Straightforward microwave-assisted synthesis of 2-thiazolines using Lawesson's reagent under solvent-free conditions

Article abstract of DOI:10.1016/j.tet.2008.07.027

2-Thiazolines are synthesized from carboxylic acids and 1,2-aminoalcohols in the presence of Lawesson's reagent under solventless conditions. The developed method is valid for either substituted or unsubstituted aminoalcohols and a wide variety of aromatic, heteroaromatic and aliphatic carboxylic acids; thus it constitutes a general synthetic method for these kinds of compounds. The role of Lawesson's reagent is dual: to transform the 1,2-aminoalcohol into 1,2-aminothiol and to activate its reaction with the carboxylic acid leading to the formation of a thiazoline ring, all in one pot.

Full text of DOI:10.1016/j.tet.2008.07.027

Tetrahedron 64 (2008) 9280–9285
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Straightforward microwave-assisted synthesis of 2-thiazolines using
Lawesson’s reagent under solvent-free conditions
*
*
´
´
Julio A. Seijas , M. Pilar Vazquez-Tato , Jose Crecente-Campo
´
Dpto. Qu´ımica Organica, Facultad de Ciencias, Universidad de Santiago de Compostela, Aptdo. 280, 27080-Lugo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Thiazolines are synthesized from carboxylic acids and 1,2-aminoalcohols in the presence of Lawesson’s
reagent under solventless conditions. The developed method is valid for either substituted or un-
substituted aminoalcohols and a wide variety of aromatic, heteroaromatic and aliphatic carboxylic acids;
thus it constitutes a general synthetic method for these kinds of compounds. The role of Lawesson’s
reagent is dual: to transform the 1,2-aminoalcohol into 1,2-aminothiol and to activate its reaction with
the carboxylic acid leading to the formation of a thiazoline ring, all in one pot.
Received 18 June 2008
Received in revised form 8 July 2008
Accepted 9 July 2008
Available online 15 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
of benzoxazoles and benzothiazoles by irradiation with micro-
waves under solvent-free conditions.30 The effective action of LR in
Thiazoline rings are found in a large number of biologically
active natural products. Thus, some thiazoline derivatives present
interesting activities, such as: anti-HIV,1 anti-cancer,2–4 cell division
inhibition,5 pheromone activity,6 metal binders,7 antibiotic8–10 and
this coupling prompted us to explore its use in the synthesis of
a thiazoline ring. Earlier, Nishio25 had demonstrated the possibility
of converting (1,2)-N-acylamino alcohols into thiazolines in the
presence of LR using conventional heating in the presence of
toluene; however, this procedure requires the previous formation
of the amide bond, which is not always a straightforward step from
aminoalcohol and carboxylic acid.
radioprotective.11,12 Furthermore,
a thiazoline ring is a good
directing group for ruthenium catalyzed carbonylation of aromatic
rings13 and synthesis of chalcogenobenzenes.14 General method-
ologies for the synthesis of thiazolines include the coupling of
imidates or esters with aminothiols,15–17 the cyclodehydration of
hydroxy thioamides,2,18–21 the condensation of nitriles with
mercaptoalcohols.22,23 They can also rely on the formation of an
intermediate amide from carboxylic acid and aminoalcohols and its
conversion into the corresponding thioamide (obtained by thio-
2. Results and discussion
Hence, in this paper the possibility of activating the formation of
the amide bond between carboxylic acid and 1,2-aminoalcohol
using LR under solventless conditions is studied. Furthermore, LR
can act as a thionating agent and allows for the replacement of the
hydroxyl by the thiol group, leading to a 2-thiazoline ring in a
one-pot conversion.
As a model, the reaction of benzoic acid (1a) and 2-amino-
ethanol (2) was used to study the conditions necessary to carry out
the transformation (Scheme 1). So, benzoic acid, aminoalcohol
2 and LR (molar ratio 1:1.5:0.5, respectively) were irradiated
with microwaves at 190 ꢀC for 4 min (the same conditions used for
the synthesis of benzoazoles30). This yielded 2-thiazoline 5a in 60%,
as well as the presence of several by-products. In order to improve
the yield, different times, temperatures and reagent ratios were
studied. We found that the best conditions are: irradiation for 8 min
of a mixture 1:1.5:0.75 of the above mentioned reagents, at 150 ꢀC/
300 W. This yields 80% of the 2-thiazoline 5a. Lower temperatures
lead to a considerable amount of unreacted starting materials.
These reaction conditions were applied to a variety of sub-
stitution patterns for the benzoic acids (electron-donating and
11
nation using P2S5 or Lawesson’s reagent24,25), followed by cycli-
zation to thiazoline. There have also been some reports on the use
of microwaves to prepare a thiazoline ring, i.e., the irradiation of
2-aminoethanethiol with N-acylbenzotriazoles followed by the
addition of thionyl chloride and a new irradiation step,26 or the
preparation of 2-arylthiazolines from aryl keto nitriles and cyste-
amine.27 The fact that microwave-assisted organic synthesis
(MAOS) is seldom used for 2-thiazolines is surprising since the use
of MAOS in heterocyclic chemistry28 has proven to be a useful tool,
specially when solventless reactions are sought.29–34
Recently, our group has demonstrated the usefulness of Law-
esson’s reagent (LR) for activating carboxylic acids in the synthesis
* Corresponding authors. Tel.: þ34 982285900; fax: þ34 982285872.
E-mail addresses: julioa.seijas@usc.es (J.A. Seijas), pilar.vazquez.tato@usc.es
´
(M.P. Vazquez-Tato).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.027

J.A. Seijas et al. / Tetrahedron 64 (2008) 9280–9285
9281
Table 2
R2
R2
R2
H2N
HO
Synthesis of 2-thiazolines from 2-amino-2-methyl-1-propanol (3)
N
LR
R2
R3
R1 CO2H
+
R1
Entry
Acid
R1
Product
6a41
Yield %
MW, 150 °C
R3
S
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Ph
77
71
70
67a
76
22
22
77
72
73
81
82
61
40
5a-n, R2=H, R3= H
6a-n, R2=CH3, R3=H
7a-n, R2= H, R3=Ph
1a-n
2, R2=H, R3=H
3-MeC6H4
4-MeOC6H4
2,3-(MeO)2C6H3
2-Naphthyl
4-ClC6H4
6b
3, R2= CH3, R3=H
4, R2=H, R3= Ph
6c42
6d (R1¼2-HO-3-MeOC6H3)
6e
6f
Scheme 1.
