Real Multicomponent Reactions: Synthesis of Highly Substituted 2-Aminothiazoles

Article abstract of DOI:10.1002/ejoc.201800701

Allenyl isothiocyanates, which can be easily generated by flash vacuum pyrolysis, are known to readily form 1,3-thiazoles with various nucleophiles. This is also true for heterocyclic aromatic amines and sterically hindered amines that are in other aspects used as non-nucleophilic bases. The chemistry of these synthetically useful cumulenes is now expanded to the field of multicomponent reactions with the mentioned amines and selected electrophiles. In an efficient, catalyst-free three-component reaction (3-CR) sequence, highly substituted heterocyclic compounds are formed containing the 2-amino-1,3-thiazole skeleton. The reaction conditions and mechanisms leading to these potentially bioactive molecules were investigated and optimized for the synthesis of a small compound library.

Full text of DOI:10.1002/ejoc.201800701

A Journal of
Accepted Article
Title: Real Multicomponent Reactions: Synthesis of Highly Substituted
2 Aminothiazoles
Authors: Frank Richter, Jennifer Seifert, Marcus Korb, Heinrich Lang,
and Klaus Banert
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800701
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800701
Supported by

10.1002/ejoc.201800701
European Journal of Organic Chemistry
FULL PAPER
Real Multicomponent Reactions: Synthesis of Highly Substituted
2-Aminothiazoles
Frank Richter,[a] Jennifer Seifert,[a] Marcus Korb,[b] Heinrich Lang,[b] and Klaus Banert*[a]
Dedicated to Professor Holger Butenschön on the occasion of his 65th birthday
Abstract: Allenyl isothiocyanates, which can be easily generated by
flash vacuum pyrolysis, are known to readily form 1,3-thiazoles with
various nucleophiles. This is also true for heterocyclic aromatic
amines and sterically hindered amines that are in other aspects used
as non-nucleophilic bases. The chemistry of these synthetically
useful cumulenes is now expanded to the field of multicomponent
reactions with the mentioned amines and selected electrophiles. In
an efficient, catalyst-free three-component reaction (3-CR) sequence,
highly substituted heterocyclic compounds are formed containing the
2-amino-1,3-thiazole skeleton. The reaction conditions and
mechanisms leading to these potentially bioactive molecules were
investigated and optimized for the synthesis of a small compound
library.
Introduction
The 2-amino-1,3-thiazole scaffold is well known for its versatile
bioactivity.[1] It recently evolved from leading structure to highly
Figure 1. Derivatives of 2-aminothiazole with high anticancer activity.
potent drugs in many therapeutic areas, such as treatment of
prion disease, chronic myelogenous (CML) and acute
step, and atom economy.[10] Such processes with two or more
lymphocytic leukemia (ALL).[2] In the last two decades 2-
bond-forming transformations, that take place under the same
aminothiazoles and also 2-aminobenzothiazoles[3] were
extensively investigated. They show anti-inflammatory,
catalysts, and in which subsequent, mostly intramolecular
antibacterial, antiviral, anticonvulsant, antidiabetic, and
reaction conditions without adding additional reagents and
reactions result as a consequence of the functionalities formed
in the previous step, are called domino reactions.[11] The often
interchangeably used terms cascade or tandem process share
this mechanistic point of view, but do not regard the used
number of starting materials. Each “one-pot synthesis” that
combines three or more reactants after simultaneous addition at
antileishmanial properties and antiproliferative activity towards
cancer cells.[4] Thus, some derivatives of 2-aminothiazole with
high anticancer activity are depicted in Figure 1.[5]
The growing interest in this privileged structural motive
intensifies the need for new aminothiazole comprising
compounds. The most common methods for the synthesis of 2-
the onset of the reaction in a unique ordered manner under the
aminothiazoles are the Hantzsch thiazole synthesis[6] (reaction
same reaction conditions is called
a
real or “ideal”
of α-haloketones with thioureas) and the reaction of α-
thiocyanoketones[7] or alk-2-ynyl thiocyanates[8] with amines.
