Parallel solution phase synthesis of a library of amino acid derived 2-arylamino-[1,3,4]-oxadiazoles

Article abstract of DOI:10.1016/j.tetlet.2008.05.110

A mild method for the synthesis of peptidomimetic 2-arylamino 5-substituted 1,3,4-oxadiazoles from Boc-protected α-amino acid derived hydrazides has been developed, and applied in a parallel solution-phase synthesis. The optimized reaction conditions involve a one-pot reaction of Boc-protected amino acid hydrazides with arylisothiocyanates in the presence of either Hg(II) chloride, Mukaiyama's reagent (2-chloro-N-methylpyridinium iodide) or polymer supported Mukaiyama's reagent, with triethylamine in dichloromethane at ambient temperature. The 1,3,4-oxadiazole products were obtained in good to excellent yields without any detectable epimerization. The reactions proceed via initial formation of thiosemicarbazides, followed by dehydrothiolative cyclization to the 1,3,4-oxadiazoles.

Full text of DOI:10.1016/j.tetlet.2008.05.110

Tetrahedron Letters 49 (2008) 4746–4749
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Parallel solution phase synthesis of a library of amino acid
derived 2-arylamino-[1,3,4]-oxadiazoles
*
Julia I. Gavrilyuk, Alan J. Lough, Robert A. Batey
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild method for the synthesis of peptidomimetic 2-arylamino 5-substituted 1,3,4-oxadiazoles from
Received 30 April 2008
Revised 22 May 2008
Accepted 23 May 2008
Available online 29 May 2008
Boc-protected a-amino acid derived hydrazides has been developed, and applied in a parallel solution-
phase synthesis. The optimized reaction conditions involve a one-pot reaction of Boc-protected amino
acid hydrazides with arylisothiocyanates in the presence of either Hg(II) chloride, Mukaiyama’s reagent
(2-chloro-N-methylpyridinium iodide) or polymer supported Mukaiyama’s reagent, with triethylamine
in dichloromethane at ambient temperature. The 1,3,4-oxadiazole products were obtained in good to
excellent yields without any detectable epimerization. The reactions proceed via initial formation of thio-
semicarbazides, followed by dehydrothiolative cyclization to the 1,3,4-oxadiazoles.
Ó 2008 Elsevier Ltd. All rights reserved.
1,3,4-Oxadiazole derived compounds are known to display a
wide range of biological activities including anti-inflammatory,
analgesic, antibacterial, fungicidal, antimicrobial, hypoglycemic,
antimalarial, antitubercular, antidepressant and other activities.1
1,3,4-Oxadiazoles can also serve as bioisosteric replacements of
amide and ester functionalities,2 and can participate in hydrogen
bonding interactions as hydrogen bond acceptors. As such, their
peptidomimetic ability has been explored3 and reported in the
development of Phe-Gly mimetics of dermorphin (Tyr-D-Ala-
Phe-Gly-Tyr-Pro-Ser-NH2) and Substance P (Arg-Pro-Lys-Pro-Gln-
Gln-Phe-Phe-Gly-Leu-Met-NH2).4 In addition to their utility as
bioactive molecules, 1,3,4-oxadiazoles are useful intermediates
for organic synthesis,5 particularly as electron-deficient azadienes
in inverse electron demand Diels–Alder reactions.6
As part of our interest in the synthesis of peptidomimetic het-
erocycle-peptide hybrid molecules,7 we now report an approach
to the synthesis of amino acid derived 2-arylamino-[1,3,4]-oxadi-
azoles. Most of the synthetic methods available for the construc-
tion of 1,3,4-oxadiazoles involve rather forcing conditions and/or
high temperatures that are unsuitable for use with amino acids
or peptides.8 Thus, we aimed to develop a reliable method, mild
enough to avoid epimerization problems, and that would be com-
patible with orthogonal protecting groups. In addition, it was
desirable that the approach be applicable to parallel solution-
phase synthesis and, potentially suitable for combinatorial solid-
phase library production. We envisaged that an approach based
ously applied to amino acid derived 1,3,4-oxadiazoles, dehydrothio-
lation of simple acylthiosemicarbazides to give 1,3,4-oxadiazoles
has been reported using a variety of reagents including lead oxide,
mercury oxide, mercury acetate, copper sulfate, bromine, I2/NaOH
and DCC.9 Moreover, the strategy we envisaged is similar to those
we have previously employed for the synthesis of
a-amino acid
and peptide derived 5-aminotetrazoles and 2-iminohydantoins,7,10
involving activation of thiourea intermediates.