7
8
9
10
11
12
13
14
1g
1h
1i
1j
1k
1l
4-BrC6H4
3-Pyridyl
2-Thienyl
2-Furyl
6g
6h
6i
withdrawing groups in the aromatic ring) and for the amino-
alcohols (2, 3 and 4, Scheme 1). For 2-aminoethanol (2), the pres-
ence of an electron-donating group (methoxy or methyl
substituents) in the ring of the acid gave similar yields as for
unsubstituted benzoic acid (Table 1, entries 2 and 3). It is note-
worthy that for acid 1d, the 2-thiazoline obtained is mainly the
2-demethylated compound (53%), due to demethylation in the
hindered ortho-position (Table 1, entry 4). Similar behaviour has
been observed in previous reactions with LR.30,35 Also the con-
densated aromatic acid 2-naphthoic acid gave 83% of 2-thiazoline
5e (Table 1, entry 5). Meanwhile, the presence of halogen atoms
slightly reduced the yields to 60 and 57%, respectively (Table 1,
entries 6 and 7).
6j
C6H4CH2
6k43
CH3(CH2)5
CH3(CH2)8
HOOC(CH2)7
6l
6m
1m
1n
6n (Bis-thiazoline)b
Reactions were heated at 150 ꢀC for 4 min. All yields are for isolated product with
previous purification by flash chromatography.
a
Non-demethylated compound in the hindered ortho-position was obtained in
7% yield.
b
Reagents ratio: dicarboxylic acid/2-amino-2-methyl-1-propanol/LR is 1:3:1.5.
five-membered ring and gives thiazoles 8e–i as by-products (Table
3, entries 5–9). These oxidation compounds were produced in small
amounts, lower than 20%.
The reaction is also compatible with heteroaromatic acids, so
pyridyl, furyl and thienyl derivatives gave 50–63% yields (Table 1,
entries 8–10). Even this conversion is applicable to non-conjugated
carboxylic acids such as phenylacetic acid, which yielded 72% of
2-thiazoline 5k (Table 1, entry 11). Aliphatic acids like heptanoic
and decanoic acids led to the corresponding 2-thiazolines in 86%
yield (Table 1, entries 12 and 13). It is even possible to obtain a bis-
thiazoline (5n) in 61% yield from a dicarboxylic acid like azelaic acid
(Table 1, entry 14).
The positive results obtained with these reaction conditions
were checked with substituted 1,2-aminoalcohols to verify its wide
application, since most of previously described methods for the
synthesis of 2-thiazolines reduce their examples to benzoic acids
and unsubstituted aminoalcohol 2. Thus, the reactivity of 2-amino-
2-methyl-1-propanol (3) with the same carboxylic acids studied
above gave similar results (Table 2), yet the reaction required
a shorter time (4 min).40 However, lower yields were obtained for
halogenated benzoic acids (Table 2, entries 6 and 7).
As for the reaction mechanism, it can proceed through the
activation of the carboxylic acid by LR, as previously described,45 to
promote the formation of the amide. Then, after replacement of the
hydroxyl by a thiol group it could cyclize to 2-thiazoline in the
presence of LR as was suggested by Nishio.25 A similar mechanism
was postulated by Metzger in the formation of 2-thiazolines from
46
hydroxyamides with P4S10
.
However, we found that when
a mixture of benzoic acid and LR was irradiated, and then amino-
alcohol 3 was added and irradiated again, it led to a complex
mixture of reaction products. On the contrary, the irradiation of
aminoalcohol 3 together with LR for 1 min, followed by the addi-
tion of benzoic acid and irradiation at 150 ꢀC for 4 min yielded 73%
of 2-thiazoline 6a. This suggests a first step where the LR acts as
a thionating agent to exchange the hydroxyl for a thiol group (9).
Then, an activated species must be formed, which favours the
reaction with carboxylic acids, has been proposed in the synthesis
of benzoxazoles and benzothiazoles from 2-aminophenol and
2-aminothiophenol, respectively.30 In fact, when the aminoalcohol
3 was irradiated with LR an 1,3,2-thiazaphospholidine-2-meth-
oxyphenyl-2-sulfide (10) was isolated and this was transformed,
upon irradiation with benzoic acid, into a 2-thiazoline 6a in good
The irradiation of carboxylic acids with LR in the presence of
2-amino-1-phenylethanol (4) led to 2-thiazolines 7a–n in lower
yields (Table 3). This is probably due to the presence of the phenyl
group in 1,2-aminoalcohol, which induces the aromatization of the
Table 3
Table 1
Synthesis of 2-thiazolines from 2-amino-1-phenylethanol (4)
Synthesis of 2-thiazolines from 2-aminoethanol (2)
Entry
Acid
R1
Product
7a44
7b
7c
Yield %a
Entry
Acid
R1
Product
Yield %
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
Ph
69
71
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
Ph
5a36
80
86
79
53a
83
60
57
61
63
50
72
86
86
61
3-MeC6H4
4-MeOC6H4
2,3-(MeO)2C6H3
2-Naphthyl
4-ClC6H4
4-BrC6H4
3-Pyridyl
2-Thienyl
2-Furyl
3-MeC6H4
4-MeOC6H4
2,3-(MeO)2C6H3
2-Naphthyl
4-ClC6H4
4-BrC6H4
3-Pyridyl
2-Thienyl
2-Furyl
5b27
66
5c27
7d (R1¼2-HO-3-MeOC6H3)
47b
5d (R1¼2-HO-3-MeOC6H3)
7e (þ8e)
7f (þ8f)
7g (þ8g)
7h (þ8h)
7i25 (þ8i)
7j25
52 (14)
38 (7)
33 (13)
21 (20)
44 (13)
42
40
62
64
28
5e37
5f38
5g11
5h23
9
9
5i23
10
11
12
13
14
10
11
12
13
14
5j38
C6H4CH2
7k25
7l
7m
C6H4CH2
5k38
CH3(CH2)5
CH3(CH2)8
HOOC(CH2)7
CH3(CH2)5
CH3(CH2)8
HOOC(CH2)7
5l
5m39
7n (Bis-thiazoline)c
5n (Bis-thiazoline)b
Reactions were heated at 150 ꢀC for 8 min. All yields are for isolated product with
previous purification by flash chromatography.
