Easy access to 2-alkyl and 2-arylthiazolines using a modified heteropolyacid catalysis: Application to the synthesis of bacillamide A

Article abstract of DOI:10.1080/00397911.2011.552834

A straightforward access to 2-alkyl and 2-arylthiazolines by condensation of-aminothiols on nitriles, catalyzed by phosphotungstic acid (2%) under microwave irradiation, is described. This method has been directly applied to a short and efficient synthesi

Full text of DOI:10.1080/00397911.2011.552834

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Easy Access to 2-Alkyl and 2-
Arylthiazolines Using a Modified
Heteropolyacid Catalysis: Application to
the Synthesis of Bacillamide A
F. Fache a , F. Cros a , O. Piva a & F. Lefebvre a
a Université de Lyon, Institut de Chimie de Lyon, Villeurbanne,
France
Accepted author version posted online: 27 Oct 2011.Published
online: 26 Mar 2012.
To cite this article: F. Fache , F. Cros , O. Piva & F. Lefebvre (2012): Easy Access to 2-Alkyl and 2-
Arylthiazolines Using a Modified Heteropolyacid Catalysis: Application to the Synthesis of Bacillamide
A, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:14, 2098-2109
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Synthetic Communications1, 42: 2098–2109, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.552834
EASY ACCESS TO 2-ALKYL AND 2-ARYLTHIAZOLINES
USING A MODIFIED HETEROPOLYACID CATALYSIS:
APPLICATION TO THE SYNTHESIS OF BACILLAMIDE A
F. Fache, F. Cros, O. Piva, and F. Lefebvre
´
Universite de Lyon, Institut de Chimie de Lyon, Villeurbanne, France
GRAPHICAL ABSTRACT
Abstract A straightforward access to 2-alkyl and 2-arylthiazolines by condensation of
b-aminothiols on nitriles, catalyzed by phosphotungstic acid (2%) under microwave
irradiation, is described. This method has been directly applied to a short and efficient
synthesis of bacillamide A (16).
Keywords Bacillamide A; heteropolyacid; microwave irradiation; thiazoline synthesis
INTRODUCTION
The 2-thiazoline ring is present in numerous biologically active compounds
such as telomestatin,[1] cyclothiazomycin,[2] and largazole.[3] 2-Thiazolines have also
found applications in flavor chemistry[4] and as radioprotective agents.[5] Several
methodologies is available for the formation of such derivatives, which have been
extensively reviewed by Gaumont et al.[6] A further aromatization of theses hetero-
cycles can lead to thiazoles, rings present in a large number of natural compounds.[7]
This aromatization may proceed smoothly[8] compared to the drastic conditions
applied for the aromatization of thiazolidines.[9] In the course of our studies on
the applications of heterogeneous catalysis to fine chemistry,[10] we were attracted
by the results published by Mohammed poor-Battork et al., who synthesized
2-arylthiazolines from 2-aminoethanethiol and various aromatic nitriles catalyzed
by phosphotungstic acid under solvent-free conditions.[11] However, only aromatic
Received December 3, 2010.
´
´
Address correspondence to F. Fache, Universite de Lyon, Institute de Chimie de Lyon, Universite
Lyon 1, CPE Lyon, CNRS UMR 5246, ICBMS Equipe SURCOOF, Bat. Raulin 43, Bd du 11 Novembre
1918, 69622 Villeurbanne cedex, France. E-mail: fache@univ-lyon1.fr
2098

SYNTHESIS OF 2-ALKYL AND 2-ARYLTHIAZOLINES
2099
nitriles were used as substrates, thereby limiting the scope of the method. In parti-
cular, nothing was reported on the possible application of these conditions to
cysteine. Microwave irradiation has already been used to synthesize thiazolines from
acylbenzotriazoles by Katritzky et al.,[12] from aryl keto nitriles by Sukanta and
Biehl,[13] and from aldehydes by Kodomari et al.,[14] but only with 2-aminoetha-
nethiol or aminothiophenol as sulfur-containing nucleophiles, without mention of
the use of natural cysteine. As we planned to obtain functionalized thiazolines for
natural product synthesis, there was a need for a more general method.
Here we report the direct access to 2-alkyl or 2-arylthiazolines from
b-aminothiols and nitriles under microwave irradiation using a catalytic amount
of phosphotungstic acid. To select the best reaction parameters, we first studied
the reaction between 2-aminoethanethiol and undecanitrile in both conventional
heating conditions or microwave irradiation and in the presence or absence of
heteropolyacid (HPA) (Table 1).
Using conventional oil-bath heating conditions, only moderate conversions
were observed (Table 1, entries 1 and 2). Under microwave irradiation, the conversion
was better, and the greatest isolated yield was obtained only when both microwave
irradiation and HPA were used (Table 1, entries 4 and 5). It is difficult to conclude
whether it is a real microwave effect. The article very recently published by Obermayer
and Kappe[15] showed that most of the literature reports claiming this effect are in fact
a result of artifacts of the experimental protocols. Nevertheless, if we compare entries
3 and 5, performed in the same conditions except for the heating mode, it is clear that
microwave activation and conventional heating led to different results. Profiles of
power, temperature, and pressure registered in the seal tube during a typical experi-
ment are depicted in Fig. 1. An initial power of 100 W was necessary to reach very
rapidly (about 1 min) the desired temperature (120 ꢀC), and a power of 35 W was suf-
ficient to maintain this value. The inside pressure was kept around 2 bar, a relatively
low pressure for the reaction vessel, which could bear up to 20 bar.
Table 1. Influence of reaction parameters
Heating conditions
Entry Microwave Conventional heating
Isolated
Conversiona (%) yield (%)
HPA
1
ꢁ
ꢁ
ꢁ
þ
þ
80 ꢀC, 5 h
80 ꢀC, 5 h
120 ꢀC, 3 h
120 ꢀC, 3 h
120 ꢀC, 3 h
—
40
35
25
26
32
40
60
2
H3PW12O40
H3PW12O40
—
3b
4
50
60
5
H3PW12O40
100
aMeasured by 1H NMR.
bPerformed in a sealed tube.

