3-Methyl-4H-[1,2,4]-oxadiazol-5-one: A versatile synthon for protecting monosubstituted acetamidines

Article abstract of DOI:10.1016/j.tet.2004.09.030

The utilization of 3-methyl-4H-[1,2,4]-oxadiazol-5-one as a versatile protected acetamidine is demonstrated through employment in a variety of synthetic sequences. The potassium salt (2a) or the neutral form (2b) is alternatively shown to be superior for

Full text of DOI:10.1016/j.tet.2004.09.030

Tetrahedron 60 (2004) 10907–10914
3-Methyl-4H-[1,2,4]-oxadiazol-5-one: a versatile synthon for
protecting monosubstituted acetamidines
*
Alan E. Moormann, Jane L. Wang, Katherine E. Palmquist, Michele A. Promo,
Jeffery S. Snyder, Jeffrey A. Scholten, Mark A. Massa, James A. Sikorski† and R. Keith Webber
Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield MO 63017, USA
Received 28 May 2004; revised 9 September 2004; accepted 10 September 2004
Available online 29 September 2004
Abstract—The utilization of 3-methyl-4H-[1,2,4]-oxadiazol-5-one as a versatile protected acetamidine is demonstrated through
employment in a variety of synthetic sequences. The potassium salt (2a) or the neutral form (2b) is alternatively shown to be superior
for various synthetic reactions (i.e., alkylation, Michael addition, Mitsunobu) to incorporate side chains for further synthesis. The 3-methyl-
4H-[1,2,4]-oxadiazol-5-one moiety was found to be stable to acid or base under non-aqueous conditions. It was also found to be stable to
many reagents commonly used for organic synthesis. Despite this stability, the free acetamidine may be released by mild reduction including
Lindlar hydrogenation or dissolving metal reductions. Alternatively, the hydroxyl amidine may be formed via alkaline hydrolysis.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
the utility of this conversion as a component of a synthetic
sequence. The work described here explores the synthetic
utility of the use of 3-methyl-4H-[1,2,4]-oxadiazol-5-one as
a protected acetamidine. We have found this heterocycle to
be stable to many synthetic conditions and have used it in
extended synthetic schemes. The mild reaction conditions
for the selective generation of acetamidines and hydroxy-
acetamidines is described as well.
Amidine groups are found in many medicinal drugs, for
example, cardiovascular, anti-diabetic, antibacterial, anti-
protozoal, anthelmintic, anti-inflammatory, central nervous
system, antineoplastic and others.1,2 N-monosubstituted
acetamidines have been useful as arginine mimetics and
they have been utilized in nitric oxide synthase (NOS)
inhibitors in particular.3,4 The basic nature of the amidine
and its facile hydrolysis to the corresponding amide makes
the synthesis and purification of compounds containing
them troublesome. For our needs we sought a versatile
method to prepare highly functionalized N-monosubstituted
acetamidines. This investigation led to the introduction of
the acetamidine in a protected form that enabled facile
synthetic manipulations.
2. Results and discussion
The utility of 3-methyl-4H-[1,2,4]-oxadiazol-5-one is
dependent upon a consistent route for preparation. We
utilized a procedure described by Hett et al. (Scheme 1),
which is suitable for the kilogram scale synthesis of the
potassium salt 2a.7 A simple bubbling of HCl through an
ether suspension of 2a affords the protonated form of the
heterocycle 2b.
A survey of the literature revealed that oxadiazol-5-ones
have been previously described as precursors to ami-
dines.5a–c,6a–d These prior investigations did not explore
Scheme 1.
Keywords: Protected amidine; 3-Methyl-4H-[1,2,4]-oxadiazol-5-one.
* Corresponding author. Tel.: C1 636 247 7553; fax: C1 636 247 5400; e-mail: alan.e.moormann@pfizer.com
† Current address: AtheroGenics, Inc., 8995 Westside Parkway, Alpharetta, GA 30004, USA. Tel: C1 678 336 2733; fax: C1 678 336 2501.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.030

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A. E. Moormann et al. / Tetrahedron 60 (2004) 10907–10914
Scheme 2.
Schemes 2–4 examine the reactivity of the potassium salt
2a with activated halides. These schemes also show the
feasibility of unmasking the acetamidine in the presence of
other sensitive groups and the stability of the oxadiazolone
ring to further synthetic manipulations.
retaining the protected amidine 10. Alternatively, sonication
of 9 in the presence of zinc and HOAc released the
acetamidine 11 without altering the phthalimide. In both
deprotections the double bond was retained.
A facile reaction of the a-chloroketoester 12 with 2a
afforded the a-ketoester 13 (Scheme 4). Deprotection of 13
via hydrogenation with Lindlar’s catalyst in MeOH yielded
the acetamidine 14 and a small amount of the imidazole 15.
The mixture was separated and it was determined that 14
slowly cyclizes to form the imidazole 15.
The potassium salt 2a readily reacts with benzyl bromides to
form the benzyl adducts (Scheme 2). The heterocycles 4a
and 4b were subsequently hydrolyzed in aqueous hydroxide
to afford the N-hydroxy amidines 5a and 5b. Heating 4a
with Lindlar’s catalyst in MeOH at reflux or with zinc in
HOAc at 60 8C reduced the N–O bond to afford the
acetamidine.
The protonated form of the heterocycle, 2b, was found to
undergo the Mitsunobu reaction with dihydroxy-olefinic
alcohol 16 in a preferential reaction of the allylic alcohol to
the alkyl alcohol (Scheme 5). The reaction afforded a
mixture of N and O-alkylated products 17 and 18. These
isomers were separable by chromatography and the
structures confirmed by NMR. Only the protonated form
2b was successful in this reaction. Attempts to use the
potassium salt 2a directly or via in situ generation of 2b,
failed to afford the Mitsunobu product. Although the alkyl
Mono-alkylation of the allylic dibromide 7 was accom-
plished by limiting the amount of 2a (Scheme 3). This
produced a mixture favoring the mono-alkylated derivative
8, along with a small amount of the di-alkylated derivative
that was separable by chromatography. The oxadiazolinone
8 was further elaborated to the phthalimide protected amino
derivative 9 using potassium phthalimide. The phthalimide
was removed with hydrazine to yield the free amine while
Scheme 3.
Scheme 4.

A. E. Moormann et al. / Tetrahedron 60 (2004) 10907–10914
10909
alcohols were found to be much less reactive than allylic
alcohols, a mixture of O and N- alkylated products of the
alkyl alcohol was observed when a large excess of
Mitsunobu reagents were utilized along with extended
reaction time.
