2,5-dihydro-1,3-thiazoles as scaffolds in the synthesis of O,N-diacyl O,N-acetals in a one-pot reaction

Article abstract of DOI:10.5560/ZNB.2012-0146

The Asinger reaction is a very powerful tool to form 2,5-dihydro-1,3- thiazoles in high yields. Treating these heterocyclic imines with acid chlorides followed by adding sodium carboxylates led to a large number of new O,N-diacyl O,N-acetals. Using chiral

Full text of DOI:10.5560/ZNB.2012-0146

2,5-Dihydro-1,3-thiazoles as Scaffolds in the Synthesis of O,N-Diacyl
O,N-Acetals in a One-pot Reaction
Timo Stalling, Fabian Brockmeyer, Denis Kro¨ger, Almuth Schwa¨blein, and
Ju¨rgen Martens
Institut fu¨r Reine und Angewandte Chemie, Carl von Ossietzky Universita¨t Oldenburg,
26 111 Oldenburg, Germany
Reprint requests to Professor Ju¨rgen Martens. Fax: +49(0)441 798 3329.
E-mail: juergen.martens@uni-oldenburg.de
Z. Naturforsch. 2012, 67b, 1045 – 1055 / DOI: 10.5560/ZNB.2012-0146
Received May 29, 2012
Dedicated to Professor Heribert Offermanns on the occasion of his 75th birthday
The Asinger reaction is a very powerful tool to form 2,5-dihydro-1,3-thiazoles in high yields.
Treating these heterocyclic imines with acid chlorides followed by adding sodium carboxylates led
to a large number of new O,N-diacyl O,N-acetals. Using chiral starting materials, a high diastereo-
selectivity was observed in several cases. X-Ray structures document the constitution and clarify the
relative configuration of the prepared O,N-diacyl O,N-acetals.
Key words: Imines, Acetals, N-Acyliminium Ion, Carboxylates, Stereochemistry
Introduction
possibility of a higher diversity of products due to the
formation of a 2,5-dihydrothiazole starting from two
For more than 60 years the chemistry of 2,5- completely different carbonyl compounds in a one-pot
dihydro-1,3-thiazoles is a key element in the course reaction. For that purpose, one of the carbonyl com-
of developing pharmaceutically active molecules [1]. pounds has to be transformed into an α-chlorocarbonyl
Several processes based on this reactive class of sub- compound. Furthermore, the modified Asinger reac-
stances are still in progress represented by the syn- tion is more feasible by reason of the abstinence from
thesis of penicillamine and cysteine [2, 3]. Further- gaseous ammonia and elemental sulfur. Instead, the
more, other remarkable investigations on this fam- mentioned α-chlorocarbonyl compound reacts with
ily of heterocycles and its related biological useful sodium hydrogen sulfide generating in situ thiols,
structure elements characterize special fields of re- which undergo directly a reaction with the two remain-
search in general [4]. The synthesis of 2,5-dihydro-1,3- ing reagents.
thiazoles, which belong to the class of cyclic imines,
2,5-Dihydro-1,3-thiazoles could be converted into
was first reported by F. Asinger in 1956 [5]. The a large number of different products by functional-
Asinger reaction is a multi-component reaction (MCR) izing their reactive C=N double bond [6 – 10]. Ac-
of two molecules of one ketone, bearing a proton cordingly, we were successful in generating differ-
in α-position, with ammonia and sulfur forming 2,5- ent types of amide structures, especially enantio- or
dihydro-1,3-thiazoles. Till this day the Asinger four- diastereospecifically formed products [11 – 18]. How-
component reaction (A-4CR) has been optimized more ever, the derivatizations often had to be initiated
and more, ending in the most efficient and elegant ac- by the addition of an acid chloride generating reac-
cess to these heterocycles: the modified Asinger reac- tive chloroamides [19 – 24]. These intermediates were
tion [3]. Laying the foundation of this reaction in the quenched directly with different hydroxy compounds
environment of Asinger, the modified Asinger reac- to prepare stable alkoxyamides.
tion was accomplished by H. Offermanns amongst oth-
Considering the vast number of O,N-diacyl O,N-
ers [3]. The modified Asinger reaction established the acetals and their diverse applications [25 – 28], subject
c
ꢀ 2012 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
Brought to you by | University of California
Authenticated
Download Date | 1/19/16 2:42 PM

1046
T. Stalling et al. · The Synthesis of O,N-Diacyl O,N-Acetals
Table 1. Prepared 2,5-dihydro-1,3-thiazoles 1.
Imine
R1
R2
R3
CH3
R4
CH3
Yielda (%)
88 [35]
65 [36]
58
Scheme 1. One-pot synthesis of O,N-diacyl O,N-acetals
starting from 2,5-dihydro-1,3-thiazoles.
1a
1b
1c
1d
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
CH3
-(CH2)5-
CH3
H
CH3
C(CH3)3
89 [37]
of the present study is a synthesis route which enables
the preparation of new O,N-diacyl O,N-acetals starting
from 2,5-dihydro-1,3-thiazoles in a one-pot synthesis
(Scheme 1).
a
All yields are isolated yields.
expected, the desired 2,5-dihydro-1,3-thiazoles 1 were
Treatment of the 2,5-dihydro-1,3-thiazoles with var- obtained in good yields (up to 89%) (Table 1).
ious acid chlorides followed by the addition of sodium In order to gain chiral starting materials for the reac-
carboxylates led to the target O,N-diacyl O,N-acetals. tions, different substituents of the carbonyl compounds
Additionally, we investigated the diastereoselectivity were chosen. This approach offers the possibility to in-
of this reaction by varying the substituents at the thia- vestigate the diastereoselectivity of C2- as well as C5-
zole ring and applying a diverse series of acid chlorides chiral imines 1.
and sodium salts.
However, this efficient synthesis route to O,N-diacyl Conversion of the 2,5-dihydro-1,3-thiazoles into
O,N-acetals has attracted limited attention [29, 30], O,N-diacyl O,N-acetals
whereas the synthesis by esterification of the respective
hydroxy species with acetic anhydride is a commonly
Among the most efficient possibilities to take advan-
used method [31 – 34]. It is worth mentioning that the tage of the reactive imine bond of the 2,5-dihydro-1,3-
second described pathway implies a complex and pro- thiazoles 1 is the addition of an acyl chloride [19 – 24].
tracted two-step sequence compared to the investigated
procedure based on imines.
As outlined in Scheme 3, firstly, the imines 1 were
reacted with several acyl chlorides in acetonitrile
to generate chloroamides which are in equilibrium
with reactive N-acyliminium ions. These intermediates
were then quenched directly with the sodium salts of
different carboxylic acids. The O,N-diacyl O,N-acetals
2, 3 and 4 were smoothly obtained in moderate to good
Results and Discussion
Synthesis of 2,5-dihydro-1,3-thiazoles
By means of the modified Asinger reaction [3] yields via that nucleophilic substitution (Tables 2, 3
four different 2,5-dihydro-1,3-thiazoles 1 were pre- and 4).
pared as precursors for the intended route. The synthe-
Starting from the imines 1a and 1b the O,N-diacyl
sis was realized by using an α-chloroaldehyde, a sec- O,N-acetals 2 were obtained as racemates after workup
ond variable carbonyl compound (aldehyde or ketone), by column chromatography or recrystallization (Ta-
aqueous ammonia and sodium hydrogen sulfide in ble 2). The results demonstrate the variability of the
dichloromethane (Scheme 2).
acyl chloride and the carboxylic acid. Most notably,
In addition to the established cyclic imines 1a–b and a high conversion could be reached by using sodium
1d, we report on compound 1c for the first time. As benzoate as nucleophile. Accordingly, the O,N-diacyl
O,N-acetal 2f was obtained in 87% yield. Even if the
yield was only moderate, the synthesis of formic ester
(2e) was also possible.
Apart from the 2,5-dihydro-1,3-thiazoles 1a and 1b,
the imines 1c and 1d were converted to the O,N-
diacyl O,N-acetals 3 and 4 via the described synthesis
route. The characteristic attribute of the 2,5-dihydro-
Scheme 2. Synthesis of the 2,5-dihydro-1,3-thiazoles 1 (R1,
R2 = alkyl, aryl; R3, R4 = H, alkyl) [3].
