A novel rearrangement reaction of N-acyliminium ions leading to heterobicycles arylated at bridgehead atom

Article abstract of DOI:10.1002/hc.21131

Starting with thiazolines, an important class of heterocyclic imines, a novel rearrangement reaction of corresponding N-acyliminium ions is described. Furthermore, a new class of heterobicyclic compounds arylated at a single bridgehead atom is obtained diastereospecifically.

Full text of DOI:10.1002/hc.21131

Heteroatom Chemistry
Volume 25, Number 1, 2014
A Novel Rearrangement Reaction of
N-Acyliminium Ions Leading to Heterobicycles
Arylated at Bridgehead Atom
Wiebke Germer, Timo Stalling, Uwe Kramer, Wolfgang Saak,
and Ju¨rgen Martens
Carl von Ossietzky Universita¨t Oldenburg, D-26129, Oldenburg, Germany
Received 7 August 2013; revised 7 October 2013
The Asinger reaction is a simple multicom-
ABSTRACT: Starting with thiazolines, an important
ponent reaction that allows the synthesis of 3–
class of heterocyclic imines, a novel rearrangement
thiazolines with a variety of substituents [3–5].
reaction of corresponding N-acyliminium ions is de-
Thiazolines and their derivatives are interesting
scribed. Furthermore, a new class of heterobicyclic
substances on account of their similarity to thi-
compounds arylated at a single bridgehead atom is
azolidines, which are an important structural el-
ꢀC
obtained diastereospecifically. 2013 Wiley Periodi-
ement in a variety of physiologically active sub-
stances commonly utilized as remedies [6]. One
well-known example is penicillin [7], composed of
a thiazoline- and a β–lactam ring, and other exam-
ples include remedies used to treat diabetes mellitus
[8].
cals, Inc. Heteroatom Chem. 25:20–27, 2014; View
this article online at wileyonlinelibrary.com. DOI
10.1002/hc.21131
The primary aim of this work was to synthesize
thiazolidines 3 with an aryl group attached to the
carbon atom in 4-position next to the nitrogen, start-
ing from thiazoline 1 by means of an intermolecular
Friedel–Crafts reaction in the last step (Scheme 1).
The imine 1 should therefore be N-acylated, followed
by a trapping reaction of the resulting carbenium–
iminium ion by MeOH to give methoxythiazolidines
2. Finally, the methoxy group in 4–position should be
substituted by an aryl group. Molecules similar to the
target compounds could be regarded as privileged
chiral auxiliaries in stereoselective operations [9].
Recently we presented an efficient approach to tri-
cyclic lactams via intramolecular Friedel–Crafts cy-
clization with comparable methoxyamides (R = Ar;
Scheme 1) as stable intermediates [10]. Herein, we
wish to extend this methodology to the intermolecu-
lar type of Friedel–Crafts reactions. However, mod-
ifying the reaction conditions we were faced with
surprising results.
INTRODUCTION
Five-membered heterocyclic compounds containing
nitrogen, such as thiazolines, oxazolines, and im-
idazolines, can be found in a variety of natural
compounds with many of them demonstrating in-
teresting biochemical properties. Importantly, small
chiral heterocyclic molecules find a wide use as
chiral building blocks and ligands in asymmetric
synthesis of many natural products, as well as in
medicinal and agriculture applications [1]. Several
methods for the synthesis of thiazolines have been
reported, including acid-catalyzed condensation of
amino derivatives with carboxylic acids, esters, ni-
triles, benzimidates, or intramolecular cyclization of
carboxamide derivatives [2].
Correspondence to: Ju¨rgen Martens; e-mail: juergen.martens@
uni-oldenburg.de.
ꢀC
2013 Wiley Periodicals, Inc.
20

Novel Rearrangement Reaction of N-Acyliminium Ions Leading to Heterobicycles Arylated at Bridgehead Atom 21
SCHEME 1 Reaction pathway leading to 4-aryl substituted N-acyl S,N-heterocycles.
SCHEME 2 Reaction pathway leading to aryl substituted N-acyl S,N-heterocycles 3 and 4. Reagents and conditions: GP A:
(i) 1.1 equiv acyl chloride, CH2Cl2, 0◦C—r.t., 2 h; (ii) 3.7 equiv MeOH, 1.1 equiv Et3N, CH2Cl2, 0◦C—r.t., overnight; GP B: 10
equiv Ar-H, 2.5 equiv AlCl3, CH2Cl2, 0◦C—r.t., 5 days; GP C: (i) 2.5 equiv AlCl3, 0◦C—r.t., CH2Cl2, 2 h; (ii) 10 equiv Ar-H,
CH2Cl2, 0◦C – r.t., 5 days.
RESULTS AND DISCUSSION
For the Asinger reaction, the corresponding α-
chloroaldehyde, NaHS and aqueous NH3 were uti-
lized in CH2Cl2 to form thiazoline 1, as described by
us previously [11]. The intended reaction pathway
based on 3-thiazoline 1 including all reagents and
yields are shown in Scheme 2 (GP A and B).