After exploring the reactivity of 2a and 2b, several fluoro-
olefins were synthesized to demonstrate the flexibility and
chemical stability of the oxadiaxolinone when incorporated
into a synthetic sequence. Schemes 6–8 exemplify the use of
a Michael addition, alkylation and Mitsunobu reaction,
respectively.
Scheme 5.
Scheme 6.
Scheme 7.
Scheme 8.

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A. E. Moormann et al. / Tetrahedron 60 (2004) 10907–10914
The Michael addition was successful with 2b to afford the
saturated aldehyde 19 (Scheme 6). As with the Mitsunobu
reaction only the protonated form successfully produced
product. The aldehyde 19 was further elaborated using
Wittig conditions to the fluoro-olefinic ester 21 in high yield
with no alteration of the heterocycle. The oxadiazolinone
was further shown to be stable during reduction of the ester
group in 21 with Red-Al to afford the alcohol 22. The
alcohol 22 was then converted to the bromide 23, using
PPh3/CBr4 in CH2Cl2, to set up for further potential
elaboration.
!1 ppm. Column chromatography was performed using
either Biotage Flash 40 or 12 system. Reverse phase
chromatography was performed on a Gilson semi-prepara-
tive HPLC with a YMC Combiprep ODS-A semi-prep
column eluting with acetonitrile/water (0.01% TFA) at
20 mL/min. Mass spectra were obtained on a HP series
1100MSD, and high-resolution mass spectra were obtained
with a PerSeptive Biosystems Mariner TOF. All solvents
and reagents were purchased from Sigma-Aldrich.
4.1.1. Preparation of 3-methyl-1,2,4-oxadiaxolin-5-one
(2b). Oxadiazolone 2a7 (30.0 g, 0.217 mol) was suspended
in Et2O (150 mL) and cooled in an ice bath. HCl gas was
bubbled through the slurry until the exotherm ceased. The
mixture was stirred for 2 h, the solid filtered and the filtrate
concentrated. The residue was dried under high vacuum to
yield 15.5 g (71.4%) of 2b. 1H NMR (DMSO-d6): d 1.82 (s,
3H); 13C NMR (CDCl3): d 11.8, 162.5, 168.2; MS(CI) calcd
for C3H4N2O2: [MCH] 101. Found: [MCH] 101; Anal.
calcd for C3H4N2O2: C, 36.01; H, 4.03; N, 27.99. Found: C,
35.76; H, 3.99; N, 28.26.
A selective alkylation of an allyl mesylate in the presence
the alkyl mesylate utilizing the potassium salt 2a afforded
29 (Scheme 7). Further elaboration to the iodo-olefin 30
afforded an analog of 23 where the amidine precursor is
transposed in relation to the halide.
The one carbon shorter homolog of 29 was prepared using a
Mitsunobu reaction to yield 36 (Scheme 8). Further elabo-
ration as for 30 afforded the corresponding homolog 37.
4.1.2. 4-Benzyl-3-methyl-1,2,4-oxadiazol-5(4H)-one (4a).
Benzyl bromide (1.13 g, 6.59 mmol) in acetone (15 mL)
was added at ambient temperature to a suspension of 2a
(1 g, 7.25 mmol), and tetrabutylammonium bromide
(0.21 g, 0.66 mmol) in acetone (20 mL). The mixture was
stirred 18 h, then quenched with brine and EtOAc. The
organic layer was separated and the aqueous layer was
extracted three times with EtOAc. The combined organic
layers were washed with brine and dried over Na2SO4. The
filtrate was concentrated and the product was dried under
vacuum to yield 1.12 g (89%) 4a as a white solid, mp 64–
65 8C. 1H NMR (CDCl3): d 2.12 (s, 3H), 4.74 (s, 2H), 7.26
(m, 2H), 7.36 (m, 3H); 13C NMR (CDCl3): d 10.9, 46.0,
127.6, 129.0, 129.5, 134.2, 156.8, 159.9; HRMS calcd for
C10H10N2O2: [MCH] 191.0821. Found: [MCH]191.0822;
Anal. calcd for C10H10N2O2: C, 63.15; H, 5.39; N, 14.73.
Found: C, 63.22; H, 5.36; N, 14.79.
3. Conclusions
3-Methyl-4H-[1,2,4]-oxadiazol-5-one 2 was demonstrated
to be selective and versatile for the incorporation of the
acetamidine in a protected form. The oxadiazolone ring was
stable and robust, through multiple synthetic manipulations.
Furthermore, the incorporated oxadiazolone produced
products, which could be purified by silica chromatography
and often by recrystallization. Catalytic reduction using
Lindler’s catalyst or zinc/HOAc selectively reduced the N–O
bond, releasing the acetamidine in the presence of olefins
and other reducible groups. The released acetamidine was
often isolated pure. When purification was required, simple
reverse-phase chromatography afforded clean product.
Only the protonated form of the oxadiazolone 2b partici-
pated in Michael additions and Mitsunobu reactions while
the salt 2a participated in alkylation reactions. Both the
Mitsunobu and alkylation reactions were selective for the
allylic versus alkyl sites. Weak nucleophilic hydrides
reduced a distal carbonyl to an alcohol without altering
the oxadiazolinone. The oxadiazolinone ring was found to
be stable to mild acidic conditions, but was hydrolyzed to
afford the N-hydroxyamidine in 1 N NaOH. Hydrazine
reacted with phthalimide 8 to release the amine 34 in the
presence of the oxadiazolone ring.
4.1.3. 4-(4-Bromobenzyl)-3-methyl-1,2,4-oxadiazol-
5(4H)-one (4b). 4-Bromobenzyl bromide (1.65 g,
6.59 mmol) was allowed to react as in 4a to yielded
1
1.60 g (90%) of 4b as a white solid, mp 108–109 8C. H
NMR (CDCl3): d 2.14 (s, 3H), 4.69 (s, 2H), 7.13 (d, 2H),
7.50 (d, 2H); 13C NMR (CDCl3): d 10.9, 45.4, 123.5, 129.3,
132.7, 132.8, 149.5, 160.1; HRMS calcd for C10H9N2O2Br:
[MCH] 268.9926. Found: [MCH] 268.9923; Anal. calcd
for C10H9N2O2Br: C, 44.63; H, 3.37; N, 10.41. Found: C,
44.76; H, 3.40; N, 10.37.