Brought to you by | University of California
Authenticated
Download Date | 1/19/16 2:42 PM

T. Stalling et al. · The Synthesis of O,N-Diacyl O,N-Acetals
1047
Table 2. Racemic O,N-diacyl O,N-acetals 2 containing one stereogenic centera.
Imine
O,N-Acetal
R1
R2
R3
R4
Yieldb (%)
1a
1a
1a
1a
1a
1a
1b
2a
2b
2c
2d
2e
2f
CH3
CH3
CH3
CH3
H
C6H5
CH3
C2H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
72
69
55
63
43
87
76
trans-CH=CHC6H5
C6H5
C6H5
CH3
CH3
2g
trans-CH=CHC6H5
-(CH2)5-
a
All reactions were performed with an imine-acyl chloride-sodium carboxylate ratio of 1 : 1.1 : 4; b all yields are isolated yields.
Table 3. Racemic O,N-diacyl O,N-acetals 3 containing two
stereogenic centersa.
Imine O,N-Acetal
R1
R2
Yieldb (%)
drc
1c
1c
1c
1c
3a
3b
3c
3d
CH3
H
C6H5
H
C6H5
C6H5
CH3
65
60
84
62
87 : 13
61 : 39
76 : 24
85 : 15
CH3
a
All reactions were performed with an imine-acyl chloride-sodium
b
carboxylate ratio of 1 : 1.1 : 4; all yields are isolated total yields;
c
diastereomeric ratio according to the 1H NMR spectrum of the
crude product.
Table 4. Racemic O,N-diacyl O,N-acetals 4 containing two
stereogenic centersa.
Scheme 3. One-pot synthesis of the O,N-diacyl O,N-acetals
2, 3 and 4 (R1, R2 = alkyl, aryl; R3, R4 = H, alkyl;
R5 = alkyl, aryl, aralkenyl; R6 = H, alkyl, aryl).
Imine O,N-
R1
R2
Yieldb
(%)
drc
1,3-thiazoles 1c and 1d is their stereogenic center.
Generating the O,N-diacyl O,N-acetals 3 and 4 starting
from the racemic imines 1c and 1d led to the formation
of two racemic diastereomers (Tables 3 and 4). Due at-
tention needs to be paid to the fact that the configu-
ration at the existing stereogenic center of the imines
can influence the formation of the new chirality center
formed in the reaction [18, 38].
Acetal
1d
1d
1d
1d
1d
1d
4a
4b
4c
4d
4e
4f
CH3
H
C6H5
H
C6H5
C6H5
CH3
CH3
CH3
55
78
80
77
72
83
71 : 29
65 : 35
92 : 8
90 : 10
> 95 : 5
74 : 26
CH3
CH3 trans-CH=CHC6H5
a
All reactions were performed with an imine-acyl chloride-sodium
b
carboxylate ratio of 1 : 1.1 : 4; all yields are isolated total yields;
c
diastereomeric ratio according to the 1H NMR spectrum of the
All O,N-diacyl O,N-acetals (3 and 4) were obtained
in moderate to very good yields. The use of sodium
crude product.
Brought to you by | University of California
Authenticated
Download Date | 1/19/16 2:42 PM

1048
T. Stalling et al. · The Synthesis of O,N-Diacyl O,N-Acetals
benzoate in the synthesis of 3c and 4c led to yields
similar to that of the formation of 2f (see above). The
mentioned influence of the configuration at the existing
stereogenic center of the imines on the stereochemical
course of the reaction causes a diastereoselective for-
mation of the products 3 and 4. In one case the O,N-
diacyl O,N-acetal was even formed diastereospecifi-
cally (4e). On the whole, no crucial difference between
the diastereoselectivities of the formations of the O,N-
diacyl O,N-acetals 3 and 4 could be noticed, although
the highest diastereoselectivities were obtained starting
from the imine 1d.
We were able to obtain single crystals of the ma-
jor diastereomer of 3a and 4e to verify the proposed
structures by single-crystal X-ray diffraction analysis
(Figs. 1 and 2). Additionally, the relative configuration
of the two stereocenters was determined.
Fig. 2 (color online). Molecular structure of the major
diastereomer (R*,R*)-4e in the crystal. The crystallographic
atom numbering does not follow the IUPAC nomenclature.
The structure of the major diastereomer of 3a doc-
uments the expected trans-configuration between the
carboxyl and the phenyl group (Fig. 1). In contrast, figuration of all O,N-diacyl O,N-acetals 3 and 4 were
a cis-configuration between the carboxyl group and the appointed congruent to the configurations documented
tert-butyl group has been revealed by the X-ray crys- by the X-ray crystal structure analyses of 3a and 4e.
tal structure of the major diastereomer of 4e (Fig. 2). That circumstance points out the different influences
In compliance with the NMR data, the relative con- of the existing stereogenic center of the imines on the
creation of the new chiral center.
As shown in Fig. 3, the N-acyliminium ions lead-
ing to the amides 3 are attacked by the carboxylate
trans to the phenyl group. The reason for this reaction
course is the bulkiness of the phenyl group. The like-
wise voluminous carboxylate avoids the bulky phenyl
group [18, 38] and attacks from the less hindered side
resulting predominantly in trans-configurated amides
3. On the other hand, the attack of the carboxylate
on the N-acyliminium ions occurs cis to the tert-butyl
group during the reaction to O,N-diacyl O,N-acetals
4 (Fig. 4). In that case the existing stereogenic cen-
Fig. 1 (color online). Molecular structure of the major dia- Fig. 3. Preferred attack of the carboxylate leading to trans-
stereomer (R*,R*)-3a in the crystal. The crystallographic configurated O,N-diacyl O,N-acetals 3. For the sake of clar-
atom numbering does not follow the IUPAC nomenclature.
ity, the methyl groups are omitted.
Brought to you by | University of California
Authenticated
Download Date | 1/19/16 2:42 PM

T. Stalling et al. · The Synthesis of O,N-Diacyl O,N-Acetals
1049
recorded on a Bruker Tensor 27 spectrometer equipped with
a “GoldenGate” diamond ATR unit. The following start-
ing materials were prepared by literature procedures: cin-
namoyl chloride [39], 2-chloro-2-methylpropanal [40] and
(RS)-2-chloro-2-phenylpropanal [41]. The sodium carboxy-
lates were dried in vacuum by heating to 200 ◦C in the pres-
R
ence of Sicapentꢀ. All other starting materials were com-
mercially available and used without further purification. In
cases of diastereomeric products (3a–d and 4a–f), only the
major one is described.
Fig. 4. Preferred attack of the carboxylate leading to cis-
configurated O,N-diacyl O,N-acetals 4. For the sake of clar-
ity, the methyl groups are omitted.
2,2,5,5-Tetramethyl-2,5-dihydrothiazole (1a) [35]
To a suspension of sodium hydrogen sulfide hydrate
(26.66 g, 0.36 mol), acetone (57.93 g, 1.00 mol) and 25%
aqueous ammonia solution (60.66 g, 0.91 mol) 2-chloro-
2-methylpropanal (35.66 g, 0.34 mol) was added dropwise
while the temperature was kept between 5 ◦C and 10 ◦C. Af-
terwards the suspension was warmed to room temperature,
ter is further away from the reaction center. On ac-
count of this, the direct influence on the creation of
the new stereogenic center is less important. In fact,
the bulky tert-butyl group displaces the amido moiety
to the opposite site [18, 38]. The attack of the carboxy-
late occurs, therefore, evasively on the amido moiety and 133 mL of dichloromethane was added. The resulting re-
action mixture was stirred for 2 h at room temperature. The
phases were separated, and the aqueous phase was extracted
with dichloromethane (2 × 10 mL). The combined organic
phases were dried over magnesium sulfate, and the solvent
was removed at the rotary evaporator. The residue was re-
crystallized from petroleum ether 40/60. The title compound
was obtained as a colorless solid (41.94 g, 0.29 mol, 88%).