2100
F. FACHE ET AL.
Figure 1. Profiles of power, temperature, and pressure registered inside the sealed tube during a typical
experiment. (Figure is provided in color online.)
We thus applied microwave conditions to a large variety of b-aminothioles
and nitriles (Table 2). Isolated yields up to 95% were obtained, and even
di-thiazolines can be synthesized starting from dicyano derivatives (Table 2, entries
3 and 5), giving access to potential ligands for catalysis.[16] It is noteworthy that
aliphatic nitriles have been used with success as numerous published methods are
only applied to aryl derivatives; the poor isolated yield of compound 1 is due to
its volatility.[5]
Among the various nitriles used in this study, two of them turned out to be of
particular interest, ethyl cyanoacetate (Table 2, entries 7 and 10) and diethoxy acet-
onitrile (Table 2, entries 6, 8, and 9), as they allowed the introduction of an additional
interesting functional group on which further chemical transformations could be
performed. More specifically, compound 9 can be easily aromatized into compound
11, which is the key intermediate of numerous syntheses as shown in Fig. 2.[17]
Compound 11 has been previously prepared in two steps by a classical Hantszch syn-
thesis from diethoxyacetamide and ethyl 3-bromopyruvate using P2S5, a particularly
hazardous reagent.[18]
As an illustration, we applied the method described therein to the synthesis of
bacillamide A, an algicide against dinoflagellates (Scheme 1).
Bacillamide A was isolated and its structure elucidated for the first time in 2003
by Jeong et al. in Japan,[19] and since this discovery many other thiazole alkaloids
with similar skeletons have been identified.[20] Nevertheless, to our knowledge, only
one synthesis of this molecule has been reported so far.[21]
The first step of the synthesis was the illustration of our method applied to
cysteine and 2,2-diethoxyacetonitrile, which gave compound 9 with 68% isolated
yield. Compound 9 was easily aromatized into compound 11 following the method
described by Williams et al.[8b] Acidic hydrolysis of the acetal 11 gave the aldehyde
12, and a Grignard reaction using methylmagnesium bromide led to alcohol 13,
easily oxidized by Dess–Martin periodinan. Every attempt to increase our yield
for the Grignard reaction became a failure: working at low temperature (ꢁ78 ꢀC)
or with CeCl3 to limit side reactions were unsuccessful. Alkylation according to
Barbier procedure with Zn and methyl bromide also was not possible. Saponification
of the ester 14 followed by peptidic coupling with tryptamine using the classical

SYNTHESIS OF 2-ALKYL AND 2-ARYLTHIAZOLINES
2101
Table 2. Microwave-assisted synthesis of thiazolines from nitriles using HPA
Compound
R
H
H
R0
Producta
Yield (%)b
1
2
C3H7
30
60
C
10H21
__-(CH2)4-_
Ph
3
4
H
H
60
80
5
6
H
90
82
H
H
7
8
9
54
95c
68
COOEt
COOEt
10
50
aFor details reaction conditions, see Experimental section.
bIsolated yields.
c80 ꢀC, 2 h.
reagents N,N0-dicyclohexylcarbodiimide (DCC) and HOBt led to bacillamide in
seven steps with an overall yield of 5.6%.
In summary, we have developed a general microwave-assisted straightforward
method for the synthesis of alkyl and aryl functionalized 2-thiazolines. It gives access

2102
F. FACHE ET AL.
Figure 2. Natural products synthesized starting from compound 11.[17]
to intermediates of interest in total synthesis and avoids the use of P2S5 as the source
of sulfur. Finally, we report its application to the synthesis of the natural product
bacillamide A. We believe that this procedure provides a valuable addition to current
methodologies.
EXPERIMENTAL
Infrared (IR) spectra were recorded on a Perkin-Elmer Spectrum One FTIR
1
spectrometer as thin films or directly with solids. H and 13C NMR spectra were
recorded respectively at 300 and 75 MHz in solution in CDCl3 using the residual sol-
vent peak as a reference standard (7.26 ppm and 77.36 ppm respectively). Chemical
shifts are reported in parts per million (ppm) on the d scale. Multiplicities are
described as s (singlet), d (doublet), dd, ddd, etc. (doublet of doublets, doublet of
Scheme 1. Synthesis of bacillamide A starting from cysteine via the 2-thiazoline intermediate 9.

