Versatile strategies for the solid phase synthesis of small heterocyclic scaffolds: [1,3,4]-Thiadiazoles and [1,3,4]-oxadiazoles

Article abstract of DOI:10.1016/j.tet.2005.03.084

New robust protocols for the solid phase synthesis of 5-alkylthio-, 5-alkyl/aryl-, and 5-acylamino-2-alkylamino-[1,3,4]-thiadiazoles are described based on a common resin bound thiosemicarbazide. A protocol for the solid phase synthesis of 2-alkyl/aryl-amino-5-alkylamino-[1,3,4]-oxadiazoles from a resin bound semicarbazide is likewise reported. The protocols have been verified by the preparation of four small libraries that all gave products in good to excellent yields and purity.

Full text of DOI:10.1016/j.tet.2005.03.084

Tetrahedron 61 (2005) 5565–5575
Versatile strategies for the solid phase synthesis of small
heterocyclic scaffolds: [1,3,4]-thiadiazoles and [1,3,4]-oxadiazoles
*
Rune Severinsen, John Paul Kilburn and Jesper F. Lau
Medicinal Chemistry Research, Novo Nordisk A/S, Novo Nordisk Park, 2760 Maaloev, Denmark
Received 7 January 2005; revised 11 March 2005; accepted 23 March 2005
Available online 27 April 2005
Abstract—New robust protocols for the solid phase synthesis of 5-alkylthio-, 5-alkyl/aryl-, and 5-acylamino-2-alkylamino-[1,3,4]-
thiadiazoles are described based on a common resin bound thiosemicarbazide. A protocol for the solid phase synthesis of 2-alkyl/aryl-amino-
5-alkylamino-[1,3,4]-oxadiazoles from a resin bound semicarbazide is likewise reported. The protocols have been verified by the preparation
of four small libraries that all gave products in good to excellent yields and purity.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
phase synthesis strategies for the preparation of [1,3,4]-
thiadiazoles6 1 and [1,3,4]-oxadiazoles7 2. However, the
reported strategies proceeded with the aid of a relatively
large ‘spacer’ and thus the products were inapplicable in the
context of lead-like criteria and investigations were thus
directed towards reducing the generic scaffold size. In this
communication we would like to present both new and
revised solid phase synthesis strategies for the formation of
substituted [1,3,4]-thiadiazoles 3 and [1,3,4]-oxadiazoles 4.
Parallel synthesis has over the last 20 years evolved into a
well established and essential medicinal chemist’s tool for
the rapid preparation of screening libraries as well as
accelerating the lead optimization process.1 Initially screen-
ing libraries were designed with focus on diversity and
number of compounds,2 but later Lipinski invited awareness
towards the importance of their ‘drug-like’ physiochemical
properties.3 More recently the concept of ‘lead-like’ was
introduced by Teague et al.4,5 They investigated a number of
drugs and their corresponding leads and found that size and
lipophilicity in general increases through the lead-optimiz-
ation process. Based on these findings they suggest that
screening libraries should consist of lead-like compounds
with physiochemical properties in the range Mw!350 and
1!c log P!3.
2. Results and discussion
An obvious attachment point to a solid support for
thiadiazole 3 and oxadiazole 4 is the secondary hetero-
arylamine. One possible approach for such an attachment is
to use a backbone amide linker (BAL)8 either as a di- or a
trialkoxybenzyl amine. In general the resin bound tertiary
amines formed when employing such resins do not undergo
acidolytic cleavage. However, a few examples are known
where substituted anilines9 or aminothiazoles10 have been
released under acidic conditions. Due to the heteroaromatic
character of the thiadiazole- and oxadiazole amines we
expected that these would undergo acidolytic cleavage.
Hence, the commercially available 2-(3,5-dimethoxy-4-
formylphenoxy)ethoxymethyl polystyrene11 was treated
with a range of primary amines under standard reductive
amination conditions to yield the respective resin bound
benzyl amine derivates 5 as depicted in Scheme 1. In our
previous paper we reported the transformation of a resin
bound primary amine to an isothiocyanate upon treat-
ment with di-(2-pyridyl)-thionocarbonate (DPT).6 The
In recent publications we have described several novel solid
Keywords: [1,3,4]-Thiadiazoles; [1,3,4]-Oxadiazoles; Heterocycles; Lead-
like; Libraries.
*
Corresponding author. Tel.: C45 44434392;
e-mail: jrla@novonordisk.com
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.084

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R. Severinsen et al. / Tetrahedron 61 (2005) 5565–5575
Table 1. Conditions used to convert resin bound benzyl amine 5a into
benzyl-thiocarbamic acid O-pyridin-2-yl ester 6a
Reagents and conditions
% Purity 7a
20 8C
50 8C
80 8C
5 equiv DPT in DCM
5 equiv DPT in DCP
5 equiv DPT in DMSO
5 equiv DPT in NMP
10 equiv DPT in NMP
20
0
16
15
22
—
20
57
85
95
—
—
10
73
71
All reactions were run for 12 h. Results are given as percentage purity of the
corresponding formation of 7a (LC–MS, UV peak integration at 214 nm).
thiocarbamic acid O-pyridin-2-yl ester 6 was subsequently
substituted by treatment with hydrazine in DMSO at 50 8C
to form the pivotal thiosemicarbazide 7. The results are
given in Table 1.
Thiosemicarbazide 7 is a versatile intermediate and several
derivatisations leading to heterocyclic systems could be
imagined from this intermediate. As depicted in Scheme 1
we have investigated three different transformations of
thiosemicarbazide 7 to substituted [1,3,4]-thiadiazoles.
Scheme 1. Reagents and condition. (i) (a) R1NH2, 5% AcOH, NMP/MeOH,
1 h; (b) NaBH3CN, NMP/MeOH, 12 h; (ii) DPT, NMP, 50 8C, 16 h;
(iii) H2NNH2$H2O, DMSO, 50 8C 14 h; (iv) DPT, DCM, 3 h; (v) (a) 1,4-
dioxane/MeOH/NaOHaq (1 N), 30 min; (b) R2Br, 1,4-dioxane, 14 h;
(c) TFA/DCM, 2 h (vi) R2CHO, TMOF/NMP, (2C14) h; (vii) (a) FeCl3,
DCM/MeOH, (2C14) h; (b) TFA/DCM, 2 h; (viii) FmocNCS, DCM,
DIPEA, 14 h; (ix) (a) EDC, NMP, 50 8C, 14 h; (b) DMF/piperidine
(2C20) min; (c) R2COOH, DIIC, DMAP, DIPEA, NMP/DCM;
(d) TFA/DCM, 2 h.
Resin bound thiosemicarbazide 7 was treated with 10 equiv
DPT in DCM to give immobilized thione 8.6 Alkylation of
Table 2. Representative results and structures from the library of
2-alkylthio-5-alkylamino-[1,3,4]-thiadiazoles (9)
Purity (%)
70
Yield (%)
65
9a13
9b
isothiocyanate was subsequently reacted with hydrazine to
give a thiosemicarbazide.
70
60
In this approach, where the immobilized secondary amine
has to be converted to the thiosemicarbazide 7, the
intermediate can not be an isothiocyanate. It has been
reported that secondary amines react with DPT to give the
corresponding 2-pyridyl thiocarbamates.12 However, the
conversion of this to a thiosemicarbazide by treatment with
a hydrazine has to our knowledge not been reported and
therefore reaction conditions for this transformation had to
be developed.
9c
70
95
56
72
9d14
9e
95
50
9f
90
90
81
71
9g
The immobilized amines 5 were treated with DPT under a
range of conditions to investigate the formation of the
reactive species 6. A small amount of resin 6 was cleaved
with TFA/DCM (50:50) but due to lack of stability of the
intermediate released from resin 6 under the cleavage
conditions the reaction could not be monitored directly.
Instead the reaction was investigated by treatment of resin 6
with hydrazine hydrate and monitoring the formation of
thiosemicarbazide 7 by cleavage of a small amount of the
resin with TFA/DCM (50:50). LC–MS analysis was
performed on the crude residue. When applying the
conditions we previously developed for conversion of a
resin bound primary amine to a thiosemicarbazide only
minimal conversion was observed. Replacing the solvent
with 1,3-dichloropropane (DCP) and heating to 50 8C did
not improve the result. However, when the reaction was
performed in N-methyl-2-pyrrolidinone (NMP) for 16 h,
almost complete conversion was suggested as interpreted by
a negative chloranil test result. The resin bound benzyl-
9h
95
82
9i
9j
90
90
78
73
9k
9l
90
60
90
90
72
45
64
58
9m
9n
Purity is determined by LC–MS of the crude cleavage product (UV peak
integration at 214 nm) and yield is determined by NMR with internal
reference.

R. Severinsen et al. / Tetrahedron 61 (2005) 5565–5575
5567
Table 4. Representative results and structures from the library of N-(5-
alkylamino-[1,3,4]thiadiazol-2-yl)-amide (13)
thione 8 with primary alkyl- or benzyl bromides in
1,4-dioxane yielded a mixture N- and S-alkylated products.
Applying DIPEA in the alkylation procedure did not
improve the selectivity for S-alkylation. However, when
the resin was treated with a mixture of 1,4-dioxane,
methanol and aqueous sodium hydroxide prior to alkylation,
only S-alkylation was observed. Employing this procedure
thione 8 was treated with a range of alkylating agents to give
the corresponding monoalkylated products. Subsequent
cleavage with TFA/DCM yielded [1,3,4]-thiadiazoles 9.