Only a few protocols have been published that build up
2-aminothiazole scaffolds by multicomponent syntheses.[9]
The “one-pot strategy” is considered the most efficient way to
accomplish the synthesis of pharmaceutically relevant structures.
In contrast to conventional multi-step reactions, it allows a fast
way to build up substance libraries with the advantage of pot,
multicomponent process.[12] It is, however, possible to describe a
multicomponent reaction (MCR) as a domino-like sequence, if
an intramolecular reaction at an additional functional group is
included. In this case, the MCR is properly characterized not
only by the number of components but also the overall number
of reactive centers.[13]
Highly reactive allenyl isothiocyanates 2, which are easily
available on large scale by flash vacuum pyrolysis (FVP) of
propargyl thiocyanates 1, provide a convenient access to 2-
aminothiazole products 4 by nucleophilic addition of ammonia
and primary or secondary amines (3, R2NH) accompanied by
intramolecular ring closure (Scheme 1).[14] Thus, substrates 2
turned out to be synthetic equivalents of the dipolar synthons 2’
in these two-component reactions (2-CR). However, the
resulting carbanionic intermediate B1 can be utilized to
introduce further functionalization into the final product 5.
[a]
Dr. F. Richter, J. Seifert, Prof. Dr. K. Banert
Organic Chemistry, Chemnitz University of Technology
Strasse der Nationen 62, 09111 Chemnitz (Germany)
E-mail: klaus.banert@chemie.tu-chemnitz.de
Homepage: https://www.tu-chemnitz.de/chemie/org/index.html.en
Dr. M. Korb, Prof. Dr. H. Lang
[b]
Inorganic Chemistry, Chemnitz University of Technology
09107 Chemnitz (Germany)
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800701
European Journal of Organic Chemistry
FULL PAPER
Scheme 1. Two- and three-component reactions of allenyl isothiocyanates 2
to prepare functionalized thiazoles 4 and 5, respectively (FVP = flash vacuum
pyrolysis).
We here report on catalyst-free four-center three-component
reactions (4C-3CRs) to build up highly substituted 2-
aminothiazoles from simple allenyl isothiocyanates 2, amines,
and electrophiles (E+).
Scheme 3. Proposed reaction mechanisms leading to the formation of 5d
and 7 (relative stereochemistry is shown).
Results and Discussion
The temperature limitation due to the polymerization
tendency[16] of allene 2a does not allow working significantly
above room temperature. Below this, the yield of unwanted side
product 7 increases (Table 1, Entries 2 and 3). The solvent
dependence of this reaction was investigated covering a range
of polar coordinating to nonpolar noncoordinating solvents.
Protic alcohols lead to rapid protonation of carbanionic
intermediate B2 and no other product than 4 is formed. As it is
shown in Table 1, a correlation between the polarity of the used
solvent and product ratio 5d/4d is evident. The results indicate
that highly polar solvents like DMF shift the product ratio in favor
of the desired MCR product 5 (Entry 1), but with low yield. The
2-CR is favored in less polar solvents (Table 1, Entries 10–12)
and high overall yields are achieved. In a compromise between
selectivity and absolute yield of 5, THF was used as the solvent
of choice for further studies (Table 1, Entry 7).
To explain the formation of heterocyclic three-component
product 5d, the nucleophilic addition-cyclization-addition domino
sequence shown in Scheme 3 is suggested. After nucleophilic
addition of 3d to the isothiocyanate moiety of 2a, the dipolar
intermediate most probably cyclizes to form the thiazole
heterocycle (Pathway A → B2). Under optimized reaction
conditions, proton transfer to generate 4d cannot compete with
the successive nucleophilic attack on electrophile trans-6
leading to final product 5d.
The lithium salt of diisopropylamine (3d) is widely used as non-
nucleophilic base (Scheme 2). However, the free amine base is
a good nucleophile towards slim allenyl isothiocyanates like 2a.