Several Boc-protected amino acids (Phe, Leu, Ala) were first
converted to the corresponding hydrazides 1 following a literature
procedure using EDCI activation.11 Reaction of the hydrazides 1
with arylisothiocyanates in CH2Cl2 for 20 min at room temperature
provided the corresponding Boc-thiosemicarbazides 2a–h quanti-
tatively, without the need for chromatographic purification12 (Ta-
ble 1). Deprotection of 2 using 20% TFA/CH2Cl2 solution and
treatment of the resulting thiosemicarbazides with HgCl2 in the
presence of triethylamine in acetonitrile for 12 h at room temper-
ature gave the desired oxadiazole products 3a–h in 78–85% iso-
lated yields (Table 1).
The yields of the oxadiazoles were improved, and the purifica-
tion protocol simplified, if the Boc group was not removed prior
to the dehydrothiolative cyclization. Thus, reaction of Boc-pro-
tected hydrazides 1 with arylisothiocyanates gave the correspond-
ing thiosemicarbazides 2,12 which on treatment with triethylamine
and HgCl2 led to the Boc-protected 1,3,4-oxadiazoles 4 (Table
2).13,14 This method was suitable for parallel solution-phase syn-
thesis, using semi-automated flash chromatographic purification.
Twenty-four examples were prepared in parallel fashion starting
from Boc-Ala-OH, Boc-Leu-OH and Boc-Phe-OH in combination
with eight different arylisothiocyanates (Table 2). The products 4
were obtained in good to excellent yields, after reaction for 12 h
at ambient temperature.
upon the dehydrothiolative cyclization of a-amino acid or peptide
derived acylthiosemicarbazides would generate the corresponding
1,3,4-oxadiazoles. Although such a strategy has not been previ-
* Corresponding author. Tel./fax: +1 416 978 5059.
E-mail address: rbatey@chem.utoronto.ca (R. A. Batey).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.110

J. I. Gavrilyuk et al. / Tetrahedron Letters 49 (2008) 4746–4749
4747
Table 1
Synthesis of amino acid derived acylthiosemicarbazides
2 and 5-substituted
2-arylamino 1,3,4-oxadiazoles 3a
1
1
R
S
R
H
N
H
N
(a)
Boc
Boc
N
H
N
N
H
N
H
NH
2
2
H
R
O
R
O
1
2
(quant)
1
R
2
H
N
(b), (c)
O
H N
2
N
N
3
Entry
Products
R1
R2
Yield of 3b
%
1
2
3
4
5
6
7
8
2/3a
2/3b
2/3c
2/3d
2/3e
2/3f
2/3g
2/3h
Me
i-Pr
Bn
Bn
Bn
Bn
Bn
Bn
H
H
H
4-Me
2-Br
3-Br
80
78
85
80
79
78
80
80
4-NO2
3,4,5-(MeO)3
a
Reagents: (a) ArNCS (1.0 equiv), CH2Cl2, rt, 20 min. (b) 20% TFA/CH2Cl2, rt, 1.5 h.
(c) HgCl2 (1.1 equiv), Et3N (1.1 equiv), MeCN, rt, 12 h.
b
Isolated yields obtained after column chromatographic purification (1% Et3N in
EtOAc:Hexanes 1:4).
Figure 1. X-ray crystal structure of the 1,3,4-oxadiazole 4Ce. Thermal ellipsoids are
shown at 30% probability.
The structure of the product oxadiazole 4Ce was confirmed by
X-ray crystallography (Fig. 1).15 The solid-state conformation of
4Ce revealed that the oxadiazole and bromophenyl rings were
coplanar, maximizing conjugation of the anilino-N lone-pair.
A selection of eight of the N-Boc-protected compounds 4 were
treated with 50% TFA/CH2Cl2 solution to give the deprotected
compounds 3 as their TFA salts. The products were obtained in
excellent yields and high purities without the need for chromato-
graphic separation (Table 3). The yields and purities of the com-
pounds 3a–f,h obtained in this manner (i.e., synthesized via 4)
were comparable to the results for the syntheses of these com-
pounds where N-Boc deprotection preceded oxadiazole formation
(i.e., Table 1). In general, however, synthesis and storage via the
N-Boc-protected compounds 4 is preferable due to the greater
long-term stability of 4 and the TFA salt of 3, compared to the
free-base form of 3.