The results are given in Table 2.
Purity (%)
95
Yield (%)
63
13a
13b
13c
91
82
78
73
59
65
13d16
Intermediate resin bound thiosemicarbazide 7, was an ideal
starting point for the synthesis of substituted 5-alkyl-
[1,3,4]thiadiazol-2-yl amines 11. The formation of imine
10 by reaction with aldehydes was therefore investigated.
Treatment with aldehydes in a mixture of trimethyl
orthoformate (TMOF), NMP and acetic acid (5:5:1) yielded
a mixture of products. When applying the same conditions
in the absence of acid, the intermediate resin bound
thiosemicarbazone 10 was formed. Cyclization of 10 was
achieved by treating the resin with a solution of iron(III)
chloride in DCM/MeOH.6 Subsequent cleavage with TFA/
DCM yielded substituted 5-alkyl-[1,3,4]thiadiazol-2-yl
amines 11. The results are given in Table 3.
13e16
90
71
13f
13g
13h
90
89
85
80
64
60
13i
87
86
13j
90
94
74
75
Table 3. Representative results and structures from the library of
substituted 5-alkyl-[1,3,4]thiadiazol-2-yl amines (11)
13k
Purity (%)
Yield (%)
11a
11b
11c15
11d
11e
11f
95
91
86
98
81
65
92
98
99
99
98
95
73
69
72
61
65
47
70
71
76
73
66
61
13l
90
71
13m
13n
13o
13p
70
90
67
72
71
49
51
43
11g
11h
11i
13q
13r
13s
59
96
95
48
72
66
11j
11k
11l
13t
13u
13v
61
70
90
31
59
66
Purity is determined by LC–MS of the crude cleavage product (UV peak
integration at 214 nm) and yield is determined by NMR with internal
reference.
13x
95
85
The chemistry discussed above yields substituted 5-thio-
1,3,4-thiadiazoles 9 and substituted 5-alkyl-1,3,4-thia-
diazoles 11. As a continuation of this work we sought to
synthesize substituted 5-carboxamide-1,3,4-thiadiazoles 13.
To our knowledge, a solid phase synthesis of this scaffold
Purity is determined by LC–MS of the crude cleavage product (UV peak
integration at 214 nm) and yield is determined by NMR with internal
reference.

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R. Severinsen et al. / Tetrahedron 61 (2005) 5565–5575
Table 6. Representative results and structures from library of N,N-dialkyl-
[1,3,4]oxadiazoles-2,5-diamine (16)
has never been reported. Treatment of thiosemicarbazide 7
with a mixture of fmoc-isothiocyanate and DIPEA in DCM
yielded resin bound hydrazine-1,2-dicarbothioamide 12.
A range of different conditions were applied in an attempt
to cyclizise intermediate 12 as shown in Table 5.
1,3-Diisopropyl carbodiimide (DIIC) in dry DMSO or
NMP resulted only in partial cyclization. A mixture of
triphenylphosphine and hexachloroethane in dry THF gave
good conversion, but the reagent generated acidic con-
ditions resulting in partial resin cleavage. Addition of
DIPEA to minimize cleavage resulted in incomplete
cyclization. However, treating the resin with 1-(3-dimethyl-
Purity (%)
Yield (%)
16a
16b
16c
95
95
90
81
76
73
16d
95
83
aminopropyl)-3-ethylcarbodiimide
hydrochloride
16e
16f
83
75
73
58
(EDC$HCl) in DMSO at 80 8C gave almost complete
conversion and good yield, similarly EDC$HCl in NMP
gave complete conversion and good yield at 50 8C. The
latter procedure was chosen for cyclization in the library
synthesis due to the lower temperature associated with NMP
as the solvent. Immobilized 5-fmoc-amino-1,3,4-thia-
diazoles were subsequently deprotected with 20% piper-
idine in NMP. The resulting 5-amino-1,3,4-thiadiazoles
were then acylated with different carboxylic acids using
DIIC in DCM/NMP. Cleavage with TFA/DCM yielded
substituted 5-carboxamide-1,3,4-thiadiazoles 13. A small
library based on this protocol was prepared. The results are
given in Table 4.
16g
90
95
95
95
95
60
85
87
81
89
16h17
16i17
16j
16k
Encouraged by the results obtained with the [1,3,4]-
thiadiazole scaffolds we decided to investigate the possi-
bility of preparing the analogous [1,3,4]-oxadiazole deriva-
tive 16 (Scheme 2). Hence, a resin bound amine 5 was
treated with triphosgene and DIPEA in DCM, followed by
reaction of the formed reactive intermediate with hydrazine
hydrate in DMSO to yield semicarbazide intermediate 14.
16l
95
95
72
65
16m
Purity is determined by LC–MS of the crude cleavage product (UV peak
integration at 214 nm) and yield is determined by NMR with internal
reference.
Subsequent addition of various thiocyanates under basic
conditions gave the substituted thiobisurea 15. Again, a
range of conditions for the cyclization were investigated.
The results are given in Table 5. As for the cyclization of 12,
EDC$HCl in dry NMP were the preferred reaction
conditions to convert resin bound 15 into 2,5-diamino-
1,3,4-oxadiazole 16. Cleavage was realized upon treatment
with TFA/DCM. The developed protocol was used to
generate a small library of substituted 2,5-diamino-1,3,4-
oxadiazoles 16. The results are displayed in Table 6.
Table 5. Selected results for the cyclization of 12 and for the cyclization of
15
Scheme 2. Reagent and conditions. (i) (a) CO(OCCl3)2, DIPEA, DCM, 5 h;
(b) H2NNH2$H2O, DMSO, 14 h; (ii) R2NCS; DCM, DIPEA, 6 h; (iii) (a)
EDC$HCl, dry NMP, 50 8C, 14 h, (b) TFA/DCM, 2 h.
Reagents and conditions
Cyclization Cyclization
of 12 (%)
of 15 (%)
1
2
3
4
5
DIIC in dry NMP (20 8C)
DIIC in dry NMP (80 8C)
DIIC in dry DMSO (80 8C)
PPh3 and C2Cl6 in THF (20 8C)
PPh3 and C2Cl6 in THF/DIPEA
(20 8C)
EDC$HCl in dry DMSO (50 8C)
EDC$HCl in dry DMSO (80 8C)
EDC$HCl in dry NMP (50 8C)
25
63
12
95
42
0
33
5
67
23
3. Conclusion
In conclusion, we have studied and developed four new
versatile solid phase synthesis protocols for the preparation
of ‘lead-like’ substituted [1,3,4]-oxadiazoles and [1,3,4]-
thiadiazoles. Treating the highly applicable resin bound
thiosemicarbazide with a variety of reagents and conditions
yielded, after TFA-mediated cleavage, 5-alkylthio-,
5-alkyl, and 5-acylamino-2-alkylamino-[1,3,4]-thiadiazoles
in good yield and purity. In another investigation resin
6
7
8
71
96
99
54
89
97
Results are given as percentage purity of product determined by using
LC–MS of the crude cleavage product (UV peak integration at 214 nm). All
reactions were run over 14 h.

R. Severinsen et al. / Tetrahedron 61 (2005) 5565–5575
5569
bound semicarbazide was treated with isothiocyanates
and the resulting intermediates after cyclodehydration and
TFA-mediated cleavage yielded substituted 2,5-dialkyl-
amino-[1,3,4]-oxadiazoles in good yield and purity.
0.45 mmol) and the mixture was shaken for 12 h at 50 8C.
The resin was filtered before washing with DMSO (3!).
A solution of hydrazine hydrate (216 mg, 4.50 mmol) in
DMSO (15 mL) was added and the resin was then agitated
14 h at 50 8C before excess reagent was removed by
filtration. The resin was washed with DMSO (3!), MeOH/
THF (1:1 v/v) (2!), and DCM (3!).
4. Experimental
4.1. General
4.4. Synthesis of 5-amino-3H-1,3,4-thiadiazole-2-thione
(8)
All reactions where performed in standard glassware or
Teflon apparatus suitable for solid-phase synthesis. Starting
materials were commercially available and used without
further purification. 2-(3,5-Dimethoxy-4-formylphenoxy)
ethoxymethyl polystyrene, (200–400 mesh, polystyrene-
divinylbenzene 1%, 0.45 mmol/g) was purchased from
A solution of DPT (97 mg, 0.42 mmol) in DCM (3 mL) was
added to a portion of resin 7 (100 mg, 0.042 mmol). The
mixture was agitated for 3 h before excess reagent was
removed by filtration and washing using NMP (3!) and
DCM (3!).
