One-step synthesis of thiazolo[3,2-a]pyridines by a multicomponent reaction of β-enaminonitriles, α,β-unsaturated aldehydes, and 2-aminothiol hydrochlorides

Article abstract of DOI:10.1016/j.tet.2010.02.051

A wide library of 3,7,8,8a-tetrahydro-2H-thiazolo[3,2-a]pyridines has been prepared by simple heating in acetonitrile of β-enaminonitriles, α,β-unsaturated aldehydes and 2-aminothiol hydrochlorides. Chemical yields depend on the nature, hindrance, and position of the substituents. The scope, limitations, and stereocontrol associated to this three-component reaction have been studied in detail. In general, the diastereoinduction observed in the three new stereogenic centers generated in the pro-chiral α,β-unsaturated aldehyde is low.

Full text of DOI:10.1016/j.tet.2010.02.051

Tetrahedron 66 (2010) 2815–2822
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-step synthesis of thiazolo[3,2-a]pyridines by a multicomponent reaction of
b-enaminonitriles, a,b-unsaturated aldehydes, and 2-aminothiol hydrochlorides
´
´
˜
Monica Perez Perrino, Rafael del Villar-Guerra, M. Carmen Sanudo,
*
´
Luis A. Calvo, Alfonso Gonzalez-Ortega
´
´
Departamento de Quımica Organica, Facultad de Ciencias, Universidad de Valladolid, Dr. Mergelina s/n, 47011 Valladolid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A wide library of 3,7,8,8a-tetrahydro-2H-thiazolo[3,2-a]pyridines has been prepared by simple heating in
Received 17 December 2009
Received in revised form
12 February 2010
Accepted 12 February 2010
Available online 17 February 2010
acetonitrile of b-enaminonitriles, a,b-unsaturated aldehydes and 2-aminothiol hydrochlorides. Chemical
yields depend on the nature, hindrance, and position of the substituents. The scope, limitations, and
stereocontrol associated to this three-component reaction have been studied in detail. In general, the
diastereoinduction observed in the three new stereogenic centers generated in the pro-chiral
saturated aldehyde is low.
a,b-un-
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction
b
a
-Enaminonitriles
-Unsaturated aldehydes
,
b
Heterocycles
Thiazolo[3,2-a]pyridines
1. Introduction
the reaction of b-ketoesters, a,b-unsaturated oxo-compounds and
cysteamine, in which the involvement of enaminoester in-
termediates has been claimed to account for the stereogenic control
of three chiral centers.11
In an effort to find new alternatives for multicomponent domino
reactions and take advantage of the three chiral center stereo-
control shown by the reaction, we now describe a detailed and
extensive study on the preparation of 3,7,8,8a-thiazolo[3,2-a]pyri-
The poly-functionality of b-enaminones and related compounds
(b-enaminoesters and b-enaminonitriles) makes these synthons
useful intermediates for heterocyclic synthesis.1–3 From all the
reported reactions, only a few of them were described as multi-
component reactions. The preparation of dihydropyridines4 by
different modified Hantzsch reactions is probably the most largely
mentioned procedure. Although in less extension, it has also been
described the preparation of pyridones5 and tetrahydropyr-
imidines.6 In all these cases, only the enamino group becomes part
of the heterocycle, remaining the accompanying withdrawing
group (ketone, ester, nitrile) untransformed. The presence of an
isonitrile group provides an exceptional reactivity, giving complex
reactions (Three-Component Reactions (3CR) and Four-Component
Reactions (4CR)), which lead to isoxazoles7 and dihydropyr-
idines4g,8 with a wide variety of substitutions.
dines from b-enaminonitriles, a,b-unsaturated aldehydes, and 1,2-
aminothiols. Different substitution patterns and sizes were chosen
in order to determine the influence on yields and diaster-
eoselectivity. The results are accompanied by a brief study re-
garding the optimization of the reaction conditions carried out with
simple commercial substrates. A range of alkyl or aryl substituents
has also been tested and we have attempted to determine the scope
and limitations derived from their nature and position.
In a recent study on tetrahydro[1,4]thiazepines9 we found that
2. Results and discussion
the reaction of
b-enaminocrotonitrile, acrolein, and cysteamine
afforded 3,7,8,8a-tetrahydro-5-methyl-2H-thiazolo[3,2-a]pyridine-
6-carbonitrile in good yield. Multicomponent reactions for the
synthesis of thiazolo[3,2-a]pyridines have precedent in the prep-
aration of polycyclic N/O, N/S, and N/N aminals.10 Closely related is
2.1. Optimization of the reaction conditions
For simplicity, optimization of the reaction conditions was car-
ried out using b-aminocrotonitrile 2, acrolein 8, and cysteamine 14
(Scheme 1), which do not lead to diastereomeric mixtures. It was
observed that the rate of reagents, solvent, pH media, temperature,
and reaction time influences the final outcome. Due to the large
* Corresponding author. Tel.: þ34 983 423 013; fax: þ34 983 423 209.
´
E-mail address: algon@qo.uva.es (A. Gonzalez-Ortega).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.051

2816
M.P. Perrino et al. / Tetrahedron 66 (2010) 2815–2822
R2
R3
R4
1 L= C4H8N, R1= H
2 L= NH2, R1= Me
3 L= NH2, R1= Et
4 L= NH2, R1= CH2Ph
5 L= NH2, R1= i-Pr
6 L= NH2, R1= t-Bu
7 L= NH2, R1= Ph
8
R2 = R3 = R4 = H
NC
9
R2 = Me, R3 = R4 = H
O
10 R2 = Pr, R3 = R4 = H
11
R2 R3
R1
L
NC
R1
R4
R
2 = Ph, R3 = R4 = H
H
12 R2 = R3= Me, R4 = H
13 R2 = R3 = H, R4 = Me
1-7
H
S
8-13
N
R6
R5
19-36
19 R1=R2=R3=R4=R5=R6 = H
28 R1=R5= Me, R2=R3=R4=R6 = H
20 R1=R3=R4=R5=R6 = H, R2 = Me
21 R1=R4=R5=R6 = H, R2=R3 = Me
22 R1 = Me, R2=R3=R4=R5=R6 = H
23 R1=R2 = Me, R3=R4=R5=R6 = H
24 R1 = Me, R2 = Pr, R3=R4=R5=R6 = H
29 R1 = Me, R5 = Ph, R2=R3=R4=R6 = H
30
R
1 = Me, R6 = Et, R2=R3=R4=R5 = H
R6
R5
31 R1 = Me, R6 = Ph, R2=R3=R4=R5 = H
32 R1 = Et, R2=R3=R4=R5=R6 = H
33 R1 = CH2Ph, R2=R3=R4=R5=R6 = H
34 R1 = i-Pr, R2=R3=R4=R5=R6 = H
H2N
HCl
SH
25
R
1 = Me, R2 = Ph, R3=R4=R5=R6 = H
14-18
26 R1=R2=R3 = Me, R4=R5=R6 = H
27 R1=R4 = Me, R2=R3=R5=R6 = H
35
R
1 = t-Bu, R2=R3=R4=R5=R6 = H
14 R5 = R6 = H
36 R1 = Ph, R2=R3=R4=R5=R6 = H
15 R5 = Me, R6 = H
16 R5 = Ph, R6 = H
17 R5 = H, R6 = Et
18
R
5 = H, R6 = Ph
Scheme 1. Numeration of the starting materials and the final products.
number of side reactions that can take place, the use of an appro-
priate rate of reagents is an important factor that has to be con-
sidered for good results. Among the proportions tested, the rate
The best yield (75%) is obtained when an excess of cysteamine
hydrochloride is used. This slightly acidic medium stabilizes the b-
enaminonitrile, catalyzes the formation of N/S aminals while
slowing down cysteamine oxidative self-coupling. Use of free-acid
cysteamine led to complex mixtures.
1:2:2 (b-enaminonitrile/aldehyde/1,2-aminothiol) led to the best
yield of 3,7,8,8a-tetrahydro-5-methyl-2H-thiazolo[3,2-a]pyridine-
6-carbonitrile 22 (75%) (Table 1,entry 4). Other solvents different
from acetonitrile, such as water, toluene, and ethanol, do not
improve former results.