It was recently shown that even triacetonamine (3a, TAA) reacts
nicely with 1.0 to 1.5 equivalents of 2a to give the desired
product 2,2,6,6-tetramethyl-1-(5-methylthiazol-2-yl)piperidin-4-
one (4a) in isolated yields of 74 to 91%, respectively.[15] Both
reactions served as a starting point for the development of the
title MCR since we expected that sterically crowded or
electronically deactivated amines will selectively attack the
highly reactive allenyl isothiocyanate (2a) also in the presence of
a second electrophile.
Because of a very short reaction time of less than 10 min
(indicated by TLC and NMR), the reaction of 3d, allenyl
isothiocyanate (2a), and trans-β-nitrostyrene (trans-6) as second
electrophile was chosen as model MCR (Scheme 3). The
reaction was optimized at 0°C and with addition of 1.5
equivalents of allene 2a and trans-6 to the nucleophile.
Scheme 2. Basic 2-CR of allenyl isothiocyanate (2a) with sterically hindered
amines 3.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800701
European Journal of Organic Chemistry
FULL PAPER
Table 1. Solvent dependence studies on the model MCR performed with
2a, 3d, and trans-6 at 0°C.
After the successful MCRs of 3a and 3d with allenyl
isothiocyanate (2a) and trans-6, a series of acyclic, secondary
amines and aromatic 1H-imidazole were also applied. In the
latter case with imidazole, we observed very fast reactions;
however, the yields of the desired products 5i,j were
disappointing low (Table 2, Entries 9 and 10). Whereas no 2-CR
product 4i was isolated, 4j could be obtained as main product in
even better yields than 5j. In previous studies, imidazoles and
similar nitrogen heterocycles, such as benzimidazoles,
pyrazoles, 1,2,3-triazoles, benzotriazoles, 1,2,4-triazoles, etc.,
turned out to form thiazole products with 2a or substituted allenyl
isothiocyanates in simple two component reactions with
excellent yields.[14f]
With steric hindrance being only of minor influence,
N-isopropyl-tert-butylamine (3b) was found to be one of the best
nucleophiles in this series of amines (Entry 2). The 3-CR product
5b was isolated in good yield of 72% and the corresponding 2-
CR product was not observed. A similar result was observed
after reacting 3d with the substituted allenyl isothiocyanate 2b in
the presence of trans-6 (Entry 8), and this outcome was even
better than that of treating the parent compound 2a analogously
(Entry 4).
Yield [%][a]
Ratio
5d:4d
97: 3
Entry
Solvent
4d
5d
7
1
DMF
1
28
28
27
40
47
39
62
20
20
30
16
4
0
2
MeCN
5
22
29
17
0
85:15
84:16
89:11
78:22
74:26
87:13
34:66
48:52
38:62
20:80
6:94
3[b]
4
MeCN
5
Acetone
1,4-Dioxane
EtOAc
THF
5
5[c]
6
13
14
9
8
7
0
8
Et2O
39
22
49
66
67
0
9
t-BuOMe
CH2Cl2
CHCl3
11
0
10
11
12
0
Toluene
9
[a] NMR yield. [b] Additional experiment at –40°C. [c] Reaction at 10°C.
Table 2. Scope of 4C-3CR of allenes 2 with amines 3 and trans-β-nitrostyrene
(trans-6).
NMR spectroscopic analyses of some experiments indicated
the formation of an alternate MCR product especially in
acetonitrile at lower temperatures (Table 1, Entry 3). This elusive
species could only be isolated after quick workup and flash
column chromatography due to rapid reaction with excessive
allene 2a. It was conclusively identified as 5,6-dihydro-4H-1,3-
thiazine 7.
The formation of 7 can be explained by two plausible
mechanisms (Scheme 3). Starting from ionic intermediate A,
intermolecular nucleophilic attack of the urea sulfur on trans-β-
nitrostyrene (trans-6) is followed by nucleophilic attack at the
allenyl moiety and intramolecular thiazine ring closure. It is also
possible, that tautomerism of A leads to thiourea D, which
undergoes rapid [4+2] cycloaddition in the presence of trans-6.
However, we found no spectroscopical evidence for the
formation of D. In any case, three new stereocenters are formed
at C-4, C-5 and C-6 in all-trans configuration of the substituents
as indicated by 1H NMR coupling constants and NOESY
experiments.