1
Novabiochem. H and 13C NMR spectra were recorded on
a Bruker DRX400 spectrometer. Chemical shifts (d) are
given in parts per million (ppm) and are relative to TMS
as internal standard. Coupling constants are given in Hertz
(J values in Hz). The following abbreviations are used: sZ
singlet, br sZbroad singlet, dZdoublet, tZtriplet, mZ
multiplet, ddZdouble of doublets. IR spectra were recorded
on a FT/IR Perkin–Elmer spectrometer, model Spectrum
one. Electrospray (ES) mass spectra and LC–MS analyses
were recorded on a PE Sciex API 3000 instrument with an
HP1100 HPLC equipped with binary pump, column
compartment, diode array detector, single quadrupole
mass spectrometer detector and a C18 column ((Waters
Xterra MS C-18X) 3 mm) at 40 8C with a flow of
1.0 mL/min. Two mobile phases (mobile phase A, 100%
water, 0.01% TFA; mobile phase B, 100% acetonitrile,
0.01% TFA) were employed to run a gradient condition
from 10–100% B in 7.5 min with UV detection at 210 nm
and MS scanning range from 100–1000 amu. Injections of
1 mL were used. Unless stated, all reactions were carried out
at 20 8C and washing was performed at a ratio of 1 mL
solvent per 100 mg resin. Unless stated, reactions were
monitored by cleaving small portion of the resin and
analyzing the crude cleavage product on LC–MS. Yields
were determined by NMR studies using 2,5-dimethyl-furan
as internal standard.
4.5. Formation of 2-alkylthio-5-alkylamino-[1,3,4]-
thiadiazole (9) and resin cleavage
Typical procedure. Resin 8 (100 mg, 0.042 mmol) pre-
swollen in 1,4-dioxane was treated with a mixture of
1,4-dioxane/MeOH/NaOH(aq)(1 N) (2 mL, 7:3:1, v/v) for
30 min, before a solution of benzylbromide (22 mg,
0.126 mmol) in 1,4-dioxane (3 mL) was added. The resin
was agitated 14 h, filtered to remove excess reagents and
washed with NMP (3!), MeOH/THF (1:1 v/v) (2!) and
DCM (3!). The resin was subsequently cleaved with TFA/
DCM (2 mL, 1:1 v/v) for 2 h before the liquors were
transferred to a 10 mL round bottom flask and concen-
trated in vacuo. The residue was re-dissolved in aceto-
nitrile (5 mL) and a sample (1 mL) was removed and
concentrated in vacuo for NMR concentration studies
and LC–MS analysis. The rest of the crude products
were purified by preparative HPLC yielding the title
compounds 9.
4.5.1. Benzyl-(5-benzylsulfanyl-[1,3,4]thiadiazol-2-yl)-
amine (9a). White solid, mp 95.2–95.9 8C; nmax (KBr)
703, 1027, 1092, 1207, 1357, 1426, 1452, 1479, 1547, 3029,
3248 cmK1
;
1H NMR (DMSO-d6): dZ4.30 (s, 2H,
PhCH2S), 4.40 (d, JZ5.2 Hz, 2H, PhCH2NH), 7.33 (m,
10H, ArH), 8.29 (t, JZ5.2 Hz, 1H, NH); 13C NMR (DMSO-
d6): dZ38.7 (SCH2), 48.2 (NHCH2), 127.5, 127.8, 127.9,
128.7, 128.8, 129.4, 137.4, 138.8, 150.0, 169.9 (ArC). HR-
MS (Q-TOF-ES) m/zZ314.0780, calcd for [C33H34N4OSC
H]C 314.0785.
4.2. General procedure for reductive amination of
2-(3,5-dimethoxy-4-formylphenoxy) ethoxymethyl
polystyrene (5)
Typical procedure. A solution of benzyl amine (480 mg,
4.50 mmol) in NMP/MeOH/AcOH (10 mL, 5:5:1 v/v) was
added to 2-(3,5-dimethoxy-4-formylphenoxy) ethoxy-
methyl polystyrene resin (1.0 g, 0.45 mmol) pre-swollen
in NMP. The mixture was agitated for 30 min before a
solution of NaBH3CN (422 mg, 6.75 mmol) in MeOH/NMP
(10 mL, 1:1 v/v) was added. The mixture was shaken for a
further 18 h. Excess reagents were removed by filtration
and the resin was washed with NMP (3!), MeOH/THF
(1:1 v/v) (2!) and DCM (3!). The resin was dried in
vacuo overnight at 40 8C.
4.5.2. Benzyl-(5-phenethylsulfanyl-[1,3,4]thiadiazol-2-
yl)-amine (9b). Isolated as a pale oil; H NMR (DMSO-
d6): dZ2.92 (t, JZ7.5 Hz, 2H, PhCH2CH2S), 3.31 (t, JZ
7.5 Hz, 2H, PhCH2CH2S), 4.47 (d, JZ4.9 Hz, 2H, PhCH2-
NH), 7.26 (m, 6H, ArH), 7.35 (d, JZ4.3 Hz, 4H, ArH), 8.31
(t, JZ4.9 Hz, 1H, PhCH2NH). ES-MS m/z 328 MHC.
1
4.5.3. Benzyl-(5-cyclopropylmethylsulfanyl-1,3,4] thia-
diazol-2-yl)-amine (9c). Isolated as a pale oil; H NMR
1
(DMSO-d6): dZ0.25 (m, 2H, CH(CH2CH2)), 0.51 (m, 2H,
CH(CH2CH2)), 1.07 (m, 1H, CH(CH2CH2)), 3.02 (d, JZ
7.1, 2H, SCH2cPr), 4.46 (d, JZ5.6 Hz, 2H, PhCH2NH),
7.29 (m, 1H, ArH), 7.34 (d, JZ4 Hz, 4H, ArH), 8.29 (t, JZ
5.6 Hz, 1H, PhCH2NH). ES-MS m/z 278 MHC.
4.3. Formation of thiosemicarbazide (7)
Typical procedure. A solution of DPT (1.04 g, 4.50 mmol)
in dry NMP (15 mL) was added to resin 5 (1.0 g,

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R. Severinsen et al. / Tetrahedron 61 (2005) 5565–5575
4.5.4. (5-Benzylsulfanyl-[1,3,4]thiadiazol-2-yl)-methyl-
HR-MS (Q-TOF-ES) m/zZ292.0937, calcd for
[C33H34N4OSCH]C 292.0942.
1
amine (9d).14 Isolated as a pale oil; H NMR (DMSO-d6):
dZ2.83 (d, JZ3.9 Hz, 3H, CH3NH), 4.30 (s, 2H, SCH2Ph),
7.32 (m, 5H, ArH), 7.71 (q, JZ3.9 Hz, 1H, CH3NH).
ES-MS m/z 238 MHC.
4.5.12. Cyclopropylmethyl-(5-yclopropylmethyl-sulfa-
nyl-[1,3,4]thiadiazol-2-yl)-amine (9l). Isolated as a pale
oil; 1H NMR (DMSO-d6): dZ0.25 (m, 4H, CH(CH2CH2)),
0.50 (m, 4H, CH(CH2CH2)), 1.07 (m, 2H, CH(CH2CH2)),
3.01 (d, JZ7.1 Hz, 2H, SCH2cPr), 3.12 (dd, J1Z5.5 Hz,
J2Z6.6 Hz, 2H, cPrCH2NH), 7.89 (t, JZ5.5 Hz, 1H, NH).
ES-MS m/z 242 MHC.
4.5.5. Methyl-(5-phenethylsulfanyl-[1,3,4]thiadiazol-2-
yl)-amine (9e). Isolated as a pale oil; H NMR (DMSO-
1
d6): dZ2.86 (d, JZ4.8 Hz, 2H, CH3NH), 2.94 (t, JZ
7.6 Hz, 2H, PhCH2CH2), 3.31 (t, JZ7.6, 2H, PhCH2CH2),
7.26 (m, 5H, ArH), 7.74 (q, JZ4.8 Hz, 1H, CH3NH).
ES-MS m/z 252 MHC.
4.5.13. (5-Phenethylsulfanyl-[1,3,4]thiadiazol-2-yl)-pyri-
din-4-ylmethyl-amine (9m). Isolated as a pale oil; 1H NMR
(DMSO-d6): dZ2.94 (t, JZ7.3 Hz, 2H, CH2CH2Ph), 3.33
(t, JZ7.3 Hz, 2H, CH2CH2Ph), 4.58 (d, JZ5.8 Hz, 2H,
CH2NH), 7.24 (m, 5H, ArH), 7.46 (d, JZ5.5 Hz, 2H, ArH),
8.44 (t, JZ5.8 Hz, NH), 8.58 (d, JZ6.1 Hz, 2H, ArH).
ES-MS m/z 329 MHC.
4.5.6. (5-Cyclopropylmethylsulfanyl-[1,3,4]thiadiazol-2-
yl)-methyl-amine (9f). Isolated as a pale oil; 1H NMR
(DMSO-d6): dZ0.26 (m, 2H, CH(CH2CH2)), 0.53 (m, 2H,
CH(CH2CH2)), 1.05 (m, 1H, CH(CH2CH2)), 2.85 (d, JZ
4.7 Hz, 3H, CH3NH), 3.01 (d, JZ7.0 Hz, SCH2), 7.71
(q, JZ4.7 Hz, 1H, NH). ES-MS m/z 202 MHC.
4.5.14. (5-Cyclopropylmethylsulfanyl-[1,3,4]thiadiazol-
2-yl)-pyridin-4-ylmethyl-amine (9n). Isolated as a pale
oil; 1H NMR (DMSO-d6): dZ0.25 (m, 2H, CH(CH2CH2)),
0.55 (m, 2H, CH(CH2CH2)), 1.07 (m, 1H, CH(CH2CH2)),
3.01 (d, JZ7.1 Hz, 1H, SCH2cPr), 3.03 (d, JZ7.5 Hz, 1H,
SCH2cPr), 4.57 (d, JZ5.2, 2H, PyCH2NH), 7.45 (br s, 2H,
ArH), 8.43 (t, JZ5.2 Hz, 1H, NH), 8.59 (br s, 2H, ArH).
