Reactions of 2-methylthiazolines and N-methyl cyclic ketene-N,S-acetals with acid chlorides

Article abstract of DOI:10.1016/j.tetlet.2004.09.182

Carbon-carbon bond formation occurs under mild conditions when 2-methylthiazolines react with acid chlorides to form N-acyl-β-keto cyclic ketene-N,S-acetals. N-Methyl cyclic ketene-N,S-acetals, generated from 2-methyl-thiazolines, can react further with acid chlorides to form N-methyl-β-keto cyclic ketene-N,S-acetals.

Full text of DOI:10.1016/j.tetlet.2004.09.182

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8899–8903
Reactions of 2-methylthiazolines and N-methyl cyclic
ketene-N,S-acetals with acid chlorides
Aihua Zhou and Charles U. Pittman, Jr.*
Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA
Received 14 July 2004; revised 13September 2004; accepted 28 September 2004
Available online 18 October 2004
Abstract—Carbon–carbon bond formation occurs under mild conditions when 2-methylthiazolines react with acid chlorides to form
N-acyl-b-keto cyclic ketene-N,S-acetals. N-Methyl cyclic ketene-N,S-acetals, generated from 2-methyl-thiazolines, can react further
with acid chlorides to form N-methyl-b-keto cyclic ketene-N,S-acetals.
Ó 2004 Elsevier Ltd. All rights reserved.
Carbon–carbon bond formation is one of the most
important reactions in organic synthesis. Formation
of C–C bonds under mild conditions is especially valu-
able. We demonstrate, herein, facile nucleophilic addi-
tions of both 2-methylthiazolines 1 and N-methyl
cyclic ketene-N,S-acetals [e.g., 2-(3-substituted thiazoli-
din-2-ylidene)-1-alkyl- or arylethanones] 2 to acid
chlorides to form N-substituted-b-keto cyclic ketene-
N,S-acetals [e.g., 2-(3-substituted thiazolidin-2-ylidene)-
1-alkyl- or arylethanones], 3 and 4, respectively, under
mild conditions.1,2 2-Methylthiazolines have been pre-
pared and employed in organic synthesis for about
70years.3,4 They appear in drugs5,6 and natural prod-
ucts.7 However, their reactions with acid chlorides to
form N-acyl-b-keto cyclic ketene-N,S-acetals 3 have
not been reported previously. N-Methyl cyclic ketene-
N,S-acetals 2 have never been reported. Their structure
combines both an enamine and a thioether function,
which suggests they should be explored as a new class
of carbon nucleophiles.
2-Methylthiazolines1wereconvertedintothemorenucleo-
philic N-methyl cyclic ketene-N,S-acetals 2 by N-methyl-
ation followed by treatment with sodium hydride.8–10
Treating 2 with acid chlorides formed the corresponding
N-methyl-b-keto cyclic ketene-N,S-acetals 4 (Scheme 1).
The 4-keto analogs of 4 have been reported.11,12
Reacting 2-methylthiazolines 1a–d with 3equiv of acid
chloride and 3equiv of triethylamine in refluxing aceto-
nitrile generated N-acyl-b-keto cyclic ketene-N,S-acetals
3a–f. (Table 1). High yields of N-acyl-b-keto cyclic
ketene-N,S-acetals 3a–f were achieved when benzoyl
and trimethylacetyl chlorides were used. These acid
chlorides have no a-protons. Acid chlorides, which have
a-protons, were also tried. N-Acyl-b-keto cyclic ketene
O
R4
H
N
R4
O
O
O
O
O
(1) CH3I
R4
C
Cl
R4
R4
CH3
CH3
R4C Cl
CH3NO2
(2) NaH
THF
N
S
S
N
S
N
S
N
S
Et3N, THF
Et3N, CH3CN
R1 R2 R3
R1 R2 R3
R1 R2 R3
R1 R2 R3
R1 R2 R3
4
3
1
2
Scheme 1.
Keywords: 2-Methylthiazolines; N-Methyl cyclic ketene-N,S-acetals; Acid chlorides.
*
Corresponding author. Tel.: +1 601 325 7616; fax: +1 601 325 7611; e-mail: cpittman@ra.msstate.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.182