Leuchs and co-workers described the addition of
acid chlorides to linear imines by substituting the re-
active chloride by a more resistant hydroxy or alkoxy
group without isolating the addition product [12].
This reaction type was then applied to heterocyclic
imines like 1 by Schwarze and co-workers [13].
By implementing Leuchs’ and co-workers’ method,
compounds 2 were produced as substrates for the
arylation and acetyl and benzoyl chloride were used.
The methoxy-substituted N-acyl amines 2 are stable
SCHEME 3 N-acyliminium ions I, II and proposed rear-
and can be stored over long periods of time. Start-
ing from compounds 2, the resonance-stabilized N-
acyliminium ions I and II (Scheme 3) can be gen-
erated in situ by treatment with a Lewis acid like
aluminum trichloride. These electrophilic ions I and
II are investigated to react by nucleophilic partners
rangement to annulated heterocycles III, IV.
such as electron-rich arenes. The reaction conditions
in this final step are similar to the Friedel–Crafts
alkylation of arenes. The arylation was performed
under cooling in an argon atmosphere. Adding
Heteroatom Chemistry DOI 10.1002/hc

22 Germer et al.
TABLE 1 Conversion of Methoxythiazolidine 2. Residues, Conditions, and Yields
Entry
Amide
R
Ar
GPa
Product (Yield)b
drc
1
2
3
4
5
6
7
8
2a
2a
2a
2b
2a
2a
2a
2b
CH3
CH3
CH3
C6H5
CH3
CH3
CH3
C6H5
4-Methoxyphenyl
B
B
B
B
C
C
C
C
3a (91%)
3b (83%)
3c (64%)
3d (87%)
4a (89%)
4b (59%)
4c (80%)
4d (48%)d
–
–
–
2,5–Dimethoxyphenyl
2,4-Dimethoxyphenyl
4-Methoxyphenyl
–
4-Methoxyphenyl
≥95:5
≥95:5
≥95:5
≥95:5
3,4-Dimethoxyphenyl
2,4-Dimethoxyphenyl
4-Methoxyphenyl
aGP = General Procedure (for details, see the Experimental section).
bIsolated yields.
cDiastereomeric ratio according to the 1H NMR of the crude product.
d Cyclohexylidene 5 (see Scheme 4) was isolated as a by-product (26% yield).
of the cyclohexyl group occurs, producing the ionic
species III and IV (Scheme 3). There are very few
substances described in the literature that resemble
these rearranged bicyclic products, and yet they all
exhibit hydrogen atoms attached to the bridgehead
atoms [14]. The possibility of a carbon–carbon bond
at a bridgehead atom of this kind of a ring system,
as well as this special case of the rearrangement re-
action for the applied heterocyclic iminium ions, is
not described in the literature.
The annulated structure 4 was elucidated by one-
and two-dimensional NMR spectroscopy. Although
1
the H NMR spectroscopic data for both the origi-
nally targeted products 3 and the corresponding re-
arranged compounds 4 are very similar, there exists
a crucial difference. In the spectrum of 3a, the peak
for the single hydrogen atom is a singlet at 4.75 ppm;
whereas in the spectrum for the corresponding rear-
ranged product 4a, there is instead a doublet for this
hydrogen atom at 4.65 ppm. The usually expected
doublet of doublets cannot be resolved as a result
of the fact that the bonding angle between the re-
garded proton and a proton from the neighboring
CH2 group is nearly 90◦. Thus, this bonding angle
renders the vicinal coupling constant to approach
zero, allowing only the interaction of the second pro-
FIGURE 1 X-ray crystal structure of 4-arylthiazolidine 3c
(only one enantiomer is shown). The atom numbering does
not follow the IUPAC nomenclature.
aluminum trichloride to a mixture of arene and 4-
methoxythiazolidine 2 led to the desired final prod-
ucts 3a–d in good yields of up to 91% (Table 1,
entries 1–4). The constitution of 4-arylthiazolidines
3 could be unequivocally verified by single-crystal
XRD analysis of compound 3c (Fig. 1).
1
ton of the CH2 group to be visible in the H NMR
spectrum.
The proposed annulated structure was con-
firmed by single-crystal XRD analysis of 4a, and
the X-ray crystal structure is provided in Fig. 2.
The single-crystal XRD analysis reveals that both
bonds connecting the seven-membered ring to the
thiazolidine cycle are positioned on one side of the
five-membered heterocycle. During preparation of
bicyclic compounds 4, the two cis isomers were
produced exclusively, as depicted by the high dias-
teromeric ratio of dr ≥ 95:5 in the 1H NMR spectro-
scopic data of the crude product. This fact can eas-
ily be explained as the nucleophile approaches the
In contrast, stirring the thiazolidine 2 and alu-
minum trichloride for 2 h at room temperature (r.t.)
before adding this mixture dropwise to the arene
(Scheme 2, GP C) gives the bicyclic compounds 4a–
d in good yields of up to 89% (Table 1, entries 5–
8) surprisingly. The annulated products 4 consist of
a heterocyclic five-membered ring originating from
the thiazolidine and a condensed seven-membered
ring with a carbon–carbon connection to the arene
on one of the bridgehead atoms.