ES-MS m/z 279 MHC.
4.5.7. (5-Benzylsulfanyl-[1,3,4]thiadiazol-2-yl)-(4-meth-
oxy-benzyl)-amine (9g). Isolated as a pale oil; H NMR
(DMSO-d6): dZ3.73 (s, 3H, CH3O), 4.30 (s, 2H, SCH2Ph),
4.35 (d, JZ5.5 Hz, 2H, CH2NH), 6.89 (d, JZ6.6 Hz, 2H
ArH), 7.30 (m, 7H, ArH), 8.21 (t, JZ5.5 Hz, NH). ES-MS
m/z 344 MHC.
1
4.5.8. (4-Methoxy-benzyl)-(5-phenethylsulfanyl-1,3,4]
thiadiazol-2-yl)-amine (9h). Isolated as a pale oil; 1H
NMR (DMSO-d6): dZ2.94 (t, JZ7.6 Hz, 2H, PhCH2CH2),
3.31 (t, JZ7.5 Hz, 2H, PhCH2CH2), 3.73 (s, 3H, CH3O),
4.38 (d, JZ5.6 Hz, 2H, CH2NH), 6.91 (d, JZ8.6 Hz, 2H,
ArH), 7.25 (m, 7H, ArH), 8.23 (t, JZ5.6 Hz, 1H, NH).
ES-MS m/z 358 MHC.
4.6. Formation of substituted thiosemicarbazide (10)
General procedure. A solution of 4-methoxybenzaldehyde
(57 mg, 0.42 mmol) in TMOF/NMP (1:1, v/v, 3 mL) was
added to resin 7 (100 mg, 0.042 mmol) and the resulting
mixture agitated for 2 h. Excess reagents were removed by
filtration before a new portion of aldehyde was added to the
resin and the mixture was agitated for 14 h. Excess reagents
were removed by filtration and the resin was washed with
NMP (3!), THF/MeOH (1:1 v/v) (2!) and DCM (3!).
4.5.9. (5-Cyclopropylmethylsulfanyl-[1,3,4]thiadiazol-2-
yl)-(4-methoxy-benzyl)-amine (9i). Isolated as a pale oil;
1H NMR (DMSO-d6): dZ0.26 (m, 2H, CH(CH2CH2)), 0.53
(m, 2H, CH(CH2CH2)), 1.07 (m, 1H, CH(CH2CH2)), 3.01
(d, JZ7.1 Hz, 2H, SCH2), 3.73 (s, 3H, CH3O), 4.37 (d, JZ
6.4 Hz, CH2NH), 6.89 (d, JZ8.6 Hz, 2H, ArH), 7.27 ((d,
JZ8.6 Hz, 2H, ArH), 8.21 (t, JZ6.4 Hz, 1H NH). ES-MS
m/z 307 MHC.
4.7. Formation of 5-alkyl-[1,3,4]thiadiazol-2-yl) alkyl
amine (11)
General procedure. FeCl3 (34 mg, 0.21 mmol) dissolved in
DCM/MeOH (2 mL, 2:1 v/v) was added to resin 10 and
agitated for 2 h. Excess reagents were removed by filtration
and the, a new protion of FeCl3 was added and the mixture
aggitated for 14 h. The resin was filtered and washed with
DCM (2!), NMP (2!), MeOH/DCM (1:1 v/v) (2!) and
DCM (5!). The resin was subsequently treated with TFA/
DCM (2 mL, 1:1 v/v) for 2 h before the liquors were
transferred to a 10 mL round bottom flask and concentrated
in vacuo. The residue was re-dissolved in acetonitrile
(5 mL) and a sample (1 mL) was removed and concentrated
in vacuo for NMR concentration studies and LC–MS
analysis. The rest of the crude products were purified by
preparative HPLC yielding title products 11.
4.5.10. (5-Benzylsulfanyl-[1,3,4]thiadiazol-2-yl)-cyclo-
propylmethyl-amine (9j). Isolated as a pale oil; H NMR
1
(DMSO-d6): dZ0.20 (m, 2H, CH(CH2CH2)), 0.45 (m, 2H,
CH(CH2CH2)), 1.03 (m, 1H, CH(CH2CH2)), 3.11 (dd, J1Z
6.6 Hz, J2Z5.6 Hz, CHCH2NH), 4.30 (s, 2H, SCH2), 7.23
(m, 5H, ArH), 7.89 (t, JZ5.6 Hz, 1H NH). ES-MS m/z 278
MHC.
4.5.11.
Cyclopropylmethyl-(5-phenethylsulfanyl-
[1,3,4]thiadiazol-2-yl)-amine (9k). White solid, mp 66.9–
67.2 8C; nmax (KBr) 1045, 1205, 1278, 1327, 1542, 3003,
3232 cmK1 1H NMR (DMSO-d6): dZ0.22 (m, 2H,
;
CH(CH2CH2)), 0.47 (m, 2H, CH(CH2CH2)), 1.07 (m, 1H,
CH(CH2CH2)), 2.94 (t, JZ7.4 Hz, 2H, PhCH2CH2), 3.13
(dd, J1Z5.5 Hz, J2Z7.1 Hz, 2H, cPrCH2NH), 3.31 (t, JZ
7.4 Hz, 2H, PhCH2CH2), 7.25 (m, 5H, ArH), 7.91 (t, JZ
5.5 Hz, 1H, NH); 13C NMR (DMSO-d6): dZ3.3, 10.3,
34.96, 36.40, 50.0, 126.3, 128.3, 128.5, 139.4, 149.4, 169.3.
4.7.1. Benzyl-[5-(4-methoxy-phenyl)-[1,3,4]thiadiazol-2-
yl]-amine (11a). Isolated as a pale oil; H NMR (DMSO-
d6): dZ3.30 (s, 3H, OCH3), 4.52 (d, JZ5.8 Hz, 2H,
NHCH2), 7.02 (d, JZ9.1 Hz, 2H, ArH), 7.28 (m, 1H,
ArH), 7.37 (m, 4H, ArH), 7.67 (d, JZ9.1 Hz, 2H, ArH),
8.35 (t, JZ5.8 Hz, 1H, NHCH2). ES-MS m/z 298 MHC.
1

R. Severinsen et al. / Tetrahedron 61 (2005) 5565–5575
5571
4.7.2. Benzyl-[5-(4-bromo-phenyl)-[1,3,4]thiadiazol-2-
yl]-amine (11b). Isolated as a pale oil; H NMR (DMSO-
d6): dZ4.54 (d, JZ5.8 Hz, 2H, NHCH2), 7.28 (m, 1H,
ArH), 7.38 (m, 4H, ArH), 7.69 (m, 4H, ArH), 8.53 (t, JZ
5.8 Hz, 1H, NHCH2). ES-MS m/z 346 MHC.
(DMSO-d6): dZ3.74 (s, 3H, OCH3), 4.75 (d, JZ5.1 Hz,
2H, NHCH2), 6.92 (d, JZ8.5 Hz, 2H, ArH), 7.32 (d, JZ
8.6 Hz, 2H, ArH), 7.46 (m, 3H, ArH), 7.75 (d, JZ8.1 Hz,
2H, ArH), 8.46 (t, JZ5.1 Hz, 1H, NHCH2). ES-MS m/z
298 MHC.
1
4.7.3. Benzyl-(5-isobutyl-[1,3,4]thiadiazol-2-yl)-amine
(11c).15 White solid, mp 119.2–119.9 8C; nmax (KBr) nmax
(KBr) 721, 1138, 1201, 1433, 1454, 1598, 1649, 2962,
4.7.11. (4-Methoxy-benzyl)-(5-pyridin-3-yl-[1,3,4]thia-
diazol-2-yl)-amine (11k). Isolated as a pale oil; H NMR
1
(DMSO-d6): dZ3.74 (s, 3H, OCH3), 4.58 (d, JZ5.1 Hz,
2H, NHCH2), 6.93 (d, JZ9.1 Hz, 2H, ArH), 7.32 (d, 2H,
JZ8.5 Hz, 2H, ArH), 7.58 (m, 1H, ArH), 8.23 (m, 1H,
ArH), 8.58 (t, JZ5.1 Hz, 1H, NHCH2), 8.65 (m, 1H, ArH),),
8.99 (s, 1H, ArH). ES-MS m/z 299 MHC.
1
3366 cmK1; H NMR (DMSO-d6): dZ0.91 (d, JZ6.5 Hz,
6H, CH(CH3)2), 1.90 (m, 1H, CH(CH3)2), 2.69 (d, JZ
7.1 Hz, 2H, CH2CH(CH3)2), 4.48 (s, 2H, NHCH2), 7.28 (m,
1H, ArH), 7.38 d, JZ4.5 Hz, 4H, ArH), 8.52 (s, 1H,
NHCH2); 13C NMR (DMSO-d6): dZ21.8, 28.6, 38.1, 48.2,
127.3, 127.6, 128.4, 138.1, 157.3, 168.3. HR-MS (Q-TOF-
ES) m/zZ248.1216, calcd for [C33H34N4OSCH]C
248.1221.