4. Experimental
4.1. General
4.1.4. 3-Methyl-4-(4-nitrobenzyl)-1,2,4-oxadiazol-5(4H)-
one (4c). 4-Nitrobenzyl bromide (1.42 g, 6.59 mmol) was
allowed to react as in 4a to yielded 1.35 g (87%) of 4c as a
1
white solid, mp 150–152 8C. H NMR (CDCl3): d 2.17 (s,
3H), 4.85 (s, 2H), 7.45 (d, 2H), 8.25 (d, 2H); 13C NMR
(CDCl3): d 10.9, 45.2, 124.8, 128.5, 141.7, 156.2; HRMS
calcd for C10H9N3O4: [MCH] 236.1963. Found: [MCH]
236.1959; Anal. calcd for C10H9N3O4: C, 51.07; H, 3.86; N,
17.87. Found: C, 51.19; H, 3.88; N, 17.83.
1H NMR spectra were recorded on either a Varian Unity
Plus 300 (300 MHz) or a Varian Unity Inova 400
(400 MHz) spectrometer. All NMR spectra are 400 MHz
unless stated otherwise. All proton chemical shifts are
recorded in ppm (d) relative to trimethylsilane. All fluorine
chemical shifts are recorded in ppm (d) relative to a
reference of C6H5CF3 in benzene (Varian standard sample),
which has a 19F chemical shift of K64 ppm, with an error of
4.1.5. (1Z)-N-Benzyl-N0-Hydroxyethanimidamide (5a).
4a (190 mg, 1.0 mmol) was suspended in 5% NaOH

A. E. Moormann et al. / Tetrahedron 60 (2004) 10907–10914
10911
(2 mL) at 60 8C for 3 h. The mixture was neutralized with
1 N HCl to pH 7–8. The solid was collected, washed with
cold water several times and air dried to yield 100 mg (61%)
of 5a as a white solid, mp 138–139 8C. 1H NMR (CD3OD):
d 1.76 (s, 3H), 4.35 (s, 2H), 7.26 (m, 5H); 13C NMR
(CD3OD): d 13.5, 45.5, 114, 126.5, 127.2, 128.4; HRMS
calcd For C9H12N2O: [MCH] 165.1028. Found: [MCH]
165.0987; Anal. calcd for C9H12N2O: C, 65.83; H, 7.37; N,
17.05. Found: C, 65.83; H, 7.39; N, 17.06.
with H2O (50 mL), and the filtrate was extracted with
EtOAc. The organic layer was dried over MgSO4, and
concentrated to yield 1.32 g (52%) of 9 as a yellow solid. 1H
NMR (300 MHz, CDCl3): d 2.21 (s, 3H), 4.06 (d, 2H), 4.32
(d, 2H), 5.59 (m, 2H), 7.71 (m, 2H) 7.89 (m, 2H); LC–MS
calc for C15H13N3O4: [MCH] 300. Found: [MCH] 300;
Anal calcd for C15H13N3O4: C, 60.20; H, 4.38; N, 14.04.
Found: C, 59.98; H, 4.34; N, 14.10.
4.1.10. N-Benzylethanimidamide (10). Phthalimide 9
(150 mg, 0.5 mmol) was dissolved/suspended in EtOH
(3.0 mL). Hydrazine hydrate (50 mg, 1.0 mmol) was
added and the mixture was stirred at reflux for 30 min.
The reaction mixture was concentrated and the residue
dissolved in dilute K2CO3. The insoluble material was
filtered and the filtrate was chromatographed using reverse
phase to yield 10 mg of 10 (7.5%) isolated as the TFA salt.
1H NMR (MeOD): d 2.25 (s, 3H), 3.55 (dd, JZ6.4, 1.2 Hz,
2H), 4.29, 4.28 and 4.27, 4.270 (d of d, JZ5.2, 1.2 Hz, 2H),
5.78–5.71 (m, 1H), 5.97–5.90 (m, 1H); 19F NMR (MeOD): d
K77.37; HRMS calcd for C7H11N3O2: [MCH] 170.0924.
Found: [MCH] 170.0916.
4.1.6. (1Z)-N-(4-Bromobenzyl)-N0-hydroxyethanimida-
mide (5b). 4b (270 mg, 1.0 mmol) was allowed to react as
in 5a to give 200 mg (83%) of 5b as a white solid, mp 129–
1
130 8C. H NMR (CD3OD): d 1.74 (s, 3H), 4.31 (s, 2H),
7.22 (d, 2H), 7.47 (d, 2H); 13C NMR (CD3OD): d 13.5, 44.5,
120.1, 120.5, 128.4, 131.5; Anal. calcd for C9H11BrN2O: C,
44.47; H, 4.56; N, 11.52. Found: C, 44.69; H, 5.59; N, 11.66.
4.1.7. Preparation of (iminoethyl)benzylamine (6).
Method A: Oxadiazolone 4a (380 mg, 2.0 mmol) was
combined with MeOH (2 mL), HOAc (2 mL), water
(2 mL) and zinc dust (570 mg, 8.7 mmol). The mixture
was heated at 60 8C for 4 h. LCMS indicated product
formation with no starting material. The reaction mixture
was filtered and the filtrate concentrated. The crude product
was purified by Reverse phase HPLC (0–100% acetonitrile
with 0.01% HOAc) isolated as the HOAc salt to yield
300 mg (72%) of 6 as a clear oil. 1H NMR (CD3OD): d 1.86
(s, 3H), 4.46 (s, 2H), 7.37 (m, 5H); 13C NMR (CDCl3): d
17.7, 46.0, 127.6, 127.9, 128.2, 128.8, 134.7, 164.0; HRMS
calcd for C9H12N2: [MCH] 149.1079. Found: [MCH]
149.1041.
4.1.11. N-[(2E)-4-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-
9
yl)but-2-enyl]ethanimidamide (11). Phthalimide
(150 mg, 0.5 mmol) and zinc (101 mg; 1.5 mmol) were
dissolved/suspended in HOAc (10 mL) and sonicated for
10 min. The resulting mixture was filtered and concentrated.
The residue was chromatographed using reverse phase
chromatography to yield 96 mg (18%) of 11 isolated as the
1
TFA salt. H NMR (MeOD): d 2.23 (s, 3H), 4.04 (dd, JZ
11.2, 6.4 Hz, 1H), 4.23 (dd, JZ5.2, 1.2 Hz, 2H), 4.31 (d of
d, JZ16.0, 4.8 Hz, 1H), 5.83–5.69 (m, 2H), 7.73–7.51 (m,
4H); 19F NMR (MeOD): d K77.38; HRMS calcd for
C14H15N3O2: [MCH] 258.1164. Found: [MCH] 258.1152.