SYNTHESIS OF 2-ALKYL AND 2-ARYLTHIAZOLINES
2103
doublets of doublets, etc.), t (triplet), q (quartet), and m (multiplet). Coupling
constants, J, are reported in hertz. Microwave-assisted synthesis was carried out
in an Initiator single-mode microwave cavity producing controlled irradiation at
2.45 GHz (Biotage AB, Uppsala). The reactions were run in sealed vessels (0.5 to
20 mL), and magnetic stirring was used. Variable power was employed to reach
the temperature desired and then to maintain it in the vessel during the period of
time programmed. Flash column chromatography purifications were performed with
Geduran Si from Merck (particle size 60–200 mm). Analytical thin-layer chromatgra-
phy (TLC) was performed on 0.25 mm thick plates precoated with Merck Kieselgel
60 F254 silica gel. TLC was visualized under UV (254 nm) and by oxidative staining
with aqueous phosphomolybdic acid. When necessary, reactions were performed
under an argon atmosphere and in dried flasks. Tetrahydrofuran (THF) was freshly
distilled from sodium benzophenone under nitrogen, and CH2Cl2 was distilled from
CaH2. Phosphotungstic acid was purchased from Acros and used as received.
Typical Procedure for the 2-Thiazoline Synthesis
b-Aminothiol (1 mmol) 1.1 mmol of nitrile, and 0.02 mmol (58 mg) of
H3PW12O40 were stirred in 1 mL of EtOH in a sealed tube under microwave
irradiation at 120 ꢀC for 3 h. After evaporation of the solvent, the reaction mixture
was purified by flash chromatography.
2-(Propyl)-2-thiazoline (1)[5]
1
Isolated yield 30% (39 mg); colorless liquid; Rf 0.3 (AcOEt=hexanes 1:9); H
NMR (300 MHz, CDCl3) d 4.22 (t, J ¼ 7.5 Hz, 2H, CH2N), 3.30 (t, J ¼ 8.3 Hz, 2H,
13
=
CH2C N), 2.53 (t, J ¼ 7.5 Hz, 2H, CH2S), 1.65–1.72 (m, 2H, CH2CH3), 0.97 (t,
=
J ¼ 7.2 Hz, 3H, CH3); C NMR (75 MHz, CDCl3) d 173.5 (C N), 38.5 (CH2N),
37.9 (CH2C N), 29.7 (CH2S), 19.1 (CH2CH3), 13.8 (CH3); IR (neat) (cmꢁ1) 2961,
=
2926, 1642, 1549 HRMS calcd. for C6H11NS (Mþ) 129.0612; found 129.0616.
2-(Decyl)-2-thiazoline (2)
1
Isolated yield 60% (136 mg); colorless liquid; Rf 0.3 (AcOEt=hexanes 1:9); H
NMR (300 MHz, CDCl3) 4.16 (t, J ¼ 7.5 Hz, 2H, CH2N), 3.22 (t, J ¼ 8.3 Hz, 2H,
=
=
CH2C N), 2.45 (t, J ¼ 7.5 Hz, 2H, CH2S), 1.55–1.62 (m, 2H, CH2CH2C N),
1.22–1.26 (m, 14H, CH2), 0.83 (t, J ¼ 7.2 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
=
=
172.0 (C N), 64.7 (CH2N), 34.6 (CH2C N), 34.1 (CH2S), 32.1, 29.8, 29.7, 29.5,
29.4, 27.7, 22.9 (CH2CH2CH2), 14.3 (CH3); IR (neat) (cmꢁ1) 2960, 2930, 1640;
HRMS calcd for C13H25NS (Mþ) 227.1708, found 227.1707.
2,2’-Tetramethylenebis(2-thiazoline) (3)[22]
Isolated yield 60% (137 mg); colorless liquid; Rf 0.3 (AcOEt); 1H NMR
(300 MHz, CDCl3) 4.18 (t, J ¼ 8.3 Hz, 4H, CH2N), 3.24 (t, J ¼ 8.5 Hz, 4H,
CH2C N), 2.48–2.52 (m, 4H, CH2S), 1.68–1.70 (m, 4H, CH2CH2); 13C NMR
=
=
=
(75 MHz, CDCl3) 171.5 (C N), 64.7 (CH2N), 34.2 (CH2C N), 34.1 (CH2S), 27.1