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A. Zhou, C. U. Pittman, Jr. / Tetrahedron Letters 45 (2004) 8899–8903
Table 1. The reaction of 2-methylthiazoline with acid chlorides
O
H
N
R4
CH3
O
O
CH3CN, Et3N (3eq.)
R4
N
S
+
3R4
C Cl
S
reflux
3hrs
R1 R2 R3
R1 R2 R3
3
1
Entry
Substituents in 1
R4 in RCOCl
Product 3
Yield 3 (%)
R1
R2
R3
1a
1b
1c
1d
1a
1b
1a
1a
H
H
H
C6H5
C6H5
3a
3b
3c
3d
3e
3f
92
88
85
90
93
85
0
H
H
CH3
H
Et
CH3
H
H
C6H5
C6H5
CH3
H
H
H
(CH3)3C
(CH3)3C
(CH3)2CH
CH3(CH2)2
H
H
CH3
H
H
H
3g
3h
H
H
H
0
The ratio of 1/acid chloride/Et3N = 1:3:3. All yields are isolated yields.
acetals 3g–h did not form using propionyl chloride and
iso-butyryl chloride. Competing base-catalyzed elimina-
tion of HCl from acid chlorides containing a-protons
occurred to form the corresponding ketenes, which leads
to other reactions.
to NEt3 produces the reactive intermediate N-acyl cyclic
ketene-N,S-acetal 8. Nucleophilic attack by electron-
rich 8 on a second equivalent of acid chloride generates
9 and then 10, which loses a proton to give 3. The b-car-
bon nucleophilicity of N-acyl cyclic ketene acetals
derives from the electron-donating ability of both nitro-
gen and sulfur and the high stability of the resulting 2-
substituted thiazolinium cation, even with an N-acyl
group present. Thus, a second acid chloride can con-
tinue to react with intermediate 8 to form N-acyl-b-keto
cyclic ketene-N,S-acetal 3.
2-Ethylthiazolines 5 were also synthesized and reacted
with benzoyl and trimethylacetyl chlorides, generating
N-acyl cyclic ketene-N,S-acetals 6 (Table 2). Unlike
the reactions in Table 1, N-acyl-b-keto cyclic-N,S-
ketene acetals were not formed. A second equivalent
of acid chloride does not react with N-acyl-cyclic
ketene-N,S-acetals 6a–c. Indeed, N-acyl-cyclic ketene-
N,S-acetals 6a–c were stable enough to be separated
by column chromatography. In each case, only the iso-
mer with the methyl cis to sulfur was obtained.
Replacing the N-acyl function of 8 with a methyl group
should increase the b-carbonÕs nucleophilicity. Thus, N-
methyl cyclic ketene-N,S-acetals 2 were synthesized and
characterized for the first time (Table 3). These com-
pounds are extremely sensitive to acids, acidic surfaces
and water. Thus, the isolation of 2a–d requires basic
media or base-treated glassware surfaces. To prepare
2a–d, amino alcohols 11 were reacted with acetyl chlo-
ride plus Et3N in dichloromethane to afford 2-hydroxy-
amides, followed by the treatment with LawessonÕs
reagent (or P2S5) to generate the corresponding 2-meth-
ylthiazolines 1a–d.13,14. N-Methylation of 1a–d with
iodomethane in nitromethane afforded N-methyl-2-
methylthiazolinium iodides 12a–d.15–17 Treatment of
12a–d with sodium hydride in THF generated the very
acid sensitive and previously unreported N-methyl cyclic
ketene-N,S-acetals 2a–d (Table 3). Their N,O analogs
have been reported.18,19
The formation of 3a–f and 6a–c may proceed as shown
in Scheme 2. The consumption of 1equiv of acid chlo-
ride generates intermediate 7. Loss of a proton from 7
Table 2. The reaction of 2-ethylthiazoline with acid chlorides
CH3
H
N
CH3
S
O
O
C
CH3CN, Et3N
R4
N
S
+
3R4
Cl
reflux
3h
R1 R2 R3
R1 R2 R3
5
6
N-Methyl cyclic ketene-N,S-acetals 2a–d combine both
a thioether and an enamine structure within the same
functional group. Due to their high reactivity, they were
used immediately after being prepared and character-
ized. N-Methyl cyclic ketene-N,S-acetals reacted with
acid chlorides in THF at room temperature in the
presence of Et3N to form N-methyl-b-keto cyclic
ketene-N,S-acetals 4 in good isolated yields (Table 4).
Entry Substituents in R4 in RCOCl Product 6 Yield 6 (%)
5
R1 R2 R3
5a
5b
5c
H
H
H
H
H
H
H
(CH3)3C
CH3 (CH3)3C
C6H5
6a
6b
6c
87
84
89
H
The ratio of 5/acid chloride/Et3N = 1:3:3. All yields are isolated yields.

