-7.22 (m, 5H), 7.18 (d, J ) 9 Hz, 2H), 5.18 (bd, J ) 7 Hz,
1H), 3.81 (m, 1H), 2.06 (m, 2H), 1.80-1.50 (m, 6H). FAB-MS
m/z for C20H19ClN2S calcd 355 (M + H+), obsd 355. Anal.
Calcd: C, 67.69; H, 5.40; N, 7.89; S, 9.03. Obsd: C, 67.75; H,
5.56; N, 7.68; S, 8.78.
2-(4-(4-F lu or op h en yl)-2-th ia zoyla m in o)a ceta m id e (14).
Rink amide MBHA resin (364 mg, 0.55 mmol/g substitution) was
weighed out into a polyethylene reaction vessel. A Symphony/
Multiplex multiple peptide synthesizer was first used to couple
Fmoc-glycine-OH to the resin according to the following proce-
dure. The resin was swollen with DMF (5 mL, 5 min, 3×) and
subsequently treated with 20% piperidine in DMF (5 mL, 2.5
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H NMR,
13C NMR, and IR spectra of compound 2 are provided.
Reproductions of 1H NMR spectra of compounds 5-14 are also
included (12 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of this journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O971542A