1
Following the reaction by H NMR (CD3CN), at 77 ꢀC, a rapid
formation of 22 was observed after 1 h; however, prolongation of
time (up to 3 h) diminishes yields due to final product degradation.
Table 1
Preparation of 3,7,8,8a-tetrahydro-2H-tiazolo[3,2-a]pyridines 19–36
Entry Starting material Time (h) R1
R2 R3 R4 R5 R6 Tetrahydro-2H-thiazolo[3,2-a]pyridines Yielda (%) Ratio
a
/
bb
Otherc (%)
CN
1
2
1þ8þ14
1þ9þ14
2
2
H
H
H
H
H
H
H
H
H
H
H
48
29
19
N
S
Me
N
Me
CN
CN
Me
1:1
H
S
H
S
α/
20 20
β
N
Me Me
CN
3
4
1þ12þ14
2þ8þ14
2
2
H
Me Me
H
H
H
H
H
H
17
75
21
N
S
CN
CN
22
Me
H
H
H
H
37 (12)
N
Me
S
N
Me
Me
N
Me
Me
N
CN
Me
CN
Me
CN
Me
H
S
5
6
2þ9þ14
2
3
Me
Me
Me
Pr
H
H
H
H
H
H
41
32
1:1
1:1
H
S
38 (10)
N
α/
23 23
β
β
Pr
N
Pr
Pr
N
Me
S
CN
NH
CN
Me
CN
Me
CN
39 (10)
Me
H
S
2þ10þ14
H
N
S
43 (15)
α/
24 24
Ph
N
Ph
N
Ph
Me
S
CN
NH
CN
Me
CN
Me
CN
40(6)
Me
7
2þ11þ14
3
Me
Ph
H
H
H
H
56
2:3
H
S
H
S
N
43 (30)
α
/
β
25 25

M.P. Perrino et al. / Tetrahedron 66 (2010) 2815–2822
2817
Table 1 (continued)
Entry Starting material Time (h) R1
R2 R3 R4 R5 R6 Tetrahydro-2H-thiazolo[3,2-a]pyridines Yielda (%) Ratio
a
/
bb
Otherc (%)
Me Me
CN
Me
S
CN
43 (28)
8
2þ12þ14
2þ13þ14
2þ8þ15
2
2
2
Me
Me
Me
Me Me
H
H
H
H
H
30
61
68
NH
N
Me
S
26
Me
Me
CN
Me
CN
Me
Me
CN
Me
H
S
H
S
9
H
H
H
H
Me
H
H
3:2
1:1
N
N
N
α
/
β
27 27
CN
Me
CN
H
CN
Me
H
S
10
Me
N
N
Me
28 /28
S
37 (<5)
N
N
α
β
Me
Me
CN
Me
CN
CN
Me
H
S
H
S
11
12
2þ8þ16
2þ8þ17
4
3
Me
Me
H
H
H
H
H
H
Ph
H
H
N
50
60
2:3
1:1
2:3
N
Me
29α/29β
37 (<5)
37 (9)
Ph
Ph
CN
CN
Me
CN
Me
H
S
H
S
Et
N
Me
N
α/
30 30
β
β
N
Et
Et
CN
Me
CN
Me
CN
Me
H
S
H
S
13
14
2þ8þ18
3þ8þ14
3
2
Me
Et
H
H
H
H
H
H
H
H
Ph
H
15
N
37 (16)
N
α/
31 31
N
Ph
Ph
CN
Et
CN
Et
45d
N
S
S
N
32
CN
CN
Ph
41 (15)
15
16
4þ8þ14
5þ8þ14
2.5
CH2Ph
H
H
H
H
H
H
H
H
H
H
31
Ph
N
N
33
CN
CN
2
i-Pr
20d
i
N
Pr
34
i
S
N
Pr
CN
CN
17
6þ8þ14
7þ8þ14
3
2
t-Bu
H
H
H
H
H
H
H
H
H
H
0
t
42 (20)
N
N
Bu
35
S
S
t
N
Bu
CN
CN
Ph
18
Ph
47
Ph
36
N
a
Isolated yield.
Ratio determined by 1H NMR of the crude mixture.
b
c
Confirmed its presence by 1H NMR in the reaction mixture. Only some representative pyridines were isolated for their description.
Yields were determined from the 1H NMR spectrum of the crude reaction mixture.
d
Care should be taken for not prolonging heating times un-
necessarily. Surprisingly, reactions carried out at room temperature
gave a complex mixture that considerably simplifies after 6 h. After
12 h of reaction at rt, results are comparable to that obtained after
45 min at 77 ꢀC.
aldehyde: 2-aminothiol hydrochloride) in refluxing acetonitrile for
2 h.
2.2. Scope and limitations
According to former observations we decided to use as general
In order to study the scope and limitations of this reaction, we
have designed different experiments (Table 1). We focused on the
procedure
a rate of 1:2:2 (b-enaminonitrile: a,b-unsaturated

2818
M.P. Perrino et al. / Tetrahedron 66 (2010) 2815–2822
hindrance of the substituents. The hindrance of R1 clearly di-
minishes the yield of 3,7,8,8a-tetrahydro-2H-thiazolo[3,2-a]pyri-
dines. Effectively, the 75% yield obtained for 22 (R1¼Me) drops to
20% in the case of 34 (R1¼i-Pr) and is almost null for 35 (R1¼t-Bu)
(Table 1, entries 4, 16, and 17).
nature of R1 but to the efficiency of the amino moiety (pirrolidine or
ammonia) to behave as a leaving group.
2.3. Mechanistic insights
The steric effect is even higher for substituent R6. A less bulky
substituent as the ethyl group (30) shows a steric effect high
enough to lower the yield up to 60%, whereas a phenyl group (31,
R6¼Ph) gives only 15% (Table 1, entries 12 and 13).
The fact that experimental results were equally reproducible
whether the synthesis of the final thiazolo[3,2-a]pyridine is ach-
ieved in the one step multicomponent way or indistinctly from
43(a, b) (previously prepared12), suggests that the reaction pro-
On the one hand, the increase of the hindrance of R1 and R6 does
not involve an appreciable lowering of the enaminonitrile conver-
sion, but it produces a remarkable increase of the rate of pyridine-3-
carbonitriles 37–42 (Table 1, see entries 4, 13, 17), which are formed
in all the reactions as a side-product. On the other hand, raising the
number and size of substituents R2 and R3 a noticeable decrease of
the yield of thiazolo[3,2-a]pyridines 23–26 (Table 1, entries 5–8),
and pyridine-3-carbonitriles 37–40 is observed (Table 1, entries
ceeds by nitrogen exchange between
b-enaminonitrile 1–7 and
aminothiol 14–18 (Scheme 2). When the steric hindrance of R1 and
R4 hinders this step, formation of pyridine-3-carbonitrile (Hantzsch
reaction) is observed in some extension (Table 1, entries 4–18).
From intermediate 43(a, b) several alternatives can be devised
(developed) for the formation of aminals 19–36 (Scheme 2). Al-
though we have not been able to isolate reaction intermediates,
which support the proposed pathway, San Feliciano’s mechanistic
proposal11,13 for the multi-step synthesis of 3,7,8,8a-tetrahydro-2H-
oxa(and thia)zolo[3,2-a]pyridines is probably closely related to our
reaction.
4–8). Moreover, formation of intermediate 43 resulting from
b-
crotonitrile 2 nitrogen-exchange occurs to a high extent (Scheme 2).
HCl
Michael addition of enamine 43a to unsaturated aldehydes 8–13
affords intermediate 44(a, b) (Scheme 2). As the size and number of
substituents attached to C-b increases, conjugate addition leading
to 44 or 45 is hindered, and therefore reaction tends to stop upon
formation of 43 (Table 1, entries 4–8).
H2N
HS
R6
R5
CN
R1
CN
CN
R1
R1
NH
14-18
HN
S
Formation of intermediate 44(a, b) could be also explained if the
reaction followed an opposite sequence (first conjugate addition
and then nitrogen exchange). However, compounds analogous to
45, prepared by other alternative procedures,14 undergo cyclization
so quick that nitrogen exchange could hardly take place (Scheme 2).
Finally, formation of aminals 19–36 might occur by cyclization of
intermediate 44a (via 46, Scheme 3), or through the mayor tauto-
mer 44b followed by cyclization to 45, equilibration to 46 and
formation of the final aminal. Although some authors succeeded to
isolate compounds of type 45 (when R4 is an ester11), we were not
able to detect compound 45, probably due to the low stability of our
enamine 45 (R4¼Alkyl, H). Intermediate 46 should explain the
observed stereochemistry.