Reactions were heated at 150 ꢀC for 8 min, except for entry 8 (4 min). All yields are
for isolated product with previous purification by flash chromatography.
a
Yields in brackets correspond to by-products shown in column 4.
Non-demethylated compound in the hindered ortho-position was obtained in
a
b
Non-demethylated compound in the hindered ortho-position was obtained in
8% yield.
8% yield.
b
c
Reagents ratio: dicarboxylic acid/2-aminoethanol/LR is 1:3:1.5.
Reagents ratio: dicarboxylic acid/2-amino-1-phenylethanol/LR is 1:3:1.5.

9282
J.A. Seijas et al. / Tetrahedron 64 (2008) 9280–9285
yield (Scheme 2). However, it is noticeable that in the previously
described reaction of 1,2-aminoalcohols with LR heating under
conventional conditions (reflux in xylene), no replacement of the
hydroxyl group by a thiol takes place; this leads to 1,3,2-oxaza-
phospholidines-2-sulfides.47
4.3. Data of previously unreported compounds
4.3.1. 2-(2-Hydroxy-3-methoxyphenyl)-2-thiazoline (5d)
Mp 74–74.5 ꢀC (hexane). 1H NMR
d
3.32 (t, 2H, J¼8.4 Hz, CH2S),
3.88 (s, 3H, OCH3), 4.45 (t, 2H, J¼8.4 Hz, CH2N), 6.78 (t, 1H, J¼7.9 Hz,
ArH), 6.93 (dd, 1H, J¼8.2, 1.6 Hz, ArH), 7.03 (dd, 1H, J¼7.9, 1.3 Hz,
Ar–H). 13C NMR
d 32.1 (SCH2), 56.5 (OCH3), 63.5 (NCH2), 114.9, 116.7,
CH3
CH3
CH3
CH3
118.3, 122.5 (CAr), 148.7 (C–OH), 149.8 (C–OCH3), 172.8 (C]N). IR
(KBr, film): 2949, 2843, 1599 (C]N), 1468, 1257, 1013, 781,
731 cmꢁ1. MS (EI): m/z (%) 210 (Mþþ1, 40), 209 (Mþ, 100), 181 (49),
180 (32), 166 (38), 153 (85), 149 (47), 148 (41),131 (49), 121 (29), 106
(33), 61 (52). Anal. Calcd for C10H11NO2S: C, 57.39; H, 5.30; N, 6.69;
S, 15.32. Found: C, 57.43; H, 5.57; N, 6.47; S, 14.89.
H2N
HO
H2N
HS
LR
MW
3
9
CH3
CH3
CH3
H3C
Ph CO2H
MW, 150 °C
N
4.3.2. 2-Hexyl-2-thiazoline (5l)
NH
P
Ph
Oil. 1H NMR
d
0.87 (t, 3H, J¼6.6 Hz, CH3), 1.23–1.40 (m, 6H,
OCH3
S
S
3ꢂCH2), 1.63 (quint, 6H, J¼4.8 Hz, CH2), 250 (tt, 2H, J¼7.9 and
1.8 Hz, CH2C]N), 3.26 (t, 2H, J¼8.4 Hz, CH2S), 4.20 (t, 2H, J¼8.4 Hz,
S
6a
10
CH2N). 13C NMR
d 14.2 (CH3), 22.7, 27.7, 29.0, 31.7, 33.9, 34.6 (CH2),
Scheme 2.
64.7 (NCH2), 172.2 (C]N). MS (EI): m/z (%) 171 (Mþ, 5), 129 (13), 114
(24), 101 (100), 61 (20), 60 (64), 59 (22), 55 (14). IR (KBr, film): 2925,
2855, 1629 (C]N), 1455, 1194, 1150, 973, 674 cmꢁ1. Anal. Calcd for
C9H17NS: C, 63.10; H, 10.00; N, 8.18; S, 18.72. Found: C, 63.24; H,
10.04; N, 7.99; S, 18.76.
3. Conclusion
In summary, a new, simple, fast, efficient and versatile method
for the synthesis of 2-thiazolines from 1,2-aminoalcohols and car-
boxylic acid employing Lawesson’s reagent is presented. In this
solvent-free procedure, the LR has two roles, to transform the 1,2-
aminoalcohol into the 1,2-aminothiol and, to bring about a reaction
with the carboxylic acid leading to the formation of 2-thiazoline
ring. All these transformations are carried out in a one-pot reaction.
The method is competitive with previous ones, both with con-
ventional or microwave heating, since it leads to good yields and
requires shorter reaction times. Moreover, it has a wider range of
examples than the previously described synthesis both for the kind
of carboxylic acids (aromatic and aliphatic) and 1,2-aminoalcohols
used. In fact, 42 2-thiazolines were synthesized of which 24 had not
been previously prepared. The process can also be used for parallel-
synthesis of 2-thiazolines since the reaction conditions (reaction
time, power setting and temperature) for each kind of 1,2-amino-
alcohol are similar.
4.3.3. 1,7-Bis(4,5-dihydrothiazol-2-yl)heptane (5n)
Oil. 1H NMR
d
1.21–1.36 (m, 6H, 3ꢂCH2), 1.58 (quint, 4H,
J¼7.4 Hz, 2ꢂCH2), 2.45 (tt, 4H, J¼7.9, 1.3 Hz, 2ꢂCH2C]N), 3.23 (t,
4H, J¼8.4 Hz, 2ꢂCH2S), 4.20 (tt, 4H, J¼8.4, 1.3 Hz, 2ꢂCH2N). 13C
NMR d 27.6, 29.11, 29.13, 33.9, 34.5 (CH2), 64.7 (NCH2), 171.9 (C]N).
IR (KBr, film): 3300, 2928, 2854, 1639 (C]N), 1547, 1439, 1196,
984 cmꢁ1. MS (EI): m/z (%) 271 (Mþþ1, 30), 270 (Mþ, 21), 269
(Mþꢁ1, 58), 237 (44), 211 (50), 209 (52), 172 (50), 170 (64), 114 (75),
101 (100), 61 (50), 60 (64). Anal. Calcd for C13H22N2S2: C, 57.73; H,
8.20; N, 10.36; S, 23.71. Found: C, 57.93; H, 8.50; N, 10.51; S, 23.73.