This indicates that if sufficient time is provided
prior to the addition of the arene, a rearrangement
Heteroatom Chemistry DOI 10.1002/hc

Novel Rearrangement Reaction of N-Acyliminium Ions Leading to Heterobicycles Arylated at Bridgehead Atom 23
SCHEME 4 Cyclohexylidene 5 formed by elimination; (a)
1.1 equiv AlCl3, CH2Cl2, 0◦C—r.t., 5 days.
in perfect accordance with reports of similar elimi-
nations after rearrangement [16].
CONCLUSIONS
It can be assessed that based on heterocyclic imines
as a starting material, 4-arylthiazolidines can be pre-
pared in good yields by the addition of acyl chlorides
to the C N double bond and then substituting the
group in 4-position with various arenes. By changing
the reaction conditions of the last step, a novel rear-
rangement reaction resembling the semipinacol re-
arrangement can be realized. This reaction is highly
diastereoselective and leads to a class of new arylated
bicyclic heterocycles in good yields.
FIGURE 2 X-ray crystal structure of 5-arylthiazolidine 4a
(only one enantiomer is shown). The atom numbering does
not follow the IUPAC nomenclature.
substrate from the sterically less hindered face forc-
ing both alkyl groups to a cis-orientation. The rel-
ative configurations of all other compounds 4 were
assigned by analogy.
To identify the driving force for the observed re-
arrangements, presumably the sec-carbon and tert-
carbon atoms in the resonance structures of the N-
acyliminium ion I, II and the thionium ion III, IV are
responsible, respectively. The rearrangement of res-
onance structure I into III can be classified as a sig-
matropic [1,2] rearrangement because a sigma bond
is migrating to the neighboring atom. It shows sim-
ilarities to the Wagner–Meerwein rearrangement,
which is a known side reaction in the Friedel–
Crafts alkylation. But by definition, there are no het-
eroatoms allowed as direct neighbors of the starting
or ending point of the migrating bond. This special
case is known in the semipinacol rearrangement [15]
where an oxygen atom stabilizes the ionic interme-
diate. Therefore, the observed rearrangement resem-
bles the semipinacol rearrangement, except for the
fact that the involved heteroatom is not oxygen, but
rather sulfur.
Cyclohexylidene 5 was isolated as a by-product
in the conversion of 2b to give rearranged 5-
arylthiazolidine 4d (see Scheme 2) (26% yield).
Knowing the possibility of elimination, the specific
formation of 5 was intended to realize without us-
ing an aromatic component (Scheme 4). This goal
was successfully gained in moderate yield of 35%.
Considering a possible mechanism, intermediate III
(Scheme 3) could easily eliminate a proton to form
an endocyclic C-C double bond. This assumption is
EXPERIMENTAL
Synthetic procedures under argon atmosphere were
performed on a vacuum line using standard Schlenk
techniques. Preparative column chromatography
was carried out using Grace SiO2 (0.035–0.070 mm,
type KG 60) with n-hexane and EtOAc as eluents.
TLC was performed on Machery–Nagel SiO2 F254
plates on aluminum sheets. Melting points were
obtained on a melting point apparatus of Labora-
1
tory Devices and are uncorrected. H and 13C NMR
spectra were recorded with a Bruker AMX R 500
1
(measuring frequency: H NMR = 500.1 MHz, 13C
NMR = 125.8 MHz) or a Bruker Avance III 500
1
(measuring frequency: H NMR = 499.9 MHz, 13C
NMR = 125.7 MHz) spectrometer in the CDCl3 so-
lution. Chemical shifts are referenced to tetram-
ethylsilane (0.00 ppm). Assignments of the sig-
nals were supported by measurements applying
DEPT and COSY techniques. Mass spectra (CI-MS,
EI-MS, HRMS) were obtained with a Finnigan-
MAT 95. The IR spectra were recorded with a
Bruker Tensor 27 spectrometer equipped with a
“golden gate” diamond ATR (attenuated total reflec-
tion) unit. 2,2-Dimethyl-1-thia-3-azaspiro[4.5]dec-3-
ene (1) was prepared according to a published proce-
dure [11]. CH2Cl2 was refluxed with calcium hydride
Heteroatom Chemistry DOI 10.1002/hc

24 Germer et al.
and freshly distilled prior to use. MeOH was refluxed
with Mg and freshly distilled prior to use. Et3N was
dried over molecular sieves and freshly distilled prior
to use.
was purified by column chromatography (silica
gel; n–hexane/EtOAc, 4:1; Rf = 0.56) and finally
by crystallization from n–hexane to give product
2b as a colorless solid. Yield: 24.92 g, 90%. Mp:
68◦C. IR (ATR): 3062, 2971, 2928, 2857, 2827, 1644,
1609, 1581, 1446, 1357, 1073, 736, 698 cm−1 1H
.