Method B: Oxadiazolone 4a (190 mg, 1.0 mmol) and
Lindlar’s catalyst Pd–CaCO3 (290 mg) were combined in
MeOH (10 mL). The mixture was heated at 60 8C for 2 h.
LCMS indicated a new product with 4a consumed. The
reaction mixture was filtered and washed with MeOH. The
filtrate was concentrated to dryness to yield 6 quantitively.
4.1.12. Ethyl 4-(3-methyl-5-oxo-1,2,4-oxadiazol-4(5H)-
yl)-3-oxobutanoate (13). Chloroester 12 (5.0 g, 0.03 mol)
was added drop wise to a mixture of Cs2CO3 (13 g,
0.04 mol), NaI (50 mg) and 2a (6 g, 0.04 mol) dissolved/
suspended in DMSO (40 mL), and stirred for 3 h at ambient
temperature. The reaction was quenched with NH4Cl
solution and the product extracted into EtOAc. The residue
was chromatographed over silica, eluting with EtOAc/
hexane to yield 5.3 g (58%) of 13 as a yellow oil. 1H NMR
(CDCl3): d 1.33, (t, JZ9.6 Hz, 3H), 2.20 (s, 3H), 3.60 (s,
2H), 4.25 (q, JZ9.2 Hz, 2H), 4.63 (s, 2H); MS(CI) calcd for
C9H12N2O5: [MCH] 229. Found: [MCH] 229; Anal. calcd
for C9H12N2O5: C, 47.37; H, 5.30; N, 12.28. Found: C,
47.40; H, 5.46; N, 11.86.
4.1.8. 4-[(2E)-4-Bromobut-2-enyl]-3-methyl-1,2,4-oxa-
diazol-5(4H)-one (8). Trans-1,4-dibromo-2-butene (7)
(50 g, 0.23 mol) was dissolved in acetone (500 mL).
Oxadiazolone 2a (16 g, 0.12 mol) was added, followed by
tetrabutylammonium bromide (3.9 g, 0.012 mol). The reac-
tion mixture was stirred at ambient temperature for 18 h,
diluted with brine and the product was extracted into
EtOAc. The organic extract was washed with brine, dried
over MgSO4, filtered and concentrated to a yellow semi-
solid residue. The product 8 was extracted from the residue
into CH2Cl2 and concentrated to an oily residue. This
residue was triturated with hot hexane to remove unreacted
7, then chromatographed on silica, eluting with EtOAc/
hexane to yield 14.2 g (50%) of 8 as a yellow oil. 1H NMR
(300 MHz, CDCl3): d 2.2 (s, 3H), 3.9 (d, 2H), 4.2 (d, 2H),
5.7 (d of t, 1H), 5.9 (d of t, 1H).
4.1.13. Ethyl 4-(ethanimidoylamino)-3-oxobutanoate
(14) and ethyl (2-methyl-1H-imidazol-5-yl)acetate (15).
Ester 13 (80 mg; 0.35 mmol) was added to 5% Pd–C
(10 mg) in EtOH (20 mL) and placed under 40 psi hydrogen
gas for 4 h. The reaction mixture was filtered and
concentrated at ambient temperature. The residue was
chromatographed using reverse phase. Two products were
isolated:
4.1.9. 2-[(2E)-4-(3-Methyl-5-oxo-1,2,4-oxadiazol-4(5H)-
yl)but-2-enyl]-1H-isoindole-1,3(2H)-dione (9). Bromide
8 (2 g, 8.58 mmol), tetrabutylammonium bromide (0.26 g,
0.86 mmol) and potassium phthalimide (1.9 g, 10.3 mmol)
were dissolved in acetone (20 mL) and stirred for 2 h at
ambient temperature. The solid was filtered and washed
1
Ester 14 was the first component off the column. H NMR
(MeOD): d 1.25 (t, JZ7.2 Hz, 3H), 2.35 (s, 3H), 3.59

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A. E. Moormann et al. / Tetrahedron 60 (2004) 10907–10914
(s, 2H), 4.15 (q, JZ9.6 Hz, 2H), 4.91 (s, 2H); HRMS calcd
for C8H14N2O3: 187.1083, found: 187.1064.
(33.2 g, 0.218 mol) was added drop wise over a 20 min.
period. After stirring 1 h a deep orange-red color developed,
where the mixture was cooled to K78 8C. Aldehyde 19
(31.2 g, 0.199 mol) dissolved in THF (60 mL) was added to
the reaction mixture over a 45 min period. The mixture was
stirred 4 h at K78 8C then quenched with saturated NH4Cl
solution. After warming to ambient temperature the mixture
was diluted with H2O (100 mL) and the product extracted
into EtOAc. The organic layer was dried over MgSO4 and
concentrated to yield 47.9 g (98%) of 21 as a dark amber oil.
1H NMR (CDCl3): d 1.285 (t, JZ6.8 Hz, 3H), 2.26 (s, 3H),
2.85 (q, JZ6.4 Hz, 2H), 3.64 (t, JZ7.2 Hz, 2H), 4.24 (q,
JZ7.2 Hz, 2H), 5.85 (dt, JZ19.6, 8.8 Hz, 1H); 13C NMR
(CDCl3): d 10.46, 14.21, 24.97, 25.02, 41.10, 41.14, 62.11,
117.01, 117.21, 148.11, 150.70, 156.55, 159.34, 160.46,
160.81; 19F NMR (CDCl3): d K117.43 (d, JZ20.4 Hz);
MS(CI) calcd for C10H13FN2O4: [MCH] 245. Found: [MC
H] 245.
Imidazole 15 was the second component off the column. 1H
NMR (MeOD): d 1.24 (t, JZ7.2 Hz, 3H), 2.35 (s, 3H), 3.58
(s, 2H), 4.14 (q, JZ6.0 Hz, 2H), 6.70 (s, 1H); HRMS calcd
for C8H12N2O2: [MCH] 169.0977. Found: [MCH]
169.0933.
Heating converted 14 to 15.