2104
F. FACHE ET AL.
(CH2CH2); IR (neat) (cmꢁ1) 2939, 2855, 1625, 1542, 1436, 922; HRMS calcd for
C10H17N2S2 (M þ H)þ 229.0833, found 229.0832.
2-Phenyl(2-thiazoline) (4)
Data were in accord with the literature.[12] Isolated yield: 80% (130 mg).
2,2’-(1,4-phenylene)bis[2-thiazoline] (5)
Data were in accord with the literature.[12] Isolated yield: 90% (223 mg).
2-(Diethoxymethyl)-2-thiazoline (6)[23]
1
Isolated yield: 82% (155 mg); colorless liquid; Rf 0.3 (AcOEt=hexanes 2:8); H
NMR (300 MHz, CDCl3) 5.16 (s, 1H, CHO), 4.28 (t, J ¼ 8.3 Hz, 2H, CH2N),
13
3.53–3.74 (m, 4H, CH2CH3), 3.24 (t, J ¼ 8.3 Hz, 4H, CH2S), 1.22 (t, J ¼ 7.1 Hz,
=
6H, CH3); C NMR (75 MHz, CDCl3) 171.5 (C N), 99.4 (CHO), 64.7 (CH2N),
62.7 (CH2O), 32.7 (CH2S), 15.3 (CH3); IR (neat) (cmꢁ1) 2977, 2931, 2886, 1686,
1627, 1523, 1444, 1370, 1332, 1061, 993. HRMS calcd. for C8H16NO2S (M þ H)þ
190.0902, found 190.0902.
2-Thiazoline-2-acetic Acid, Ethyl Ester (7)[24]
1
Isolated yield: 54% (94 mg); colorless liquid; Rf 0.3 (AcOEt=hexanes 3:7); H
NMR (300 MHz, CDCl3) 7a: 4.02 (m, 2H, CH2O), 3.72 (m, 2H, CH2N), 3.27 (m,
=
2H, CH2S), 3.13 (m, 2H, CH2C N), 1.19 (m, 3H, CH3); 7b: 8.16 (s, 1H, NH),
=
4.66 (s, 1H, HC C), 4.13 (m, 2H, CH2O), 3.72 (m, 2H, CH2N), 3.53 (m, 2H,
13
CH2S), 1.19 (m, 3H, CH3); C NMR (75 MHz, CDCl3) 7a 169.8 (C O), 165.5
=
=
(C N), 62.0 (CH2N), 42.8 (OCH2), 41.4 (CH2CO), 24.7 (CH2S), 14.4 (CH3); 7b
=
=
=
169.8 (C O), 166.9 (C CH), 87.5 (C CH), 77.4 (OCH2), 62.0 (CH2N), 24.4
(CH2S), 14.5 (CH3); IR (neat) (cmꢁ1) 2981, 2936, 1736, 1655, 1549, 1444, 1370,
1335; HRMS calcd for C7H11NO2S (M)þ 173.0511, found 173.0511.
2-(Diethoxymethyl)-benzothiazole (8)
1
Isolated yield: 95% (225 mg); colorless liquid; Rf 0.3 (AcOEt=hexanes 1:9); H
NMR (300 MHz, CDCl3) 8.10 (d, J ¼ 9 Hz, 1Haro), 7.89 (d, J ¼ 9 Hz, 1Haro), 5.81 (s,
1H, CHO), 3.70–3.82 (m, 4H, OCH2), 1.30 (t, J ¼ 7.1 Hz, 6H, CH3); 13C NMR
=
(75 MHz, CDCl3) 170.3 (C N), 155.2, 135.4, 126.3, 125.7, 123.8, 122.1 (6Caro),
99.4 (OCH), 62.7 (OCH2), 15.4 (CH3); IR (neat) cmꢁ1 3062, 2977, 2930, 2884,
1521, 1435, 1317, 1060, 761, 731. HRMS calcd for C12H16NO2S (M þ H)þ
238.0902; found 238.0904.
Ethyl 2-(Diethoxymethyl)-2-thiazoline-4-carboxylate (9)
Isolated yield: 68% (178 mg); colorless liquid; Rf 0.35 (AcOEt=hexanes 3:7);
1
[a]D ꢁ2.1 (c 1, CHCl3); H NMR (300 MHz, CDCl3) 5.23 (s, 1H, CHO), 5.14 (t,