General Procedure A (GP A) for Preparation of
Methoxythiazolidines 2a–b
NMR (500 MHz, CDCl3): δ (ppm) 1.21–1.33 (m, 2H,
C8H2), 1.49–1.69 (m, 4H, C7,9H2), 1.72–2.06 (m, 4H,
Under argon atmosphere, 1 equiv of imine 1, dis-
solved in anhydrous CH2Cl2 (0.5 mL per mmol
imine), was cooled down to 0–5◦C. 1.1 equiv of the
respective acyl chloride was added dropwise. After
stirring for 2 h at r.t., 7.4 equiv of anhydrous MeOH
were added dropwise at 0–5◦C. Thereupon, the solu-
tion was stirred for 10 min at r.t., before 1.1 equiv
of anhydrous Et3N, dissolved in anhydrous CH2Cl2
(0.2 mL per mmol imine) was added dropwise at
0–5◦C. After having been stirred overnight at r.t.,
the solution was poured into ice water (0.7 mL per
mmol imine). The phases were separated, and the
aqueous phase was extracted with CH2Cl2 (0.2 mL
per mmol imine). The recombined organic phases
were washed with saturated NaHCO3 solution (1 ×
0.5 mL per mmol imine), HCl solution (1 × 0.5 mL
per mmol imine, 4%), water (2 × 0.5 mL per mmol
imine) and dried with MgSO4. The solvent was re-
moved on a rotary evaporator. The purification of
the crude product is described in the experiments.
C
6,10H2), 1.97 (s, 3H, C2CH3), 2.00 (s, 3H, C2CH3),
3.08 (s, 3H, OCH3), 4.99 (s, 1H, C4H), 7.38–7.49
(m, 5H, 5×ArCH). 13C NMR (126 MHz, CDCl3): δ
(ppm) 22.60, 24.30, 25.47, 31.29, 31.70, 33.10, 38.78,
55.26, 58.86, 71.09, 99.84, 127.57, 128.50, 130.07,
138.09, 171.05. MS (CI, isobutane): m/z (%) = 320.1
(17) [MH]+, 288.0 (100) [MH – CH4O]+. HRMS (CI,
isobutane): m/z calcd. for [C18H26NO2S]+: 320.1684;
found: 320.1684.
General Procedure (GP B) for Preparation of
Arylthiazolidines 3a–d
Under argon atmosphere, 2.5 equiv of aluminum
trichloride was added in a period of 1 h to a solu-
tion of 1 equiv of the respective methoxythiazolidine
2, dissolved in anhydrous CH2Cl2 (6 mL per mmol
thiazolidine), and 10 equiv of the respective aromatic
component at 0–5◦C. After stirring for 5 days at r.t.,
the solution was poured into ice (10 g per mmol thia-
zolidine) and stirred fiercely until the ice was totally
melted. The phases were separated, and the aque-
ous phase was extracted with CH2Cl2 (3 × 2 mL per
mmol thiazolidine). The recombined organic phases
were washed with NaOH solution (1 × 2 mL per
mmol thiazolidine, 2%), water (2 × 2 mL per mmol
thiazolidine) and dried with MgSO4. The solvent was
removed on a rotary evaporator. The purification of
the crude product is described in the experiments.
(RS)-3-Acetyl-2,2-dimethyl-4-methoxy-1-thia-3-
aza-spiro[4.5]decane (2a). Following GP A, 2,5-
dihydrothiazole 1 (4.59 g, 0.025 mol), acetyl chloride
(2.17 g, 0.028 mol), anhydrous MeOH (7.0 mL, 0.173
mol), and anhydrous Et3N (4.0 mL, 0.028 mol) were
used. The crude product was crystallized from
n–hexane to give product 2a as a colorless solid.
Yield: 5.53 g, 86%. mp: 58◦C. IR (ATR): 2972, 2931,
1
2854, 1647, 1446, 1379, 1076 cm−1. H NMR (500
MHz, CDCl3): δ (ppm) 1.21–1.34 (m, 2H, C8H2),
1.55–2.01 (m, 8H, C6,7,9,10H2), 1.80 (s, 3H, C2CH3),
1.90 (s, 3H, C2CH3), 2.24 (s, 3H, NCOCH3), 3.45
(s, 3H, OCH3), 4.91 (s, 1H, C4H). 13C NMR (126
MHz, CDCl3): δ (ppm) 22.15, 24.17, 25.14, 25.43,
30.70, 32.20, 32.97, 37.65, 55.53, 58.66, 71.12, 99.36,
169.37. MS (CI, isobutane): m/z (%) = 258.0 (58)
[MH]+, 226.0 (100) [MH – CH4O]+. HRMS (CI,
isobutane): m/z calcd. for [C13H24NO2S]+: 258.1527;
found: 258.1526.
(RS)-3-Acetyl-4-(4-methoxyphenyl)-2,2-dimethyl-
1-thia-3-azaspiro[4.5]decane (3a). Following GP
B, methoxythiazolidine 2a (5.00 g, 0.019 mol),
methoxybenzene (21.01 g, 0.194 mol), and alu-
minum trichloride (6.48 g, 0.049 mol) were used.