M. p. 51 ◦C. – 1H NMR (125.8 MHz, CDCl3): δ = 1.56, 1.68
(2s, 12H, 2 × C(CH3)2), 6.84 (s, 1H, CH) ppm. – 13C NMR
(500.1 MHz, CDCl3): δ = 29.9, 33.7 (2 × C(CH3)2), 65.5
(C(CH3)2), 89.2 (C(CH3)2), 165.7 (C=N) ppm.
leading predominantly to cis-configurated O,N-diacyl
O,N-acetals 4.
Conclusion
Starting from different achiral and chiral 2,5-
dihydro-1,3-thiazoles 1, which were obtained by the
modified Asinger reaction, we succeeded in the syn-
thesis of the new O,N-diacyl O,N-acetals 2, 3 and 4
in moderate to very good yields in a one-pot reac-
tion. With C2-chiral as well as C5-chiral starting mar-
terials we observed high diastereoselectivity in certain
cases. All relative configurations were clarified by X-
ray crystal structure analyses. The presented study has
2,2-Dimethyl-1-thia-4-azaspiro[4.5]dec-3-ene (1b) [36]
To a suspension of sodium hydrogen sulfide hydrate
(22.40 g, 0.30 mol), cyclohexanone (29.50 g, 0.30 mol) and
opened new routes to O,N-diacyl O,N-acetals based 25% aqueous ammonia solution (16.95 g, 0.32 mol) 2-
chloro-2-methylpropanal (21.33 g, 0.20 mol) was added
dropwise while the temperature was kept between 5 ◦C and
10 ◦C. Afterwards the suspension was warmed to room tem-
perature and 50 mL of dichloromethane was added. The re-
sulting reaction mixture was stirred for 15 h at room tem-
perature. The phases were separated, and the aqueous phase
on 2,5-dihydro-1,3-thiazoles and similar heterocycles
which are known for the pharmacological relevance of
their structural elements.
Experimental Section
Preparative column chromatography was carried out us- was extracted with dichloromethane (2 × 20 mL). The com-
ing Grace SiO2 (0.035 – 0.070 mm, type KG 60) with n- bined organic phases were dried over magnesium sulfate,
hexane and ethyl acetate as eluents. TLC was performed and the solvent was removed at the rotary evaporator. The
on Merck SiO2 F254 plates on aluminum sheets. 1H and crude product was purified by fractional distillation (76 ◦C,
13C NMR spectra were recorded on a Bruker Avance DRX 1 mbar). The title compound was obtained as a colorless oil
500 instrument. Multiplicities of carbon signals were deter- (24.18 g, 0.13 mol, 65%). B. p. 76 ◦C/1 mbar. – 1H NMR
mined with DEPT experiments. Assignments of proton and (125.8 MHz, CDCl3): δ = 1.24 – 1.50, 1.52 – 2.06 (2m, 10H,
carbon resonances were made with H,H-COSY and HMQC -(CH2)5-), 1.51 (s, 6H, C(CH3)2), 6.94 (s, 1H, CH) ppm. –
experiments. MS and HRMS spectra were obtained with 13C NMR (500.1 MHz, CDCl3): δ = 24.1 (C(CH3)2), 24.8,
a Finnigan MAT 95 (EI and CI) and a Waters Q-TOF Pre- 30.1, 42.1 (-(CH2)5-), 62.7 (C(CH3)2), 95.7 (C-(CH2)5-),
mier (ESI, positive mode) spectrometer. IR spectra were 165.6 (C=N) ppm.
Brought to you by | University of California
Authenticated
Download Date | 1/19/16 2:42 PM

1050
T. Stalling et al. · The Synthesis of O,N-Diacyl O,N-Acetals
(RS)-2,2,5-Trimethyl-5-phenyl-2,5-dihydrothiazole (1c)
cooled to 0 – 5 ◦C before 1.1 equivalents of the acyl chlo-
ride was added dropwise. After stirring for 16 h at room tem-
perature four equivalents of the respective dried sodium car-
boxylate were added. After stirring for 16 h at room tem-
perature the solvent was removed at the rotary evapora-
tor. The residue was extracted with 100 mL of n-hexane-
dichloromethane (1:1) and filtered. The solvent was removed
at the rotary evaporator. The purification of the crude product
is described in the individual experimental details.
To a suspension of sodium hydrogen sulfide hydrate
(27.91 g, 0.38 mol), acetone (47.00 g, 0.81 mol) and 25%
aqueous ammonia solution (50.05 g, 0.95 mol) (RS)-2-
chloro-2-phenylpropanal (64.31 g, 0.38 mol) was added
dropwise while the temperature was kept between 5 ◦C
and 10 ◦C. Afterwards again 25% aqueous ammonia solu-
tion (9.10 g, 0.14 mol) and 10 mL of dichloromethane were
added. The resulting reaction mixture was stirred for 15 h
at 10 ◦C. The phases were separated, and the aqueous phase
was extracted with dichloromethane (2 × 10 mL). The com-
bined organic phases were dried over magnesium sulfate, and
the solvent was removed at the rotary evaporator. The crude
product was purified by fractional distillation (90 – 92 ◦C,
0.65 mbar). The title compound was obtained as a yellow oil
(45.19 g, 0.22 mol, 58%). B. p. 90 – 92 ◦C/0.65 mbar. – IR
(ATR): ν = 2973, 2926, 1647, 1445, 1363, 1127, 932, 760,
697 cm−1. – 1H NMR (500.1 MHz, CDCl3): δ = 1.73, 1.75
(2s, 6H, C(CH3)2), 1.95 (s, 3H, CCH3), 7.08 (s, 1H, CH),
7.20 – 7.39 (m, 5H, CHAr) ppm. – 13C NMR (125.8 MHz,
CDCl3): δ = 28.6 (CCH3), 32.9, 33.6 (C(CH3)2), 71.6
(CCH3), 89.7 (C(CH3)2), 126.3, 127.3, 128.6, 143.3 (CAr),
163.0 (C=N) ppm. – MS (CI, isobutane): m/z (%) = 206.2
(100) [M+H]+. – HRMS (CI, isobutane): m/z = 206.0998
(calcd. 206.1003 for C12H16NS, [M+H]+).
(RS)-3-Benzoyl-2,2,5,5-tetramethyl-1,3-thiazolidin-4-yl
acetate (2a)
Following the GP, dihydrothiazole 1a (2.86 g,
19.97 mmol), benzoyl chloride (3.09 g, 21.98 mmol)
and sodium acetate (6.56 g, 79.97 mmol) were used. The
crude product was crystallized from petroleum ether 40/60.
The title compound was obtained as a colorless solid
(4.42 g, 14.38 mmol, 72%). M. p. 123 ◦C. – IR (ATR):
ν = 2974, 2935, 1735, 1664 cm−1. – 1H NMR (500.1 MHz,
CDCl3): δ = 1.20, 1.65, 1.98, 2.00 (4s, 12H, 2 × C(CH3)2),
2.05 (COCH3), 6.27 (s, 1H, CH), 7.31 – 7.40 (m, 5H,
CHAr) ppm. – 13C NMR (125.8 MHz, CDCl3): δ = 20.6
(COCH3), 23.0, 30.8, 30.9 (2 × C(CH3)2), 52.2 (C(CH3)2),
73.0 (C(CH3)2), 93.5 (CH), 125.6, 126.3, 128.3, 128.6,
129.8, 137.5 (CAr), 168.9, 170.7 (2 × CO) ppm. – MS (CI,
isobutane): m/z (%) = 308.1 (100) [M+H]+. – HRMS (EI,
70 eV): m/z = 307.1243 (calcd. 307.1242 for C16H21NO3S,
[M]+).
(RS)-2-tert-Butyl-5,5-dimethyl-2,5-dihydrothiazole (1d) [37]
To a suspension of sodium hydrogen sulfide hydrate
(20.35 g, 0.27 mol), pivalaldehyde (25.75 g, 0.30 mol) and
25% aqueous ammonia solution (38.68 g, 0.58 mol) 2-
chloro-2-methylpropanal (26.63 g, 0.25 mol) was added
dropwise while the temperature was kept between 5 ◦C and
10 ◦C. The resulting reaction mixture was stirred for 3 h at
room temperature. Afterwards 100 mL of dichloromethane
was added to the suspension. The phases were separated,
and the aqueous phase was extracted with dichloromethane
(2 × 10 mL). The combined organic phases were dried over
magnesium sulfate, and the solvent was removed at the ro-
tary evaporator. The crude product was purified by frac-
tional distillation (59 ◦C, 1.33 mbar). The title compound
was obtained as a colorless oil (38.03 g, 0.22 mol, 89%).