SYNTHESIS OF 2-ALKYL AND 2-ARYLTHIAZOLINES
2105
J ¼ 9.2 Hz, 1H, CHCO2Et), 4.24 (q, J ¼ 7.2 Hz, 2H, CH2OCO), 3.48–3.77 (M, 8H),
13
3.58–3.69 (m, 2H), 1.29 (t, J ¼ 7.2 Hz, 3H, CH3CH2OCO), 1.26 (t, J ¼ 7.2 Hz, 6H,
=
CH3CH2O); C NMR (75 MHz, CDCl3) 174.2 (C O), 170.5 (C N), 99.0 (O-C-
=
=
O), 78.0 (CN ), 62.9, 62.5, 61.8 (3CH2O), 34.3 (CH2S), 15.1 (CH3O), 14.2
(CH3CH2); IR (neat) (cmꢁ1) 2978, 2932, 1739, 1623, 1184, 1062; HRMS calcd for
C11H20NO4S (M þ H)þ 262.1112; found 262.1111.
Ethyl 2-Ethoxycarbonylmethylenethiazolidine-4-carboxylate (10)[25]
Isolated yield: 65% (159 mg); colorless liquid; Rf 0.25 (AcOEt=hexanes 3:7);
1
[a]D ꢁ9.2 (c 1, CHCl3); H NMR (300 MHz, CDCl3) 10b: 8.49 (s, 1H, NH), 5.04
=
(t, J ¼ 8.9 Hz, 1H, CHCO2Et), 4.76 (s, 1H, CH C); 10a: 4.59 (t, J ¼ 5.7 Hz, 1H,
CHCO2Et); Mixture: 4.06–4.24 (M, 4H, OCH2CH3), 3.71–3.77 (m, 2H, CH2CO2Et),
3.58–3.69 (m, 2H, CH2S), 3.44–3.56 (m, 2H, CH2S), 1.21–1.29 (M, 6H, CH3); 13C
=
=
=
NMR (75 MHz, CDCl3) d, 170.7 (C O), 170.0 (C O), 169.4 (C O), 167.8
=
=
=
(C N), 167.1 (C CH), 80.1 (C CH), 78.0, 62.4, 62.2, 62.1, 60.6, 59.2, 40.3
(OCH2), (CHCO2Et), 36.4, 31.6, (CH2S), 24.7, 14.8, 14.4, 14.3 (3 CH3); IR (neat)
(cmꢁ1) 3320, 2982, 2937, 1741, 1657, 1571, 1192, 1042; HRMS calcd for
C10H15NO4S (Mþ) 245.0722; found 245.0722.
Ethyl 2-(Diethoxymethyl)-4-thiazolecarboxylate (11)
A solution of ethyl 2-(diethoxymethyl)-2-thiazoline-4-carboxylate (9) (235 mg,
0.9 mmol) in dry CH2Cl2 (8 mL) was cooled to 0 ꢀC and DBU (269 mL, 1.8 mmol)
was added. After 10 min of stirring, bromotrichloromethane (88 mL, 0.9 mmol) was
introduced dropwise via syringe over a period of 10 min. The reaction was complete
after 1 h. Upon washing with saturated aqueous NH4Cl (10 mL), the aqueous phase
was extracted twice with EtOAc (2 ꢂ 10 mL). The combined organic layers were
dried (MgSO4), filtered, and concentrated in vacuo. The desired product (11) was
obtained quantitatively as an oil and used without further purification (233 mg,
0.9 mmol). Isolated yield >99%. Data were in accord with the literature.[2]
Ethyl 2-Formyl-4-thiazolecarboxylate (12)
A solution of ethyl 2-(diethoxymethyl)-4-thiazolecarboxylate (11) (233 mg,
0.9 mmol) was heated at reflux in acetone (25 mL) with aqueous 2 N hydrochloric
acid (2.5 mL) for 1 h. After cooling and concentration, the reaction mixture was
extracted with chloroform (3 ꢂ 10 mL), and the combined organic extracts were
dried (MgSO4) and concentrated in vacuo. An amount of 158 mg (0.85 mmol) of
the title compound was obtained in an acceptable pure form and used in the next
step without further purification. Isolated yield 95%. Data were in accord with the
literature.[2]
Ethyl 2-(1-Hydroxyethyl)-4-thiazolecarboxylate (13)[26]
A solution of methyl magnesium bromide (1.4 M in THF=toluene, 570 mL,
0.8 mmol) was added dropwise to a solution of ethyl 2-formyl-4-thiazolecarboxylate