The reaction of TAA (3a) with 1.25 equivalents of allenyl
isothiocyanate (2a) and trans-6 mixed simultaneously in
equimolar amounts gave the desired three-component product
2,2,6,6-tetramethyl-1-[5-(3-nitro-2-phenylpropyl)thiazol-2-
yl]piperidin-4-one (5a) in 72% isolated yield. Addition of more 2a
(up to 2 equivalents) or trans-β-nitrostyrene (trans-6, up to 3
equivalents) did not lead to higher yields. Various bases (NEt3,
DABCO, DMAP, TMEDA, TEEDA, 2,4,6-trimethylpyridine, aq.
KOH, aq. LiOH) tested in the four-center three-component
reaction of TAA (3a), allenyl isothiocyanate (2a), and trans-6 did
not increase the reaction rate noticeably when used in catalytic
(about 0.1 mol%) to substoichiometric amounts (up to 10 mol%).
Entry
R1
R2
R3
Yield[a]
5a
1[b]
2
C(Me)2CH2C(O)CH2C(Me)2
H
4a
4b
4c
4d
4e
4f
0
0
72
72
65
62
61
61
58
68
24
13
iPr
iPr
iPr
iPr
iPr
Me
iPr
tBu
Ph
H
5b
5c
5d
5e
5f
3
H
19
9
4
iPr
H
5
4-MeC6H4
4-MeOC6H4
Ph
H
33
27
22[c]
0
6[b]
7
H
H
4g
4h
4i
5g
5h
5i
8[d]
9[d]
10[d]
iPr
CH2OMe
H
CH=N−CH=CH
CH=N−CH=CH
0
CH2OMe
4j
33
5j
[a] Isolated yields. [b] Entry 1: 24 h reaction time at rt, Entry 6: 10 h reaction
time. [c] NMR yield. [d] Educts in equimolar amounts; reaction at rt.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800701
European Journal of Organic Chemistry
FULL PAPER
latter information is also obtained easily from the corresponding
1
vicinal H,1H NMR coupling constant. The formation of 9 could
be explained by liberation of the acid HX from intermediate B3
followed by regio- and stereoselective Diels−Alder reaction of
short-lived 4,5-dimethylidenethiazole F with trans-6. Under the
alkaline reaction conditions, however, the configuration at the
CH−NO2 unit should be variable, and most probably, the trans
configuration of
9 is thermodynamically favored. Hence,
treatment of 2d with 3d and cis-6[17] also led to 9 exclusively,
obviously under thermodynamic control of the configuration by
base-catalyzed epimerization. With 3d in THF (without 6), 2d did
not afford the desired product of the 2-CR, whereas 4k is formed
in 19% yield if methanol is used instead of THF. Consequently, a
protic solvent is necessary to promote tautomerism of
intermediate B3 with generation of 4k and to avoid creation of
short-lived F.
Highly
reactive
4,5-dimethylidenethiazoles
could
be
synthesized only by flash pyrolysis so far.[18] Although, they were
not observed directly by spectroscopic means several simple
addition and dimerization products could be characterized.[18c,18d]
The formation of Diels−Alder products from these compounds is
discussed contradictory in literature, but was reported to be
accomplished by in situ generation of so-called ”o-dimethylene
thiazole” from the sulfur dioxide adduct at high temperatures in
the presence of various dienophiles.[18c]
Figure 2. ORTEP of the molecular structures of 6-nitro-5-phenyl-4,5,6,7-
tetrahydrobenzothiazole 9 (50% ellipsoid probability). Hydrogen atoms and
disordered parts of the compounds have been omitted for clarity.
Scheme 4. Multicomponent domino sequence leading to product 9.