A. Zhou, C. U. Pittman, Jr. / Tetrahedron Letters 45 (2004) 8899–8903
8901
O
H
R4
CH3
O
O
C
R4
CH3CN, Et3N
reflux
N
S
N
S
+
2R4
Cl
R1 R2 R3
R1 R2 R3
3
1
Et3N
O
H
NEt3
H
R4
CH2
O
O
H
N
R4
R4
S
N
S
Cl
Cl
R1 R2 R3
R1 R2 R3
7
10
O
H
R4
O
O
Cl
H
N
Cl
C
R4
R4
R4
N
S
S
O
R1 R2 R3
R1 R2 R3
9
8
Scheme 2. The reaction mechanism for 2-methylthiazoline with acid chlorides.
Table 3. The synthesis of N-methyl cyclic ketene-N,S-acetals
CH2
CH3
CH3
(1)
CH3COCl
Et3N
CH3
CH3
H2N
OH
NaH
THF
CH3I
N
S
N
S
N
S
CH3NO2
Lawesson's
reagent
(2)
R1 R2 R3
R1 R2 R3
R1 R2 R3
R1 R2 R3
11
1
12
2
Entry
Substituents in 11
1
12
2
Yield of 2 from 11 (%)
R1
R2
R3
11a
11b
11c
11d
H
H
H
1a
1b
1c
1d
12a
12b
12c
12d
2a
2b
2c
2d
43
41
36
40
H
Et
H
CH3
H
H
CH3
CH3
H
All yields are isolated yields starting from 11.
Acid chlorides, with or without a-protons, could be
employed. The reactions were completed within
10min. The conversion of 2a to the corresponding N-
methyl-b-keto cyclic ketene-N,S-acetals 4i–o, using acid
chlorides with a-protons, contrasts sharply with the
failed of attempts to convert 1a to 3g,h (in Table 1).
N-Methyl cyclic ketene-N,S-acetals 2a–d, are stronger
carbon nucleophiles than their N-acyl analogs, 6, so
reactions of 2a–d with acid chlorides are faster. Thus,
the conversions of 2a to 4i–o, occur before competing
formation of ketenes occurs. This faster rate allows the
use of ambient temperature and shorter reaction times.
Do N-methyl b-keto cyclic ketene-N,S-acetals have
enough nucleophilicity to react with a second acid chlo-
ride at higher temperatures as illustrated by the conver-
sion of 4i to 13 (in Scheme 3)? To test this question, 4i
was reacted with benzoyl chloride in refluxing THF in
the presence of Et3N. Surprisingly, the main product
of the reaction was 4a (82%) instead of 13. Different