B. p. 59 ◦C/1.33 mbar. – 1H NMR (500.1 MHz, CDCl3):
δ = 0.95 (s, 9H, C(CH3)3), 1.45 (s, 6H, C(CH3)2), 5.51
(d, 4J = 2.5 Hz, 1H, CHC(CH3)3), 6.98 (d, 4J = 2.5 Hz,
1H, CH) ppm. – 13C NMR (125.8 MHz, CDCl3): δ =
26.7 (C(CH3)3), 29.0, 29.7 (C(CH3)2), 36.0 (C(CH3)3), 63.5
(C(CH3)2), 95.2 (CHC(CH3)3), 168.5 (C=N) ppm.
(RS)-3-Acetyl-2,2,5,5-tetramethyl-1,3-thiazolidin-4-yl
acetate (2b)
Following the GP, dihydrothiazole 1a (2.86 g,
19.97 mmol), acetyl chloride (1.71 g, 21.79 mmol) and
sodium acetate (6.56 g, 79.97 mmol) were used. The
crude product was crystallized from diethyl ether. The
title compound was obtained as a colorless solid (3.38 g,
13.78 mmol, 69%). M. p. 43 ◦C. – IR (ATR): ν = 2983,
1674, 1340, 1212 cm−1. – 1H NMR (500.1 MHz, CDCl3):
δ = 1.25, 1.55, 1.79, 1.91 (4s, 12H, 2 × C(CH3)2), 2.11
(s, 3H, OCOCH3), 2.20 (s, 3H, NCOCH3), 6.40 (s, 1H,
CH) ppm. – 13C NMR (125.8 MHz, CDCl3): δ = 20.8,
23.0 (2 × COCH3), 26.1, 29.9, 30.4, 31.8 (2 × C(CH3)2),
51.8 (C(CH3)2), 68.5 (C(CH3)2), 92.6 (CH), 169.6, 170.2
(2 × CO) ppm. – MS (CI, isobutane): m/z (%) = 246.2 (100)
[M+H]+. – HRMS (CI, isobutane): m/z = 246.1163 (calcd.
246.1164 for C11H20NO3S, [M+H]+).
(RS)-3-Propanoyl-2,2,5,5-tetramethyl-1,3-thiazolidin-4-yl
acetate (2c)
General Procedure (GP) for the synthesis of the O,N-diacyl
O,N-acetals 2, 3 and 4
Following the GP, dihydrothiazole 1a (1.43 g,
Under argon atmosphere one equivalent of the respective 9.98 mmol), propanoyl chloride (1.01 g, 10.92 mmol)
2,5-dihydrothiazole dissolved in anhydrous acetonitrile was and sodium acetate (3.28 g, 39.99 mmol) were used. The
Brought to you by | University of California
Authenticated
Download Date | 1/19/16 2:42 PM

T. Stalling et al. · The Synthesis of O,N-Diacyl O,N-Acetals
1051
crude product was crystallized from diethyl ether. The 129.1, 129.6, 137.5 (CAr), 164.5 (CO), 170.0 (CHO) ppm.
title compound was obtained as a colorless solid (1.42 g, – MS (CI, isobutane): m/z (%) = 294.1 (100) [M+H]+. –
5.47 mmol, 55%). M. p. 42 ◦C. – IR (ATR): ν = 2974, 2939, HRMS (CI, isobutane): m/z = 294.1163 (calcd. 294.1164
1727, 1677, 1354, 1218 cm−1. – 1H NMR (500.1 MHz, for C15H20NO3S, [M+H]+).
CDCl3): δ = 1.14 (t, 3J = 7.9 Hz, 3H, CH2CH3), 1.35, 1.53,
(RS)-3-Acetyl-2,2,5,5-tetramethyl-1,3-thiazolidin-4-yl
1.80, 1.91 (4s, 12H, 2 × C(CH3)2), 2.08 (s, 3H, COCH3),
benzoate (2f)
2.46 (q, 3J = 7.9 Hz, 2H, CH2CH3), 6.49 (s, 1H, CH) ppm.
–
13C NMR (125.8 MHz, CDCl3): δ = 9.07 (CH2CH3),
Following the GP, dihydrothiazole 1a (2.86 g,
19.97 mmol), acetyl chloride (1.71 g, 21.79 mmol) and
sodium benzoate (11.52 g, 79.94 mmol) were used. The
crude product was purified by column chromatography on
silica gel (solvent: n-hexane-ethyl acetate, 4 : 1, Rf = 0.48).
The title compound was obtained as a colorless oil (5.34 g,
17.37 mmol, 87%). – IR (ATR): ν = 2986, 2929, 1748,
1344, 1211, 705 cm−1. – 1H NMR (500.1 MHz, CDCl3):
δ = 1.26, 1.59, 1.88, 1.94 (4s, 12H, 2 × C(CH3)2), 2.14 (s,
20.5 (COCH3), 23.1, 29.5, 29.8, 23.8 (2 × C(CH3)2), 26.9
(CH2CH3), 53.2 (C(CH3)2), 68.5 (C(CH3)2), 101.5 (CH),
169.1, 173.4 (2 × CO) ppm. – MS (CI, isobutane): m/z
(%) = 260.2 (100) [M+H]+. – HRMS (CI, isobutane):
m/z = 260.1321 (calcd. 260.1320 for C12H22NO3S,
[M+H]+).
(RS)-2,2,5,5-Tetramethyl-3-[(2E)-3-phenylprop-2-enoyl]-
1,3-thiazolidin-4-yl acetate (2d)
3H, COCH3), 6.64 (s, 1H, CH), 7.38–8.11 (m, 5H, CHAr
)
ppm. – 13C NMR (125.8 MHz, CDCl3): δ = 21.5, 21.3, 22.9,
29.8, 30.7 (5 × CH3), 54.8 (C(CH3)2), 73.6 (C(CH3)2), 91.7
(CH), 123.5, 124.7, 126.9, 128.7, 128.8, 135.8 (CAr), 167.8,
171.7 (2 × CO) ppm. – MS (CI, isobutane): m/z (%) = 308.0
(100) [M+H]+. – HRMS (CI, isobutane): m/z = 308.1315
(calcd. 308.1320 for C16H22NO3S, [M+H]+).
Following the GP, dihydrothiazole 1a (2.86 g,
19.97 mmol), cinnamoyl chloride (3.66 g, 21.97 mmol)
and sodium acetate (6.56 g, 79.97 mmol) were used. The
crude product was purified by column chromatography on
silica gel (solvent: n-hexane-ethyl acetate, 3 : 2, Rf = 0.80).
The title compound was obtained as a colorless solid
(4.20 g, 12.60 mmol, 63%). M. p. 149 ◦C. – IR (ATR):
ν = 2995, 2977, 2932, 1718, 1668, 740 cm−1. – 1H NMR
(500.1 MHz, CDCl3): δ = 1.40, 1.57, 1.88, 2.02 (4s, 12H,
2 × C(CH3)2), 2.09 (s, 3H, COCH3), 6.76 (s, 1H, NCH),
6.96 (d, 3J = 15.4 Hz, 1H, CH=CHPh), 7.30 – 7.50 (m,
5H, CHAr), 7.68 (d, 3J = 15.4 Hz, 1H, CH=CHPh) ppm.
(RS)-2,2-Dimethyl-4-[(2E)-3-phenylprop-2-enoyl]-1-thia-
4-azaspiro[4.5]decan-3-yl acetate (2g)
Following the GP, dihydrothiazole 1b (3.66 g,
19.97 mmol), cinnamoyl chloride (3.66 g, 21.79 mmol)
and sodium acetate (6.56 g, 79.97 mmol) were used. The
crude product was purified by column chromatography on
silica gel (solvent: n-hexane-ethyl acetate, 9 : 1, Rf = 0.37).