The crude product was crystallized from n–hexane
to give product 3a as a colorless solid. Yield: 5.89
g, 91%. mp 109◦C. IR (ATR): 3003, 2929, 2855,
1639, 1608, 1511, 1452, 1375, 1244, 1031, 832 cm−1
.
1H NMR (500 MHz, CDCl3): δ (ppm) 0.91–2.36
(m, 10H, 5×CH2), 1.91 (s, 3H, NCOCH3), 2.00
(s, 3H, CCH3CH3), 2.01 (s, 3H, CCH3CH3), 3.81
(s, 3H, OCH3), 4.75 (s, 1H, C4H), 6.88 (d, 3J =
8.02 Hz, 2H, C3’,5’H), 7.35 (d, 3J = 8.02 Hz, 2H,
(RS)-3-Benzoyl-2,2-dimethyl-4-methoxy-1-thia-3-
azaspiro[4.5]decane (2b). Following GP A, 2,5-
dihydrothiazole 1 (15.87 g, 0.087 mol), benzoyl
chloride (13.50 g, 0.095 mol), anhydrous MeOH
(25.0 mL, 0.616 mol), and anhydrous Et3N (13.5
mL, 0.095 mol) were used. The crude product
C
2’,6’H). 13C NMR (126 MHz, CDCl3): δ (ppm) 22.88,
24.46, 25.53, 25.95, 29.02, 32.26, 36.19, 41.12,
55.17, 58.29, 71.76, 79.42, 113.51, 129.44, 131.32,
Heteroatom Chemistry DOI 10.1002/hc

Novel Rearrangement Reaction of N-Acyliminium Ions Leading to Heterobicycles Arylated at Bridgehead Atom 25
159.11, 169.77. MS (CI, isobutane): m/z (%) = 334.0
The crude product was crystallized from n–hexane
to give product 3d as a colorless solid. Yield: 3.29 g,
87%. mp 122◦C. IR (ATR): 3065, 2979, 2937, 2851,
1645, 1610, 1583, 1514, 1445, 1368, 1246, 1029,
(100) [MH]+. HRMS (CI, isobutane): m/z calcd. for
[C19H28NO2S]+: 334.1841; found: 334.1841.
(RS)-3-Acetyl-4-(2,5-dimethoxyphenyl)-2,2-dime-
thyl-1-thia-3-azaspiro[4.5]decane (3b). Following
GP B, methoxythiazolidine 2a (1.00 g, 0.004 mol),
1,4-dimethoxybenzene (5.25 g, 0.038 mol), and
aluminum trichloride (1.33 g, 0.001 mol) were used.
The crude product was crystallized from n–hexane
to give product 3b as a colorless solid. Yield: 1.09 g,
83%. mp 132◦C. IR (ATR): 3055, 2968, 2928, 2855,
841, 738, 706 cm−1 1H NMR (500 MHz, CDCl3):
.
δ (ppm) 0.94–1.20 (m, 4H, 2×CH2), 1.30–1.39 (m,
1H, CHH), 1.50–1.94 (m, 4H, 2×CH2), 2.11 (s, 3H,
CCH3CH3), 2.13 (s, 3H, CCH3CH3), 2.27–2.35 (m,
1H, CHH), 3.75 (s, 3H, OCH3), 4.84 (s, 1H, C4H),
6.63–6.69 (m, 2H, 2×ArCH), 6.81–6.98 (m, 4H,
4×ArCH), 7.19–7.31 (m, 3H, 3×ArCH). 13C NMR
(126 MHz, CDCl3): δ (ppm) 23.05, 24.20, 25.37,
29.38, 32.32, 35.34, 40.81, 55.03, 57.99, 71.62, 79.18,
112.90, 125.60, 127.95, 128.44, 129.90, 131.21,
139.34, 158.84, 170.61. MS (CI, isobutane): m/z (%)
= 396.0 (100) [MH]+. HRMS (EI): m/z calcd. for
[C24H29NO2S]+: 395.1919; found: 395.1918.
2826, 1646, 1497, 1446, 1384, 1211, 1046, 821 cm−1
.
1H NMR (500 MHz, CDCl3): δ (ppm) 0.96–1.30 (m,
4H, 2×CH2), 1.38–1.45 (m, 1H, CHH), 1.55–1.93
(m, 4H, 2×CH2), 1.78 (s, 3H, NCOCH3), 1.96 (s, 3H,
CCH3CH3), 2.01 (s, 3H, CCH3CH3), 2.25–2.31 (m,
1H, CHH), 3.73 (s, 3H, OCH3), 3.79 (s, 3H, OCH3),
5.44 (s, 1H, C4H), 6.76 (s, 2H, 2×ArCH), 7.15 (s,
1H, ArCH). 13C NMR (126 MHz, CDCl3): δ (ppm)
22.75, 24.48, 25.05, 25.51, 28.88, 32.23, 34.40, 40.75,
55.50, 55.77, 58.57, 71.36, 71.63, 110.67, 113.38,
114.36, 128.98, 150.42, 153.62, 169.81. MS (CI,
isobutane): m/z (%) = 364.0 (100) [MH]+. HRMS
(CI, isobutane): m/z calcd. for [C20H30NO3S]+:
364.1946; found: 364.1947.