4.3.4. 4,4-Dimethyl-2-(3-methylphenyl)-2-thiazoline (6b)
Oil. 1H NMR
d
1.47 (s, 6H, 2ꢂCH3), 2.38 (s, 3H, Ar–CH3), 3.20 (s,
2H, CH2S), 7.25–7.30 (m, 2H, ArH), 7.60 (dt, 1H, J¼7.0, 1.3 Hz, ArH),
7.67 (d, 1H, J¼0.9 Hz, ArH). 13C NMR
d
21.5 (ArCH3), 27.8 (2ꢂCH3),
45.2 (SCH2), 79.0 (C–(CH3)2), 125.9, 128.5, 128.9, 132.0, 133.7, 138.4
(CAr), 164.6 (C]N). IR (KBr, film): 2966, 2923, 1596 (C]N), 1582,
1460, 1359,1274,1160, 955, 893, 787, 693 cmꢁ1. MS (EI): m/z (%) 206
(Mþþ1, 34), 205 (Mþ, 49), 190 (MþꢁCH3, 100), 159 (36), 118 (66), 88
(95, SCH2CH(CH3)þ2 ), 84 (57), 55 (47), 51 (49). Anal. Calcd for
4. Experimental
4.1. General methods
C12H15NOS: C, 70.20; H, 7.36; N, 6.82; S, 15.62. Found: C, 70.49; H,
Melting points were measured in open capillaries and are
uncorrected. 1H NMR spectra were recorded at 300 MHz (1H) and
75 MHz (13C) in CDCl3. Mass spectra were recorded in a low-reso-
lution spectrometer. Infrared spectra were measured on FTIR
instrument (cmꢁ1). The reactions were irradiated in an open vessel
with microwaves in a monomode oven Discover CEM.
7.02; N, 6.50; S, 15.42.
4.3.5. 2-(2-Hydroxy-3-methoxyphenyl)-4,4-dimethyl-2-
thiazoline (6d)
Mp 106–108 ꢀC (hexane). 1H NMR
d
1.46 (s, 6H, 2ꢂCH3), 3.13 (s,
2H, CH2S), 3.87 (s, 3H, OCH3), 6.77 (t, 1H, J¼7.9 Hz, ArH), 6.93 (dd,
1H, J¼7.9, 1.3 Hz, ArH), 7.00 (dd, 1H, J¼7.9, 1.8 Hz, ArH). 13C NMR
4.2. General procedure
d
27.9 (2ꢂCH3), 43.5 (SCH2), 56.5 (OCH3), 78.0 (C–(CH3)2), 115.0,
116.7, 118.3, 122.1 (CAr), 148.7 (C–OH), 150.0 (C–OCH3), 168.6 (C]N).
IR (KBr, film): 2964, 2928, 1593 (C]N), 1566, 1462, 1256, 1173, 999,
735 cmꢁ1. MS (EI): m/z (%) 238 (Mþþ1, 26), 237 (Mþ, 93), 181 (37),
165 (49), 153 (62), 150 (44), 149 (100), 88 (28), 71 (49), 57 (60), 55
(75). Anal. Calcd for C12H15NO2S: C, 60.73; H, 6.37; N, 5.90; S, 13.51.
Found: C, 61.04; H, 6.60; N, 5.83; S, 13.88.
Synthesis of 4,4-dimethyl-2-phenyl-2-thiazoline (6a). A mixture
of benzoic acid (1a) (122 mg, 1 mmol), 2-amino-2-methyl-1-prop-
anol (3) (133 mg, 1.5 mmol) and Lawesson’s reagent (303 mg,
0.75 mmol) was irradiated in an open vessel with microwaves in
a monomode oven (Discover CEM, 300 W and temperature control
set at 150 ꢀC measured with an IR sensor) for 4 min. The crude was
dissolved in dichloromethane (30 mL) and washed with 10% aq
NaOH (3ꢂ15 mL), dried (Na2SO4) and evaporated to give 4,4-
dimethyl-2-phenyl-2-thiazoline (6a) pure as per NMR, further
purification by flash chromatography (AcOEt/hexane, 5:95) gave
147 mg (77%), as an oil.
4.3.6. 4,4-Dimethyl-2-naphthyl-2-thiazoline (6e)
Mp 51–53 ꢀC. 1H NMR
d
1.52 (s, 6H, 2ꢂCH3), 3.27 (s, 2H, CH2S),
7.48–7.55 (m, 2H, ArH), 7.83–7.92 (m, 3H, ArH), 7.99 (dd, 1H, J¼8.4,
1.8 Hz, ArH), 8.26 (d, 1H, J¼1.3 Hz, ArH). 13C NMR
d
27.8 (2ꢂCH3),
45.3 (SCH2), 79.2 (C–(CH3)2), 125.2, 126.7, 127.5, 127.9, 128.3, 129.0,

J.A. Seijas et al. / Tetrahedron 64 (2008) 9280–9285
9283
129.1, 131.3, 133.1, 134.9 (CAr), 164.3 (C]N). IR (KBr, film): 2968,
2928, 1607, 1277, 1169, 928, 822, 748 cmꢁ1. MS (EI): m/z (%) 242
(Mþþ1, 5), 241 (Mþ, 29), 226 (MþꢁCH3, 23), 154 (35), 153 (100), 127
(21), 126 (17), 88 (40, SCH2CH(CH3)þ2 ), 73 (15), 55 (28). Anal. Calcd
for C15H15NS: C, 74.65; H, 6.26; N, 5.80; S, 13.29. Found: C, 74.41; H,
6.69; N, 5.67; S, 13.21.
2924, 2854, 1647 (C]N), 1543, 1462, 1379, 1259 cmꢁ1. MS (EI): m/z
(%) 200 (Mþþ1, 17), 199 (Mþ, 8), 142 (31), 130 (31), 129 (100), 114
(25), 89 (23), 88 (89), 73 (26), 60 (33), 58 (38), 55 (72), 54 (64). Anal.
Calcd for C11H21NS: C, 66.27; H, 10.62; N, 7.03; S, 16.08. Found: C,
66.69; H, 11.00; N, 7.01; S, 16.11.