4-Chloro-3-isothiocyanatobuta-1,2-diene
(2c)
and
2-
Benzaldehydes 10 were also found to be suitable second
electrophiles in the reaction of amines 3a, 3d, or 3h and allenes
2a or 2b (Table 3). The 3-CR products 11a−h were obtained in
moderate to good yields (43 – 81%) while best yields were
achieved with moderately electron-poor electrophiles such as 4-
nitrobenzaldehyde. However, imidazole as amine component led
to low yields (Table 3, Entry 8). The structures of 11 were
confirmed not only by spectroscopic data but also by single
crystal X-ray diffraction analysis of 11g (Figure 3). The
known[14f,15] simple two-component products 4a, 4d, and 4i were
also observed in these transformations, but their yields were not
determined.
isothiocyanatobuta-2,3-dienyl acetate (2d) on the other hand do
not lead to 5k, the expected product of a 3-CR, when the
substrates were exposed to 3d and trans-6 (Scheme 4). Instead
of 5k, a 4,5-cyclohexenothiazole was formed in 20% (from 2c) or
61% yield (from 2d). At first, we thought that product 8 was
generated via ring closure of intermediate E. But after
assignment of the 13C NMR signals of C-4 and C-5 of the
thiazole moiety and long-range 13C,1H shift correlation with the
CH−Ph and CH−NO2 1H NMR signals, the structure of isomeric
9 proved to be correct. This was confirmed by single crystal X-
ray diffraction analysis of 9 (Figure 2), which shows the trans
configuration of the substituents at the cyclohexane ring. The
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800701
European Journal of Organic Chemistry
FULL PAPER
Table 3. Scope of 4C-3CR of allenes 2 with amines 3 and benzaldehydes
10.
Entry
R1
R2
R3
Ar
Yield [%][a]
Scheme 5. Synthesis of the 3-CR products 13a,e.
1
2
3
4
5
6
7
8
C(Me)2CH2C(O)CH2C(Me)2
C(Me)2CH2C(O)CH2C(Me)2
C(Me)2CH2C(O)CH2C(Me)2
C(Me)2CH2C(O)CH2C(Me)2
C(Me)2CH2C(O)CH2C(Me)2
H
4-C6H4NO2
C6F5
11a
11b
11c
11d
11e
11f
74
68
56
43
43
50
81
27
H
Conclusions
H
C6H4Cl
In summary, we report on the synthesis of highly substituted 2-
amino-1,3-thiazoles
H
2,4-C6H3(NO2)2
Ph
via
an
efficient,
catalyst-free
H
multicomponent sequence. In contrast to other one-pot
procedures, this 3-CR exhibits the true step-economic nature of
real multicomponent reactions since all reactants need to be
present at the same time. The presented method is capable of
creating various substitution patterns at 4- and 5-position of the
heterocyclic ring, resulting either from a nucleophilic addition-
cyclization-addition or Diels−Alder cycloaddition domino
sequence. To our knowledge, the latter represents the first
example of generating a 4,5-dimethylidenethiazole under mild
conditions. A small library of compounds was created illustrating
the scope of the reactions.
iPr
iPr
iPr
iPr
H
CH2OMe
H
4-C6H4NO2
4-C6H4NO2
4-C6H4NO2
11g
11h
CH=N−CH=CH
[a] Isolated yields.
Experimental Section
Warning
Synthesis and handling of neat allenyl isothiocyanates carry the risk of
highly exothermic and vigorous polymerization.[16] Measures of
precaution must always be taken. The produced solutions of allenyl
isothiocyanates can be handled conveniently. Purification by flash
chromatography was easily performed after concentration of the solution
under reduced pressure.
Figure 3. ORTEP (50% ellipsoid probabilities) of the molecular structures of
11g (left) and 13e (right) with their atom numbering schemes. C-bonded
hydrogen atoms and a second molecule of the asymmetric unit of 11g have
been omitted for clarity.
Instruments
NMR spectra were recorded on a Varian Unity Inova 400 spectrometer
operating at 400 MHz (frequencies: 399.9 MHz for 1H and 100.6 MHz for
13C) or an ASCEND 600 FT spectrometer (Bruker) operating at 600 MHz
(1H) and 150.9 MHz (13C). Chemical shifts δ in ppm are referenced on
residual solvent signals or on tetramethylsilane (0.00 ppm for 1H and 13C).