General Procedure (GP C) for Preparation of
Rearranged Arylthiazolidines 4a–d
Under argon atmosphere, 1 equiv of the respec-
tive methoxythiazolidine 2, dissolved in anhydrous
CH2Cl2 (1.5 mL per mmol thiazolidine), was added
dropwise to a suspension of 2.5 equiv of aluminum
trichloride in anhydrous CH2Cl2 (1 mL per mmol
thiazolidinethione) at 0–5◦C. After stirring for 2 h
at r.t., the solution was added to 10 equiv of the
respective aromatic component, dissolved in anhy-
drous CH2Cl2 (1.5 mL per mmol thiazolidine), at
0–5◦C. After stirring for 5 days at r.t., the solution
was poured into ice (5 g per mmol thiazolidine) and
stirred fiercely until the ice was totally melted. The
phases were separated, and the aqueous phase was
extracted with CH2Cl2 (3 × 1 mL per mmol thiazoli-
dine). The recombined organic phases were washed
with NaOH solution (1 × 2 mL per mmol thiazoli-
dine, 2%), water (2 × 2 mL per mmol thiazolidine),
and dried with MgSO4. The solvent was removed on
a rotary evaporator. The purification of the crude
product is described in the experiments.
(RS)-3-Acetyl-4-(1,3-dimethoxyphenyl)-2,2-dime-
thyl-1-thia-3-azaspiro[4.5]decane (3c). Following
GP B, methoxythiazolidine 2a (2.00 g, 0.008 mol),
1,3-dimethoxybenzene (5.37 g, 0.039 mol), and
aluminum trichloride (2.59 g, 0.019 mol) were used.
The crude product was crystallized from n–hexane
to give product 3c as a colorless solid. Yield: 1.81
g, 64%. mp 124◦C. IR (ATR): 3001, 2928, 2852,
1
1650, 1589, 1441, 1373, 1206, 1030, 708 cm−1. H
NMR (500 MHz, CDCl3): δ (ppm) = 0.99–1.31,
1.44–1.50, 1.60–1.80, 1.87–1.97, 2.29–2.35 (5m,
10H, C6,7,8,9,10H2), 1.83 (s, 3H, COCH3), 2.01, 2.04
(2s, 6H, C(CH3)2), 3.83 (s, 3H, OCH3), 3.86 (s, 3H,
OCH3), 5.43 (s, 1H, C4H), 6.46 (d, 4J = 2.13 Hz,
3
4
1H, C2’H), 6.54 (dd, J = 8.54 Hz, J = 2.13 Hz, 1H,
C6’H), 7.51 (d, 3J = 8.54 Hz, 1H, C5’H). 13C NMR
(126 MHz, CDCl3): δ (ppm) 22.81, 24.51, 25.10,
25.57, 28.83, 32.24, 34.55, 40.67, 55.25, 55.43, 58.76,
71.07, 71.50, 97.76, 104.33, 120.66, 129.31, 157.18,
160.06, 169.83. MS (CI, isobutane): m/z (%) = 364.6
(100) [MH]+. HRMS (CI, isobutane): m/z calcd. for
[C20H30NO3S]+: 364.1946; found: 364.1942.
(3aS*,8aS*)-3-Acetyl-8a-(4-methoxyphenyl)-2,2-
dimethyloctahydro-2H-cyclohepta[d][1,3]thiazole (4a).
Following GP C, methoxythiazolidine 2a (5.00 g,
0.019 mol), methoxybenzene (21.01 g, 0.194 mol),
and aluminum trichloride (6.48 g, 0.049 mol) were
used. Analysis of the crude product by 1H NMR spec-
troscopy revealed a single diastereomer, indicating
a dr ≥ 95:5. The crude product was crystallized from
n–hexane to give product 4a as a colorless solid.
Yield: 5.79 g, 89%. mp 146◦C. IR (ATR): 3003, 2965,
2917, 2854, 2830, 1650, 1604, 1508, 1447, 1387,
(RS)-3-Benzoyl-4-(4-methoxyphenyl)-2,2-dimeth-
yl-1-thia-3-azaspiro[4.5]decane (3d). Following GP
B, methoxythiazolidine 2b (3.07 g, 0.010 mol),
methoxybenzene (10.38 g, 0.096 mol), and alu-
minum trichloride (3.20 g, 0.024 mol) were used.