4.3.13. 4,4-Dimethyl-2-nonyl-2-thiazoline (6m)
4.3.7. 2-(4-Chlorophenyl)-4,4-dimethyl-2-thiazoline (6f)
Oil. 1H NMR
d
0.82 (t, 3H, J¼6.8 Hz, CH3CH2), 1.21–1.29 (m, 18H,
1H NMR
d
1.46 (s, 6H, 2ꢂCH3), 3.22 (s, 2H, CH2S), 7.36 (d, 2H,
6ꢂ(CH2), 2ꢂ(CH3)), 1.60 (quint, 2H, J¼7.0 Hz, CH2), 2.39 (t, 2H,
J¼8.4 Hz, ArH), 7.74 (d, 2H, J¼8.4 Hz, ArH). 13C NMR
d
27.7 (2ꢂCH3),
J¼7.7 Hz, CH2C]N), 3.01 (s, 2H, SCH2). 13C NMR
d 14.3 (CH3CH2),
45.5 (SCH2), 79.2 (C–(CH3)2), 128.8, 129.8, 132.3, 137.3 (CAr), 163.3
(C]N). IR (KBr, film): 2967, 2923, 1604 (C]N), 1488, 1399, 1264,
1169, 1088, 945, 832, 610 cmꢁ1. MS (EI): m/z (%) 227 (37ClꢁMþ, 26),
226 (13), 225 (35ClꢁMþ, 64), 210 (83), 179 (52), 138 (59), 88 (100,
SCH2CH(CH3)þ2 ), 73 (51), 55 (60), 54 (53). Anal. Calcd for
22.8 (CH2), 27.7 (2ꢂCH3), 27.9, 29.2, 29.4, 29.4, 29.6, 32.0, 34.6
(CH2), 45.4 (SCH2), 78.2 (C–(CH3)2), 167.8 (C]N). IR (KBr, film):
2926, 2854,1649 (C]N),1628,1541,1464,1362,1259, 895 cmꢁ1. MS
(EI): m/z (%) 241 (Mþ, 14), 142 (42), 129 (100), 88 (SCH2CH(CH3)þ2 ,
89), 55 (65). Anal. Calcd for C14H27NS: C, 69.65; H, 11.27; N, 5.80; S,
13.28. Found: C, 69.96; H, 11.36; N, 5.63; S, 12.90.
C
11H12ClNS: C, 58.53; H, 5.36; N, 6.20; S, 14.20. Found: C, 58.87; H,
5.12; N, 6.49; S, 14.19.
4.3.14. 1,7-Bis(4,4-dimethyl-4,5-dihydrothiazol-2-yl)heptane (6n)
4.3.8. 2-(4-Bromophenyl)-4,4-dimethyl-2-thiazoline (6g)
Oil. 1H NMR
d
1.32–1.37 (m, 20H, 4ꢂCH2, 4ꢂCH3),1.59 (quint, 4H,
Oil. 1H NMR
d
1.46 (s, 6H, 2ꢂCH3), 3.22 (s, 2H, CH2S), 7.52 (d, 2H,
J¼7.5 Hz, 2ꢂCH2), 2.42 (t, 4H, J¼7.7 Hz, 2ꢂCH2C]N), 3.05 (s, 4H,
J¼8.8 Hz, ArH), 7.68 (d, 2H, J¼8.4 Hz, ArH). 13C NMR
d
27.7 (2ꢂCH3),
2ꢂSCH2). 13C NMR
d 27.8 (CH3), 29.00, 29.05, 29.1, 29.2 34.6 (CH2),
45.4 (SCH2), 79.2 (C–(CH3)2), 125.7, 130.0, 131.8, 133.6 (CAr), 161.6
(C]N). MS (EI): m/z (%) 271 (81BrꢁMþ, 30), 270 (12), 269 (79BrꢁMþ,
38), 256 (47), 254 (54), 225 (22), 223 (24), 184 (23), 182 (28), 102
(46), 88 (100, SCH2CH(CH3)þ2 ), 73 (30), 55 (54), 54 (45). IR (KBr,
film): 2955, 2924, 2854, 1736, 1605 (C]N), 1589, 1462, 1263, 1070,
1013, 949 cmꢁ1. Anal. Calcd for C11H12BrNS: C, 48.90; H, 4.48; N,
5.18; S, 11.87. Found: C, 49.12; H, 4.35; N, 5.18; S, 12.01.
45.4 (SCH2), 78.3 (C–(CH3)2), 167.7 (C]N). IR (KBr, film): 2966,
2928, 2856, 1626 (C]N), 1535, 1462, 1360, 1230, 1175, 1084, 955,
885 cmꢁ1. MS (EI): m/z (%) 326 (Mþ, 8), 311 (MþꢁCH3, 100), 239
(50), 223 (46), 198 (65), 142 (40), 129 (95), 88 (88), 55 (76), 54 (49).
Anal. Calcd for C17H30N2S2: C, 62.52; H, 9.26; N, 8.58; S, 19.64.
Found: C, 62.45; H, 9.40; N, 8.29; S, 19.45.
4.3.15. 2-(3-Methylphenyl)-5-phenyl-2-thiazoline (7b)
4.3.9. 4,4-Dimethyl-2-(3-pyridyl)-2-thiazoline (6h)
Oil. 1H NMR
d
2.42 (s, 3H, CH3), 4.63 (dd, 1H, Jgem¼15.8 Hz,
Oil. 1H NMR
d
1.42 (s, 6H, 2ꢂCH3), 3.19 (s, 2H, CH2S), 7.27 (ddd,
J¼5.7 Hz, NCH2), 4.79 (dd, 1H, Jgem¼16.3 Hz, J¼8.8 Hz, NCH2), 5.08
1H, J¼7.9, 4.8, 0.9 Hz, ArH), 8.03 (ddd, 1H, J¼7.9, 2.2, 1.8 Hz, ArH),
(dd, 1H, J¼8.8, 5.7 Hz, CH), 7.26–7.39 (m, 7H, ArH), 7.70 (dt, 1H,
8.60 (dd,1H, J¼4.8,1.3 Hz, ArH), 8.96 (d,1H, J¼1.8 Hz, ArH). 13C NMR
J¼7.0, 1.8 Hz, ArH), 7.76 (br s, 1H, ArH). 13C NMR
d 21.5 (CH3), 54.8
d
27.6 (2ꢂCH3), 45.4 (SCH2), 79.2 (C–(CH3)2), 123.4, 129.7, 135.6,
(SCH), 73.5 (NCH2), 126.0, 127.3, 128.0, 128.7, 129.1, 129.2, 132.3,
133.4, 138.6, 142.4 (Ar), 168.1 (C]N). IR (KBr, film): 3028, 2939,
2920, 1601 (C]N), 1583, 1495, 1485, 1454, 1313, 1261, 1022, 999,
789, 696 cmꢁ1. MS (EI): m/z (%) 254 (Mþþ1, 6), 253 (Mþ, 31), 136
(C8H8Sþ, 68), 135 (C7H5NSþ, 76), 131 (C9H9Nþ, 100), 103 (18), 91
(49), 77 (26), 65 (21), 51 (15). Anal. Calcd for C16H15NS: C, 75.85; H,
5.97; N, 5.53; S, 12.66. Found: C, 75.88; H, 6.03; N, 5.50; S, 12.50.