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A. Zhou, C. U. Pittman, Jr. / Tetrahedron Letters 45 (2004) 8899–8903
Table 4. The reaction of N-methyl cyclic ketene-N,S-acetals with acid chlorides
O
CH2
R4
H
O
C
CH3
N
S
CH3
Et3N, THF
rt, 20min
+
R4
Cl
N
S
R1 R2 R3
R1 R2 R3
2
4
Entry
Substituents in 2
R4 in RCOCl
Product 4
Yield 4 (%)
R1
R2
R3
2a
2b
2c
2d
2a
2b
2c
2d
2a
2a
2a
2a
2a
2a
2a
H
H
H
C6H5
C6H5
4a
4b
4c
4d
4e
4f
78
75
71
74
81
76
68
69
82
77
74
79
75
78
75
H
H
CH3
H
Et
CH3
H
H
C6H5
C6H5
CH3
H
H
H
(CH3)3C
(CH3)3C
(CH3)3C
(CH3)3C
CH3
H
H
CH3
H
Et
CH3
H
H
4g
4h
4i
CH3
H
H
H
H
H
H
CH3CH2
CH3(CH2)2
(CH3)2CH
4j
H
H
H
4k
4l
H
H
H
H
H
H
CH3(CH2)3
(CH3)2CHCH2
CH3(CH2)6
4m
4n
4o
H
H
H
H
H
H
The ratio of 2/acid chloride/Et3N = 1:2:2.1. All yields are based on isolated yields.
O
S
O
S
O
N
O
S
H
N
CH3
H
N
CH3
CH3
PhCOCl
x
PhCOCl
CH3
CH3
Et3N, THF
reflux, 2hr
Et3N, THF
reflux, 2hr
13
4a
4i
Scheme 3. The reaction of N-methyl-b-keto cyclic ketene-N,S-acetals with benzoyl chloride.
reaction times (from 20min to 20h) and different acid
chlorides (with a-protons) were also tried, but diketo
products were not generated. Clearly, once N-methyl
cyclic ketene-N,S-acetals 2 react to form N-methyl-b-
keto cyclic ketene-N,S-acetals 4, a sharp drop in nucleo-
philicity occurs. Thus, the competing reactions of acid
Table 5. The reaction of cyclic ketene-N,S-acetals with diacid chlorides
CH3
R1
N
O O
O
CH3
R2
ClCRCCl
N
S
R3
R2
S
CRC
O
S
R3
Et3N, THF
20 mins
N
R1 R2 R3
R1
CH3
2
14
Entry
Substituents in 2
R
Product
Yield (%)
R1
R2
R3
2a
2c
2a
H
Et
H
H
H
H
H
H
H
>C(CH3)2
>C(CH3)2
p-C6H4
14a
14b
14c
88
79
80
The ratio of 2/diacid chloride/Et3N = 2.2:1:2.5. All yields are isolated yields.

A. Zhou, C. U. Pittman, Jr. / Tetrahedron Letters 45 (2004) 8899–8903
8903
CH3
N
S
Cl
C
O
C O
Et3N, THF
20 mins
CH3
N
S
+
S
O
O
84%
C
C
C
C
N
Cl
Cl
H3C
O
O
CH3
N
S
15
Scheme 4. The reaction of cyclic ketene-N,S-acetals with 1,3,5-benzenetricarbonyl trichloride.
chlorides to form ketene by loss of HCl would dominate,
leading to other side reactions.
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2004.09.182.
The reactions of N-methyl cyclic ketene-N,S-acetals 2
with diacid chlorides, which have no a-protons, proceed
readily in the same way to form the bis-a,b-unsaturated
ketones 14a–c in high yields (Table 5). Using diacid
chlorides with a-protons (succinyl chloride and glutaryl
dichloride) did not afford the analogous products. Com-
pound 14b was obtained as a pair of racemic diastereo-
mers, which have almost equivalent NMR chemical
shifts. Reacting 2 with 1,3,5-benzenetricarbonyl chloride
led to the tris-a,b-unsaturated ketone 15 in 84% isolated
yield; using a ratio of 2a/triacid chloride/Et3N = 3.6:1:4
(Scheme 4).
References and notes
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The detailed synthetic and isolation procedures and the
full spectral identifications of all compounds are
provided in supplementary data. Supplementary data