1
1258, 1035, 834 cm−1. H NMR (500 MHz, CDCl3):
δ (ppm) 1.06–2.58 (m, 10H, 5×CH2), 1.32 (s, 3H,
Heteroatom Chemistry DOI 10.1002/hc

26 Germer et al.
C2CH3), 1.75 (s, 3H, C2CH3), 2.24 (s, 3H, COCH3),
3.81 (s, 3H, OCH3), 4.65 (d, 3J = 10.33 Hz, 1H,
C3aH), 6.86 (d, 3J = 7.89 Hz, 2H, C3’,5’H), 7.50 (d, 3J =
7.89 Hz, 2H, C2’,6’H). 13C NMR (126 MHz, CDCl3): δ
(ppm) 22.55, 28.26, 29.99, 33.90, 41.31, 25.42, 29.17,
29.77, 55.22, 61.97, 71.44, 72.38, 113.50, 128.01,
138.20, 158.30, 167.81. MS (CI, isobutane): m/z
(%) = 334.0 (100) [MH]+. HRMS (CI, isobutane):
m/z calcd. for [C19H28NO2S]+: 334.1841; found:
334.1842.
13C NMR (126 MHz, CDCl3): δ = 22.73, 29.54, 33.53,
35.48, 36.30, 25.39, 29.65, 29.94, 55.21, 55.49, 68.25,
71.26, 71.47, 100.73, 103.36, 103.44, 125.77, 158.39,
159.80, 167.94. MS (CI, isobutane): m/z (%) = 364.1
(100) [MH]+. HRMS (CI, isobutane): m/z calcd. for
[C20H30NO3S]+: 364.1946; found: 364.1947.
(3aS*,8aS*)-3-Benzoyl-8a-(4-methoxyphenyl)-2,2-
dimethyloctahydro-2H-cyclohepta[d][1,3]thiazole (4d).
Following GP C, methoxythiazolidine 2b (4.00
g, 0.013 mol), methoxybenzene (13.52 g, 0.125
mol), and aluminum trichloride (4.17 g, 0.031 mol)
were used. Analysis of the crude product by 1H
NMR spectroscopy revealed a single diastereomer,
indicating a dr ≥ 95:5. The crude product was
purified by column chromatography (silica gel;
n–hexane/EtOAc, 7:3; Rf = 0.59) and finally by
crystallization from n–hexane to give product 4d as
a colorless solid. Yield: 2.36 g, 48%. mp 140◦C. IR
(ATR): 2935, 2854, 1636, 1606, 1579, 1508, 1443,
(3aS*,8aS*)-3-Acetyl-8a-(3,4-dimethoxyphenyl)-
2,2-dimethyloctahydro-2H-cyclohepta[d][1,3]thiazole
(4b). Following GP C, methoxythiazolidine 2a
(5.00 g, 0.019 mol), 1,2-dimethoxybenzene (26.84 g,
0.194 mol), and aluminum trichloride (6.48 g, 0.049
mol) were used. Analysis of the crude product by 1H
NMR spectroscopy revealed a single diastereomer,
indicating a dr ≥ 95:5. The crude product was
purified by column chromatography on silica gel
(n-hexane/EtOAc, 3:2; Rf = 0.2) to obtain product
4b as a colorless solid. Yield: 4.17 g, 59%. mp 96◦C.
IR (ATR): 3005, 2953, 2935, 2857, 2841, 1636, 1603,
1
1375, 1282, 826 cm−1. H NMR (500 MHz, CDCl3):
δ (ppm) 0.62–0.78, 0.93–1.04, 1.12–1.25, 1.34–1.42,
1.55–1.64, 1.66–1.82, 1.84–1.98, 2.42–2.51 (m, 10H,
5×CH2), 1.52 (s, 3H, C2CH3), 1.88 (s, 3H, C2CH3),
3.81 (s, 3H, OCH3), 4.34–4.44 (m, 1H, C3aH), 6.86
1
1589, 1514, 1444, 1385, 1264, 1024, 828 cm−1. H
NMR (500 MHz, CDCl3): δ (ppm) 1.11–2.58 (m,
10H, 5×CH2), 1.34 (s, 3H, C2CH3), 1.75 (s, 3H,
C2CH3), 2.23 (s, 3H, COCH3), 3.88 (s, 3H, OCH3),
3.91 (s, 3H, OCH3), 4.64 (d, 3J = 10.31 Hz, 1H,
C3aH), 6.78 (d, 3J = 8.35 Hz, 1H, C5’H), 7.00 (d, 3J =
8.35 Hz, 1H, C6’H), 7.28 (s, 1H, C2’H). 13C NMR (126
MHz, CDCl3): δ = 22.64, 28.23, 29.98, 33.98, 41.15,
25.40, 29.13, 29.72, 55.78, 55.87, 62.36, 71.40, 72.31,
109.96, 112.01, 117.46, 138.70, 147.93, 148.83,
167.64. MS (CI, isobutane): m/z (%) = 364.0 (100)
[MH]+. HRMS (EI): m/z calcd. for [C20H29NO3S]+:
363.1868; found: 363.1868.
(m, 3J = 8.86 Hz, 2H, C2"’,6"’H), 7.24–7.27 (m, 2H,
3
C
3",5"H), 7.39–7.43 (m, 3H, C2",4",6"H), 7.46 (m, J =
8.86 Hz, 2H, C3"’,5"’H). 13C NMR (126 MHz, CDCl3):
δ (ppm) 22.49, 27.33, 29.76, 34.70, 41.52, 29.45,
30.15, 55.29, 63.35, 71.94, 72.58, 113.35, 125.20,
128.42, 128.53, 128.73, 137.88, 139.67, 158.54,
169.02. MS (CI, isobutane): m/z (%) = 396.6 (100)
[MH]+. HRMS (EI): m/z calcd. for [C24H29NO2S]+:
395.1919; found: 395.1911.