4.1.14. 4-[(2E)-5-Hydroxypent-2-enyl]-3-methyl-1,2,4-
oxadiazol-5(4H)-one (17) and (3E)-5-[(3-methyl-1,2,4-
oxadiazol-5-yl)oxy]pent-3-en-1-ol (18). Dihydroxy-olefin
16 (109 mg, 1.0 mmol), Ph3P (262 mg, 1.0 mmol) and 2b
(100 mg, 1.0 mmol) were dissolved in THF (5.0 mL). The
reaction mixture was cooled in an ice bath before adding
DEAD (174 mg, 1.0 mmol) drop wise. TLC (EtOAc)
indicated that 16 was consumed and two new products
were present. The reaction mixture was concentrated and
chromatographed, eluting with EtOAc/hexane. The first
compound to elute was identified as the O-alkylated
4.1.17.
4-[(3E)-4-Fluoro-5-hydroxypent-3-enyl]-3-
methyl-1,2,4-oxadiazol-5(4H)-one (22). Ester 21 (6.2 g,
25.4 mmol) was dissolved in THF (100 mL) and cooled to
K5 8C. Red-Al 68% in toluene (8.5 mL, 27.9 mmol) was
added drop wise to the cooled solution. The reaction mixture
was monitored by TLC every 0.5 h until the starting
material was consumed. The reaction was quenched with
75 mL of saturated Rochelle’s salt. The product was
extracted into CH2Cl2 (2!150 mL), dried over MgSO4
and concentrated. The residue was chromatographed over
silica, eluting with EtOAc/hexane to yield 2.1 g (41%) of 22
1
derivative 18, 13 mg (7%). H NMR (CDCl3): d 2.23 (s,
3H), 2.32 (q, JZ15 Hz, 2H), 3.68 (t, JZ12.4 Hz, 2H), 4.15
(dd, JZ6, 1.2 Hz, 2H), 5.55, (pent. JZ5.6 Hz, 1H), 5.73,
(pent, Hz, JZ8.4 Hz, 1H); MS(CI) calcd for C8H12N2O3:
[MCH] 185. Found: [MCH] 185; Anal. calcd for
C8H12N2O3: C, 36.01; H, 4.03; N, 27.99. Found: C, 35.76;
H, 3.99; N, 28.26.
1
The second product to elute was the N-alkylated derivative
17, 26 mg (14%). 1H NMR (CDCl3): d 2.25 (s, 3H), 2.36 (q,
JZ6.4 Hz, 2H), 3.70 (t, JZ6.0 Hz, 2H), 4.89 (dd, JZ6.0,
0.8 Hz, 2H), 5.80 (pent, JZ6.4 Hz, 1H), 5.94 (pent, JZ
7.2 Hz, 1H); MS(CI) calcd for C8H12N2O3: [MCH] 185.
Found: [MCH] 185; Anal. calcd for C8H12N2O3: C, 36.01;
H, 4.03; N, 27.99. Found: C, 36.18; H, 4.14; N, 27.86.
as an oil. H NMR (CDCl3): d 2.22 (s, 3H), 2.43 (q, JZ
8.0 Hz, 2H), 3.62–3.56 (m, 2H), 4.12 (d, JZ20 Hz, 2H),
5.14–5.05 (m, 1H); 13C NMR (CDCl3): d 10.66, 14.38,
24.16, 24.25, 42.35, 57.50, 60.63, 103.54, 103.77, 156.55,
159.80, 162.32, 171.46; 19F NMR (CDCl3): d K106.69 (dd,
JZ42.0, 30.4 Hz); MS(CI) calcd for C8H11FN2O3: [MCH]
203. Found: [MCH] 203; Anal. calcd for C8H11FN2O3$0.1
H2O: C, 47.10; H, 5.53; N, 13.73. Found: C, 46.96; H, 5.41;
N, 13.40.
Dihydroxy-olefin 16 (109 mg, 1.0 mmol) and 2b (100 mg,
1 mol) were dissolved in THF (5.0 mL). Ph3P–polymer
(3.0 mmol/g) (500 mg, 1.5 mmol) was added and the
mixture was slowly stirred while adding DEAD (174 mg,
1.0 mmol). The products were identical to the reaction
with unbound Ph3P: O-alkylated 34 mg (18%) of 18, and
N-alkylated 50 mg (27%) of 17.
4.1.18. 4-[(3E)-5-Bromo-4-fluoropent-3-enyl]-3-methyl-
1,2,4-oxadiazol-5(4H)-one (23). Alcohol 22 (800 mg,
3.98 mmol) and CBr4 (3.28 g, 9.9 mmol) were dissolved
in CH2Cl2 and cooled to K5 8C. Ph3P–polymer (3.0 mmol/
g) (3.98 g, 12.0 mmol) was added to the reaction mixture
and stirred for 18 h. The reaction mixture was filtered and
concentrated. The residue was chromatographed over silica,
eluting with EtOAc/hexane to yield 600 mg (57%) of 23 as
4.1.15. 3-(3-Methyl-5-oxo-1,2,4-oxadiazol-4(5H)-yl)pro-
panal (19). Oxadiazolone 2b (729 mg, 7.24 mmol) was
dissolve in ethanol (15 mL) then combined with acrolein
(0.53 mL, 7.24 mmol) and triethylamine (0.10 mL,
0.723 mmol) and stirred for 18 h. The reaction mixture
was partitioned between H2O/EtOAc. The organic layer was
washed with brine, dried over MgSO4 and concentrated
producing 1.3 g of 19 (100% crude) as a pale orange oil. 1H
NMR (CDCl3): d 2.36 (s, 3H), 3.04 (t, JZ6 Hz, 2H), 3.80
(t, JZ6 Hz, 2H), 9.73 (s, 1H); 13C NMR (CDCl3): d 18.6,
40.8, 58.6, 95.1, 157.0, 198.9; MS(CI) calcd for C6H8N2O3:
[MCH] 157. Found: [MCH] 157.
1
an oil. H NMR (CDCl3): d 2.28 (s, 3H), 2.46 (q, JZ
12.0 Hz, 2H), 3.68 (t, JZ6.8 Hz, 2H), 4.10 (d, JZ22.8 Hz,
2H), 5.35–5.26 (m, 1H);); 13C NMR (CDCl3): d 10.67,
25.13, 27.85, 31.97, 41.66, 41.92, 105.47, 105.70, 156.25,
169.32; 19F NMR (CDCl3): d K105.27 (dd, JZ44.0,
22.4 Hz); MS(CI) calcd for C8H10BrFN2O2: [MCH] 265
and 267. Found: [MCH] 265 and 267; Anal. calcd for
C8H10BrFN2O2$0.05 EtOAc: C, 36.55; H, 3.89; N, 10.40; F,
7.05; Br, 29.65. Found: C, 36.92; H, 3.89; N, 10.35; F, 6.69:
Br, 29.75.