HS
R6
H2N
R5
43(b)
R6
R5
2-7
43(a)
R2
R3
R4
O
8-13
8-13
R3 R2
R2
R3
R3 R2
R4
CN
R1
R4
O
CN
R1
R4
O
CN
R1
14-18
O
S
NH
HN
R2
R3 R2
NH2
R3
HS
R5
R6
R4
O
CN
R4
CN
R1
R6
44(a)
45
R5
R1
NH
44(b)
O
S
HN
R5
44(b)
R6
HS
R3 R2
R6
44(a)
R4
CN
R5
N
H
R1
45
19-36
O
R3 R2
R3 R2
R2
R4
CN
R4
CN
R1
R4
CN
R1
R1
S
N
N
N
HS
R6
R6
37-42
R5
R
3 = H
R5
46
45
Scheme 2. Different theoretical routes for the formation of thiazolo[3,2-a]pyridines
19–36.
R3 R2
R4
CN
R1
When R4 or R5 is a Me group, there is no decrease in yields
(Table 1, entries 9 and 10) although the overall reaction proceeds
slower. This effect is enhanced if R5 is a Ph group, where up to 4 h
are necessary to get a 50% yield (Table 1, entry 11).
H
S
N
19-36
R6
R5
Finally, the lower reactivity and yield observed when enami-
nonitrile 1 (R1¼H) is used (Table 1, entries 1–3) is not due to the
Scheme 3. Formation of aminals 19–36 by cyclization of intermediates 44(a,b).

M.P. Perrino et al. / Tetrahedron 66 (2010) 2815–2822
2819
2.4. Stereochemistry: scope and limitations
thiazolopyridine (Scheme 5). In this case, this is the most stable
diastereomer and therefore, epimerization is not observed at all
even when heating.
The experiments shown in Table 1 were selected with the idea of
determining the individual effect caused by each substituent on the
reaction. Only one of the substituents R2 to R6 is not constituted by
a proton, which results in formation of a maximum of two chiral
carbons in the final bicycle. In general, the diastereomers formed
could be well separated by flash chromatography and their relative
stereochemistry assigned by NOESY experiments and from the
1H NMR coupling constants.
The diastereoselective induction observed in the addition to
aldehydes 8–13 is rather low compared with that observed for the
preparation of other similar 3,7,8,8a-tetrahydro-2H-oxazolo[3,2-
a]pyridines15,16 and 3,7,8,8a-tetrahydro-2H-thiazolo[3,2-a]pyri-
dines.11 Results depend on the nature and position of the
substituent.
Regarding substituent R6, sterical repulsions from the nearest
substituent R1 make conformation 46d the most stable one, leading
the reaction to the selective formation of cis-R6/H8a diastereomers
(Scheme 6). Analogous stereochemistry was also found in the
synthesis of 3-phenyl substituted tetrahydrooxazolopyridines from
N-substituted dihydropyridines.17
H
CN
CN
H
R1
R1
R6
S
N
N
H
H
H
H
HS
R6
46d
46c
H
N
R6
Substituents with reduced size, such as Me, do not induce se-
S
lectivity at all in any position, except in C-8 (27, R4¼Me, entry 9)
H(8a)
where a small selectivity 60:40 (27a/27b) was shown at rt and
Scheme 6. Sterical repulsions between R6 and R1 leading the reaction to cis-R6/H8a
diastereomers.
40:60 (27a/27b) upon heating. Some selectivity (around 40:60,
Table 1, entries 7, 11, 13) is also achieved when increasing the size of
R2, R5, or R6, but not high enough to be synthetically useful. Epi-
merization in little extent of 25, R2¼Ph was observed after 1 h of
heating (Table 1, entry 7).
3. Experimental
3.1. Instrumentation
2.5. Stereochemistry: interpretation
Melting points were measured on a Reichert-Jung Thermo Galen
and are uncorrected. IR spectra were obtained on a Perkin–Elmer
1720 X spectrometer. NMR spectra were recorded on a Bruker
AC300 spectrometer, and chemical shifts are given downfield from
SiMe4 as an internal standard. 13C NMR spectra were carried out
with complete 1H decoupling and the assignments were made by
additional DEPT experiments.
During cyclization, the thiol group should approach preferably
from the side opposite to R2, according to the trans-addition path-
way described for the iodolactonization of 1,4-dihydropyridines and
tetrahydrooxazolopyridines.17 Consequently, the configuration of
the final bicycle should be majorly trans-H7,H8a/cis-H8,H8a
(Scheme 4). Since this is not the most stable diastereomer, equili-
bration with epimerization of C8a takes place as the temperature
increases and heating is prolonged. This has been observed in the
3.2. Materials
conversion of 27
a
(cis-H8-H8a) to 27
b
(trans-H8-H8a).
The starting b-enaminonitriles were purchased from the usual
suppliers (2) or prepared by literature procedures (120, 3–621, 722).
The corresponding 2-aminothiol hydrochlorides were purchased
from the usual suppliers (14) or prepared by literature procedures
R4
HS
H
H7
N
R2
N
S
H8
R2
R4
(15–1823). All the
the usual suppliers.
a,b-unsaturated aldehydes were purchased from
H
H8a
46
trans- H7,H8a
cis- H8,H8a
H
Scheme 4. Cyclization of SH group through a trans-addition pathway.
3.3. General procedure
The influence of substituent R4 is similar to that reported for the
diastereoselective formation of perhydrothiazolopyridines18,19
(Scheme 5). The thiol group should attack preferably through the
less sterically hindered conformation 46b leading to a cis-R5/H8a
3.3.1. Synthesis of tetrahydrothiazolo[3,2-a]pyridines (19–36). A
solution of b-enaminonitrile (4.4 mmol), a,b-unsaturated aldehyde
(8.8 mmol) and 2-aminothiol hydrochlorides (8.8 mmol) in 25 cm3
of dry acetonitrile was refluxed for the time specified in Table 1. At
the end of the reaction the solvent was removed and the residue
was poured in 50 cm3 of water and extracted with dichloro-
methane (3ꢁ50 cm3). The organic layer was dried over Na2SO4 and
removed in vacuo. The product was chromatographed on silica gel
(0.040–0.063 mm) using dichloromethane (19, 20, 22–31, 33),
hexane/ethyl acetate (4:1) (36) or hexane/ethyl acetate (3:1) (21) as
eluent.
CN
CN
R1
R5
N
H
H
HS
R1
H
N
H
HS
H
H
H
H
R5
46b
46a
3.4. Characterization of products
H(8a)
3.4.1. 2,3,8,8a-Tetrahydro-7H-thiazolo[3,2-a]pyridine-6-carbonitrile
(19). Yellow oil; Rf¼0.35 (CH2Cl2); IR (film): 3436, 2931, 2871, 2853,
2184,1729,1615,1463,1382,1325,1306, 1235,1178, 1153,1137,1055,
R5
N
cis R5-H8a
S
919, 863 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d¼1.61–1.78 (m, 1H,
H
CHH–CH–S), 2.21–2.39 (m, 3H, CHH–CH–S and CH2–C]), 2.94–2.98
(m, 2H, CH2–S), 3.51–3.59 (m, 1H, CHH–N), 3.62–3.70 (m, 1H, CHH–
N), 4.49 (dd, J¼3.0 and 9.8 Hz, 1H, S–CH–N), 6.84 (s, 1H, HC]); 13C
Scheme 5. Attack of SH group through the less sterically hindered conformation 46b
leading to a cis-R5/H8a thiazolopyridine.

2820
M.P. Perrino et al. / Tetrahedron 66 (2010) 2815–2822
NMR (75.4 MHz, CDCl3):
d
¼21.8 (CH2–C]), 26.7 (CH2–CH–S), 29.8
J¼1.6 Hz, 3H, CH3–C]), 2.22–2.29 (m, 1H, CHH–CH–S), 2.48–2.56
(m, 1H, CH–CH3), 3.00–3.05 (m, 2H, S–CH2), 3.63–3.80 (m, 2H, N–
CH2), 4.55 (dd, J¼3.0 and 11.2 Hz,1H, S–CH–N); 13C NMR (75.4 MHz,
(CH2–S), 54.5 (CH2–N), 60.0 (S–CH–N), 76.5 (]C–CN), 122.0 (CN),
143.8 (]CH); GC–MS (EI): m/z¼166 (Mþ, 100), 168 ([Mþ2]þ, 4);
Anal. Calcd for C8H10N2S: C, 57.80; H, 6.06; N, 16.85. Found: C,
58.92; H, 5.94; N, 16.56.