149.6, 151.8 (CAr), 161.6 (C]N). IR (KBr, film): 2968, 2928, 1607
(C]N), 1416, 1269, 1173, 945, 810, 704, 623 cmꢁ1. MS (EI): m/z (%)
192 (Mþ, 10), 177 (MþꢁCH3, 8), 105 (29), 88 (33, SCH2CH(CH3)þ2 ), 73
(13), 58 (100), 54 (14). Anal. Calcd for C10H12N2S: C, 62.46; H, 6.29;
N, 14.57; S, 16.68. Found: C, 62.40; H, 6.25; N, 14.29; S, 16.30.
4.3.10. 4,4-Dimethyl-2-(2-thienyl)-2-thiazoline (6i)
Oil. 1H NMR
d
1.44 (s, 6H, 2ꢂCH3), 3.22 (s, 2H, CH2S), 7.03 (t, 1H,
4.3.16. 2-(4-Methoxyphenyl)-5-phenyl-2-thiazoline (7c)
J¼4.4 Hz, ArH), 7.40 (d, 2H, J¼4.4 Hz, ArH). 13C NMR
d
27.6 (2ꢂCH3),
Mp 83–84 ꢀC (hexane). 1H NMR
d 3.84 (s, 3H, OCH3), 4.58 (dd,
45.9 (SCH2), 78.8 (C–(CH3)2), 127.5, 129.5, 130.4, 137.6 (CAr), 157.3
(C]N). IR (KBr, film): 2926, 2854, 1601 (C]N), 1462, 1362, 1261,
1041, 710 cmꢁ1. MS (EI): m/z (%) 197 (Mþ, 35), 182 (MþꢁCH3, 100),
151 (39), 110 (77), 88 (SCH2CH(CH3)þ2 , 67), 73 (56), 55 (99). Anal.
Calcd for C9H11NS2: C, 54.78; H, 5.62; N, 7.10; S, 32.50. Found: C,
54.89; H, 5.62; N, 7.04; S, 32.07.
1H, Jgem¼15.8 Hz, J¼5.7 Hz, NCH2), 4.76 (dd, 1H, Jgem¼15.8 Hz,
J¼8.8 Hz, NCH2), 5.06 (dd, 1H, J¼8.8, 5.7 Hz, CH), 6.94 (d, 2H,
J¼8.8 Hz, ArH), 7.27–7.38 (m, 5H, ArH), 7.84 (d, 2H, J¼8.8 Hz, ArH).
13C NMR
d 54.9 (SCH), 55.6 (OCH3), 73.3 (NCH2), 114.1, 126.2, 127.3,
127.9, 129.1, 130.3, 142.4 (Ar), 162.3 (C–OCH3), 167.2 (C]N). IR (KBr,
film): 2999, 2937, 1607 (C]N), 1508, 1310, 1254, 1175, 1024, 1013,
849, 768, 702 cmꢁ1. MS (EI): m/z (%) 270 (Mþþ1, 8), 269 (Mþ, 44),
147 (C9H9NOþ, 100), 136 (C8H8Sþ, 49), 135 (C7H5NSþ, 50), 132 (20),
91 (18), 77 (24), 51 (8). Anal. Calcd for C16H15NOS: C, 71.34; H, 5.61;
N, 5.20; S, 11.90. Found: C, 71.22; H, 5.44; N, 4.89; S, 11.76.
4.3.11. 2-(2-Furyl)-4,4-dimethyl-2-thiazoline (6j)
Oil. 1H NMR
d
1.44 (s, 6H, 2ꢂCH3), 3.17 (s, 2H, CH2S), 6.44 (dd,1H,
J¼3.5, 1.8 Hz, ArH), 6.84 (dd, 1H, J¼3.5, 0.9 Hz, ArH), 7.48 (dd, 1H,
J¼1.8, 0.9 Hz, ArH). 13C NMR
d
27.6 (2ꢂCH3), 45.0 (SCH2), 78.9 (C–
(CH3)2), 111.9, 113.9, 144.8, 148.2 (CAr), 154.0 (C]N). IR (KBr, film):
2968, 2928, 1611 (C]N), 1475, 1265, 969, 899, 749 cmꢁ1. MS (EI):
m/z (%) 181 (Mþ, 34), 166 (MþꢁCH3, 100), 135 (29), 94 (46), 73 (42),
55 (55). Anal. Calcd for C9H11NOS: C, 59.64; H, 6.12; N, 7.73; S, 17.69.
Found: C, 59.53; H, 6.11; N, 7.50; S, 18.06.