The title compound was obtained as a colorless solid
(5.67 g, 15.18 mmol, 76%). M. p. 124 – 125 ◦C. – IR (ATR):
ν = 2991, 2933, 1730, 1658, 1449, 1193, 731 cm−1. – 1H
NMR (500.1 MHz, CDCl3): δ = 1.20 – 1.38, 1.53 – 1.90,
2.82 – 3.25 (3m, 10H, -(CH2)5-), 1.40, 1.52 (2s, 6H,
C(CH3)2), 2.09 (s, 3H, COCH3), 6.78 (s, 1H, NCH), 6.96
(d, 3J = 15.5 Hz, 1H, CH=CHPh), 7.34 – 7.54 (m, 5H,
CHAr), 7.65 (d, 3J = 15.5 Hz, 1H, CH=CHPh) ppm.
–
13C NMR (125.8 MHz, CDCl3): δ = 20.4 (COCH3),
23.9, 29.8, 29.9, 30.7 (2 × C(CH3)2), 51.8 (C(CH3)2), 73.9
(C(CH3)2), 91.4 (NCH), 118.7 (CH=CHPh), 127.9, 128.0,
128.7, 128.8, 129.7, 135.0 (CAr), 144.3 (CH=CHPh), 165.5,
170.4 (2 × CO) ppm. – MS (CI, isobutane): m/z (%) = 334.2
(100) [M+H]+. – HRMS (CI, isobutane): m/z = 334.1476
(calcd. 334.1477 for C18H24NO3S, [M+H]+).
(RS)-3-Benzoyl-2,2,5,5-tetramethyl-1,3-thiazolidin-4-yl
formate (2e)
–
13C NMR (125.8 MHz, CDCl3): δ = 20.4 (COCH3),
Following the GP, dihydrothiazole 1a (1.43 g,
9.98 mmol), benzoyl chloride (1.55 g, 11.03 mmol)
and sodium formate (2.72 g, 40.00 mmol) were used. The
crude product was purified by column chromatography on
silica gel (solvent: n-hexane-ethyl acetate, 1 : 1, Rf = 0.86).
The title compound was obtained as a colorless solid
(1.25 g, 4.26 mmol, 43%). M. p. 113 – 116 ◦C. – IR (ATR):
ν = 2976, 2931, 1718, 1661, 1444, 1068, 698 cm−1. – 1H
NMR (500.1 MHz, CDCl3): δ = 1.20, 1.65, 2.05, 2.10 (4s,
12H, 2 × C(CH3)2), 6.45 (s, 1H, CH), 7.19–8.01 (m, 5H,
CHAr), 7.91 (s, 1H, CHO) ppm. – 13C NMR (125.8 MHz,
CDCl3): δ = 23.2, 30.9, 31.1, 31.6 (2 × C(CH3)2), 52.7
24.1, 24.4 (C(CH3)2), 25.1, 25.3, 25.4, 25.8, 30.0 (-
(CH2)5-), 51.0 (C(CH3)2), 80.2 (C-(CH2)5-), 92.2 (NCH),
119.5 (CH=CHPh), 127.9, 128.0, 128.7, 128.8, 129.7,
135.0 (CAr), 142.8 (CH=CHPh), 165.8, 170.5 (2 × CO)
ppm. – MS (ESI): m/z (%) = 395.9 (100) [M+Na]+.
– HRMS (ESI): m/z = 395.9245 (calcd. 395.9245 for
C21H27NNaO3S, [M+Na]+).
(4R∗,5R∗)-3-Benzoyl-2,2,5-trimethyl-5-phenyl-
1,3-thiazolidin-4-yl acetate (3a)
Following the GP, dihydrothiazole 1c (2.05 g,
(C(CH3)2), 73.0 (C(CH3)2), 94.1 (CH), 125.6, 128.5, 128.6, 9.98 mmol), benzoyl chloride (1.55 g, 10.76 mmol)
Brought to you by | University of California
Authenticated
Download Date | 1/19/16 2:42 PM

1052
T. Stalling et al. · The Synthesis of O,N-Diacyl O,N-Acetals
and sodium acetate (3.28 g, 39.99 mmol) were used. 1659, 1344, 1211, 705 cm−1. – 1H NMR (500.1 MHz,
A mixture of both racemic diastereomers was obtained as CDCl3): δ = 1.56, 1.72 (C(CH3)2), 1.98 (CCH3), 2.13
the crude product (2.40 g, 6.49 mmol, 65%, dr = 87:13). (COCH3), 6.98 (s, 1H, CH), 7.08 – 7.69 (m, 10H, CHAr
)
For analysis, the racemic diastereomers were crystallized ppm. – 13C NMR (125.8 MHz, CDCl3): δ = 25.0, 26.6,
from n-hexane to give the major racemic diastereomer as 30.1, 30.4 (4 × CH3), 60.8 (C(CH3)2), 73.3 (CCH3), 92.5
a colorless solid. M. p. 89 – 94 ◦C. – IR (ATR): ν = 3065, (CH), 126.6, 127.6, 128.4, 128.5, 128.6, 128.7, 128.9, 129.3,
2986, 2927, 1741, 1656, 1358, 1208, 698 cm−1. – 1H NMR 130.0, 130.1, 133.8, 143.5 (CAr), 166.0, 169.3 (2 × CO)
(500.1 MHz, CDCl3): δ = 1.47, 1.87 (2s, 6H, C(CH3)2), ppm. – MS (CI, isobutane): m/z (%) = 370.1 (23) [M+H]+,
2.05 (s, 3H, CCH3), 2.08 (s, 3H, COCH3), 6.90 – 6.91 (m, 248.1 (100). – HRMS (CI, isobutane): m/z = 370.1477
2H, CHAr), 6.92 (s, 1H, CH), 7.27 – 7.73 (m, 8H, CHAr
)
(calcd. 370.1477 for C21H24NO3S, [M+H]+).
ppm. – 13C NMR (125.8 MHz, CDCl3): δ = 20.8 (COCH3),
26.3, 29.8, 30.7 (C(CH3)2, CCH3), 61.0 (C(CH3)2), 72.8
(CCH3), 93.4 (CH), 125.6, 127.2, 127.7, 128.4, 129.9,
137.2, 143.1 (CAr), 169.4, 170.4 (2 × CO) ppm. – MS (CI,
isobutane): m/z (%) = 370.1 (23) [M+H]+, 310.0 (100). –
HRMS (CI, isobutane): m/z = 370.1477 (calcd. 370.1477
for C21H24NO3S, [M+H]+).
(4R∗,5R∗)-3-Acetyl-2,2,5-trimethyl-5-phenyl-
1,3-thiazolidin-4-yl formate (3d)
Following the GP, dihydrothiazole 1c (4.10 g,
19.97 mmol), acetyl chloride (1.71 g, 21.79 mmol) and
sodium formate (5.44 g, 79.99 mmol) were used. A mix-
ture of both racemic diastereomers was obtained as the
crude product (3.63 g, 12.37 mmol, 62%, dr = 85:15).
For analysis, the racemic diastereomers were purified by
column chromatography on silica gel (solvent: n-hexane-
(4R∗,5R∗)-3-Benzoyl-2,2,5-trimethyl-5-phenyl-
1,3-thiazolidin-4-yl formate (3b)
Following the GP, dihydrothiazole 1c (2.05 g, ethyl acetate, 4 : 1, Rf = 0.42) to give the major racemic
9.98 mmol), benzoyl chloride (1.55 g, 10.76 mmol) diastereomer as a colorless solid. M. p. 116 – 118 ◦C. – IR
and sodium formate (2.72 g, 40.00 mmol) were used. (ATR): ν = 2979, 2933, 1715, 1664, 1496, 1444, 1088,
A mixture of both racemic diastereomers was obtained as 797 cm−1. – 1H NMR (500.1 MHz, CDCl3): δ = 1.54,
the crude product (2.13 g, 5.99 mmol, 60%, dr = 61:39). 1.64 (2s, 6H, C(CH3)2), 1.85 (s, 3H, CCH3), 2.09 (s, 3H,
For analysis, the racemic diastereomers were purified by COCH3), 7.39 (s, 1H, CH), 7.25 – 7.72 (m, 5H, CHAr),
column chromatography on silica gel (solvent: n-hexane- 8.33 (s, 1H, CHO) ppm. – 13C NMR (125.8 MHz, CDCl3):
ethyl acetate, 4 : 1, Rf = 0.37) to give the major racemic δ = 24.8, 26.7, 29.9, 31.7 (4 × CH3), 60.0 (C(CH3)2),
diastereomer as a colorless solid. M. p. 146 – 148 ◦C. – IR 73.4 (CCH3), 91.2 (CH), 126.4, 126.5, 127.5, 128.3, 128.5,
(ATR): ν = 2978, 2937, 1720, 1657, 1584, 1449, 1067, 143.1 (CAr), 160.4 (CO), 168.8 (CHO) ppm. – MS (CI,
700 cm−1. – 1H NMR (500.1 MHz, CDCl3): δ = 1.45, 1.86 isobutane): m/z (%) = 294.1 (100) [M+H]+. – HRMS
(2s, 6H, C(CH3)2), 2.10 (s, 3H, CCH3), 7.14 (s, 1H, CH), (CI, isobutane): m/z = 294.1164 (calcd. 294.1164 for
6.90 – 7.80 (m, 5H, CHAr), 7.96 (s, 1H, CHO) ppm. – 13C C15H20NO3S, [M+H]+).