CDCl3):
d
¼19.8 (CH3–C]), 19.9 (CH3–CH), 28.6 (CH3–CH), 28.9
(CH2–S), 36.6 (CH2–CH–S), 50.9 (CH2–N), 61.6 (S–CH–N), 81.1 (]C–
CN), 122.5 (CN), 150.4 (]C–CH3); Anal. Calcd for C10H14N2S: C,
61.82; H, 7.26; N, 14.42. Found: C, 62.49; H, 7.32; N, 14.08.
3.4.2. (7R,8aS)-7-Methyl-2,3,8,8a-tetrahydro-7H-thiazolo[3,2-a]pyr-
idine-6-carbonitrile (20
3362, 2958, 2925, 2869, 2180, 1612, 1438, 1410, 1359, 1216, 1175,
923 cmꢂ1; 1H NMR (300 MHz, CDCl3):
a
). Yellow oil; Rf¼0.27 (CH2Cl2); IR (film):
3.4.7. (7R,8aR)-5,7-Dimethyl-2,3,8,8a-tetrahydro-7H-thiazolo[3,2-
d
¼1.24 (d, J¼7.0 Hz, 3H, CH3),
a]pyridine-6-carbonitrile (23
(film): 3517, 2956, 2927, 2849, 2174, 1589, 1424, 1374, 1307, 1259,
1190, 1119, 1056 cmꢂ1 1H NMR (300 MHz, CDCl3):
b). Yellow oil; Rf¼0.34 (CH2Cl2); IR
1.40 (ddd, J¼10.9, 11.4 and 12.9 Hz, 1H, CHH–CH–S), 2.27 (ddd,
J¼3.6, 4.7, and 12.9 Hz, 1H, CHH–CH–S), 2.45–2.58 (m, 1H, CH–CH3),
3.01 (t, J¼6.1 Hz, 2H, S–CH2), 3.65–3.70 (m, 2H, N–CH2), 4.57 (dd,
J¼3.6 and 10.9 Hz, 1H, S–CH–N), 6.91 (d, J¼1.7 Hz, 1H, HC]); 13C
;
d
¼1.12 (d,
J¼7.0 Hz, 3H, CH3–CH), 1.74 (m, 1H, CHH–CH–S), 1.97 (ddd, J¼2.8,
2.9, and 12.9 Hz, 1H, CHH–CH–S), 2.18 (s, 3H, CH3–C]), 2.55–2.60
(m,1H, CH–CH3), 2.94–3.08 (m, 2H, CH2–S), 3.59–3.66 (m,1H, CHH–
N), 3.77–3.85 (m, 1H, CHH–N), 4.52 (dd, J¼3.2 and 10.7 Hz, 1H, S–
NMR (75.4 MHz, CDCl3):
d
¼19.0 (CH3), 27.6 (CH–CH3), 29.7 (CH2–S),
37.0 (CH2–CH–S), 54.4 (CH2–N), 60.2 (S–CH–N), 81.7 (]C–CN),121.6
(CN), 142.9 (]CH); GC–MS (EI): m/z¼180 (Mþ, 100), 182 ([Mþ2]þ,
5); Anal. Calcd for C9H12N2S: C, 59.96; H, 6.71; N, 15.54. Found: C,
60.55; H, 6.76; N, 15.08.
CH–N); 13C NMR (75.4 MHz, CDCl3):
d
¼19.6 (CH3–C]), 21.7 (CH3–
CH), 28.5 (CH3–CH), 29.0 (CH2–S), 33.6 (CH2–CH–S), 51.1 (CH2–N),
58.4 (S–CH–N), 81.0 (]C–CN), 122.8 (CN), 150.8 (]C–CH3); Anal.
Calcd for C10H14N2S: C, 61.82; H, 7.26; N, 14.42. Found: C, 62.49; H,
7.32; N, 14.08.
3.4.3. (7R,8aR)-7-Methyl-2,3,8,8a-tetrahydro-7H-thiazolo[3,2-a]pyr-
idine-6-carbonitrile (20
2959, 2927, 2870, 2187, 1617, 1440, 1397, 1325, 1250, 1172, 1089, 911,
851, 692 cmꢂ1; 1H NMR (300 MHz, CDCl3):
b
). Yellow oil; Rf¼0.29 (CH2Cl2); IR (film):
3.4.8. 5-Methyl-7-propyl-2,3,8,8a-tetrahydro-7H-thiazolo[3,2-a]pyr-
d
¼1.15 (d, J¼7.0 Hz, 3H,
idine-6-carbonitrile (24
(film): 3369, 2956, 2928, 2870, 2180, 1692, 1585, 1422, 1378, 1342,
1306, 1263, 1168, 1120, 1057, 866, 745 cmꢂ1 1H NMR (300 MHz,
CDCl3):
aþ
b
). Yellow oil; Rf¼0.35 (CH2Cl2); IR
CH3), 1.81 (ddd, J¼5.1, 9.1, and 13.4 Hz, 1H, CHH–CH–S), 2.03 (ddd,
J¼3.7, 4.0, and 13.4 Hz, 1H, CHH–CH–S), 2.55–2.66 (m, 1H, CH–CH3),
2.97–3.02 (m, 2H, S–CH2), 3.51–3.60 (m, 1H, N–CHH), 3.66–3.74 (m,
1H, N–CHH), 4.56 (dd, J¼3.7 and 9.1 Hz, 1H, S–CH–N), 6.80 (s, 1H,
;
d
¼0.86–0.92 (m, 3H, CH2–CH3), 1.15–1.47 (m, 4H, CH–
CH2CH2CH3), 1.48–1.68 (m, 1H, S–CH–CHH), 2.02–2.10 (m, 1H,
S–CH–CHH), 2.18 (s, 3H, CH3–C]), 2.25–2.39 (m, 1H, ]C–CH),
2.96–3.02 (m, 2H, S–CH2), 3.61–3.80 (m, 2H, N–CH2), 4.45–4.49 (m,
HC]); 13C NMR (75.4 MHz, CDCl3):
d
¼20.8 (CH3), 26.7 (CH–CH3),
30.0 (CH2–S), 33.7 (CH2–CH–S), 54.7 (CH2–N), 57.9 (S–CH–N), 83.9
(]C–CN), 121.6 (CN), 143.1 (]CH); GC–MS (EI): m/z¼180 (Mþ, 100),
182 ([Mþ2]þ, 5); Anal. Calcd for C9H12N2S: C, 59.96; H, 6.71; N,
15.54. Found: C, 60.55; H, 6.76; N, 15.08.
1H, S–CH–N); 13C NMR (75.4 MHz, CDCl3):
d
¼13.9 (CH2CH3), 14.0
(CH2CH3), 19.4 (CH2CH3), 19.5 (]C–CH3), 19.8 (CH2CH3), 19.8 (]C–
CH3), 28.9 (S–CH2), 28.9 (S–CH2), 30.7 (CH2CH2CH3), 33.1
(CH2CH2CH3), 33.5 (]C–CH), 33.6 (]C–CH), 36.1 (S–CHCH2), 38.3
(S–CHCH2), 50.9 (N–CH2), 51.1 (N–CH2), 58.6 (S–CH–N), 61.7 (S–CH–
N), 79.3 (]C–CN), 79.9 (]C–CN), 122.3 (CN), 123.4 (CN), 150.9
(]C–CH3), 151.8 (]C–CH3); GC–MS (EI): m/z¼179 (100), 222 (Mþ,
21), 224 ([Mþ2]þ, 3).