4.3.17. 2-(2-Hydroxy-3-methoxyphenyl)-5-phenyl-2-
thiazoline (7d)
Mp 109–111 ꢀC (hexane/CH2Cl2). 1H NMR
d 3.93 (s, 3H, OCH3),
4.62 (dd, 1H, Jgem¼15.8 Hz, J¼5.7 Hz, NCH2), 4.80 (dd, 1H,
Jgem¼15.8 Hz, J¼8.8 Hz, NCH2), 5.03 (dd, 1H, J¼8.8, 5.7 Hz, CH), 6.82
(t, 1H, J¼7.9 Hz, ArH), 6.98 (dd, 1H, Jortho¼8.4 Hz and Jmeta¼1.3 Hz,
Ar–H), 7.06 (dd, 1H, Jortho¼7.9 Hz and Jmeta¼1.3 Hz, Ar–H), 7.26–7.36
4.3.12. 2-Hexyl-4,4-dimethyl-2-thiazoline (6l)
Oil. 1H NMR
d
0.81 (t, 3H, J¼6.2 Hz, CH3CH2), 1.23–1.28 (br s, 12H,
(m, 5H, ArH). 13C NMR
d 53.1 (SCHPh), 56.5 (OCH3), 71.4 (NCH2),
3ꢂ(CH2), 2ꢂ(CH3)), 1.54 (quint, 6H, J¼7.1 Hz, CH2), 2.38 (t, 2H,
115.0, 116.6, 118.5, 122.5, 127.3, 128.3, 129.2, 141.3(CAr), 148.8, 150.0
(CAr–O), 172.2 (C]N). IR (KBr, film): 2939, 2841, 1597 (C]N), 1464,
1256, 1088, 1022, 729, 700 cmꢁ1. MS (EI): m/z (%) 286 (Mþþ1, 14),
285 (Mþ, 70), 162 (35), 153 (64), 136 (C8H8Sþ, 42), 135 (C7H5NSþ,
J¼8.4 Hz, CH2C]N), 3.00 (s, 2H, SCH2). 13C NMR (75 MHz, CDCl3)
d
14.2 (CH3CH2), 22.7 (CH2), 27.7 (2ꢂCH3), 27.8, 28.8, 31.6, 34.6
(CH2), 45.4 (SCH2), 78.2 (C–(CH3)2), 167.8 (C]N). IR (KBr, film):

9284
J.A. Seijas et al. / Tetrahedron 64 (2008) 9280–9285
100),121 (32),104 (43),103 (41), 91 (65), 78 (34), 77 (59), 65 (32), 51
(38). Anal. Calcd for C16H15NO2S: C, 67.34; H, 5.30; N, 4.91; S, 11.24.
Found: C, 67.26; H, 5.38; N, 4.93; S, 11.10.
96), 124 (19), 104 (38), 103 (22), 91 (30), 77 (Phþ, 22), 55 (11). Anal.
Calcd for C15H21NS: C, 72.82; H, 8.56; N, 5.66; S, 12.96. Found: C,
72.43; H, 9.03; N, 5.39; S, 12.77.
4.3.18. 2-(2-Naphthyl)-5-phenyl-2-thiazoline (7e)
4.3.23. 2-Nonyl-5-phenyl-2-thiazoline (7m)
Mp 66–67 ꢀC (hexane). 1H NMR
d
4.68 (dd, 1H, Jgem¼15.8 Hz,
Oil. 1H NMR
d
0.90 (t, 3H, J¼6.8 Hz, CH3), 1.29–1.42 (m, 12H,
J¼5.7 Hz, NCH2), 4.85 (dd, 1H, Jgem¼15.8 Hz, J¼8.8 Hz, NCH2), 5.14
(dd, 1H, J¼8.8, 5.7 Hz, CH), 7.26–7.41 (m, 5H, ArH), 7.50–7.59 (m, 2H,
ArH), 7.86–7.93 (m, 3H, ArH), 8.06 (dd, 1H, J¼8.8, 1.8 Hz, ArH), 8.32
6ꢂCH2), 1.71 (sex, 2H, J¼7.9 Hz, CH2), 2.57 (tt, 2H, J¼7.7, 1.3 Hz,
CH2CN), 4.36 (ddt, 1H, Jgem¼15.6 Hz, J¼5.5, 1.3 Hz, NCH2), 4.54 (ddt,
1H, Jgem¼15.6 Hz, J¼9.0, 1.3 Hz, NCH2), 4.94 (dd, 1H, J¼9.0, 5.5 Hz,
(d, 1H, J¼1.3 Hz, ArH). 13C NMR
d
54.9 (SCHPh), 73.4 (NCH2), 125.0,
CH), 7.22–7.34 (m, 5H, ArH). 13C NMR
d 14.3 (CH3), 22.9, 29.4, 29.5,
126.9, 127.3, 127.8, 128.0, 128.1, 128.5, 129.1, 129.8, 133.1, 135.1, 142.2
(Arr), 168.3 (C]N). IR (KBr, film): 3059, 3028, 1607 (C]N), 1495,
1454, 1311, 1186, 1013, 928, 860, 822, 750, 698, 474 cmꢁ1. MS (EI):
m/z (%) 290 (Mþþ1, 10), 289 (Mþ, 44), 167 (C12H9Nþ, 100), 153 (26)
136 (C8H8Sþ, 56), 135 (C7H5NSþ, 55), 127 (45), 121 (18), 91 (21), 77
(23), 51 (11). Anal. Calcd for C19H15NS: C, 78.86; H, 5.22; N, 4.84; S,
11.08. Found: C, 78.56; H, 5.44; N, 4.87; S, 11.02.
29.5, 29.7, 32.1, 34.6 (CH2), 55.1 (SCH), 73.0 (NCH2), 127.2, 127.8,
129.0, 142.6 (Ar), 171.3 (C]N). IR (KBr, film): 2926, 2854, 1649
(C]N), 1632, 1543, 1493, 1454, 997, 760, 698 cmꢁ1. MS (EI): m/z (%)
289 (Mþ, 11), 177 (100), 172 (37), 136 (C8H8Sþ, 46), 135 (C7H5NSþ,
87), 104 (53), 103 (34), 91 (45), 77 (Phþ, 31), 57 (28), 55 (46). Anal.
Calcd for C18H27NS: C, 74.68; H, 9.40; N, 4.84; S, 11.08. Found: C,
74.47; H, 9.55; N, 4.67; S, 10.82.