2106
F. FACHE ET AL.
(12) (158 mg, 0.8 mmol) in 5 mL THF at 0 ꢀC, and the mixture was stirred for 12 h.
Saturated aqueous ammonium chloride solution (10 mL) was added, and the mixture
was concentrated in vacuo. The aqueous layer was further extracted with chloroform
(3 ꢂ 10 mL) and the combined organic extracts were dried (MgSO4) and concen-
trated in vacuo. The residue was purified by flash chromatography (silica) eluting
with light petroleum–ethyl acetate (5:5) to give the title compound (13) as oil.
1
Isolated yield: 30% (60 mg); colorless liquid; Rf 0.3 (AcOEt=hexanes 5:5); H
NMR (300 MHz, CDCl3) 8.11 (s, 1Hthiazole), 5.20 (q, J ¼ 6.5 Hz, 1H, CHOH), 4.40
13
(q, J ¼ 7.2 Hz, 2H, CH3CH2), 1.64 (d, J ¼ 6.5 Hz, 3H, (CH3CH), 1.37 (t, J ¼ 7.2 Hz,
=
3H, CH3CH2); C NMR (75 MHz, CDCl3) 177.5 (C N), 161.7 (C O), 147.2
=
=
=
(C CO2Et), 127.7 (C CH), 68.6 (CHOH), 61.8 (CH2O), 24.5 (CH3CH2), 14.7
(CH3); IR (neat) cmꢁ1 3409, 3122, 2982, 2932, 1722, 1218, 1100, 1018. HRMS calcd.
for C8H11NO3S (M)þ 201.0460; found 201.0459.
Ethyl 2-Acetylthiazole-4-carboxylate (14)
To a solution of 13 (48 mg, 0.24 mmol) in 1.5 mL of CH2Cl2 was added 0.88 mL
(1.1 eq, 0.264 mmol) of a commercial Dess–Martin reagent solution (0.3 M in
CH2Cl2). The reaction mixture was stirred at room temperature under argon for
2 h. After addition of water (5 mL) and extraction with 3 ꢂ 5 mL of CH2Cl2, the
organic phase was dried over MgSO4, filtered, and concentrated. The residue was
purified by flash chromatography (silica) eluting with light petroleum–ethyl acetate
(7:3) to give the title compound (14). Isolated yield: 94% (45 mg). Data were in
accord with the literature.[7b]
2-Acetylthiazole-4-carboxylic Acid (15)
Compound 14 (55 mg, 0.28 mmol) was added to a solution of LiOH (10 mg,
0.42 mmol) in 2.4 mL THF and 0.6 mL H2O. The reaction mixture was stirred at
room temperature for 24 h and extracted with AcOEt (10 mL). The aqueous phase
was then acidified with HCl 1 N to pH 1–2 and extracted with AcOEt (10 mL).
The organic phase was dried over anhydrous Na2SO4 and filtered, and the solvent
was removed in vacuo to give 31 mg of pure 15. Isolated yield: 65%; data were in
accord with the literature.[21]
Bacillamide A (16)[21]
DCC (30 mg, 0.145 mmol), HOBt (18 mg, 0.133 mmol), and tryptamine (25 mg,
0.156 mmol) were mixed with acid 15 (27 mg, 0.158 mmol) in 1 mL of dichloro-
methane at 0 ꢀC and stirred overnight at room temperature. After extraction with
dichloromethane and water, the organic phase was dried on MgSO4 and evaporated.
The crude sample was separated by preparative TLC (CH2Cl2=MeOH 96:5) to give
the final compound 16 (24 mg, 0.078 mmol).
Isolated yield: 50%; solid, mp. 168–169 ꢀC (lit. 169–170 ꢀC[21]) Rf 0.5 (CH2Cl2=
MeOH 96:5); 1H NMR (400 MHz, CDCl3) 8.40 (s, 1Hthiazole), 8.09 (bs, 1H, NH), 7.67
(d, J ¼ 8 Hz, 1Haro), 7.40 (m, 2Haro), 7.11–7.24 (m, 3H), 3.82 (q, J ¼ 8 Hz, 2H,
CH2CH2NH), 3.13 (t, J ¼ 8 Hz, 2H, CH2CH2NH), 2.61 (s, 3H, CH3); 13C NMR