Proline derived 1,3,4-oxadiazoles 6 can also be synthesized
using these two approaches (Table 4). In the first approach, initial
formation of the Pro-derived thiosemicarbazide was followed by
Boc-deprotection using 20% TFA/CH2Cl2, and then immediate cycli-
zation to give 6a–h. This approach had the advantage of not requir-
ing isolation of any of the intermediates. However, the crude
products 6a–h were obtained with only 80–87% purity,16 necessi-
tating flash chromatographic purification of 6. In the second
approach, the intermediate thiosemicarbazides were first cyclized
to give 5a–h, and subsequently deprotected using 50% TFA/CH2Cl2
Table 2
Parallel synthesis of N-Boc-protected 5-substituted 2-arylamino 1,3,4-oxadiazoles 4
using HgCl2 and Et2Na
1
1
R
R
2
H
N
R
H
N
O
(a), (b)
Boc
Boc
N
H
NH
N
H
2
N
N
O
1
4
Entry
Product
R1
R2
Yieldb
%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4Aa
4Ab
4Ac
4Ad
4Ae
4Af
4Ag
4Ah
4Ba
4Bb
4Bc
4Bd
4Be
4Bf
4Bg
4Bh
4Ca
4Cb
4Cc
4Cd
4Ce
4Cf
Me
Me
Me
Me
Me
Me
Me
Me
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
H
85
88
86
87
97
99
80
98
92
88
80
89
98
99
85
96
89
89
80
87
99
99
75
97
2-Me
3-Me
4-Me
2-Br
3-Br
4-NO2
3,4,5-(MeO)3
H
2-Me
3-Me
4-Me
2-Br
3-Br
4-NO2
3,4,5-(MeO)3
H
2-Me
3-Me
4-Me
2-Br
Table 3
Boc group deprotection of 4 into 3
1
1
R
R
2
2
H
N
R
H
N
R
O
O
50% TFA
H N
2
BocHN
N
N
N
N
CH Cl
2
2
4
3 (TFA salt)
Entry
Product
R1
R2
Yield,a % (Purityb %)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
Me
i-Pr
Bn
Bn
Bn
Bn
Bn
Bn
H
H
H
4-Me
2-Br
3-Br
99 (94)
98 (97)
99 (95)
99 (91)
97 (92)
98 (95)
98 (97)
99 (93)
3-Br
4-NO2
3,4,5-(MeO)3
4Cg
4Ch
3h
3i
3,4,5-(MeO)3
3-Me
a
Reagents: (a) ArNCS (1.0 equiv), CH2Cl2, rt, 20 min. (b) HgCl2 (1.1 equiv), Et3N
(1.1 equiv), MeCN, rt, 12 h.
b
a
Isolated yields obtained after column chromatographic purification
Yield of the unchromatographed product.
Determined by HPLC/LCMS with the UV absorption measured at 254 nm.
b
(EtOAc:Hexanes 1:4).