NMR (125.8 MHz, CDCl3): δ = 26.4, 29.9, 31.1 (3 × CH3),
61.4 (C(CH3)2), 72.8 (CCH3), 94.01 (CH), 125.6, 127.2,
127.7, 128.4, 128.5, 128.6, 129.1, 129.7, 129.8, 133.5,
137.2, 143.2 (CAr), 165.1 (CO), 170.5 (CHO) ppm. – MS
(CI, isobutane): m/z (%) = 356.1 (100) [M+H]+. – HRMS
(CI, isobutane): m/z = 356.1295 (calcd. 356.1294 for
C20H22NO3S, [M+H]+).
(2R∗,4R∗)-3-Benzoyl-2-tert-butyl-5,5-dimethyl-
1,3-thiazolidin-4-yl acetate (4a)
Following the GP, dihydrothiazole 1d (3.42 g,
19.96 mmol), benzoyl chloride (3.09 g, 21.98 mmol)
and sodium acetate (6.56 g, 79.97 mmol) were used. A mix-
ture of both racemic diastereomers was obtained as the
crude product (3.69 g, 11.00 mmol, 55%, dr = 71:29). For
analysis, the racemic diastereomers were purified by column
chromatography on silica gel (solvent: n-hexane-ethyl ac-
(4R∗,5R∗)-3-Acetyl-2,2,5-trimethyl-5-phenyl-
1,3-thiazolidin-4-yl benzoate (3c)
Following the GP, dihydrothiazole 1c (2.05 g, etate, 4 : 1, Rf = 0.44) to give the major racemic diastereomer
9.98 mmol), acetyl chloride (0.86 g, 10.96 mmol) and as a colorless solid. M. p. 77 – 80 ◦C. – IR (ATR): ν = 2961,
sodium benzoate (5.76 g, 39.97 mmol) were used. A mixture 2870, 1748, 1669, 1603, 1341, 1219, 699 cm−1. – 1H NMR
of both racemic diastereomers was obtained as the crude (500.1 MHz, CDCl3): δ = 1.01 (s, 9H, C(CH3)3), 1.12,
product (3.10 g, 8.39 mmol, 84%, dr = 76:24). For analysis, 1.20 (2s, 6H, C(CH3)2), 2.10 (s, 3H, COCH3), 5.84 (s, 1H,
the racemic diastereomers were purified by column chro- CHC(CH3)3), 6.06 (s, 1H, NCH), 7.19 – 7.41 (m, 5H, CHAr
)
matography on silica gel (solvent: n-hexane-ethyl acetate, ppm. – 13C NMR (125.8 MHz, CDCl3): δ = 20.8 (COCH3),
4 : 1, Rf = 0.34) to give the major racemic diastereomer as 22.0, 29.0 (C(CH3)2), 27.3 (C(CH3)3), 37.5 (C(CH3)3), 54.9
a colorless oil. – IR (ATR): ν = 3063, 2980, 2931, 1745, (C(CH3)2), 71.2 (CHC(CH3)3), 92.3 (NCH), 127.5, 128.4,
Brought to you by | University of California
Authenticated
Download Date | 1/19/16 2:42 PM

T. Stalling et al. · The Synthesis of O,N-Diacyl O,N-Acetals
1053
128.5, 128.6, 131.5, 135.9 (CAr), 168.9, 173.5 (2 × CO) (2R∗,4R∗)-3-Acetyl-2-tert-butyl-5,5-dimethyl-
ppm. – MS (CI, isobutane): m/z (%) = 336.2 (20) [M+H]+. 1,3-thiazolidin-4-yl formate (4d)
– HRMS (CI, isobutane): m/z = 336.1634 (calcd. 336.1633
Following the GP, dihydrothiazole 1d (3.42 g,
19.96 mmol), acetyl chloride (1.71 g, 21.79 mmol) and
sodium formate (5.44 g, 79.99 mmol) were used. A mixture
of both racemic diastereomers was obtained as the crude
product (3.98 g, 15.35 mmol, 77%, dr = 90:10). For anal-
ysis, the racemic diastereomers were purified by column
chromatography on silica gel (solvent: n-hexane-ethyl
acetate, 7 : 3, Rf = 0.36) to give the major racemic diastereo-
mer as a colorless solid. M. p. 65 ◦C. – IR (ATR): ν = 2974,
2871, 1720, 1675, 1437, 1282, 1137 cm−1. – 1H NMR
(500.1 MHz, CDCl3): δ = 0.94 (s, 9H, C(CH3)3), 1.32,
1.35 (2s, 6H, C(CH3)2), 2.34 (s, 3H, COCH3), 5.63 (s, 1H,
CHC(CH3)3), 6.41 (s, 1H, NCH), 8.17 (s, 1H, CHO) ppm. –
13C NMR (125.8 MHz, CDCl3): δ = 22.2, 29.7 (C(CH3)2),
23.8 (COCH3), 27.5 (C(CH3)3), 37.5 (C(CH3)3), 53.4
(C(CH3)2), 72.0 (CHC(CH3)3), 89.9 (NCH), 160.0 (CO),
171.8 (CHO) ppm. – MS (CI, isobutane): m/z (%) = 260.1
(100) [M+H]+. – HRMS (CI, isobutane): m/z = 260.1320
(calcd. 260.1320 for C12H22NO3S, [M+H]+).
for C18H26NO3S, [M+H]+).
(2R∗,4R∗)-3-Benzoyl-2-tert-butyl-5,5-dimethyl-
1,3-thiazolidin-4-yl formate (4b)
Following the GP, dihydrothiazole 1d (3.42 g,
19.96 mmol), benzoyl chloride (3.09 g, 21.98 mmol)
and sodium formate (5.44 g, 79.99 mmol) were used.
A mixture of both racemic diastereomers was obtained as
the crude product (5.01 g, 15.59 mmol, 78%, dr = 65:35).
For analysis, the racemic diastereomers were purified by
column chromatography on silica gel (solvent: n-hexane-
ethyl acetate, 7 : 3, Rf = 0.64) to give the major racemic
diastereomer as a colorless solid. M. p. 83 ◦C. – IR (ATR):
ν = 2964, 2872, 1742, 1680, 1436, 1280, 1177 cm−1. – H
1
NMR (500.1 MHz, CDCl3): δ = 1.17 (s, 9H, C(CH3)3),
1.22, 1.35 (2s, 6H, C(CH3)2), 5.97 (s, 1H, CHC(CH3)3),
6.44 (s, 1H, NCH), 7.32 – 8.12 (m, 5H, CHAr), 8.13 (s, 1H,
CHO) ppm. – 13C NMR (125.8 MHz, CDCl3): δ = 22.1,
29.0 (C(CH3)2), 27.5 (C(CH3)3), 37.6 (C(CH3)3), 55.1
(C(CH3)2), 71.5 (CHC(CH3)3), 93.2 (NCH), 127.8, 128.6,
129.9, 131.7, 133.6, 135.8 (CAr), 164.9 (CO), 174.0
(CHO) ppm. – MS (CI, isobutane): m/z (%) = 322.1 (100)
[M+H]+. – HRMS (CI, isobutane): m/z = 322.1475 (calcd.