4.1.16. Ethyl (2E)-2-fluoro-5-(3-methyl-5-oxo-1,2,4-oxa-
diazol-4(5H)-yl)pent-2-enoate (21). Triethylfluorophos-
phonate (20) (52.9 g, 0.218 mol) and LiCl (10.1 g,
0.238 mol) were dissolved in THF (100 mL). DBU
4.1.19. Ethyl (2E)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-
fluoropent-2-enoate (25a) and ethyl (2Z)-5-{[tert-butyl-
(dimethyl)silyl]oxy}-2-fluoropent-2-enoate (25b). NaH
(60% suspension in mineral oil) (1.7 g, 72.0 mmol) was

A. E. Moormann et al. / Tetrahedron 60 (2004) 10907–10914
10913
washed with hexane to remove the mineral oil, toluene
(200 mL), 20 (17.2 g, 71.0 mmol) and 248 (13.2 g;
0.07 mol) dissolved in toluene (50 mL) was reacted at
0 8C as described for Compound 21 to yield 5.9 g (30.5%) of
25a. 1H NMR (CDCl3): d 0.04 (s, 6H), 0.87 (s, 9H), 1.33 (t,
JZ7.2 Hz, 3H), 2.75–2.69 (m, 2H), 3.68 (dt, JZ0.8, 6.0 Hz,
2H), 4.28 (q, JZ7.2 Hz, 2H), 6.19 (dt, JZ33.6, 7.6 Hz, 1H);
19F NMR (CDCl3): d K121.67 (d, JZ23.2 Hz); MS(CI)
calcd for C13H25O3FSi: [MCH] 277. Found: [MCH] 277.
to a slurry of 2a (84.8 g, 0.61 mol) in MEK (0.6 l) and
heated at reflux 6.0 h where TLC (60% EtOAc/hexane)
indicated that 28 was still present. Additional 2a (17 g) was
added and the mixture was stirred at reflux for an additional
2.0 h at which time the starting material was consumed. The
reaction mixture was cooled and filtered and the solid
washed with MEK. The filtrate was concentrated to yield
1
204 g (100% crude) of 29 as a crystalline solid. H NMR
(CDCl3): d 2.29 (s, 3H), 2.63 (q, JZ6.4 Hz, 2H), 3.01 (s,
3H), 4.26 (dt, JZ0.8, 6.4 Hz, 2H), 4.31 (d, JZ19.6 Hz, 2H),
5.409 (dt, JZ19.6, 8.4 Hz, 1H); 19F NMR (CDCl3): d
K106.89 (q, JZ21.2 Hz); MS(CI) calcd for C9H13N2O5SF:
[MCH] 281. Found: [MCH] 281.
A minor component was isolated and purified and identified
as 25b the Z-isomer: H NMR (CDCl3): d 0.037 (s, 6H),
1
0.87 (s, 9H), 1.330 (t, JZ7.2 Hz, 3H), 2.47–2.42 (m, 2H),
3.68 (dt, JZ0.8, 8.0 Hz, 2H), 4.28 (q, JZ7.2 Hz, 2H), 6.00
(dt, JZ21.2, 8.0 Hz, 1H). 19F NMR (CDCl3): d K129.79 (d,
JZ33.2 Hz); MS(CI) calcd for C13H25O3FSi: [MCH] 277.
Found: [MCH] 277.
4.1.24. 4-[(2E)-2-Fluoro-5-iodopent-2-enyl]-3-methyl-
1,2,4-oxadiazol-5(4H)-one (30). Mesylate 29 (204.8 g,
0.56 mol) was dissolved in MEK (1.2 l) and solid NaI
(167 g, 1.12 mol) was added to the mixture and stirred 18 h
at which time TLC (60% EtOAc/hexane) indicated that the
starting material was consumed. The reaction mixture was
partitioned between an equal volume of H2O and the
aqueous layer was washed with Et2O then CH2Cl2 (500 mL
each). The combined organic layers were washed with 1%
Na2S2O3, dried over MgSO4 and concentrated. The residue
was chromatographed over silica, eluting with EtOAc/
hexane to yield 87.4 g (50%) of 30 as a crystalline solid. 1H
NMR (CDCl3): d 2.30 (s, 3H), 2.74 (q, JZ7.2 Hz, 2H), 3.20
(dt, JZ0.8, 6.8 Hz, 2H), 4.31 (d, JZ19.6 Hz, 2H), 5.39 (dt,
JZ19.6, 8.4 Hz, 1H); 19F NMR (CDCl3): d K108.31 (q,
JZ21.2 Hz); MS(CI) calcd for C8H10FIN2O2: [MCH] 313.
Found: [MCH] 313; Anal. calcd for C8H10FIN2O2; C,
30.79; H, 3.23; N, 8.98; I, 40.66. Found: C, 30.75; H, 2.99;
N, 8.92; I, 40.41.
4.1.20. (2E)-5-{[tert-Butyl(dimethyl)silyl]oxy}-2-fluoro-
pent-2-en-1-ol (26). Ester 25a (6.0 g, 21.7 mmol) dissolved
in THF (70 mL), Red-Al 68% in toluene (9.2 mL,
30.0 mmol) was reacted at K5 8C as described for
Compound 22 to yield 4.0 g (79%) of 26. 1H NMR
(CDCl3): d 0.04 (s, 6H), 0.87 (s, 9H), 2.29–2.21 (m, 3H, 1
exchangeable), 3.63 (dt, JZ1.2, 8.0 Hz, 2H), 4.20 (d, JZ
26.0 Hz, 2H), 5.20 (dt, JZ26.0, 12.0 Hz, 1H); 19F NMR
(CDCl3): d K109.63 (q, 28.4 Hz); MS(CI) calcd for
C11H23FO2Si: [MCH] 235. Found: [MCH] 235; Anal.
calcd for C11H23FO2Si: C, 56.37; H, 9.89. Found: C, 56.38;
H, 10.19.