4748
J. I. Gavrilyuk et al. / Tetrahedron Letters 49 (2008) 4746–4749
Table 4
Hg in the crude solid sample after aqueous work-up, while the
Synthesis of proline derived 1,3,4-oxadiazoles 5 and 6a
Hg level of the same sample after flash chromatography was not
detectable by ICP AES. The use of Mukaiyama’s reagent is of course
advantageous due to its lower toxicity; however, the products
obtained using this method must also be purified by column
chromatography to remove the organic by-products. The use of
the polymer-supported CMPI equivalent 8 avoids the toxicity/envi-
ronmental problems associated with the use of mercury salts,
while requiring only a simple filtration upon completion of the
reaction. Thus, in the case of the compound 4Ce prepared using so-
lid supported reagent 8, NMR analysis of the crude sample showed
excellent purity, and column chromatographic purification was not
required. Another operational simplification permitted by the use
of the polymer-supported reagent 8 is that all of the reagents can
be added at the same time (i.e., without the pre-treatment of the
hydrazide with the arylisothiocyanate). Thus, stirring of 1a,
2-bromophenyl isothiocyanate (1 equiv), 7 (5 equiv) and triethyl-
amine (5 equiv) for 16 h gave 4Ce in 94% yield, compared to a
95% yield (Table 5) obtained for the two-stage addition. Finally, a
R
H
N
H
N
(a)—(c)
O
NH
N
Boc
N
H
2
N
N
O
1d
6
(a), (c)
(d)
R
H
N
O
N
Boc
N
N
5
Entry
R
Products
Yield of 6b,c (%)
Yield of 5b,d (%)
1
2
3
4
5
6
7
8
H
5/6a
5/6b
5/6c
5/6d
5/6e
5/6f
5/6g
5/6h
78
75
75
77
84
86
73
82
87
88
84
84
96
95
86
98
2-Me
3-Me
4-Me
2-Br
3-Br
4-NO2
3,4,5-(MeO)3
possible concern for a-amino acid derived compounds is whether
a
Reagents: (a) ArNCS (1.0 equiv), CH2Cl2, rt, 20 min, (b) 20% TFA/CH2Cl2, rt, 1.5 h,
(c) HgCl2 (1.1 equiv), Et3N (1.1 equiv), MeCN, rt, 12 h, (d) 50% TFA/CH2Cl2, rt, 30 min.
stereochemical integrity is retained in the products. Chiral HPLC
determination (Chiralcel OD column) of independently synthesized
(R)-4Ce and (S)-4Ce verified that epimerization was not observed
(60.01%) under the reaction conditions.
In conclusion, a convenient method for the synthesis of 2-aryl-
amino 5-substituted 1,3,4-oxadiazoles from Boc-protected amino
acid derived hydrazides has been developed. Further studies on
the synthesis and applications of 1,3,4-oxadiazoles as peptidomi-
metic building blocks will be reported in due course.
b
Isolated yields obtained after column chromatographic purification based on
the starting Boc-protected hydrazide 1d.
c
Isolated yields of 6 produced using (a)–(c).
d
Isolated yields of 6 prepared by deprotection of 5 were quantitative.
to give 6a–h. The initial Boc-protected products 5 were isolated in
good yields. Again, column chromatographic purification following
the cyclization step was required, since the crude products 5 had
85–93% purity.16 Deprotection of 5a–h occurred in quantitative
yields to give 6a–h as the TFA salts in excellent purities (P98%,
as confirmed by 1H NMR analysis) without the need for chromato-
graphic purification. Overall, although both approaches required a
single chromatographic purification, purification of 5 was more
straightforward than for 6, and the overall yields of 6 were higher
via 5. In addition, the Boc-protected compounds 5 were suitable for
long-term storage.
Acknowledgements
We thank Dr. Ghotas Evindar for preliminary experiments, Dr.
Alex Young for MS analyses, and Dan Mathers for ICP AES analyses.
The Natural Science and Engineering Research Council of Canada
(NSERC) and the Ontario Research and Development Fund (ORDCF)
supported this work. J.I.G. is grateful to the University of Toronto
for fellowship support.
We were also interested in developing conditions using alterna-
tive dehydrothiolating agents for the reaction, to avoid the use of
HgCl2. As a first step, the formation of 1,3,4-oxadiazole 4Ce from
1a was compared using three different dehydrothiolating agents:
HgCl2, Mukaiyama’s reagent (2-chloro-N-methylpyridinium iodide,
References and notes
1. (a) Amir, M.; Shikha, K. Eur. J. Med. Chem. 2004, 39, 535–545; (b) Adelstein, G.
W. J. Med. Chem. 1973, 16, 309–312; (c) Morton, H. M.; Heuser, D. J.; Joyner, C.
T.; Batchelor, J. F.; White, H. L. J. Med. Chem. 1996, 39, 1857–1863; (d) Chavan,
V. P.; Sonawane, S. A.; Shingare, M. S.; Karale, B. K. Chem. Heterocycl. Compd.
2006, 42, 625–630; (e) Amir, M.; Kumar, S. Pharmazie 2005, 60, 175–180; (f)
Swain, C. J.; Baker, R.; Kneen, C.; Moseley, J.; Saunders, J.; Seward, E. M.;
Stevenson, G.; Beer, M.; Stanton, J.; Watling, K. J. Med. Chem. 1991, 34, 140–151.