3.4.4. 7,7-Dimethyl-2,3,8,8a-tetrahydro-7H-thiazolo[3,2-a]pyridine-
6-carbonitrile (21). Yellow oil; Rf¼0.34 (hexane/ethyl acetate
(3:1)); IR (film): 3071, 2972, 2868, 2190, 1622, 1459, 1405, 1310,
1277, 1149, 955, 871, 712 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d¼1.13
(s, 3H, CH3), 1.24 (s, 3H, CH3), 1.53 (dd, J¼11.4 and 13.0 Hz, 1H, CHH–
CH–S), 1.99 (dd, J¼3.8 and 13.0 Hz, 1H, CHH–CH–S), 3.02 (t,
J¼6.2 Hz, 2H, S–CH2), 3.62–3.75 (m, 2H, N–CH2), 4.59 (dd, J¼3.8 and
11.4 Hz, 1H, S–CH–N), 6.85 (s, 1H, HC]); 13C NMR (75.4 MHz,
3.4.9. (7S,8aS)-5-Methyl-7-phenyl-2,3,8,8a-tetrahydro-7H-thia-
zolo[3,2-a]pyridine-6-carbonitrile (25
a
). Yellow oil; Rf¼0.27
(CH2Cl2); IR (film): 3026, 2925, 2864, 2181, 1686, 1577, 1493, 1425,
CDCl3):
d
¼28.3 (CH3), 28.6 (CH3), 29.8 (CH2–S), 31.6 (C(CH3)2), 42.5
1342, 1299, 1265, 1232, 1058, 912, 860, 759, 730, 702 cmꢂ1; 1H NMR
(CH2–CH–S), 54.6 (CH2–N), 58.1 (S–CH–N), 86.1 (]C–CN), 121.0
(CN), 141.7 (]CH); GC–MS (EI): m/z¼179 (100), 194 (Mþ, 59), 196
([Mþ2]þ, 3); Anal. Calcd for C10H14N2S: C, 61.82; H, 7.26; N, 14.42.
Found: C, 62.11; H, 7.19; N, 14.17.
(300 MHz, CDCl3):
d
¼1.82 (ddd, J¼11.2, 11.7, and 12.9 Hz, 1H, CHH–
CH–S), 2.28 (s, 3H, CH3–C]), 2.40–2.47 (ddd, J¼2.9, 5.3, and 12.9 Hz,
1H, CHH–CH–S), 3.06 (dd, J¼5.5 and 7.0 Hz, 2H, S–CH2), 3.66–3.85
(m, 3H, N–CH2 and CH–Ph), 4.68 (dd, J¼2.9 and 11.2 Hz,1H, S–CH–N),
7.17–7.37 (m, 5H, Ph); 13C NMR (75.4 MHz, CDCl3):
d
¼19.9 (CH3), 28.9
3.4.5. 5-Methyl-2,3,8,8a-tetrahydro-7H-thiazolo[3,2-a]pyridine-6-
carbonitrile (22). Yellow oil; Rf¼0.37 (CH2Cl2); IR (film): 2930,
2854, 2179, 1690, 1630, 1590, 1422, 1326, 1247, 1174, 1103, 1050, 864,
(S–CH2), 37.8 (S–CHCH2), 41.3 (CH–Ph), 51.1 (N–CH2), 61.6 (S–CH–N),
79.6 (]C–CN),122.0 (CN),127.1 (CH, Ph),127.4 (2CH, Ph),128.6 (2CH,
Ph), 141.9 (C, Ph), 152.6 (]C–CH3); GC–MS (EI): m/z¼256 (Mþ, 100),
258 ([Mþ2]þ, 6); Anal. Calcd for C15H16N2S: C, 70.27; H, 6.29; N,
10.93. Found: C, 70.85; H, 6.23; N, 10.75.
702 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼1.62–1.75 (m, 1H, CHH–
CH2–C]), 2.19 (s, 3H, CH3), 2.21–2.28 (m, 1H, CHH–CH2–C]), 2.32–
2.37 (m, 2H, CH2–C]), 2.96–3.05 (m, 2H, S–CH2), 3.59–3.66 (m, 1H,
N–CHH), 3.75–3.84 (m,1H, N–CHH), 4.50 (dd, J¼3.0 and 10.6 Hz,1H,
3.4.10. (7S,8aR)-5-Methyl-7-phenyl-2,3,8,8a-tetrahydro-7H-thia-
S–CH–N); 13C NMR (75.4 MHz, CDCl3):
d¼19.4 (CH3), 23.8 (CH2–
zolo[3,2-a]pyridine-6-carbonitrile (25
b
). Yellow oil; Rf¼0.38
C]), 26.8 (CH2–CH2–C]), 28.9 (S–CH2), 51.0 (N–CH2), 61.8 (S–CH–
N), 73.7 (]C–CN), 123.2 (CN), 151.9 (]C–CH3); GC–MS (EI): m/
z¼180 (Mþ, 100), 182 ([Mþ2]þ, 5); Anal. Calcd for C9H12N2S: C,
59.96; H, 6.71; N, 15.54. Found: C, 61.47; H, 6.63; N, 15.13.
(CH2Cl2); IR (film): 3370, 3059, 3025, 2928, 2870, 2181, 1588,
1494, 1426, 1343, 1314, 1265, 1180, 1104, 1052, 949, 912, 864, 756,
731, 702, 648 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
¼1.91–2.00 (m,
1H, CHH–CH–S), 2.24 (ddd, J¼2.6, 2.7, and 12.8 Hz, 1H, CHH–CH–
S), 2.35 (s, 3H, CH3–C]), 2.96–3.01 (m, 2H, S–CH2), 3.72–3.83
(m, 3H, N–CH2 and CH–Ph), 4.27 (dd, J¼3.1 and 11.4 Hz, 1H, N–
3.4.6. (7R,8aS)-5,7-Dimethyl-2,3,8,8a-tetrahydro-7H-thiazolo[3,2-
a]pyridine-6-carbonitrile (23
(film): 3517, 2956, 2927, 2849, 2174, 1589, 1424, 1374, 1306, 1259,
1190, 1118, 1056 cmꢂ1 1H NMR (300 MHz, CDCl3):
¼1.23 (d,
J¼6.9 Hz, 3H, CH3–CH), 1.33–1.42 (m, 1H, CHH–CH–S), 2.20 (d,
a). Yellow oil; Rf¼0.27 (CH2Cl2); IR
CH–S), 7.32–7.17 (m, 5H, Ph); 13C NMR (75.4 MHz, CDCl3):
d
¼19.7
(CH3), 28.8 (S–CH2), 34.9 (S–CH–CH2), 39.9 (CH–Ph), 51.4 (N–
CH2), 57.9 (S–CH–N), 75.4 (]C–CN), 122.8 (CN), 126.7 (CH, Ph),
127.7 (2CH, Ph), 128.4 (2CH, Ph), 143.2 (C, Ph), 152.7 (]C–N);
;
d

M.P. Perrino et al. / Tetrahedron 66 (2010) 2815–2822
2821
GC–MS (EI): m/z¼256 (Mþ, 100), 258 ([Mþ2]þ, 6); Anal. Calcd for
C15H16N2S: C, 70.27; H, 6.29; N, 10.93. Found: C, 70.85; H, 6.23;
N, 10.75.
3.75 (dd, J¼7.4 and 10.7 Hz, 1H, N–CHH), 3.93 (dd, J¼6.3 and
10.7 Hz, 1H, N–CHH), 4.54–4.62 (m, 1H, S–CH–Ph), 4.74 (dd, J¼3.1
and 10.6 Hz, 1H, S–CH–N), 7.28–7.41 (m, 5H, Ph); 13C NMR
(75.4 MHz, CDCl3):
d
¼19.5 (CH3), 23.8 (CH2–C]), 26.7 (CH2–CH2–
3.4.11. 2,3,8,8a-Tetrahydro-5,7,7-trimethyl-7H-thiazolo[3,2-a]pyri-
dine-6-carbonitrile (26). Yellow oil; Rf¼0.41 (CH2Cl2); IR (film):
3314, 2960, 2866, 2177,1692,1583,1420,1344,1303,1265,1191,1058,
C]), 49.0 (S–CH–Ph), 58.6 (CH2–N), 63.3 (S–CH–N), 77.1 (]C–CN),
122.9 (CN), 127.5 (2CH, Ph), 128.1 (CH, Ph), 128.8 (2CH, Ph), 138.2 (C,
Ph), 151.6 (N–C]); GC–MS (EI): m/z¼179 (100), 252 (Mþ, 24), 254
([Mþ2]þ, 1); Anal. Calcd for C15H16N2S: C, 70.27; H, 6.29; N, 10.93.