4.7.12. (4-Methoxy-benzyl)-[5-(4-methoxy-phenyl)-
[1,3,4]thiadiazol-2-yl]-amine (11l). Isolated as a pale oil;
1H NMR (DMSO-d6): dZ3.73 (s, 3H, OCH3), 3.80 (s, 3H,
OCH3) 4.44 (d, JZ5.6 Hz, 2H, NHCH2), 6.92 (d, JZ
8.6 Hz, 2H, ArH), 7.01 (d, 2H, JZ9.1 Hz, 2H, ArH), 7.31
(d, JZ8.5 Hz, 2H, ArH), 7.67 (d, JZ8.5 Hz, 2H, ArH), 8.34
(t, JZ5.6 Hz, 1H, NHCH2). ES-MS m/z 328 MHC.
4.7.4. Cyclopropylmethyl-(5-phenyl-[1,3,4]thiadiazol-2-
yl)-amine (11d). Isolated as a pale oil; H NMR (DMSO-
1
d6): dZ0.27 (m, 2H, CH(CH2CH2)), 0.50 (m, 2H, CH(CH2-
CH2)), 1.12 (m, 1H, CH(CH2CH2)), 3.21 (d, JZ6.6 Hz, 2H,
CH2CH(CH2CH2)), 7.46 (m, 3H, ArH), 7.75 (m, 2H, ArH),
8.27 (s, 1H, NHCH2). ES-MS m/z 232 MHC.
4.8. Formation of hydrazine-1,2-dicarbothioamide (12)
To resin 7 (100 mg, 0.042 mmol pre-swollen in DCM
was added a mixture of fmoc-isothiocyanate (60 mg,
0.21 mmol) and DIPEA (47 mL, 0.27 mmol) in DCM
(2 mL) and the resulting mixture was agitated for 14 h.
The resin was subsequently washed with DMF (3!) and
DCM (2!).
4.7.5. Cyclopropylmethyl-(5-pyridin-3-yl-[1,3,4]thiadia-
zol-2-yl)-amine (11e). Isolated as a pale oil; 1H NMR
(DMSO-d6): dZ0.27 (m, 2H, CH(CH2CH2)), 0.50 (m, 2H,
CH(CH2CH2)), 1.13 (m, 1H, CH(CH2CH2)), 3.24 (m, 2H,
CH2CH(CH2CH2)), 7.61 (m, 1H, ArH), 8.27 (m, 2H, ArH),
8.32 (br s, 1H, NHCH2), 8.67 (d, JZ4.1 Hz, 1H, ArH), 9.01
(s, 1H, ArH). ES-MS m/z 233 MHC.
4.9. Formation of N-(5-alkylamino-[1,3,4]thiadiazol-2-
yl)-alkylamide (13)
4.7.6.
Cyclopropylmethyl-[5-(4-methoxy-phenyl)-
[1,3,4]thiadiazol-2-yl]-amine (11f). Isolated as a pale oil;
1H NMR (DMSO-d6): dZ0.26 (m, 2H, CH(CH2CH2)), 0.49
(m, 2H, CH(CH2CH2)), 1.10 (m, 1H, CH(CH2CH2)), 3.19
(m, 2H, CH2CH(CH2CH2)), 3.81 (s, 3H, OCH3), 7.04 (d,
JZ8.6 Hz, 2H, ArH), 7.69 (d, JZ9.0 Hz, 2H, ArH), 8.11 (br
s, 1H, NHCH2). ES-MS m/z 262 MHC.
General procedure. To resin 12 (100 mg, 0.042 mmol) pre-
swollen in dry NMP was added a solution of 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(80 mg, 0.42 mmol) in dry NMP (3 mL) and the mixture
was agitated for 14 h at 50 8C. Excess reagent was removed
by filtration and the resin was washed with NMP (2!),
MeOH/THF (1:1 v/v) (2!), DCM (2!) and NMP (2!).
Subsequently the resin was de-protected by treatment
with NMP/piperidine (2 mL, 80:20 v/v) for 20 min, the
de-protection procedure was repeated a further time. Excess
reagents were removed by filtration and the resin was
washed with NMP (3!) yielding the resin bound
[1,3,4]thiadiazol-2-yl) amine. A solution of benzoic acid
(49 mg, 0.40 mmol) in NMP/DCM (2 mL, 1:1 v/v) was
added to the resin followed by DIPEA (75 mL, 0.44 mmol),
DIIC (26 mg, 0.20 mmol) and a catalytic amount of DMAP
(2 mg, 1.6 mmol). The mixture was agitated for 14 h before
the excess reagents were removed by filtration followed by
washing with NMP (3!), MeOH/THF/AcOH (10:10:1 v/v)
(2!), MeOH/THF (1:1 v/v) (2!) and DCM (4!). The
resin was subsequently treated with TFA/DCM (2 mL,
1:1 v/v) for 2 h before the liquors were transferred to a
10 mL round bottom flask and concentrated in vacuo. The
residue was re-dissolved in acetonitrile (5 mL) and a sample
(1 mL) was removed and concentrated in vacuo for NMR
concentration studies and LC–MS analysis. The rest of the
crude products were purified by preparative HPLC yielding
the title compounds 13.
4.7.7. Methyl-(5-phenyl-[1,3,4]thiadiazol-2-yl)-amine
1
(11g). Isolated as a pale oil; H NMR (DMSO-d6): dZ
2.95 (s, 3H, NHCH3), 7.47 (m, 3H, ArH), 7.77 (m, 2H,
ArH), 8.10 (s, 1H, NHCH3). ES-MS m/z 192 MHC.
4.7.8. [5-(4-Bromo-phenyl)-[1,3,4]thiadiazol-2-yl]-
methyl-amine (11h). Isolated as a pale oil; nmax (KBr)
824, 976, 1067, 1154, 1202, 1399, 1497, 1553, 1678,
1
3283 cmK1; H NMR (DMSO-d6): dZ2.95 (d, JZ4.0 Hz,
3H, NHCH3), 7.69 (m, 4H, ArH), 7.98 (s, 1H, NHCH3); 13
C
NMR (DMSO-d6): dZ31.3, 122.7, 128.1, 130.1, 132.1,
154.6, 169.5. HR-MS (Q-TOF-ES) m/zZ269.9695, calcd
for [C33H34N4OSCH]C 269.9701.
4.7.9. (5-Isobutyl-[1,3,4]thiadiazol-2-yl)-methyl-amine
(11i). Isolated as a pale oil; 1H NMR (DMSO-d6): dZ
0.92 (d, JZ6.6 Hz, 6H, CH(CH3)2), 1.91 (m, 1H,
CH(CH3)2), 2.70 (d, JZ7.1 Hz, 2H, CH2CH(CH3)2), 2.90
(s, 3H, NHCH3) 8.34 (s, 1H, NHCH3). ES-MS m/z 172 MHC.
4.7.10. (4-Methoxy-benzyl)-(5-phenyl-[1,3,4]thiadiazol-
2-yl)-amine (11j). Isolated as a pale oil; 1H NMR

5572
R. Severinsen et al. / Tetrahedron 61 (2005) 5565–5575
4.9.1. Cyclopropanecarboxylic acid [5-(4-methoxy-ben-
zylamino)-[1,3,4]thiadiazol-2-yl]-amide (13a). White
solid, mp 185.3–186.1 8C; nmax (KBr) 957, 1032, 1174,
1317, 1407, 1512, 1542, 1586, 1662, 2744, 3334 cmK1; 1H
NMR (DMSO-d6): dZ0.88 (m, 4H, CH(CH2CH2)), 1.89
(m, 1H, CH(CH2CH2)), 3.73 (s, 3H, OCH3), 4.37 (s, 2H,
NHCH2), 6.91 (d, JZ8.6 Hz, 2H, ArH), 7.27 (d, JZ9.1 Hz,
6.5 Hz, 1H, CH(CH3)2), 3.13 (t, JZ4.6 Hz, 2H, CH2NH),
7.55 (t, JZ7.6 Hz, 2H, ArH), 7.65 (t, JZ7.1 Hz, 2H, ArH),
8.07 (d, JZ7.1 Hz, 2H, ArH), 8.25 (br s, 1H, NHCH2),
12.68 (br s, 1H, NHCO). ES-MS m/z 277 MHC.
4.9.9. N-(5-Phenethylamino-[1,3,4]thiadiazol-2-yl)-benz-
amide (13i). Isolated as a pale oil; H NMR (DMSO-d6):
1
2H, ArH), 8.08 (s, 1H, NHCH2), 12.30 (s, 1H, CONH); 13
C
dZ2.90 (t, JZ7.1 Hz, 2H, NHCH2CH2), 3.52 (t, JZ5.1 Hz,
2H, NHCH2CH2), 7.28 (m, 5H, ArH), 7.53 (t, JZ7.6 Hz,
2H, ArH), 7.63 (t, JZ7.1 Hz, 1H, ArH), 7.74 (br s, 1H,
NHCH2), 8.05 (d, JZ7.0 Hz, 2H, ArH), 12.49 (br s, 1H,
NHCO). ES-MS m/z 325 MHC.
NMR (DMSO-d6): dZ10.3, 15.4, 49.1, 57.0, 115.8, 130.9,
132.3, 150.8, 160.5, 166.1, 173.4. HR-MS (Q-TOF-ES)
m/zZ305.1076, calcd for [C33H34N4OSCH]C 305.1072.