SYNTHESIS OF 2-ALKYL AND 2-ARYLTHIAZOLINES
2107
=
(100 MHz, CDCl3) 191.5 (C O), 166.8 (C N), 160.7 (NH-C O), 152.1 (C-CONH),
=
=
136.7 (C indole), 129.9 (HC-S), 127.7 (C indole), 122.6 (C indole–NH), 122.4 (C
indole), 119.9 (C indole), 118.1 (C indole), 113.4 (C indole-CH2), 111.6 (C indole),
ꢁ1
=
40.3 (CH2-NH), 26.3 (CH3-C O), 25.8 (CH2); IR (neat) cm 3408, 3122, 2982,
2932, 1686, 1655, 1547, 1481, 1263. HRMS calcd. for C16H16N3O2S (M þ H)þ
314.0963; found 314.0963.
REFERENCES
1. Deeley, J.; Bertram, A.; Pattenden, G. Novel polyoxazole-based cyclopeptides from
Streptomyces sp.: Total synthesis of the cyclopeptide YM-216391 and synthetic studies
towards telomestatin. Org. Biomol. Chem. 2008, 6, 1994–2010.
2. Bagley, M. C.; Xiong, X. Stereoselective synthesis of the c-lactam hydrolysate of the
thiopeptide cyclothiazomycin. Org. Lett. 2004, 6, 3401–3404.
3. Nasveschuk, C. G.; Ungermannovan, D.; Liu, X.; Phillips, A. J. A concise total synthesis
of largazole, solution structure, and some preliminary structure activity relationships. Org.
Lett. 2008, 10, 3595–3598.
4. Fuganti, C.; Gatti, F. G.; Serra, S. A general method for the synthesis of the most power-
ful naturally occurring Maillard flavors. Tetrahedron 2007, 63, 4762–4767.
5. Robbe, Y.; Fernandez, J.-P.; Chapat, J.-P.; Soutenac-Roumanou, H.; Fatome, M.
Research of radioprotective agents: D2-Thiazolines and homologous derivatives. Eur. J.
Med. Chem. 1985, 20, 16–24.
6. Gaumont, A.-C.; Gulea, M.; Levillain, J. Overview of the chemistry of 2-thiazolines.
Chem. Rev. 2009, 109, 1371–1401.
7. (a) Sonnenschein, R. N.; Johnson, T. A.; Tenney, K.; Valeriole, F. A.; Crews, P. A reas-
signment of (ꢁ)-mycothiazole and the isolation of a related diol. J. Nat. Prod. 2006, 69,
145–147; (b) Sani, M.; Fossati, G.; Huguenot, F.; Zanda, M. Total synthesis of Tubulysins
U and V. Angew. Chem. Int. Ed. 2007, 46, 3526–3529; (c) Yokokawa, F.; Sameshima, H.;
Shioiri, T. Total synthesis of lyngbyabellin A, a potent cytotoxic metabolite from the mar-
ine cyanobacterium Lyngbya majuscula. Tetrahedron Lett. 2001, 42, 4171–4174.
8. (a) Evans, D. L.; Minster, D. K.; Jordis, U.; Hecht, S. M.; Mazzu, Jr. A. L.; Meyers, A. I.
Nickel peroxide dehydrogenation of oxygen-, sulfur-, and nitrogen-containing hetero-
cycles. J. Org. Chem. 1979, 44, 497–501; (b) Williams, D. R.; Lowder, P. D.; Gu, Y.-G.;
Brooks, D. A. Studies of mild dehydrogenations in heterocyclic systems. Tetrahedron Lett.
1997, 38, 331–334; (c) Meyers, A. I.; Tavares, F. X. Oxidation of oxazolines and thiazolines
to oxazoles and thiazoles: Application of the Kharasch–Sosnovsky reaction. J. Org. Chem.
1996, 61, 8207–8215; (d) North, M.; Pattenden, G. Synthetic studies towards cyclic
peptides: Concise synthesis of thiazoline and thiazole containing amino acids. Tetrahedron
1990, 46, 8267–8290.
9. (a) Sugiyama, H.; Yokokawa, F.; Shioiri, T. Asymmetric total synthesis of
(ꢁ)-mycothiazole. Org. Lett. 2000, 2, 2149–2152; (b) Groarke, M.; McKervey, M. A.;
Moncrieff, H.; Hieuwenhuyzen, M. Synthesis of amino acid–derived thiazoles from enan-
tiopure N-protected a-amino glyoxals. Tetrahedron Lett. 2000, 41, 1279–1282; (c)
Gududuru, V.; Hurh, E.; Dalton, J. T.; Miller, D. D. Discovery of 2-arylthiazolidine-4-
carboxylic acid amides as a new class of cytotoxic agents for prostate cancer. J. Med.
Chem. 2005, 48, 2584–2588.
10. (a) Merle, N.; Taoufik, M.; Morad, N.; Baudouin, A.; Le Roux, E.; Gauvin, R. M.;
Lefebvre, F.; Thivolle-Cazat, J.; Basset, J.-M. Development of a well-defined silica-
supported tungstenocarbyne complex as efficient heterogeneous catalyst for alkyne
metathesis. J. Organomet. Chem. 2008, 693, 1733–1737; (b) Fache, F.; Valot, F.; Lemaire,