2. Guimaraes, C. R. W.; Boger, D. L.; Jorgensen, W. L. J. Am. Chem. Soc. 2005, 127,
17377–17384 and references cited therein.
3. Orlek, B. S.; Blaney, F. E.; Brown, F.; Clark, M. S. G.; Hadley, M. S.; Hatcher, J.;
Riley, G. J.; Rosenberg, H. E.; Wadsworth, H. J.; Wyman, P. J. Med. Chem. 1991,
34, 2726–2735.
4. Borg, S.; Vollinga, R. C.; Labarre, M.; Payza, K.; Terenius, L.; Luthman, K. J. Med.
Chem. 1999, 42, 4331–4342.
7
17), and its polymer-supported equivalent 817,18 (Table 5). Each
experiment was conducted at ambient temperature for 16 h,
affording 4Ce in excellent yields (92–95%) with excellent purities
(98–99%). For compound 4Ce, synthesized using either HgCl2 or
Mukaiyama’s reagent, purification by column chromatography
was required. For compound 4Ce synthesized by the HgCl2 proto-
col, NMR analysis of the crude sample showed excellent purity.
However, ICP AES analysis revealed the presence of ꢀ200 ppm of
5. For a review, see: Warrener, R. N. Eur. J. Org. Chem. 2000, 3363–3398.
6. For example, see: (a) Ishikawa, H.; Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L.
J. Am. Chem. Soc. 2006, 128, 10596–10612; (b) Elliott, G. I.; Fuchs, J. R.; Blagg, B.
S. J.; Ishikawa, H.; Tao, H.; Yuan, Z.-Q.; Boger, D. L. J. Am. Chem. Soc. 2006, 128,
10589–10595; (c) Wilkie, G. D.; Elliott, G. I.; Blagg, B. S. J.; Wolkenberg, S. E.;
Soenen, D. R.; Miller, M. M.; Pollack, S.; Boger, D. L. J. Am. Chem. Soc. 2002, 124,
11292–11294; (d) Wolkenberg, S. E.; Boger, D. L. J. Org. Chem. 2002, 67, 7361–
7364.
7. (a) Gavrilyuk, J. I.; Evindar, G.; Batey, R. A. J. Comb. Chem. 2006, 8, 237–246; (b)
Gavrilyuk, J. I.; Evindar, G.; Batey, R. A. J. Comb. Chem. 2007, 9, 644–651.
8. For reviews on 1,3,4-oxadiazoles and leading references on their synthesis, see:
(a) Behr, L. C. In The Chemistry of Heterocyclic Compounds; Weissberger, A., Ed.;
Wiley: New York, 1962; Vol. 17, pp 263–282; (b) Nesynov, E. P.; Grekov, A. P.
Russ. Chem. Rev. (Engl. Transl.) 1964, 33, 508–514; (c) Hetzheim, A.; Möckel, K.
Adv. Heterocycl. Chem. 1966, 7, 183–224; (d) Hill, J. In Comprehensive
Heterocyclic Chemistry; Potts, K. T., Katritzky, A. R., Rees, C. W., Eds.;
Pergamon: Oxford, 1984; Vol. 6, pp 427–446; (e) Hill, J. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Table 5
Comparative study of dehydrothiolating agents used for the formation of 4Ce
(a) 2-BrC H NCS (1.0 eq),
6
4
Ph
Ph
Br
CH Cl , rt, 20 min
2
2
H
N
H
N
O
Boc
BocHN
N
H
NH
2
(b) Dehydrothiolation
Agent, Et N, rt, 16 h
3
N
N
O
1a
4Ce
Entry
Reaction conditions
Yield (%)
1
2
3
HgCl2 (1.1 equiv), Et3N (3.0 equiv), MeCN, 16 h
CMPI 7 (5.0 equiv), Et3N (5.0 equiv), MeCN, 16 h
Polymer-supported CMPI 8 (5.0 equiv), Et3N (5.0 equiv),
MeCN:CH2Cl2 (1:1), 16 h
92a
94a
95
a
Isolated yield after column chromatography.