322.1477 for C17H24NO3S, [M+H]+).
(2R∗,4R∗)-3-Acetyl-2-tert-butyl-5,5-dimethyl-
1,3-thiazolidin-4-yl acetate (4e)
Following the GP, dihydrothiazole 1d (1.71 g,
9.98 mmol), acetyl chloride (0.86 g, 10.96 mmol) and
sodium acetate (3.28 g, 39.99 mmol) were used. A pure
mixture of both racemic diastereomers was obtained as
the crude product (3.93 g, 14.37 mmol, 72%, dr > 95:5).
For analysis, the racemic diastereomers were purified by
column chromatography on silica gel (solvent: n-hexane-
ethyl acetate, 4 : 1, Rf = 0.31) to give the major racemic
diastereomer as a colorless solid. M. p. 79–80 ◦C. – IR
(ATR): ν = 2976, 2871, 1732, 1680, 1370, 1220 cm−1. –
1H NMR (500.1 MHz, CDCl3): δ = 0.95 (s, 9H, C(CH3)3),
1.31, 1.33 (2s, 6H, C(CH3)2), 2.13 (s, 3H, COCH3), 2.33 (s,
(2R∗,4R∗)-3-Acetyl-2-tert-butyl-5,5-dimethyl-
1,3-thiazolidin-4-yl benzoate (4c)
Following the GP, dihydrothiazole 1d (1.71 g,
9.98 mmol), acetyl chloride (0.86 g, 10.96 mmol) and
sodium benzoate (5.76 g, 39.97 mmol) were used. A mixture
of both racemic diastereomers was obtained as the crude
product (2.68 g, 7.99 mmol, 80%, dr = 92:8). For analysis,
the racemic diastereomers were purified by column chro-
matography on silica gel (solvent: n-hexane-ethyl acetate,
7 : 3, Rf = 0.56) to give the major racemic diastereomer as
a colorless solid. M. p. 109 – 111 ◦C. – IR (ATR): ν = 3053,
2971, 2934, 1722, 1673, 1317, 1248, 709 cm−1. – 1H
NMR (500.1 MHz, CDCl3): δ = 0.97 (s, 9H, C(CH3)3),
1.38, 1.40 (2s, 6H, C(CH3)2), 2.44 (COCH3), 5.70 (s,
1H, CHC(CH3)3), 6.61 (s, 1H, NCH), 7.40 – 8.11 (m, 5H,
CHAr) ppm. – 13C NMR (125.8 MHz, CDCl3): δ = 22.3,
29.7 (C(CH3)2), 24.0 (COCH3), 27.6 (C(CH3)3), 37.5
(C(CH3)3), 53.9 (C(CH3)2), 72.1 (CHC(CH3)3), 91.0
3H, OCOCH3), 5.64 (CHC(CH3)3), 6.32 (NCH) ppm. – 13
C
NMR (125.8 MHz, CDCl3): δ = 20.9 (OCOCH3), 22.0, 22.4
(C(CH3)2), 23.0 (COCH3), 26.5 (C(CH3)3), 37.3 (C(CH3)3),
52.0 (C(CH3)2), 71.8 (CHC(CH3)3), 90.2 (NCH), 170.2,
172.0 (2 × CO) ppm. – MS (CI, isobutane): m/z (%) = 274.1
(100) [M+H]+. – HRMS (CI, isobutane): m/z = 274.1476
(calcd. 274.1477 for C13H24NO3S, [M+H]+).
(2R∗,4R∗)-2-tert-Butyl-5,5-dimethyl-3-[(2E)-3-phenylprop-
2-enoyl]-1,3-thiazolidin-4-yl acetate (4f)
Following the GP, dihydrothiazole 1d (3.42 g,
(NCH), 128.6, 128.7, 129.0, 129.9, 133.6 (CAr), 165.6, 19.96 mmol), cinnamoyl chloride (3.66 g, 21.79 mmol)
172.3 (2 × CO) ppm. – MS (CI, isobutane): m/z (%) = 336.1 and sodium acetate (6.56 g, 79.97 mmol) were used. A pure
(100) [M+H]+. – HRMS (CI, isobutane): m/z = 336.1635 mixture of both racemic diastereomers was obtained as
(calcd. 336.1633 for C18H26NO3S, [M+H]+).
the crude product (6.02 g, 16.65 mmol, 83%, dr = 74:26).
Brought to you by | University of California
Authenticated
Download Date | 1/19/16 2:42 PM

1054
T. Stalling et al. · The Synthesis of O,N-Diacyl O,N-Acetals
For analysis, the racemic diastereomers were purified by Table 5. Crystal structure data for compounds (R∗,R∗)-3a and
(R∗,R∗)-4e.
column chromatography on silica gel (solvent: n-hexane-
(R∗,R∗)-3a
C21H23NO3S
369.46
(R∗,R∗)-4e
C13H23NO3S
273.38
0.90 × 0.62 × 0.52
monoclinic
I2/a
11.2959(7)
10.5879(5)
24.8405(18)
90
91.669(8)
90
2969.7(3)
8
1.22
2.2
ethyl acetate, 7 : 3, Rf = 0.72) to give the major racemic
diastereomer as a colorless solid. M. p. 139–141 ◦C. – IR
(ATR): ν = 2929, 2867, 1737, 1667, 1625, 1366, 1223,
1020, 976 cm−1. – 1H NMR (500.1 MHz, CDCl3): δ = 0.99
(s, 9H, C(CH3)3), 1.28, 1.34 (2s, 6H, C(CH3)2), 2.19 (s, 3H,
COCH3), 5.85 (s, 1H, CHC(CH3)3), 6.50 (d, 3J = 16.0 Hz,
1H, CH=CHPh), 6.63 (s, 1H, NCH), 7.35 – 7.69 (m, 5H,
CHAr), 7.86 (d, 3J = 16.0 Hz, 1H, CH=CHPh) ppm.
Formula
Mr
Crystal size, mm3
Crystal system
Space group
0.80 × 0.55 × 0.46
triclinic
¯
P1
˚
a, A
9.4139(9)
10.1088(11)
11.2714(12)
108.424(12)
95.482(12)
107.578(12)
948.25(17)
2
˚
b, A
˚
c, A
–
13C NMR (125.8 MHz, CDCl3): δ = 21.0 (COCH3),
α, deg
β, deg
22.0, 26.8 (C(CH3)2), 27.3 (C(CH3)3), 37.4 (C(CH3)3),
53.8 (C(CH3)2), 71.7 (CHC(CH3)3), 90.3 (NCH), 119.5
(CH=CHPh), 128.1, 128.2, 128.3, 129.0, 134.7, 134.7
(CAr), 144.1 (CH=CHPh), 168.0, 170.4 (2 × CO) ppm. –
MS (CI, isobutane): m/z (%) = 362.2 (20) [M+H]+, 302.2
(100). – HRMS (CI, isobutane): m/z = 362.1790 (calcd.
362.1790 for C20H28NO3S, [M+H]+).
γ, deg
3
˚
V, A
Z
Dcalcd, g cm−3
µ (MoKα ), cm−1
F(000), e
1.29
1.9
392
1184
hkl range
±11, ±12, −14 → 13 ±13, ±13, ±30
−1
˚
((sinθ)/λ)max, A
Refl. measured/
unique/Rint
1.271
1.259
15 730/2941/
0.0496
X-Ray structure determinations
11 946/3553/
0.0536
Param. refined
R(F)/wR(F2)a,b
(all data)
304
232
Intensity data for the single-crystal structure determi-
nations were collected on a Stoe IPDS diffractometer at
153(2) K with MoKα radiation (graphite monochromator,
0.0547/0.0680
0.0403/0.0713
GoF (F2)c
0.829
0.274/−0.211
0.890
0.260/−0.151
˚
λ = 0.71073 A). The structures were solved by Direct Meth-
−3
˚
∆ρfin (max/min), e A
ods and refined by full-matrix least-squares methods with
SHELXS-97 [42] and SHELXL-97 [43], respectively. Non-
hydrogen atoms were refined with anisotropic displacement
parameters. All H atoms were placed in calculated positions
and refined using the riding model. Crystallographic data can
be found in Table 5.
a
b
R(F) = Σ||Fo| − |F ||/Σ|Fo|;
wR(F2) = [Σw(Fo2 − F2)2/
c
c
Σw(Fo2)2]1/2
,
w = [σ2(Fo2) + (AP)2 + BP]−1
,
where P =
(Max(Fo2,0)+2F2)/3; c GoF = [Σw(Fo2 −F2)2/(nobs −nparam)]1/2
.
c
c
Acknowledgement
CCDC883999 (3a) and 884000 (4e) contain the supple-
mentary crystallographic data for this paper. These data can
The silica gel was generously supplied by Grace GmbH &
be obtained free of charge from The Cambridge Crystallo- Co. KG. T. S. and A. S. gratefully acknowledge the Heinz-
graphic Data Centre via www.ccdc.cam.ac.uk/data request/ Neumu¨ller-Stiftung for a doctoral fellowship. We thank W.
cif.