All spectra were measured at room temperature (20–25°C), if not noted
otherwise. IR spectra were recorded with FT IR spectrometer Nicolet iS5
from Thermo Fisher Scientific with solutions (in tetrachloromethane or
deuterated chloroform if necessary) or with KBr pellets. Mass spectra
The commercially available N-sulfonyl imine 12 is a reactive
imine derivative with a strong electron withdrawing group at the
nitrogen atom. Treatment of 12 with 1.5 equivalents of allene 2a
and amines 3a or 3e gives 13a in 81% and 13e in 70% yield,
respectively. The structure of 13e was also confirmed by single
crystal X-ray diffraction (Figure 3).
were recorded on
a micrOTOF QII spectrometer from Bruker.
Quantitative elementary analyses were performed on a Vario Micro Tube
from Elementar Analysensysteme GmbH Hanau. Melting points were
determined with a Boetius apparatus from Pentakon Dresden. The
values were not corrected.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800701
European Journal of Organic Chemistry
FULL PAPER
X-Ray Structure Analysis: Data were collected with an Oxford Gemini S
equipment using Mo-Kα radiation (λ = 0.71073 Å). Refinement details
and crystal date are given in the Supporting Information (Table SI1). The
structure have been deposited at the Cambridge Crystallographic Data
Centre and can be accessed by CCDC-1841003 (9), CCDC-1841004
(11g) and CCDC-1841005 (13e) via www.ccdc.cam.ac.uk/data_request/cif.
N-tert-Butyl-N-isopropyl-5-(3-nitro-2-phenylpropyl)thiazol-2-amine
(5b): According to GP-1, N-isopropyl-tert-butylamine (3b) (115 mg,
1.00 mmol) and trans-β-nitrostyrene (trans-6) (224 mg, 1.50 mmol) were
reacted with allene 2a (146 mg, 1.50 mmol) in anhydrous THF (3 mL) for
10 h at room temperature. The crude product was purified by flash
chromatography (Et2O/n-hexane 1/10 to 1/8, v/v) to give 5b (258 mg,
0.72 mmol, 72%) as a yellow oil. Rf = 0.20 (Et2O/n-hexane 1:8); 1H NMR
(400 MHz, CDCl3): δ = 1.09 (d, 3J = 7.0 Hz, 3H, CHCH3), 1.11 (d,
3J = 7.0 Hz, 3H, CHCH3), 1.28 (s, 9H, C(CH3)3), 3.06 (dd, 2J = 15.0 Hz,
3J = 8.0 Hz, 1H, CH=CCHH), 3.12 (dd, 3J = 15.0 Hz, 3J = 7.0 Hz, 1H,
CH=CCHH), 3.68 (sept, 3J = 7.0 Hz, 1H, CH(CH3)2), 3.71 (mC, 1H,
CHPh), 4.60 – 4.70 (m, 2H, CH2NO2), 6.96 (s, 1H, CH=CCH2), 7.13 –
717 (m, 2H, arom.), 7.22–7.35 (m, 3H, arom.) ppm; 13C NMR
(100 MHz, CDCl3): δ = 23.04 (q, CHCH3), 23.12 (q, CHCH3), 28.76 (q,
C(CH3)), 31.80 (t, CH=CCH2), 45.73 (d, CHPh), 47.64 (d, CH(CH3)2),
57.33 (s, C(CH3)3), 79.35 (t, CH2NO2), 127.48 (d, arom.), 127.94 (d,
Cpara), 128.91 (d, arom.), 136.43 (d, CH=CCH2), 138.32 (s, Cipso), 168.07
(s, N=CS) ppm, C-5 (s) missing; IR (CCl4): ṽ = 2974 (s), 2931 (m), 1557
(s), 1494 (m), 1455 (m) cm–1; C19H27N3O2S (361.50): calcd. C 63.13, H
7.53, N 11.62, S 8.87; found C 63.41, H 7.54, N 11.27, S 8.89%.
General Procedure 1 (GP-1): To a solution of amine 3 and the
respective electrophile 6, 10 or 12 in anhydrous THF (0.3 M) was added
2a at room temperature. After completion of the reaction as indicated by
TLC, the solvent was removed in vacuo, and the crude product was
purified by flash chromatography (Et2O/n-hexane).