J. I. Gavrilyuk et al. / Tetrahedron Letters 49 (2008) 4746–4749
4749
Pergamon: Oxford, 1996; pp 267–287; (f) Hetzheim, A. In Houben-Weyl
Methoden der Organischen Chemie; Schaumann, E., Ed.; Thieme: Stuttgart,
1994; Vol. E8c, pp 526–647; (g) Weaver, G. W. In Science of Synthesis: Houben-
Weyl Methods of Molecular Transformations; Storr, R. C., Gilchrist, T. L., Eds.;
Thieme: Stuttgart, 2003; Vol. 13, pp 219–251.
CD3OD–CD2Cl2 3:1) d 8.00 (1H, dd, J = 8.0, 1.0 Hz), 7.60 (1H, dd, J = 8.0, 1.0 Hz),
7.36 (1H, ddd, J = 8.0, 8.0, 1.2 Hz), 7.22–7.31 (5H, m), 7.02 (1H, ddd, J = 8.0, 8.0,
1.0 Hz), 5.02–5.09 (1H, m), 3.28 (1H, dd, J = 13.5, 6.5 Hz), 3.13 (1H, dd, J = 13.5,
9.0 Hz), 1.36 (9H, br s); 13C NMR (100 MHz, CD3OD:CD2Cl2 3:1) d 161.6, 159.4,
155.2, 135.4, 133.4, 132.6, 128.9, 128.3, 127.1, 124.0, 120.9, 118.7, 111.6, 80.5,
42.6, 28.5, 22.8; HRMS (ESI) m/e ([M+1]+) calcd for C21H24N4O3Br 459.1024,
found 459.1026.
9. For example, see (a) Omar, F. A.; Mahfouz, N. M.; Rahman, M. A. Eur. J. Med.
Chem. 1996, 31, 819–825; (b) Wang, X.; Li, Z.; Zhang, Z.; Da, Y. Synth. Commun.
2001, 31, 1907–1911.
10. (a) Batey, R. A.; Powell, D. A. Org. Lett. 2000, 2, 3237–3240; (b) Evindar, G.;
Batey, R. A. Org. Lett. 2003, 5, 1201–1204.
11. Confalone, P. N.; Woodward, R. B. J. Am. Chem. Soc. 1983, 105, 902–906.
12. The Boc-thiosemicarbazides 2 did not require purification for use in the next
step.
15. Crystallographic data (excluding structure factors) for the structure of
compound 4Ce have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC 683066.
16. Purities of 5 and 6 were determined by HPLC/LCMS with the UV absorption
measured at 254 nm.
17.
13. Hydrazide 1 (7.20 mmol) and arylisothiocyanate (7.20 mmol, 1.0 equiv) in
CH2Cl2 (5 ml) were stirred for 20 min at room temperature. The solvent was
removed in vacuo to give 2 which was immediately used in the next step. To a
+
N
Cl
—
+
—
N
Cl I
solution of
2 (0.36 mmol) in CH3CN (3 ml) was added HgCl2 (108.6 mg,
TfO
0.4 mmol) and triethylamine (0.088 ml, 1.10 mmol). The reaction mixture was
stirred at room temperature for 12 h. The reaction slurry was filtered through a
short plug of Celite and the solvent was removed in vacuo. The crude products
were purified using semi-automated flash chromatography (silica gel, EtOAc/
hexanes 1:4) on a Biotage SP1 instrument.
Me
7
8
O
Wang
.
14. Representative chararacterization data. (S) Isomer: {1-[5-(2-Bromophenyl-
amino)-[1,3,4]oxadiazol-2-yl]-2-phenylethyl}-carbamic acid tert-butyl ester
18. Polymer-supported CMPI equivalent 8 is prepared by treatment of Wang resin
with excess of 2-chloropyridine and triflic anhydride, see: (a) Crosignani, S.;
Gonzalez, J.; Swinnen, D. Org. Lett. 2004, 6, 4579–4582; (b) Crosignani, S.;
Swinnen, D. J. Comb. Chem. 2005, 7, 688–696.
4Ce: white solid; mp = 147–148 °C;
½
a 2D6
ꢁ
ꢂ 53:0 (MeOH,
3350, 2949, 1700, 1696, 1590, 1521,
1H NMR (300 MHz,
c 0.99); Rf = 0.27
(EtOAc–hexanes; 1:4); IR (thin film)
m
1450, 1376, 1308, 1276, 1206, 1009, 878, 720, 670 cmꢂ1
;