4.1.21. (2E)-2-Fluoropent-2-ene-1,5-diol (27). Alcohol 26
(131.0 g, 0.56 mol) was dissolved in EtOH (1.5 l) and concn
HCl (15 mL) was added and the mixture was stirred for
0.25 h. TLC (20% EtOAc/hexane) indicated that the starting
material was consumed. The mixture was concentrated and
the residue was azeotroped twice with toluene (500 mL) to
4.1.25. Ethyl (2E)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-
fluorobut-2-enoate (32a) and ethyl (2Z)-4-{[tert-butyl(di-
methyl)silyl]oxy}-2-fluorobut-2-enoate (32b). NaH (60%
suspension in mineral oil) (3.9 g, 0.10 mol), THF (300 mL),
20 (25 g, 0.10 mol) and 319 (17.4 g; 0.1 mol) was reacted at
0 8C as described for Compound 21 to yield 8.9 g (34%) of
32a. 1H NMR (CDCl3): d 0.08 (s, 6H), 0.88 (s, 9H), 1.25 (t,
JZ7.2 Hz, 3H), 4.28 (q, JZ7.2 Hz, 2H), 4.64 (dd, JZ3.6,
5.6 Hz, 2H), 6.01 (dt, JZ19.6, 5.6 Hz, 1H); 19F NMR
(CDCl3): d K123.95 (dt, JZ20.8, 3.2 Hz); MS(CI) calcd
for C12H23O3FSi: [MCH] 263. Found: [MCH] 263.
1
produce 71.8 g (100% crude) of 27 as an oil. H NMR
(CDCl3): d 2.30–2.23 (m, 2H), 3.64 (dt, JZ0.8, 8.0 Hz, 2H),
4.18 (d, JZ29.6 Hz, 2H), 5.21 (dt, JZ27.0, 11.6 Hz, 1H);
19F NMR (CDCl3): dK108.16 (q, JZ30.8 Hz); MS(CI)
calcd for C5H9O2F: [MCH] 121. Found: [MCH] 121.
4.1.22. (2E)-2-Fluoro-5-[(methylsulfonyl)oxy]pent-2-
enyl methanesulfonate (28). Dihydroxyolefin 27 (71.8 g,
0.56 mol) and Et3N (141.4 g/195 mL, 1.4 mol) were
dissolved in CH2Cl2 (1.0 l) and cooled in an ice bath.
Ms2O (243.4 g, 1.4 mol) was dissolved in CH2Cl2 (0.5 l)
and added drop wise. The reaction mixture was stirred
15 min when TLC (60% EtOAc/hexane) indicated that the
starting material was consumed. The reaction mixture was
partitioned between H2O/CH2Cl2. The organic layer was
washed with H2O, dried over MgSO4 and concentrated to
A minor component was isolated and purified and identified
as the Z-isomer 32b: 1H NMR (CDCl3): d 0.08 (s, 6H), 0.88
(s, 9H), 1.25 (t, JZ7.2 Hz, 3H), 4.28 (q, JZ7.2 Hz, 2H),
4.41 (dd, JZ6.4, 1.2 Hz, 2H), 6.19 (dt, JZ33.6, 6.4 Hz,
1H); 19F NMR (CDCl3): d K127.28 (dt, JZ35.2, 3.6 Hz);
MS (CI) calcd for C12H23O3FSi: [MCH] 263. Found: [MC
H] 263.
1
yield 164.9 g (100% crude) of 28 as a crystalline solid. H
NMR (CDCl3): d 2.55 (q, JZ10.0 Hz, 2H), 3.02 (s, 3H),
3.07 (s, 3H), 4.25 (dt, JZ1.2, 8.4 Hz, 2H), 4.82 (d, JZ
27.6 Hz, 2H), 5.50 (dt, JZ24.8, 11.2 Hz, 1H); 19F NMR
(CDCl3): d K107.91 (q, JZ27.2 Hz); MS(CI) calcd for
C7H13O6S2F: [MCNH4] 294. Found: [MCNH4] 294.
4.1.26. (2E)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-fluoro-
but-2-en-1-ol (33). Ester 32a (8.7 g, 33.0 mmol) was
dissolved in THF (100 mL) and cooled in an ice bath.
LiBH4 2.0 M in THF (33 mL, 66.0 mmol) was added and
the mixture stored at K40 8C for 18 h. The reaction was
quenched with H2O. A solid formed which was filtered and
washed with THF. The filtrate was concentrated and
chromatographed over silica, eluting with EtOAc/hexane
to yield 4.5 g (62%) of 33. 1H NMR (CDCl3): d 0.08 (s, 6H),
4.1.23. (3E)-4-Fluoro-5-(3-methyl-5-oxo-1,2,4-oxadiazol-
4(5H)-yl)pent-3-enyl methanesulfonate (29). Dimesylate
28 (164.9 g, 0.55 mol) dissolved in MEK (0.6 l) was added

10914
A. E. Moormann et al. / Tetrahedron 60 (2004) 10907–10914
0.88 (s, 9H), 4.20 (dd, JZ6.8, 2.4 Hz, 2H), 4.24 (d, JZ
19.6 Hz, 2H), 5.38 (dt, JZ20.4, 7.2 Hz, 1H); 19F NMR
(CDCl3): d K109.28 (q, JZ22.0 Hz); MS(CI) calcd for
C10H21O2FSi: [MCH] 221. Found: [MCH] 221; Anal.
calcd for C10H21O2FSi: C, 54.51; H, 9.61. Found: C, 54.44;
H, 9.78.
4.1.30. 4-[(2E)-2-Fluoro-4-iodobut-2-enyl]-3-methyl-
1,2,4-oxadiazol-5(4H)-one (37). Mesylate 36 (8.3 g,
32.0 mmol) and NaI (9.8 g, 65.0 mmol) were stirred for
30 min in MEK. TLC (40% EtOAc/hexane) indicated that
36 was consumed. The reaction mixture was partitioned
between Et2O/H2O. The aqueous layer was washed with
Et2O and the combined organic layers were washed with 1%
Na2S2O3, dried over MgSO4 and concentrated. Chromato-
graphed over silica eluting with EtOAc/hexane to yield
4.5 g (47%) of 37 as a crystalline solid. 1H NMR (CDCl3): d
2.31 (s, 3H), 3.98 (dd, JZ9.6, 0.8 Hz, 2H), 4.34 (d, JZ
19.6 Hz, 2H), 5.78 (dt, JZ16.8, 7.6 Hz, 1H); 19F NMR
(CDCl3): dK106.08 (q, JZ19.2 Hz); MS(CI) calcd for
C7H8FIN2O2: [MCH] 299. Found: [MCH] 299; Anal.
calcd for C7H8FIN2O2: C, 28.21; H, 2.71; N, 9.40. Found: C,
28.36; H, 3.04; N, 9.37.