3-Benzoyl-2,2-dimethyl-3,4,5,6,7,8-hexahydro-2H
-cyclohepta[d][1,3]thiazole (5). Method A: 8 results
as a by-product in the synthesis of 4d (Rf = 0.78;
n–hexane/EtOAc, 9:1). Yield: 0.96 g, 26%. mp 78◦C.
IR (ATR): 3061, 2978, 2922, 2851, 1646, 1628,
(3aS*,8aS*)-3-Acetyl-8a-(2,4-dimethoxyphenyl)-
2,2-dimethyloctahydro-2H-cyclohepta[d][1,3]thiazole
(4c). Following GP C, methoxythiazolidine 2a
(5.00 g, 0.019 mol), 1,3-dimethoxybenzene (26.84 g,
0.194 mol), and aluminum trichloride (6.48 g, 0.049
mol) were used. Analysis of the crude product by 1H
NMR spectroscopy revealed a single diastereomer,
indicating a dr ≥ 95:5. The crude product was
crystallized from n–hexane to give the product 4c
as a colorless solid. Yield: 5.63 g, 80%. mp 108◦C.
IR (ATR): 3000, 2967, 2933, 2862, 1650, 1501, 1441,
1599, 1578, 1492, 1445, 1362, 715, 695 cm−1 1H
.
NMR (500 MHz, CDCl3): δ (ppm) 1.33–1.38 (m, 2H,
C6H2), 1.59–1.68 (m, 4H, C5,7H2), 1.77–1.81 (m, 2H,
C4,8HH), 1.94 (s, 6H, C(CH3)2), 2.29–2.32 (m, 2H,
C
4,8HH), 7.39–7.43 (m, 2H, C3",5"H), 7.45–7.49 (m,
1H, C4"H), 7.61–7.64 (m, 2H, C2",6"H). 13C NMR (126
MHz, CDCl3): δ (ppm) 26.02, 26.40, 28.49, 27.77,
30.27, 32.16, 78.83, 121.23, 128.38, 128.53, 131.23,
132.82, 138.01, 168.29. MS (CI, isobutane): m/z (%)
= 288.4 (100) [MH]+. HRMS (EI): m/z calcd. for
[C17H21NOS]+: 287.1344; found: 287.1340. Method
B: Under argon atmosphere, methoxythiazolidine
2b (0.92 g, 2.8 mmol), dissolved in anhydrous
CH2Cl2 (9 mL), was added dropwise to a suspension
1392, 1211, 1029, 829 cm−1 1H NMR (500 MHz,
.
CDCl3): δ (ppm) 1.07–2.62 (m, 10H, 5×CH2), 1.36
(s, 3H, C2CH3), 1.73 (s, 3H, C2CH3), 2.24 (s, 3H,
COCH3), 3.80 (s, 3H, OCH3), 3.87 (s, 3H, OCH3),
3
4.77–4.98 (m, 1H, C3aH), 6.43 (d, J = 8.75 Hz, 1H,
C5’H), 6.52 (s, 1H, C3’H), 7.22–7.40 (m, 1H, C6’H).
Heteroatom Chemistry DOI 10.1002/hc

Novel Rearrangement Reaction of N-Acyliminium Ions Leading to Heterobicycles Arylated at Bridgehead Atom 27
Lalithambika, M.; Ravindranathan, T.; Bedekar, A.
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of aluminum trichloride (0.42 g, 3.2 mmol) in
anhydrous CH2Cl2 (9 mL) at 0–5◦C. After stirring
for 5 days at r.t., the solution was poured into ice
(10 g) and stirred fiercely until the ice was totally
melted. The phases were separated, and the aqueous
phase was extracted with CH2Cl2 (3 × 10 mL).
The recombined organic phases were washed with
NaOH solution (1 × 10 mL per mmol thiazolidine,
2%), water (2 × 10 mL per mmol thiazolidine),
and dried with MgSO4. The solvent was removed
on a rotary evaporator. The crude product was
crystallized from n–hexane to give the product 8 as
a colorless solid. Yield: 0.29 g, 35%.
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Crystallographic Data
CCDC–954337 contains the supplementary crystal-
lographic data for 3c and CCDC–863381 for 4a.
These data can be obtained free of charge from
the Cambridge Crystallographic data center via
www.ccdc.cam.ac.uk/data_request/cif or from the
Cambridge Crystallographic data center, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-
336-033; or e-mail: deposit@ccdc.cam.ac.uk.
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ACKNOWLEDGMENTS
The silica gel was generously supplied to us by Grace
GmbH & Co. KG. T. S. gratefully acknowledges the
Heinz-Neumu¨ller-Stiftung for a doctoral fellowship.
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Heteroatom Chemistry DOI 10.1002/hc