4.3.19. 2-(4-Chlorophenyl)-5-phenyl-2-thiazoline (7f)
4.3.24. 1,7-Bis(5-phenyl-4,5-dihydrothiazol-2-yl)heptane (7n)
Mp 76–78 ꢀC. 1H NMR
d
4.60 (dd, 1H, Jgem¼16.3 Hz, J¼5.7 Hz,
Oil. 1H NMR
d
1.40 (br s, 6H, 3ꢂCH2), 1.70 (br s, 4H, 2ꢂCH2), 2.56
NCH2), 4.78 (dd, 1H, Jgem¼16.3 Hz, J¼8.8 Hz, NCH2), 5.10 (dd, 1H,
J¼8.8, 5.7 Hz, CH), 7.26–7.43 (m, 7H, ArH), 7.82 (d, 2H, J¼8.4 Hz,
(br t, 4H, J¼7.5 Hz, 2ꢂCH2CN), 4.35 (dd, 2H, Jgem¼15.4 Hz, J¼5.3 Hz,
2ꢂNCH2), 4.54 (dd, 2H, Jgem¼15.4 Hz, J¼8.8 Hz, 2ꢂNCH2), 4.94 (dd,
ArH). 13C NMR
d
55.3 (SCHPh), 73.4 (NCH2), 127.3, 128.1, 129.0, 129.1,
2H, J¼8.8 and 5.7 Hz, 2ꢂCH), 7.29 (br s, 10H, ArH). 13C NMR
d 27.6,
129.9, 131.9, 137.6, 142.0 (Ar), 166.8 (C]N). IR (KBr, film): 3063,
3030, 1599 (C]N), 1487, 1452, 1398, 1229, 1092, 1011, 972, 930, 831,
698 cmꢁ1. MS (EI): m/z (%) 275 (37ClꢁMþ, 17), 274 (8), 273
29.1, 29.2, 34.5 (CH2), 55.1 (SCH), 72.9 (NCH2), 127.2, 127.8, 129.0,
142.6 (Ar), 171.3 (C]N). IR (KBr, film): 2928, 2854, 1647 (C]N),
1543, 1493, 1452, 1215, 760, 698 cmꢁ1. MS (EI): m/z (%) 423 (Mþþ1,
1), 305 (10), 271 (10),174 (16), 134 (22), 123 (100), 120 (87),119 (79),
118 (32), 104 (22), 102 (19), 91 (11). Anal. Calcd for C25H30N2S2: C,
71.04; H, 7.15; N, 6.63; S, 15.17. Found: C, 70.97; H, 7.43; N, 6.51; S,
15.02.
(
35ClꢁMþ, 44),151 (C8H6ClNþ,100),136 (C8H8Sþ, 79),135 (C7H5NSþ,
84), 121 (18), 91 (23), 77 (22), 51 (13). Anal. Calcd for C15H12ClNS:
C, 65.80; H, 4.42; N, 5.12; S, 11.71. Found: C, 66.22; H, 4.69; N, 5.07;
S, 11.47.
4.3.20. 2-(4-Bromophenyl)-5-phenyl-2-thiazoline (7g)
Acknowledgements
Mp 88–89 ꢀC (hexane). 1H NMR
d
4.60 (dd, 1H, Jgem¼16.3 Hz,
J¼5.7 Hz, NCH2), 4.77 (dd, 1H, Jgem¼16.3 Hz, J¼8.8 Hz, NCH2), 5.10
(dd, 1H, J¼8.8, 5.7 Hz, CH), 7.26–7.36 (m, 5H, ArH), 7.56 (d, 2H,
We acknowledge XUNTA DE GALICIA for financial support:
PGIDIT05PXIB26201PR, PR405 A 098/59-0. USC for a predoctoral
fellowship to J.C.-C, and to Dr. JoDee Anderson (financed by Xunta
(2007/000145-0) and the FEDER) for her linguistic support. This
work was undertaken as part of the EC sponsored programs D32
COST Program (Chemistry in High-Energy Microenvironments,
WG10).
J¼8.8 Hz, ArH), 7.74 (d, 2H, J¼8.4 Hz, ArH). 13C NMR
d 55.3 (SCHPh),
73.5 (NCH2), 126.0, 127.3, 128.1, 129.1, 130.1, 132.0, 132.4, 142.0 (Ar),
166.8 (C]N). IR (KBr, film): 1599 (C]N), 1583, 1481, 1452, 1393,
1223, 1068, 926, 825, 754, 694, 594 cmꢁ1. MS (EI): m/z (%) 319
(
81BrꢁMþ, 17), 317 (79BrꢁMþ, 18), 197 (56), 195 (57), 136 (C8H8Sþ,
100), 135 (C7H5NSþ, 91), 121 (20), 103 (22), 102 (21), 91 (32), 77
(Phþ, 29), 51 (18). Anal. Calcd for C15H12BrNS: C, 56.61; H, 3.80; N,
4.40; S, 10.08. Found: C, 56.78; H, 3.45; N, 4.55; S, 9.90.
Supplementary data
1H NMR spectra for all no previously synthesized compounds
are provided. Supplementary data associated with this article can
be found in the online version, at doi:10.1016/j.tet.2008.07.027.
4.3.21. 5-Phenyl-2-(3-pyridyl)-2-thiazoline (7h)
Mp 132–133 ꢀC (hexane/AcOEt). 1H NMR
d 7.26–7.43 (m, 4H,
ArH), 7.63 (d, 2H, J¼7.0 Hz, ArH), 7.77 (dt, 1H, J¼7.9, 1.3 Hz, ArH),
8.07 (s, 1H, NCH), 8.18 (d, 1H, J¼7.9 Hz, ArH), 8.61 (d, 1H, J¼4.4 Hz,
References and notes
ArH). 13C NMR
d 119.6, 124.5, 127.0, 128.7, 129.2, 131.8, 137.2 (Ar),
139.8 (NCH), 141.9, 149.7, 151.8 (Ar), 168.2 (C]N). IR (KBr, film):
1581 (C]N), 1470, 1446, 1421, 1001, 785, 756, 690 cmꢁ1. MS (EI):
m/z (%) 239 (Mþþ1, 15), 238 (Mþ, 87), 134 (C8H6Sþ, 100), 135 (11),
108 (8), 102 (8), 90 (18), 89 (23), 78 (13), 77 (14), 51 (15). Anal. Calcd
for C14H10N2S: C, 70.56; H, 4.23; N, 11.76; S, 13.46. Found: C, 70.54;
H, 4.11; N, 11.98; S, 13.60.
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4.3.22. 2-Hexyl-5-phenyl-2-thiazoline (7l)
Oil. 1H NMR
d
0.90 (t, 3H, J¼6.6 Hz, CH3), 1.29–1.42 (m, 6H,
9. Pestka, S.; Brot, N. J. Biol. Chem. 1971, 246, 7715–7722.
3ꢂCH2), 1.70 (sex, 2H, J¼7.5 Hz, CH2), 2.57 (tt, 2H, J¼7.5, 1.6 Hz,
CH2CN), 4.35 (ddt,1H, Jgem¼15.4 Hz, J¼5.7,1.3 Hz, NCH2C), 4.54 (ddt,
1H, Jgem¼15.4 Hz, J¼8.8, 1.8 Hz, NCH2), 4.94 (dd, 1H, J¼8.8, 5.7 Hz,
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