Found: C, 70.75; H, 6.23; N, 10.83.
868, 635 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d¼1.12 (s, 3H, CH3), 1.24
(s, 3H, CH3), 1.55 (dd, J¼11.7 and 12.8 Hz, 1H, CHH–CH–S), 1.98 (dd,
J¼3.2 and 12.8 Hz, 1H, CHH–CH–S), 2.18 (s, 3H, CH3–C]), 3.02–3.06
(m, 2H, S–CH2), 3.64–3.71 (m, 1H, N–CH2), 3.75–3.83 (m, 1H, N–CH2),
4.56 (dd, J¼3.2 and 11.7 Hz, 1H, S–CH–N); 13C NMR (75.4 MHz,
3.4.16. (2R,8aR)-5-Methyl-2-phenyl-2,3,8,8a-tetrahydro-7H-thia-
zolo[3,2-a]pyridine-6-carbonitrile
(29
b
). Yellow oil; Rf¼0.36
CDCl3):
d
¼19.9 (CH3–C]), 28.9 (CH2–S), 29.1 (CH3), 29.2 (CH3), 32.0
(CH2Cl2); 1H NMR (300 MHz, CDCl3):
d
¼1.80–1.89 (m,1H, CHH–CH2–
(C(CH3)2), 42.0 (CH2–CH–S), 51.1 (CH2–N), 59.2 (S–CH–N), 85.2 (]C–
CN), 121.8 (CN), 150.1 (]C–CH3); GC–MS (EI): m/z¼193 (100), 208
(Mþ, 28), 210 ([Mþ2]þ, 1); Anal. Calcd for C11H16N2S: C, 63.42; H,
7.74; N, 13.45. Found: C, 63.97; H, 7.70; N, 13.21.
C–CN), 2.20 (s, 3H, CH3), 2.20–2.26 (m, 1H, CHH–CH2–C–CN), 2.30–
2.41 (m, 2H, CH2–C–CN), 3.61 (dd, J¼7.3 and 11.2 Hz,1H, N–CHH), 4.17
(dd, J¼6.0 and 11.2 Hz,1H, N–CHH), 4.57 (dd, J¼6.0 and 7.3 Hz, 1H, S–
CH–Ph), 4.83 (dd, J¼3.2 and 9.6 Hz, 1H, S–CH–N), 7.28–7.41 (m, 5H,
Ph); 13C NMR (75.4 MHz, CDCl3):
d
¼19.5 (CH3), 23.3 (CH2–C]), 27.4
3.4.12. (8R,8aR)-5,8-Dimethyl-2,3,8,8a-tetrahydro-7H-thiazolo[3,2-
(CH2–CH2–C]), 49.2 (S–CH–Ph), 58.5 (CH2–N), 62.4 (S–CH–N), 77.2
(]C–CN), 122.6 (CN), 127.4 (2CH, Ph), 127.9 (CH, Ph), 128.8 (2CH, Ph),
139.0 (C, Ph), 151.5 (N–C]); Anal. Calcd for C15H16N2S: C, 70.27; H,
6.29; N, 10.93. Found: C, 70.75; H, 6.23; N, 10.83.
a]pyridine-6-carbonitrile (27
NMR (300 MHz, CDCl3):
a
). Yellow oil; Rf¼0.35 (CH2Cl2); 1H
d
¼1.08 (d, J¼6.5 Hz, 3H, CHCH3), 1.66–1.79
(m, 1H, CH3CH–CH2–S), 2.02–2.07 (m, 1H, CHH–C]), 2.19 (s, 3H,
]C–CH3), 2.32 (dd, J¼4.6 and 15.8 Hz, 1H, CHH–C]), 2.97–3.02 (m,
2H, N–CH2), 3.64–3.72 (m, 1H, S–CHH), 3.78–3.86 (m, 1H, S–CHH),
3.4.17. (3S,8aS)-3-Ethyl-5-methyl-2,3,8,8a-tetrahydro-7H-thia-
4.15 (d, J¼9.8 Hz, 1H, S–CH–N); 13C NMR (75.4 MHz, CDCl3):
d
¼19.3
zolo[3,2-a]pyridine-6-carbonitrile (30
a
). Yellow oil; Rf¼0.40
(CHCH3), 19.5 (]C–CH3), 28.6 (]C–CH2), 32.2 (S–CH2), 32.8
(CHCH3), 51.5 (N–CH2), 68.7 (S–CH–N), 74.2 (]C–CN), 123.0 (CN),
151.6 (]C–CH3); Anal. Calcd for C10H14N2S: C, 61.82; H, 7.26; N,
14.42. Found: C, 62.17; H, 7.22; N, 14.30.
(CH2Cl2); 1H NMR (300 MHz, CDCl3):
d
¼0.95 (t, J¼7.5 Hz, 3H,
CH2CH3), 1.53–1.64 (m, 1H, CHH–CH2–C]), 1.66–1.82 (m, 2H,
CH2CH3), 2.19 (s, 3H, ]C–CH3), 2.21–2.26 (m, 1H, CHH–CH2–C]),
2.29–2.35 (m, 2H, CH2–C]), 2.77 (dd, J¼1.0 and 10.6 Hz, 1H, S–
CHH–CH-Et), 3.06 (dd, J¼6.1 and 10.6 Hz, 1H, S–CHH–CH–Et), 4.15–
4.22 (m, 1H, CH–Et), 4.52 (dd, J¼3.5 and 10.0 Hz, 1H, S–CH–N); 13C
3.4.13. (8S,8aR)-5,8-Dimetil-2,3,8,8a-tetrahidro-7H-tiazolo[3,2-
a]piridina-6-carbonitrilo (27
NMR (300 MHz, CDCl3):
b
). Yellow oil; Rf¼0.35 (CH2Cl2); 1H
NMR (75.4 MHz, CDCl3):
d
¼10.8 (CH2CH3), 19.3 (]C–CH3), 23.3
d
¼0.98 (d, J¼6.7 Hz, 3H, CHCH3), 2.15 (s,
(CH2CH3), 25.9 (CH2–C]), 28.3 (CH2–S), 32.1 (CH2CH2–C]), 59.0
(CH–Et), 63.2 (S–CH–N), 74.8 (]C–CN), 123.1 (CN), 151.2 (]C–CH3);
Anal. Calcd for C11H16N2S: C, 63.42; H, 7.74; N, 13.45. Found: C,
63.81; H, 7.68; N, 13.38.
3H, ]C–CH3), 2.19–2.43 (m, 3H, CH3CH–CH2–C]), 2.81–2.99 (m,
2H, N–CH2), 3.41–3.49 (m, 1H, S–CHH), 3.86–3.93 (m, 1H, S–CHH),
4.69 (d, J¼2.8 Hz, 1H, S–CH–N); 13C NMR (75.4 MHz, CDCl3):
¼14.7
d
(CHCH3), 19.1 (]C–CH3), 28.2 (CHCH3), 29.0 (]C–CH2), 30.1 (S–
CH2), 51.4 (N–CH2), 67.4 (S–CH–N), 75.7 (]C–CN), 122.8 (CN), 151.6
(]C–CH3); Anal. Calcd for C10H14N2S: C, 61.82; H, 7.26; N, 14.42.
Found: C, 62.17; H, 7.22; N, 14.30.