4.1.27. 4-((2E)-4-{[tert-Butyl(dimethyl)silyl]oxy}-2-fluoro-
but-2-enyl)-3-methyl-1,2,4-oxadiazol-5(4H)-one (34).
Alcohol 33 (25.5 g, 0.115 mol), 2b (11.3 g, 0.1 mol) and
triphenylphosphine (29.7 g, 0.11 mol) were dissolved in
THF (500 mL) and cooled in an ice bath. DEAD (19.1 g/
17.3 mL, 0.11 mol) was added drop wise to the reaction
mixture. The reaction progress was monitored by TLC (60%
EtOAc/hexane). When 33 was consumed the reaction
mixture was concentrated and the residue triturated with
Et2O. The filtrate was concentrated and chromatographed
over silica, eluting with EtOAc/hexane to yield 10.4 g
(31%) of 34. 1H NMR (CDCl3): d 0.08 (s, 6H), 0.88 (s, 9H),
2.28 (s, 3H), 4.31 (dd, JZ6.4, 2.8 Hz, 2H), 4.44 (d, JZ
19.2 Hz, 2H), 5.53 (dt, JZ20.0, 6.4 Hz, 1H); 19F NMR
(CDCl3): d K109.06 (q, JZ20.8 Hz); MS(CI) calcd for
C13H23N2O3FSi: [MCH] 303. Found: [MCH] 303; Anal
calcd for C13H23N2O3FSi: C, 51.63; H, 7.67; N, 9.26.
Found: C, 51.84; H, 7.82; N, 8.95.
References and notes
1. Greenhill, J. V.; Lue, P. Prog. Med. Chem. 1993, 30, 203–326.
2. Krygowski, T. M.; Wozniak, K. In Structural Chemistry of
Amidines and Related Systems; Patai, S., Rappoport, Z., Eds.;
Amidines and Imidates; Wiley: UK, 1991; Vol. 2, pp 101–145.
3. Moore, W. M.; Webber, R. K.; Fok, K. F.; Jerome, G. M.;
Tjoeng, F. S.; Currie, M. G. Bioorg. Med. Chem. 1996, 4,
1559–1564.
4.1.28. 4-[(2E)-2-Fluoro-4-hydroxybut-2-enyl]-3-methyl-
1,2,4-oxadiazol-5(4H)-one (35). Oxadiazolone 34 (10.4 g,
34.0 mmol) was dissolved in EtOH (100 mL) and concn
HCl (1.0 mL) was added and the mixture stirred for 1 h.
TLC (60% EtOAc/hexane) indicated that 34 was consumed.
The mixture was concentrated to dryness to yield 6.9 g
(100% crude) of 35. 1H NMR (CDCl3): d 2.31 (s, 3H), 4.25
(dd, JZ6.8, 2.8 Hz, 2H), 4.44 (d, JZ21.2 Hz, 2H), 5.65 (dt,
JZ20.0, 7.2 Hz, 1H); 19F NMR (CDCl3): d K107.88 (q,
JZ21.6 Hz); MS(CI) calcd for C7H9FN2O3: [MCH] 189.
Found: [MCH] 189.
4. Peterlin-Masic, L.; Kikelj, D. Tetrahedron 2001, 57,
7073–7105.
5. (a) Bolton, R. E.; Coote, S. J.; Finch, H.; Lowdon, A.; Pegg, N.;
Vinader, M. V. Tetrahedron Lett. 1995, 36, 4471–4474.
(b) Pass, M.; Bolton, R. E.; Coote, S. J.; Finch, H.; Hindley,
S.; Lowdon, A.; McDonald, E.; McLaren, J.; Owen, M.; Pegg,
N. A.; Mooney, C. J.; Tang, C. M.; Parry, S.; Patel, C. Bioorg.
Med. Chem. Lett. 1999, 9, 431–436. (c) Kitamura, S.; Fukushi,
H.; Miyawaki, T.; Kawamura, M.; Konishi, N.; Terashita, Z.;
Naka, T. J. Med. Chem. 2001, 2438–2450.
4.1.29. (2E)-3-Fluoro-4-(3-methyl-5-oxo-1,2,4-oxadiazol-
4(5H)-yl)but-2-enyl methanesulfonate (36). Alcohol 35
(6.9 g, 34.0 mmol) and Et3N (4.0 g/5.5 mL, 40.0 mmol)
were dissolved in CH2Cl2 (100 mL). Ms2O (6.9 g, 40.0 mol)
was added drop wise 30 min. TLC (60% EtOAc/hexane)
indicated that 35 was consumed. The reaction mixture was
poured into H2O and the layers separated. The organic layer
was washed with saturated NaHCO3, dried over MgSO4 and
concentrated to yield 8.3 g (92%) of 36 as a crystalline solid.
1H NMR (CDCl3): d 2.31 (s, 3H), 3.06 (s, 3H), 4.42 (d, JZ
20.0 Hz, 2H), 4.92 (dd, JZ8.0, 1.2 Hz, 2H), 5.67 (dt, JZ
8.7, 8.0 Hz, 1H); 19F NMR (CDCl3): d K101.10 (q, JZ
19.6 Hz); MS(CI) calcd for C8H11FN2O5S: [MCH] 267.
Found: [MCH] 267; Anal. calcd for C8H11FN2O5S: C,
36.09; H, 4.16; N, 10.52. Found: C, 36.43; H, 4.06; N, 10.41.
6. (a) Takacs, K.; Harsanyi, K. Chem. Ber. 1970, 103, 2330–2335.
(b) Areschka, A.; Mahaux, J.; Verbruggen, F.; Houben, C.;
Descamps, M.; Heyndrickx, J. P.; Tornay, C.; Colot, M.;
Charlier, R. Eur. J. Med. Chem. 1977, 12, 87–91. (c) Ajzert,
K. I.; Takacs, K. Chem. Ber. 1984, 117, 2999–3003. (d) Weller,
H.; Miller, A. V.; Dickinson, K. E.; Hedberg, S. A.; Delaney,
C. L. Heterocycles 1993, 36, 1027–1038.
¨
7. Hett, R.; Krahmer, R.; Vaulont, I.; Leschinsky, K.; Snyder, J. S.;
Klein, P. H. Org. Process Res. Dev. 2002, 6, 896–897.
8. Pirrung, M. C.; Nicholas, J. G.; Webste, N. J. G. J. Org. Chem.
1987, 52, 3603–3613.
9. Chiou, S.; Shine, H. J. Heterocycl. Chem. 1989, 26, 125–128.