Saak and D. Haase for X-ray crystallography.
[1] W. Keim, H. Offermanns, Angew. Chem. Int. Ed. 2007,
[8] K. Harada in The chemistry of the carbon-nitrogen dou-
ble bond, (Ed.: S. Patai), John Wiley & Sons, London
1992, chapter 6, 255 – 298.
[9] M. Hatam, S. Koepper, J. Martens, Heterocycles 1996,
43, 1653 – 1664.
46, 6010 – 6013.
[2] W. M. Weigert, H. Offermanns, P. Scherberich, Angew.
Chem., Int. Ed. Engl. 1975, 14, 330 – 336.
[3] J. Martens, H. Offermanns, P. Scherberich, Angew.
Chem., Int. Ed. Engl. 1981, 20, 668.
[10] J. Kintscher, J. Martens, Synthesis 1992, 9, 837 – 838.
[4] For a spectacular example, see: A. Do¨mling. I. Ugi, [11] H. Gro¨ger, J. Martens, Synth. Commun. 1996, 26,
Angew. Chem. Int. Ed. 2000, 39, 3168 – 3210.
[5] F. Asinger, Angew. Chem. 1956, 68, 377.
[6] I. Ugi, K. Offermann, Chem. Ber. 1964, 97,
2276 – 2281.
1903 – 1911.
[12] H. Gro¨ger, J. Wilken, J. Martens, I. Neda, V. Pinchuk,
H. Tho¨nnessen, P. G. Jones, R. Schmutzler, Z. Natur-
forsch. 1996, 51b, 1305 – 1312.
[7] F. Asinger, H. Offermanns, Angew. Chem., Int. Ed. [13] H. Gro¨ger, Y. Saida, S. Arai, J. Martens, H. Sasai,
Engl. 1967, 6, 907. M. Shibasaki, Tetrahedron Lett. 1996, 37, 9291 – 9292.
Brought to you by | University of California
Authenticated
Download Date | 1/19/16 2:42 PM

T. Stalling et al. · The Synthesis of O,N-Diacyl O,N-Acetals
1055
[14] I. Reiners, H. Gro¨ger, J. Martens, J. Prakt. Chem. 1997, [30] V. S. Velezheva, A. I. Mel‘man, Y. I. Smushkevich, V. I.
339, 541 – 546.
[15] H. Gro¨ger, Y. Saida, H. Sasai, K. Yamaguchi, J. Mar-
Pol‘shakov, O. S. Anisimova, Pharm. Chem. J. 1990,
24, 917 – 923.
tens, M. Shibasaki, J. Am. Chem. Soc. 1998, 120, [31] N. C. Ling, C. Djerassi, J. Am. Chem. Soc. 1970, 92,
3089 – 3103. 6019 – 6035.
[16] I. Schlemminger, Y. Saida, H. Gro¨ger, W. Maison, [32] M. Sharfuddin, A. Narumi, Y. Iwai, K. Miyazawa,
N. Durot, H. Sasai, M. Shibasaki, J. Martens, J. Org.
S. Yamada, T. Kakuchi, H. Kaga, Tetrahedron: Asym-
Chem. 2000, 65, 4818 – 4825.
metry 2003, 14, 1581 – 1586.
[17] I. Schlemminger, A. Lu¨tzen, A. Willecke, W. Maison, [33] G.-S. Liu, Q.-L. Dong, Y.-S. Yao, Z.-J. Yao, Org. Lett.
R. Koch, W. Saak, J. Martens, Tetrahedron Lett. 2000,
41, 7285 – 7288.
2008, 10, 5393 – 5396.
[34] S.-C. Tuo, J.-L. Ye, A.-E Wang, S.-Y. Huang, P.-Q.
[18] I. Schlemminger, A. Willecke, W. Maison, R. Koch,
Huang, Org. Lett. 2011, 13, 5270 – 5273.
A. Lu¨tzen, J. Martens, J. Chem. Soc., Perkin Trans. 1 [35] S. Ko¨pper, K. Lindner, J. Martens, Tetrahedron 1992,
2001, 2804 – 2816. 48, 10277 – 10292.
[19] H. Leuchs, G. Wulkow, H. Gerland, Chem. Ber. 1932, [36] K. Drauz, H. G. Koban, J. Martens, W. Schwarze,
62, 1586 – 1593.
Liebigs Ann. Chem. 1985, 448 – 452.
[37] J. Martens, J. Kintscher, W. Arnold, Synthesis 1991, 6,
497 – 498.
[38] K. Johannes, J. Martens, Tetrahedron 2010, 66, 242 –
250.
[20] H. Bo¨hme, K. Hartke, Chem. Ber. 1963, 96, 600 – 603.
[21] W. Schwarze, K. Drauz, J. Martens, Chem.-Ztg. 1987,
111, 149 – 153.
[22] K. Johannes, J. Jakob, M. Hatam, J. Martens, Synthesis
2009, 12, 3279 – 3284.
[23] K. Johannes, M. Watzke, J. Martens, J. Heterocyclic
Chem. 2010, 47, 697 – 702.
[24] M. Watzke, K. Schulz, K. Johannes, P. Ullrich,
J. Martens, Eur. J. Org. Chem. 2008, 3859 – 3867.
[25] J. S. Dupont, R. R. Dykstra, US 6583095 B1, 2003.
[39] D. Raffa, B. Maggio, F. Plescia, S. Cascioferro,
S. Plescia, M. V. Raimondi, G. Daidone, M. Tolomeo,
S. Grimaudo, A. Di Cristina, R. M. Pipitone, R. Bai,
E. Hamel, Eur. J. Med. Chem. 2011, 46, 2786 – 2796.
[40] C. L. Stevens, B. T. Gillis, J. Am. Chem. Soc. 1957, 79,
3448 – 3451.
[26] J. M. Chen, X. Chen, M. Fardis, H. Jin, C. U. Kim, [41] A. Kirrmann, P. Duhamel, R. Nouri-Binorghi, Liebigs
L. N. Schacherer, WO 2004/035576 A2, 2004. Ann. Chem. 1966, 691, 33 – 40.
[27] Z. R. Cai, S. Y. Jabri, H. Jin, C. U. Kim, R. A. Lans- [42] G. M. Sheldrick, SHELXS-97, Program for the Solution
down, S. E. Metobo, M. R. Mish, R. M. Pastor, US
2007/0072831 A1, 2007.
[28] S. R. Shengule, S. G. Pyne, A. Willis, Tetrahedron
of Crystal Structures, University of Go¨ttingen, Go¨ttin-
gen (Germany) 1997. See also: G. M. Sheldrick, Acta
Crystallogr. 1990, A46, 467 – 473.
2012, 68, 1207 – 1215.
[29] A. Hassner, S. S. Burke, J. Cheng-fan I, J. Am. Chem.
Soc. 1975, 97, 4692 – 4700.
[43] G. M. Sheldrick, SHELXL-97, Program for the Refine-
ment of Crystal Structures, University of Go¨ttingen,
Go¨ttingen (Germany) 1997. See also: G. M. Sheldrick,
Acta Crystallogr. 2008, A64, 112 – 122.
Brought to you by | University of California
Authenticated
Download Date | 1/19/16 2:42 PM