4.9.2. N-[5-(4-Methoxy-benzylamino)-[1,3,4]thiadiazol-
2-yl]-benzamide (13b). Isolated as a pale oil; H NMR
1
4.9.10. Cyclopropanecarboxylic acid (5-methylamino-
[1,3,4]thiadiazol-2-yl)-amide (13j). Isolated as a pale oil;
1H NMR (DMSO-d6): dZ0.84 (m, 4H, CH(CH2CH2)), 1.86
(m, 1H, CH(CH2CH2)), 2.80 (d, JZ4.9 Hz, 3H, NHCH3),
7.17 (q, JZ4.9 Hz, 1H, NHCH3), 12.14 (s, 1H, NHCO). ES-
MS m/z 199 MHC.
(DMSO-d6): dZ3.74 (s, 3H, OCH3), 4.42 (br s, 2H,
NHCH2), 6.93 (d, JZ8.5 Hz, 2H, ArH), 7.31 (d, JZ
8.6 Hz, 2H, ArH), 7.53 (t, JZ8.5 Hz, 2H, ArH), 7.63 (t, JZ
7.3 Hz, 2H, ArH), 8.06 (d, JZ7.1 Hz, 2H, ArH), 8.14 (br s,
1H, NHCH2), 12.5 (br s, 1H, CONH). ES-MS m/z 305
MHC.
4.9.11. N-(5-Methylamino-[1,3,4]thiadiazol-2-yl)-benza-
mide (13k). Isolated as a pale oil; 1H NMR (DMSO-d6): dZ
2.88 (s, 3H, NHCH3), 7.52 (t, JZ7.6 Hz, 2H, ArH), 7.62 (t,
JZ7.6 Hz, 1H, ArH), 7.66 (br s, 1H, NHCH3), 8.04 (d, JZ
7.0 Hz, 2H, ArH), 12.54 (s, 1H, NHCO). ES-MS m/z 235
MHC.
4.9.3. Cyclopropanecarboxylic acid (5-benzylamino-
[1,3,4]thiadiazol-2-yl)-amide (13c). Isolated as a pale oil;
1H NMR (DMSO-d6): dZ0.89 (m, 4H, CH(CH2CH2)), 1.89
(m, 1H, CH(CH2CH2)), 4.47 (s, 2H, NHCH2), 7.32 (m, 4H,
ArH), 8.35 (s, 1H, NHCH2), 12.38 (s, 1H, CONH). ES-MS
m/z 275 MHC.
4.9.12. N-(5-Methylamino-[1,3,4]thiadiazol-2-yl)-2-phe-
nyl-acetamide (13l). Isolated as a pale oil; 1H NMR
(DMSO-d6): dZ2.88 (s, 3H, NHCH3), 3.74 (s, 2H,
COCH2), 7.29, (m, 5H, ArH), 8.25 (NHCH3), 12.50 (br s,
1H, NHCO). ES-MS m/z 249 MHC.
4.9.4. N-(5-Benzylamino-[1,3,4]thiadiazol-2-yl)-benza-
mide (13d).16 White solid, mp 235.9–237.1 8C; nmax
(KBr) 671, 694, 752, 892, 1304, 1492, 1539, 1649,
1
3366 cmK1; H NMR (DMSO-d6): dZ4.48 (d, JZ6.1 Hz,
2H, NHCH2), 7.27 (m, 1H, ArH), 7.37 (m, 4H, ArH), 7.52
(t, JZ7.6 Hz, 2H, ArH), 7.62 (t, JZ7.1 Hz, 1H, ArH), 7.89
((t, JZ6.1 Hz, 1H, CH2NH), 8.05 (d, JZ7.0 Hz, ArH),
12.45 (br s, 1H, CONH); 13C NMR (DMSO-d6): dZ46.6,
126.3, 126.8, 127.5, 127.7, 127.8, 131.8, 138.2, 163.6.
HR-MS (Q-TOF-ES) m/zZ311.0961, calcd for
[C33H34N4OSCH]C 311.0967.
4.9.13. N-(5-Methylamino-[1,3,4]thiadiazol-2-yl)-aceta-
mide (13m). Isolated as a pale oil; H NMR (DMSO-d6):
dZ2.08 (s, 3H, COCH3), 2.82 (d, JZ4.4 Hz, 3H, NHCH3),
7.21 (q, JZ4.4 Hz, 1H, NHCH3), 11.88 (s, 1H, NHCO).
ES-MS m/z 173 MHC.
1
4.9.14. N-{5-[(Tetrahydro-furan-2-ylmethyl)-amino]-
[1,3,4]thiadiazol-2-yl}-benzamide (13n). Isolated as a
pale oil; 1H NMR (DMSO-d6): dZ1.57 (m, 1H, CH(OCH2-
CH2CH2)), 1.86 (m, 2H, CH(OCH2CH2CH2), 1.97 (m 1H,
CH(OCH2CH2CH2), 3.39 (dd, J1Z6.0 Hz, J2Z6.8 Hz, 2H,
NHCH2), 3.66 (q, JZ7.1 Hz, 1H, CH(OCH2CH2CH2)),
3.79 (q, JZ7.1 Hz, 1H, CH(OCH2CH2CH2)), 4.04 (m, 1H,
CH(OCH2CH2CH2)), 7.55 (t, JZ7.6 Hz, 2H, ArH), 7.65 (t,
JZ7.1 Hz, 2H, ArH), 8.07 (d, JZ7.1 Hz, 2H, ArH), 8.34 (d,
JZ6.8 Hz, 1H, NHCH2), 12.68 (br s, 1H, NHCO). ES-MS
m/z 305 MHC.
4.9.5. N-(5-Benzylamino-[1,3,4]thiadiazol-2-yl)-2-phenyl-
acetamide (13e).16 Isolated as a pale oil; 1H NMR (DMSO-
d6): dZ3.70 (s, 2H, PhCH2CO), 4.43 (d, JZ5.6 Hz, 2H,
NHCH2), 7.30 (m, 10H, ArH), 7.82 (t, JZ5.6 Hz, 1H
NHCH2), 12.17 (br s, 1H, NHCO). ES-MS m/z 325 MHC.
4.9.6. Furan-2-carboxylic acid (5-benzylamino-[1,3,4]-
thiadiazol-2-yl)-amide (13f). Isolated as a pale oil; 1H
NMR (DMSO-d6): dZ4.47 (d, JZ5.6 Hz, 2H, NHCH2),
6.71 (m, 1H, C(OCHCHCH)), 7.27 (m, 1H, ArH), 7.36 (m,
4H, ArH), 7.57 (br s, 1H, C(OCHCHCH)), 7.94 (t, JZ
5.6 Hz, 1H NHCH2), 7.98 (s, 1H, C(OCHCHCH)), 12.47 (br
s, 1H, NHCO). ES-MS m/z 301 MHC.
4.9.15. Cyclopropanecarboxylic acid {5-[(furan-2-
ylmethyl)-amino]-[1,3,4]thiadiazol-2-yl}-amide (13o).
Isolated as a pale oil; 1H NMR (DMSO-d6): dZ0.85
(m, 4H, CH(CH2CH2)), 1.89 (m, 1H, CH(CH2CH2)), 4.42
(d, JZ5.0 Hz, 2H, NHCH2), 6.33 (d, JZ3 Hz, 1H,
C(OCHCHCH)), 6.41 (q, JZ1.5 Hz, 1H, C(OCHCHCH)),
7.61 (m, 1H, C(OCHCHCH)), 7.71 (t, JZ5.0 Hz, 1H
NHCH2), 12.20 (s, 1H, CONH). ES-MS m/z 265 MHC.
4.9.7. N-(5-Benzylamino-[1,3,4]thiadiazol-2-yl)-aceta-
mide (13g). Isolated as a pale oil; H NMR (DMSO-d6):
1
dZ2.10 (s, 3H, CH3O), 7.47 (s, 2H, NHCH2), 7.29 (m, 1H,
ArH), 7.35 (d, JZ4.1 Hz, 4H, ArH), 8.27 (br s, 1H,
NHCH2), 12.06 (br s, 1H, NHCO). ES-MS m/z 249 MHC.
4.9.8. N-(5-Isobutylamino-[1,3,4]thiadiazol-2-yl)-benza-
mide (13h). Isolated as a pale oil; H NMR (DMSO-d6):
dZ0.93 (d, JZ6.5 Hz, 6H, CH(CH3)2), 1.91 (hept, JZ
4.9.16. N-{5-[(Furan-2-ylmethyl)-amino]-[1,3,4]thiadia-
zol-2-yl}-benzamide (13p). Isolated as a pale oil; 1H
NMR (DMSO-d6): dZ4.47 (d, JZ5.0 Hz, NHCH2), 6.35
1

R. Severinsen et al. / Tetrahedron 61 (2005) 5565–5575
5573
(d, JZ3.0 Hz, 1H, C(OCHCHCH)), 6.42 (m, 1H,
4.10. Formation of semicarbazide (14)
C(OCHCHCH)), 7.53 (m, 2H, ArH), 7.62 (m, 2H, ArH
and C(OCHCHCH)), 7.82 (t, JZ5.0 Hz, 1H, NHCH2) 8.05
(d, JZ7.0 Hz, 2H, ArH), 12.49 (s, 1H, NHCO). ES-MS m/z
301 MHC.
Typical procedure. Resin 5 (1.0 g, 0.42 mmol) swollen in
DCM (15 mL) and DIPEA (2 mL) was agitated for 10 min
before a solution of triphosgene (380 mg, 1.3 mmol) in
DCM (10 mL) was added. The resulting mixture was
agitated for 5 h before excess reagents were removed by
filtration and the resin was washed with DCM (3!). A
solution of hydrazine hydrate (210 mg, 4.2 mmol) in DMSO
(15 mL) was added and the mixture was agitated for 14 h
before the resin was filtered and washed with DMSO (3!),
MeOH/THF/AcOH (10:10:1, v/v) (2!), MeOH/THF (1:1,
v/v) (2!) and DCM (4!). The resin was dried in vacuo
overnight at 40 8C to yield resin bound semicarbazide 14.