3.4.18. (3S,8aR)-3-Ethyl-5-methyl-2,3,8,8a-tetrahydro-7H-thia-
zolo[3,2-a]pyridine-6-carbonitrile (30
b
). Yellow oil; Rf¼0.40
(CH2Cl2); 1H NMR (300 MHz, CDCl3):
d
¼0.91 (t, J¼7.5 Hz, 3H,
CH2CH3), 1.39–1.58 (m, 2H, CH2CH2–C]), 1.64–1.80 (m, 2H,
CH2CH3), 2.22 (s, 3H, ]C–CH3), 2.28–2.36 (m, 2H, CH2–C]), 2.76 (d,
J¼11.7 Hz, 1H, S–CHH–CH–Et), 3.11 (ddd, J¼1.8, 5.7, and 11.7 Hz, 1H,
S–CHH–CH–Et), 3.88–3.94 (m, 1H, CH–Et), 4.41 (dd, J¼2.1 and
3.4.14. 2,5-Dimethyl-2,3,8,8a-tetrahydro-7H-thiazolo[3,2-a]pyri-
dine-6-carbonitrile (28
(film): 3450, 2963, 2927, 2855, 2181, 1694, 1630, 1592, 1422, 1393,
a
þ ). Yellow oil; Rf¼0.40 (CH2Cl2); IR
b
1326, 1246, 1189, 1132, 1035, 848, 698 cmꢂ1
CDCl3):
¼1.36 (d, J¼8.0 Hz, 3H, CH3–CH–S (
3H, CH3–CH–S (
3H, CH3–C] ( )), 2.16 (s, 3H, CH3–C] (
CH–S ( )), 2.31–2.35 (m, 4H, CH2–C] (
and 10.7 Hz, 1H, N–CHH (
)), 3.35 (dd, J¼7.2 and 10.1 Hz, 1H, N–
CHH ( )), 3.46–3.60 (m, 2H, CH3–CH–S (
)), 3.71 (dd, J¼5.1 and
10.2 Hz, 1H, N–CHH (
)), 3.94 (dd, J¼5.8 and 10.7 Hz, 1H, N–CHH
)), 4.59 (dd, J¼3.1 and 10.7 Hz, 1H, S–CH–N ( )), 4.64 (dd, J¼3.2
and 10.3 Hz, 1H, S–CH–N (
)); 13C NMR (75.4 MHz, CDCl3):
¼18.3
(]C–CH3 )), 18.8 (]C–CH3 )), 19.5 (S–C–CH3 )), 20.1 (S–C–
)), 23.6 (]C–CH2 )), 23.9 (]C–CH2 )), 27.2 (]C–CH2–
)), 27.6 (]C–CH2–CH2 )), 39.8 (S–CH ( )), 39.9 (S–CH ( )),
)), 58.3 (N–CH2 ( )), 63.0 (S–CH–
)), 73.6 (]C–CN ( )), 74.8 (]C–CN (
;
1H NMR (300 MHz,
11.1 Hz,1H, S–CH–N); 13C NMR (75.4 MHz, CDCl3):
d
¼11.3 (CH2CH3),
d
b
)), 1.38 (d, J¼6.5 Hz,
19.3 (]C–CH3), 25.0 (CH2CH3), 27.6 (CH2–C]), 28.2 (CH2–S), 32.6
(CH2CH2–C]), 62.2 (CH–Et), 63.9 (CH–S), 76.3 (]C–CN),123.1 (CN),
151.4 (]C–CH3); Anal. Calcd for C11H16N2S: C, 63.42; H, 7.74; N,
13.45. Found: C, 63.81; H, 7.68; N, 13.38.
a
)), 1.63–1.76 (m, 2H, CHH–CH–S (
a b)), 2.15 (s,
þ
a
b
)), 2.18–2.25 (m, 2H, CHH–
aþ
b
aþb
)), 3.19 (dd, J¼6.4
a
b
a
þb
3.4.19. 5-Methyl-3-phenyl-2,3,8,8a-tetrahydro-7H-thiazolo[3,2-
b
a]pyridine-6-carbonitrile (31
NMR (300 MHz, CDCl3):
)), 1.93 (s, 3H, CH3 (
CHH–CH2–C–CN (
)), 2.81 (d, J¼11.8 Hz,1H, S–CHH (
J¼5.6 and 11.6 Hz, 1H, S–CHH ( )), 3.47 (dd, J¼6.8 and 11.6 Hz, 1H,
S–CHH ( )), 4.66 (dd,
)), 3.55 (dd, J¼6.8 and 11.8 Hz, 1H, S–CHH (
J¼2.1 and 11.1 Hz, 1H, S–CH–N ( )), 4.79 (dd, J¼3.4 and 10.8 Hz, 1H,
S–CH–N ( )), 5.28 (dd, J¼5.6 and
)), 5.18 (d, J¼6.8 Hz, 1H, CH–Ph (
6.8 Hz,1H, CH–Ph (
)), 7.19–7.53 (m,10H, 2Ph); 13C NMR (75.4 MHz,
CDCl3): )), 19.7 (CH3 )), 24.0 (]C–CH2–CH2 )),
¼19.4 (CH3
24.6 (]C–CH2–CH2 ( )), 26.1 (]C–CH2 ( )), 28.2 (]C–CH2 ( )), 37.5
(S–CH2–CH–Ph ( )), 38.5 (S–CH2–CH–Ph ( )), 63.1 (S–CH–N ( )),
63.6 (S–CH–N ( )), 65.3 (CH–Ph ( )), 74.4 (]C–CN
)), 74.9 (]C–CN ( )), 125.2 (2CH,
Ph), 125.9 (2CH, Ph), 127.8 (CH, Ph), 127.8 (CH, Ph), 128.5 (2CH, Ph),
a
þ
b
). Yellow oil; Rf¼0.37 (CH2Cl2); 1H
(a
b
d
¼1.73–1.87 (m, 2H, CHH–CH2–C–CN
a
d
(
a
þb
b
)), 2.02 (s, 3H, CH3 (
a
)), 2.23–2.47 (m, 6H,
)), 3.01 (dd,
(b
(a
(a
a
þ
b
b
CH3
CH2
(
b
(
a
(b
a
(b
(
a
b
a
a
b
58.2 (N–CH2 (
N (
(CN (
b
a
)), 61.4 (S–CH–N (
a
b
b
b
a
)), 123.0 (CN (
a
)), 123.2
a
b
b
)), 151.8 (]C–CH3
(a
)), 151.9 (]C–CH3
(b
)); GC–MS (EI): m/
a
z¼135 (100), 194 (Mþ, 28).
d
(
b
a
(
b
(a
b
a
3.4.15. (2S,8aR)-5-Methyl-2-phenyl-2,3,8,8a-tetrahydro-7H-thia-
a
b
a
zolo[3,2-a]pyridine-6-carbonitrile (29
a
). Yellow oil; Rf¼0.36
b
b
)), 66.0 (CH–Ph (a
(CH2Cl2); 1H NMR (300 MHz, CDCl3):
d¼1.81–1.92 (m, 1H, CHH–
(b
a)), 122.9 (CN (a)), 123.0 (CN (b
CH2–C–CN), 2.11 (s, 3H, CH3), 2.25–2.41 (m, 3H, CHH–CH2–C–CN),

2822
M.P. Perrino et al. / Tetrahedron 66 (2010) 2815–2822
2. Kuckla¨nder, U. "The Chemistry of Enaminones", Part 1 In The Chemistry of
Funcional Groups; Rappoport, Z., Ed.; John Wiley: New York, NY, 1994.
3. (a) Lue, P.; Greenhill, J. V. "Enaminones in Heterocyclic Synthesis" In.
Advances in Heterocyclic Chemistry; Katritzky, A., Ed.; Academic: New York,
NY, 1977; Vol. 67, p 207; (b) Abdel-Zaher, A. E.; El-Khair, A. A. Tetrahedron
2003, 59, 8463; (c) Negri, G.; Kascheres, C.; Kascheres, A. J. J. Heterocycl.
Chem. 2004, 41, 461.
4. (a) Dondoni, A.; Massi, A.; Minghini, E.; Bertolasi, V. Tetrahedron 2004, 60,
2311; (b) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471; (c) Wan, J.-P.; Gan,
S.-F.; Sun, G.-L.; Pan, Y.-J. J. Org. Chem. 2009, 74, 2862; (d) Bartoli, G.; Bosco,
M.; Galzerano, P.; Giri, R.; Mazzanti, A.; Melchiorre, P.; Sambri, L. Eur. J. Org.
Chem. 2008, 3970; (e) Li, M.; Zuo, Z.; Wen, L.; Wang, S. J. Comb. Chem. 2008,
10, 436; (f) Sridharan, V.; Perumal, P. T.; Avendan˜o, C.; Mene´ndez, J. C. Tet-
rahedron 2007, 63, 4407; (g) Evdokimov, N. M.; Kireev, A. S.; Yakovenko, A. A.;
Antipin, M. Y.; Magedov, I. V.; Kornienko, A. J. Org. Chem. 2007, 72, 3443; (h)
Evdokimov, N. M.; Magedov, I. V.; Kireev, A. S.; Kornienko, A. Org. Lett. 2006,
8, 899.