2108
F. FACHE ET AL.
M. In Fine Chemicals through Heterogeneous Catalysis; R. A. Sheldon, H. van Bekhum
(Eds.); Wiley VCH: Weinheim, NY, 2000; pp. 461–471; (c) Saluzzo, C.; Ter Halle, R.;
Touchard, F.; Fache, F.; Schulz, E.; Lemaire, M. Recent progress in asymmetric hetero-
geneous catalysis: Use of polymer-supported catalyst. J. Organomet. Chem. 2000, 603,
30–39; (d) Ueda, T.; Kotsuki, H. Heteropoly acids: Green chemical catalysts in organic
synthesis. Heterocycles 2008, 76, 73–97.
11. (a) Mohammadpoor-Baltork, I.; Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.;
Hojati, S. F. Supported 12-tungstophosphoric acid as heterogeneous and recoverable
catalysts for the synthesis of oxazolines, imidazolines and thiazolines under solvent-free
conditions. Polyhedron 2008, 27, 750–758; (b) Mohammadpoor-Baltork, I.; Moghadam,
M.; Tangestaninejad, S.; Mirkhani, V.; Hojati, S. F. Environmentally friendly synthesis
of oxazolines, imidazolines, and thiazolines catalyzed by tungstophosphoric acid. Catal.
Commun. 2008, 9, 1153–1161.
12. Katritzky, A. R.; Cai, C.; Suzuki, K.; Singh, S. K. Facile syntheses of oxazolines and
thiazolines with N-acylbenzotriazoles under microwave irradiation. J. Org. Chem. 2004,
69, 811–814.
13. Sukanta, K.; Biehl, E. R. Synthesis of thiazolines by the reaction of aryl keto nitriles with-
cysteamine via microwave irradiation. J. Heterocycl. Chem. 2007, 44, 407–409.
14. Kodomari, M.; Tamaru, Y.; Aoyama, T. Solvent-free synthesis of 2-aryl and 2-alkyl-
benzothiazoles on silica gel under microwave irradiation. Synth. Commun. 2004, 34,
3029–3036.
15. Obermayer, D.; Kappe, C. O. On the importance of simultaneous infrared=fiber-optic
temperature monitoring in the microwave-assisted synthesis of ionic liquids. Org. Biomol.
Chem. 2010, 8, 114–121.
16. Desimoni, G.; Faita, G.; Jorgensen, K. A. C2-Symmetric chiral bis(oxazoline) ligands in
asymmetric catalysis. Chem. Rev. 2006, 106, 3561–3651.
17. (a) Patterson, A. W.; Peltier, H. M.; Ellman, J. A. Expedient synthesis of N-methyl tubu-
lysin analogues with high cytotoxicity. J. Org. Chem. 2008, 73, 4362–4369; (b) Inami, K.;
Shiba, T. Total synthesis of antibiotic althiomycin. Bull. Chem. Soc. Jpn. 1985, 58, 352–360;
(c) Bagley, M. C.; Dale, J. W.; Jenkins, R. L.; Bower, J. First synthesis of an amythiamicyn
pyridine cluster. Chem. Commun. 2004, 102–103; (d) Merritt, E. A.; Bagley, M. C. Conver-
gent synthesis of the central heterocyclic domain of Micrococcin P1. Synlett 2007, 954–958;
(e) Glover, C.; Merritt, E. A.; Bagley, M. C. Synthesis of saramycetic acid. Tetrahedron
Lett. 2007, 7027–7030; (f) Aulakh, V. S.; Ciufolini, M. A. An improved synthesis
of pyridine-thiazole cores of thiopeptide antibiotics. J. Org. Chem. 2009, 74, 5750–5753.
18. Krieger, R. I.; Krieger, W. C. (Eds.). Handbook of Pesticide Toxicology: Agents; Elsevier:
New York, 2001.
19. Jeong, S.-Y.; Ishida, K.; Ito, Y.; Okada, S.; Murakami, M. Bacillamide, a novel algicide
from the marine bacterium, Bacillus sp. SY-1, against the harmful dinoflagellate,
Cochlodinium polykrikoides. Tetrahedron Lett. 2003, 8005–8007.
20. (a) Socha, A. M.; Long, R. A.; Rowley, D. Bacillamide from a hypersaline microbial mat
bacterium. J. Nat. Prod. 2007, 70, 1793–1795; (b) Wang, W.; Joyner, S.; Khoury, K. A. S.;
Domling, A. (ꢁ)-Bacillamide C: The convergent approach. Org. Biomol. Chem. 2010, 8,
¨
529–532.
21. Figueira, V. B.; Prabhakar, S.; Lobo, A. M. Synthesis of the algicide Bacillamide. Arkivoc
2005, 14–19.
¨
22. Kuhn, R.; Drawert, F. Uber thiazoline. Justus Liebigs Ann. Chem. 1954, 590, 55–75.
¨
23. Baganz, H.; Domaschke, L. Notiz uber 2-alkoxymethyl-D2-thiazoline. Chem. Ber. 1962,
95, 1842–1843.

SYNTHESIS OF 2-ALKYL AND 2-ARYLTHIAZOLINES
2109
24. Chiba, T.; Sakaki, J.; Takahashi, T.; Auki, K.; Kamiyama, A.; Kaneko, C.; Sato, M. Studies
on amino acid derivatives, part 7: General method for the synthesis of penam and cepham
and their substituted derivatives. J. Chem. Soc., Perkin Trans. 1 1987, 8, 1845–1851.
25. Capps, N. K., Davies, G. M.; Loakes, D.; McCabe, R. W.; Joung, D. W. Synthesis of
bicyclic pyridine and dihydropyridone analogues of b-lactam antibiotics. J. Chem. Soc.,
Perkin Trans. 1 1991, 12, 3077–3086.
26. Schmidt, U.; Gleich, P.; Griesser, H.; Utz, R. Acids and peptides, 58: Synthesis of optically
active 2-(1-hydroxyalkyl)-thiazole-4-carboxylic acids and 2-(1-aminoalkyl)-thiazole-4-
carboxylic acids. Synthesis 1986, 992–994.