4.9.17. N-{5-[(Furan-2-ylmethyl)-amino]-[1,3,4]thiadia-
zol-2-yl}-2-phenyl-acetamide (13q). Isolated as a pale
oil; 1H NMR (DMSO-d6): dZ3.71 (s, 2H, COCH2),
4.42 (d, JZ5.6 Hz, NHCH2), 6.32 (d, JZ3.0 Hz, 1H,
C(OCHCHCH)), 6.40 (m, 1H, C(OCHCHCH)), 7.31 (m,
5H, ArH), 7.60 (m, 1H, 1H, C(OCHCHCH)), 7.74 (t, JZ
5.6 Hz, NHCH2), 12.20 (s, 1H, NHCO). ES-MS m/z 315
MHC.
4.11. Formation of carbamoyl thiosemicarbazide (15)
4.9.18. N-[5-(Cyclopropylmethyl-amino)-[1,3,4]thiadia-
zol-2-yl]-benzamide (13r). Isolated as a pale oil; 1H
NMR (DMSO-d6): dZ0.22 (m, 2H, CH(CH2CH2)), 0.47
(m, 2H, CH(CH2CH2)), 1.08 (m, 1H, CH(CH2CH2)), 3.13 (t,
JZ6.8 Hz, 2H, NHCH2cPr), 7.51 (m, 3H ArH), 7.61 (t, JZ
6.8 Hz, 1H, CH2NH), 8.05 (d, JZ7.0 Hz, 2H, ArH), 12.42
(br s, 1H, CONH). ES-MS m/z 275 MHC.
Typical procedure.
A solution of isothiocyanate
(0.21 mmol) dissolved in DCM (2 mL) and DIPEA
(50 mL, 0.29 mmol) was added to resin 14 and the mixture
was agitated for 6 h. Excess reagents were removed by
filtration and the resin was washed with DCM (2!), NMP
(3!), MeOH/THF (1:1, v/v) (2!) and DCM (3!) yielding
resin bound carbamoyl thiosemicarbazide 15.
4.9.19. N-[5-(Cyclopropylmethyl-amino)-[1,3,4]thiadia-
zol-2-yl]-2-phenyl-acetamide (13s). Isolated as a pale oil;
1H NMR (DMSO-d6): dZ0.19 (m, 2H, CH(CH2CH2)), 0.43
(m, 2H, CH(CH2CH2)), 1.03 (m, 1H, CH(CH2CH2)), 3.08
(t, JZ6.0 Hz, 2H, NHCH2cPr), 3.69 (s, 2H, CH2Ph) 7.29
(m, 5H ArH), 7.38 (t, JZ6.0 Hz, 1H, CH2NH), 12.11 (s, 1H,
CONH). ES-MS m/z 289 MHC.
4.12. Formation of N,N-dialkyl-[1,3,4]oxadiazoles-2,5-
diamine (16)
Typical procedure. To resin 15 (100 mg, 0.042 mmol) pre-
swollen in dry NMP was added a solution of 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(80 mg, 0.42 mmol,) in dry NMP (3 mL) and the mixture
was agitated for 14 h at 60 8C. Excess reagents were
removed by filtration and the resin was washed with NMP
(2!), MeOH/THF (1:1, v/v) (2!) and DCM (4!). The
resin was subsequently treated with TFA/DCM (2 mL,
1:1 v/v) for 2 h before the liquors were transferred to a
10 mL round bottom flask and concentrated in vacuo. The
residue was re-dissolved in acetonitrile (5 mL) and a sample
(1 mL) was removed and concentrated in vacuo for NMR
concentration studies and LC–MS analysis. The rest of the
crude products were purified by preparative HPLC yielding
the title compounds 15.
4.9.20. Furan-2-carboxylic acid [5-(cyclopropylmethyl-
amino)-[1,3,4]thiadiazol-2-yl]-amide (13t). Isolated as a
1
pale oil; H NMR (DMSO-d6): dZ0.24 (m, 2H, CH(CH2-
CH2)), 0.51 (m, 2H, CH(CH2CH2)), 1.10 (m, 1H, CH(CH2-
CH2)), 3.16 (t, JZ6.6 Hz, 2H, NHCH2cPr), 6.73 (m, 1H,
ArH), 7.59 (m, 1H, ArH), 8.01 (m, 1H, ArH) 8.11 (br s, 1H,
CH2NH), 12.66 (s, 1H, CONH). ES-MS m/z 265 MHC.
4.9.21. N-[5-(Cyclopropylmethyl-amino)-[1,3,4] thiadia-
zol-2-yl]-acetamide (13u). Isolated as a pale oil; H NMR
1
(DMSO-d6): dZ0.21 (m, 2H, CH(CH2CH2)), 0.46 (m, 2H,
CH(CH2CH2)), 1.07 (m, 1H, CH(CH2CH2)), 2.08 (s, 3H,
CH3CO) 3.10 (t, JZ6.6 Hz, 2H, NHCH2cPr), 7.35 (t, JZ
6.6 Hz, 1H, CH2NH), 11.84 (s, 1H, CONH). ES-MS m/z 213
MHC.
4.12.1. N-Benzyl-N0-(4-methoxy-benzyl)-[1,3,4]oxadia-
zole-2,5-diamine (16a). Isolated as a pale oil; H NMR
1
(DMSO-d6): dZ3.72 (s, 3H, OCH3), 4.16 (d, JZ6.1 Hz,
2H, NHCH2), 4.24 (d, JZ6.1 Hz, 2H, NHCH2), 6.87 (d, JZ
9.1 Hz, 2H, ArH), 7.24 (d, JZ8.6 Hz, 2H, ArH), 7.32 (m,
5H, ArH), 7.40 (t, JZ6.1 Hz, 1H, NH), 7.48 (t, JZ6.1 Hz,
1H, NH). ES-MS m/z 311 MHC.
4.9.22. N-{5-[(Pyridin-4-ylmethyl)-amino]-[1,3,4] thia-
diazol-2-yl}-benzamide (13v). Isolated as a pale oil; H
1
NMR (DMSO-d6): dZ4.76 (d, JZ4.6 Hz, 2H CH2), 7.53
(m, 3H, ArH), 7.82 (d, JZ6.7 Hz, 2H, ArH), 8.06 (d, JZ
7.0 Hz, 2H, ArH), 8.24 (m, 1H, CH2NH), 8.78 (d, JZ
6.7 Hz, 2H, ArH), 11.84 (s, 1H, CONH). ES-MS m/z 312
MHC.
4.12.2. N-Cyclopropylmethyl-N0-(4-methoxy-benzyl)-
[1,3,4]oxadiazole-2,5-diamine (16b). White solid, mp
104.7–105.2 8C; nmax (KBr) 823, 1034, 1177, 1252, 1302,
1515, 1569, 1660, 2927, 3298 cmK1; 1H NMR (DMSO-d6):
dZ0.23 (m, 2H, CH(CH2CH2)), 0.47 (m, 2H, CH(CH2-
CH2)), 1.04 (m, 1H, CH(CH2CH2)), 3.01 (m, 2H, CH2-
CH(CH2CH2)), 3.74 (s, 3H, OCH3), 4.25 (br s, 2H,
NHCH2), 6.91 (d, JZ9.1 Hz, 2H, ArH), 7.29 (d, JZ
7.4 Hz, 2H, ArH), 7.52 (br s, 1H, NH), 7.57 (br s, 1H, NH);
13C NMR (DMSO-d6): dZ3.39, 10.3, 45.3, 47.1,
55.1, 113.8, 129.0, 129.8, 156.8, 158.4, 158.6. HR-MS
4.9.23. 2-Phenyl-N-{5-[(pyridin-4-ylmethyl)-amino]-
[1,3,4]thiadiazol-2-yl}-acetamide (13x). Isolated as a
1
pale oil; H NMR (DMSO-d6): dZ3.72 (s, 2H, COCH2)
4.71 (d, JZ4.3 Hz, CH2NH), 7.31 (m, 6H, ArH), 7.78 (d,
JZ6.0 Hz, ArH), 8.16 (m, 1H, CH2NH), 8.77 (d, JZ6.6 Hz,
ArH), 12.27 (s, 1H, CONH). ES-MS m/z 326 MHC.

5574
R. Severinsen et al. / Tetrahedron 61 (2005) 5565–5575
(Q-TOF-ES) m/zZ275.1503, calcd for [C33H34N4OSC
CH2CH2Ph), 6.92 (t, JZ7.5 Hz, 1H, ArH), 7.29 (m, 9H,
ArH and NHCH2), 7.47 (d, JZ7.6 Hz, 2H, ArH), 9.91 (s,
1H, PhNH). ES-MS m/z 281 MHC.
H]C 275.1508.