129.0 (2CH, Ph), 141.5 (C, Ph (a)), 142.5 (C, Ph (b)), 152.0 (N–C] (b)),
152.2 (N–C] (a)).
3.4.20. 5-Benzyl-2,3,8,8a-tetrahydro-7H-thiazolo[3,2-a]pyridine-6-
carbonitrile (33). Yellow oil; Rf¼0.31 (hexane/ethyl acetate (4:1));
1H NMR (300 MHz, CDCl3):
d
¼1.66–1.76 (m, 1H, ]C–CH2–CHH),
2.18–2.29 (m, 1H, ]C–CH2–CHH), 2.34–2.39 (m, 2H, ]C–CH2),
2.72–2.98 (m, 6H, S–CH2 and ]C–CH2CH2–Ph), 3.46–3.54 (m, 1H,
CHH–N), 3.67–3.75 (m, 1H, CHH–N), 4.48 (dd, J¼3.1 and 10.4 Hz, 1H,
S–CH–N), 7.21–7.25 (m, 5H, Ph); 13C NMR (75.4 MHz, CDCl3):
d
¼23.8 (CH2–C]), 27.1 (CH2–CH–S), 29.0 (CH2–S), 34.9 (CH2CH2–
Ph), 50.8 (CH2–N), 61.9 (S–CH–N), 76.2 (]C–CN), 122.5 (CN), 126.5
(CH, Ph), 128.4 (2CH, Ph), 128.5 (2CH, Ph), 139.8 (C, Ph), 155.2 (]C–
N); Anal. Calcd for C15H16N2S: C, 70.27; H, 6.29; N, 10.93. Found: C,
70.63; H, 6.31; N, 10.75.
5. (a) Nemes, P.; Bala´zs, B.; To´th, G. Synlett 2000, 1327; (b) Paravidino, M.; Bon, R. S.;
Scheffelaar, R.; Vugts, D. J.; Znabet, A.; Schmitz, R. F.; Kanter, F. J. J.; Lutz, M.;
Spek, A. L.; Groen, M. B.; Orru, R. V. A. Org. Lett. 2006, 8, 5369; (c) Gorobets, N. Y.;
Yousefi, B. H.; Belaj, F.; Kappe, C. O. Tetrahedron 2004, 60, 8633.
6. (a) Lu, W.; Song, W.; Hong, D.; Lu, P.; Wang, Y. Adv. Synth. Catal. 2009, 351, 1768;
(b) Muravyova, E. A.; Desenko, S. M.; Musatov, V. I.; Knyazeva, I. V.; Shishkina,
S. V.; Shishkin, O. V.; Chebanov, V. A. J. Comb. Chem. 2007, 9, 797; (c) Zhang, M.;
Jiang, H.-F. Eur. J. Org. Chem. 2008, 3519.
7. (a) Do¨mling, A. Chem. Rev. 2006, 106, 17; (b) Thompson, M. J.; Chen, B. Tetra-
hedron Lett. 2008, 49, 5324; (c) Shestopalov, A. M.; Shestopalov, A. A.; Rodi-
novskayo, L. A. Synthesis 2008, 1.
3.4.21. 5-Phenyl-2,3,8,8a-tetrahydro-7H-thiazolo[3,2-a]pyridine-6-
carbonitrile (36). Yellow oil; Rf¼0.29 (hexane/ethyl acetate (4:1));
IR (film): 3366, 3058, 2929, 2851, 2189, 1965, 1817, 1693, 1586, 1494,
1325, 1248, 1146, 1034, 931, 764 cmꢂ1 1H NMR (300 MHz, CDCl3):
;
d
¼1.88–2.05 (m, 1H, ]C–CH2–CHH), 2.30–2.46 (m, 2H, ]C–CHH–
CHH), 2.58–2.68 (m, 1H, ]C–CHH), 2.75–2.92 (m, 2H, S–CH2), 3.23–
3.31 (m,1H, CHH–N), 3.36–3.44 (m,1H, CHH–N), 4.76 (dd, J¼3.3 and
7.8 Hz, 1H, S–CH–N), 7.42 (m, 5H, Ph); 13C NMR (75.4 MHz, CDCl3):
8. (a) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957; (b) Li, M.;
Zuo, Z.; Wen, L.; Wang, S. J. Comb. Chem. 2008, 10, 436.
´
´
˜
9. Calvo, L. A.; Gonzalez-Ortega, A.; Marcos, R.; Perez, M.; Sanudo, M. C. Tetrahe-
dron 2008, 64, 3691.
d
¼23.2 (CH2–C]), 26.7 (CH2–CH–C]), 29.6 (CH2–S), 53.5 (CH2–N),
10. Simon, C.; Peyronel, J.-F.; Rodriguez, J. Org. Lett. 2001, 3, 2145.
11. Caballero, E.; Puebla, P.; Medarde, M.; Honores, Z.; Sastre, P.; Lo´ pez, J. L.;
San Feliciano, A. Tetrahedron Lett. 1998, 39, 455.
62.1 (S–CH–N), 80.7 (]C–CN), 122.0 (CN), 128.5 (2CH, Ph), 128.6
(2CH, Ph), 129.7 (CH, Ph), 135.0 (C, Ph), 156.1 (]C–Ph); GC–MS (EI):
m/z¼242 (Mþ, 100), 244 ([Mþ2]þ, 6); Anal. Calcd for C14H14N2S: C,
69.39; H, 5.82; N, 11.56. Found: C, 69.62; H, 5.79; N, 11.39.
12. Compound 43 and analogous thiazolidines can be prepared in high yield
(%>85) by reaction of b-enaminonitrile with cysteamine hydrochloride (1:1.2
ratio) in acetonitrile at rt NMR spectra show that equilibrium is largely shifted
to cyclic tautomer 43b where the AB coupling system corresponding to cya-
nomethylene (CH2CN) is easily recognizable in the crude.
13. Caballero, E.; Puebla, P.; Medarde, M.; San Feliciano, A. Tetrahedron 1993, 49,
10079.
4. Conclusions
14. Catalytic hydrogenation (Ni-Raney in ethanol at rt) of 3,5-dimethyl-4-(3-ox-
obutyl)isoxazole gives 3-(1-aminoethylidene)heptane2,6-dione, which spon-
taneously cyclizes to 3-acetyl-2,6-dimethylpyridine.
15. Caballero, E.; Puebla, P.; Sa´nchez, M.; Medarde, M.; Mora´n del Prado, L.; San
Feliciano, A. Tetrahedron: Asymmetry 1996, 7, 1985.
16. Caballero, E.; Puebla, P.; Medarde, M.; Sanchez, M.; Salvado, M. A.; Garcia-
Granda, S.; San Feliciano, A. J. Org. Chem. 1996, 61, 1890.
17. Rodolfo, L.; Oscar, C.; Marta, N.; Bilal, A. S.; Javier, T.; Joan, B. Eur. J. Org. Chem.
1999, 2997.
Although the synthetic interest of the multicomponent reaction
for the preparation of thiazolopyridines is evident and their use-
fulness for the construction of libraries of compounds has been
proven, the stereochemical control is rather low and has some
limitations. The mechanistic proposal however seems to be in good
agreement with the observed stereocontrol.
18. Potekhin, A. A.; Sokolov, V. V.; Ogloblin, K. A.; Esakov, S. M. Chem. Heterocycl.
Compd. 1983, 622.
Acknowledgements
19. Kaafarani, M.; Crozet, M. P.; Surzur, J. M. Bull. Soc. Chim. Fr. 1989, 1, 114.
20. Lue, P.; Greenhill, J. In Adv. Heterocyclic. Chem.; Katritzky, A. R., Ed.; Academic:
New York, NY, 1997; Vol. 67, p 207.
21. Hackler, R. E.; Burow, K. W.; Kaster, S. V.; Wickiser, D. I. J. Heterocycl. Chem. 1989,
26, 1575.
´
The authors wish to thank the Junta de Castilla y Leon for the
grant provided.
References and notes
22. Ridge, D. N.; Hanifin, J. W.; Harten, L. A.; Johnson, B. D.; Menschik, J.; Nicolau, G.;
Sloboda, A. E.; Watts, D. E. J. Med. Chem. 1979, 22, 1385.
23. Larice, J. L.; Roggero, J.; Metzger, J. Bull. Soc. Chim. 1967, 3637.
1. Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277.