4.12.3. N,N0-Dibenzyl-[1,3,4]oxadiazole-2,5-diamine
(16c). Isolated as a pale oil; 1H NMR (DMSO-d6):
dZ4.32 (d, JZ6.1 Hz, 4H, NHCH2), 7.25 (m, 2H, ArH),
7.35 (m, 8H, ArH), 8.61 (br s, 2H, NH). ES-MS m/z
281 MHC.
4.12.11. N-Cyclopropylmethyl-N0-phenyl-[1,3,4]oxadia-
zole-2,5-diamine (16k). Isolated as a pale oil; H NMR
1
(DMSO-d6): dZ0.23 (m, 2H, CH(CH2CH2)), 0.46 (m, 2H,
CH(CH2CH2)), 1.07 (m, 1H, CH(CH2CH2)), 3.01 (m, 2H,
CH2CH(CH2CH2)), 6.93 (t, JZ7.6 Hz, 1H, ArH), 7.29 (t,
JZ8.4 Hz, 2H, ArH), 7.44 (d, JZ7.6 Hz, 2H, ArH), 7.91 (br
s, 1H, NHCH2), 10.10 (s, 1H, PhNH). ES-MS m/z 231
MHC.
4.12.4. N-Benzyl-N0-phenethyl-[1,3,4]oxadiazole-2,5-dia-
mine (16d). White solid, mp 134.8–135.9 8C; nmax (KBr)
697, 1136, 1201, 1263, 1359, 1452, 1598, 1680, 2983,
1
3170 cmK1; H NMR (DMSO-d6): dZ2.82 (t, JZ7.6 Hz,
4.12.12. N-Methyl-N0-phenethyl-[1,3,4]oxadiazole-2,5-
diamine (16l). Isolated as a pale oil; H NMR (DMSO-
2H, PhCH2CH2), 3.28 (m, 2H, PhCH2CH2), 4.26 (d, JZ
6.3 Hz, PhCH2NH), 7.27 (m, 11H, ArH and NH), 8.17 (t,
JZ6.3 Hz 1H, NH); 13C NMR (DMSO-d6): dZ34.5, 43.9,
45.8, 126.0, 126.9, 127.3, 128.2, 128.2, 128.6, 138.8, 139.1,
157.8, and 157.9. HR-MS (Q-TOF-ES) m/zZ295.1553,
calcd for [C33H34N4OSCH]C 295.1559.
1
d6): dZ2.76 (d, JZ2.0 Hz, NHCH3), 2.84 (t, JZ7.1 Hz,
2H, PhCH2CH2), 3.34 (m, 2H, PhCH2CH2), 7.25 (m, 5H,
ArH), 8.17 (br s, 1H, NH), 8.24 (s, 1H, NH). ES-MS m/z 219
MHC.
4.12.5. N-Benzyl-N0-cyclopropylmethyl-[1,3,4]oxadia-
zole-2,5-diamine (16e). Isolated as a pale oil; H NMR
4.12.13. N-Cyclopropylmethyl-N0-methyl-[1,3,4]oxadia-
zole-2,5-diamine (16m). Isolated as a pale oil; H NMR
1
1
(DMSO-d6): dZ0.22 (m, 2H, CH(CH2CH2)), 0.46 (m, 2H,
CH(CH2CH2)), 1.04 (m, 1H, CH(CH2CH2)), 2.99 (m, 2H,
CH2CH(CH2CH2)), 4.31 (d, JZ6.1 Hz, 2H, NHCH2Ph),
7.30 (m, 5H, ArH), 8.32 (br s, 1H, NH), 8.43 (br s, 1H, NH).
ES-MS m/z 245 MHC.
(DMSO-d6): dZ0.23 (m, 2H, CH(CH2CH2)), 0.47 (m, 2H,
CH(CH2CH2)), 1.04 (m, 1H, CH(CH2CH2)), 2.76 (s, 3H,
NHCH3), (3.00 (m, 2H, CH2CH(CH2CH2)), 8.17 (br s, 1H,
NH), 8.29 (br s, 1H, NH). ES-MS m/z 169 MHC.
4.12.6. N-Cyclopropylmethyl-N0-ethyl-[1,3,4]oxadiazole-
2,5-diamine (16f). Isolated as a pale oil; 1H NMR (DMSO-
d6): dZ0.23 (m, 2H, CH(CH2CH2)), 0.47 (m, 2H, CH(CH2-
CH2)), 1.04 (m, 1H, CH(CH2CH2)), 1.14 (t, JZ7.1 Hz,
3H, CH2CH3), 3.00 (m, 2H, NHCH2CH2), 3.15 (m, 2H,
CH2CH(CH2CH2)), 8.20 (br s, 1H, NH), 8.37 (br s, 1H,
NH). ES-MS m/z 183 MHC.
Acknowledgements
The authors would like to thank Corporate Research Affairs
at Novo Nordisk A/S and The Danish Academy of
Technical Sciences for financial support. We would also
like to thank Berit P. Jensen and Jan V. Andersen for their
help with HR-MS.
4.12.7. N-Cyclopropylmethyl-N0-phenethyl-[1,3,4]oxa-
diazole-2,5-diamine (16g).15 Isolated as a pale oil;
1H NMR (DMSO-d6): dZ0.23 (m, 2H, CH(CH2CH2)),
0.47 (m, 2H, CH(CH2CH2)), 1.04 (m, 1H, CH(CH2CH2)),
2.85 (t, JZ7.2 Hz, 2H, PhCH2CH2), 3.00 (m, 2H, CH2-
CH(CH2CH2)), 3.35 (m, 2H, PhCH2CH2), 7.25 (m, 5H,
ArH), 8.31 (br s, 1H, NH), 8.37 (br s, 1H, NH). ES-MS m/z
259 MHC.
References and notes
1. Dolle, R. E. J. Comb. Chem. 2004, 6, 623–679 and references
cited therein.
2. Alper, J. Science 1994, 264, 1399–1401.
3. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J.
Adv. Drug Deliv. Rev. 1997, 23, 3–25.
4.12.8. N-Benzyl-N0-phenyl-[1,3,4]oxadiazole-2,5-dia-
1
mine (16h).17 Isolated as a pale oil; H NMR (DMSO-d6):
4. Teague, S. J.; Davis, A. M.; Leeson, P. D.; Oprea, T. Angew.
Chem. Int. Ed. 1999, 38, 3743–3748.
dZ4.33 (d, JZ6.1 Hz, 2H, NHCH2), 6.91 (t, JZ7.1 Hz,
1H, ArH), 7.28 (m, 3H, ArH), 7.37 (m, 4H, ArH), 7.45 (d,
JZ7.6 Hz, 2H, ArH), 7.82 (t, JZ6.1 Hz, 1H, NHCH2), 9.95
(s, 1H, PhNH). ES-MS m/z 266 MHC.
5. Oprea, T. I.; Davis, A. M.; Teague, S. J.; Leeson, P. D.
J. Chem. Inf. Comput. Sci. 2001, 41, 1308–1315.
6. Kilburn, J. P.; Lau, J.; Jones, R. C. F. Tetrahedron Lett. 2003,
44, 7825–7828.
4.12.9. N-Ethyl-N0-phenyl-[1,3,4]oxadiazole-2,5-diamine
(16i).17 Isolated as a pale oil; 1H NMR (DMSO-d6): dZ1.18
(t, JZ7.6 Hz, 3H, CH2CH3), 3.20 (q, JZ7.1 Hz,
2H, CH2CH3), 6.95 (t, JZ7.6 Hz, 1H, ArH), 7.31 (t,
JZ8.6 Hz, 2H, ArH), 7.44 (d, JZ7.6 Hz, 2H, ArH), 8.07
(br s, 1H, NHCH2), 10.21 (s, 1H, PhNH). ES-MS m/z
205 MHC.
7. Kilburn, J. P.; Lau, J.; Jones, R. C. F. Tetrahedron Lett. 2001,
42, 2583–2586.
¨
8. Dorwald, F. Z. In Organic Synthesis on Solid Phase; Wiley-
VCH: Weinheim, 2000; pp 51–58.
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38, 1161–1164.
10. Kearney, P. C.; Fernandez, M.; Flygare, J. A. J. Org. Chem.
1998, 63, 196–200.
4.12.10. N-Phenethyl-N0-phenyl-[1,3,4]oxadiazole-2,5-
diamine (16j). Isolated as a pale oil; H NMR (DMSO-
11. Novabiochem (200–400 mesh, polystyrene-divinylbenzene
1%, 0.45 mmol/g).
12. Kim, S.; Yi, K. Y. Tetrahedron Lett. 1985, 26, 1661–1664.
1
d6): dZ2.87 (t, JZ7.0 Hz, 2H, CH2CH2Ph), 3.45 (m, 2H,

R. Severinsen et al. / Tetrahedron 61 (2005) 5565–5575
5575
13. Gin, S.; Singh, H. J. Indian Chem. Soc. 1967, 44,
145–147.
16. Okawara, T.; Tateyama, Y.; Yamasaki, T.; Furukawa, M.
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176–180.
14. Young, R. W.; Wood, K. H.; Eichler, J. A.; Vaughan, J. R.;
Anderson, G. V. J. Am. Chem. Soc. 1956, 78, 4649–4652.
15. Saikaichi, H.; Kanaoka, M. Yakugaku Zasshi 1961, 81,
4649–4652.