N,N-Diisopropyl-5-methylthiazol-2-amine (4d): N,N-Diisopropylamine
(3d) (101 mg, 1.00 mmol) was added to a solution of allene 2a (194 mg,
2.00 mmol) in anhydrous THF (3 mL) at 0°C and stirred for 10 min.
Chromatography (Et2O/n-hexane 1/10 to 1/3, v/v) gave 4d (172 mg,
0.87 mmol, 87%) as a pale yellow oil. Rf = 0.44 (Et2O/n-hexane 1:10); 1H
NMR (400 MHz, CDCl3): δ = 1.33 (d, 3J = 7.0 Hz, 12H, CH(CH3)2), 2.27
(s, 3H, CH=CCH3), 3.87 (sept, 3J = 6.5 Hz, 2H, CH(CH3)2), 6.77 (s, 1H,
CH=CCH3) ppm; 13C NMR (100 MHz, CDCl3): δ = 11.74 (q, CH=CCH3),
20.17 (q, CH(CH3)2), 50.06 (d, CH(CH3)2), 118.80 (s, CH=CCH3), 135.74
(d, CH=CCH3), 167.26 (s, N=CS) ppm; IR (CCl4): ṽ = 2971 (s), 2921 (m),
2884 (w), 1528 (s), 1504 (m), 1367 (m), 1305 (m) cm–1; HRMS (ESI):
calcd. for C10H19N2S [M + H]+ 199.1263, found 199.1268.
N-Isopropyl-5-(3-nitro-2-phenylpropyl)-N-phenylthiazol-2-amine (5c):
According to GP-1, N-isopropylaniline (3c) (135 mg, 1.00 mmol) and
trans-β-nitrostyrene (trans-6) (224 mg, 1.50 mmol) were reacted with
allene 2a (146 mg, 1.50 mmol) in anhydrous THF (3 mL) for 10 min at
0°C. Chromatography (Et2O/n-hexane 1/3 to 1/1, v/v) gave 5c (247 mg,
0.65 mmol, 65%) as a colorless, crystalline solid and N-isopropyl-5-
methyl-N-phenylthiazol-2-amine (4c) (44 mg, 0.19 mmol, 19%) as a
yellow oil.
4-Acetoxymethyl-N,N-diisopropyl-5-methylthiazol-2-amine (4k): 4-
Acetoxy-3-isothiocyanatobuta-1,2-diene (2d) (50.8 mg, 0.30 mmol) was
added slowly to a solution of N,N-diisopropylamine (3d) (30.4 mg, 0.30
mmol) in anhydrous MeOH (5 mL) at room temperature. After completion
of the reaction (overnight, TLC), flash column chromatography (Et2O/n-
hexane 1:1) gave the title compound 4k (15 mg, 0.06 mmol, 19%) as a
bright yellow oil. 1H NMR (600 MHz, CDCl3): δ = 1.32 (d, 3J = 6.8 Hz,
12H, CH(CH3)2), 2.08 (s, 3H, COCH3), 2.27 (s, 3H, C=CCH3), 3.85 (sept,
3J = 6.8 Hz, 2H, CH(CH3)2), 4.93 (s, 2H, CH2O) ppm; 13C NMR
(150 MHz, CDCl3): δ = 10.59 (q, C=CCH3), 20.09 (q, CH(CH3)2), 21.08 (q,
CH3COO), 50.01 (d, CH(CH3)2), 59.94 (t, CH2O), 118.03 (s, C=CCH3),
141.48 (s, C=CCH3), 164.57 (s, N=CS), 171.11 (s, COO) ppm; IR (CCl4):
ṽ = 3457 (w), 2971 (m), 2931 (m), 1740 (s), 1533 (s), 1508 (s), 1228 (s)
cm–1; C13H22N2O2S (270.39): calcd. C 57.75, H 8.20, N 10.36, S 11.86;
found C 57.44, H 7.97, N 10.45, S 12.24%.
4c: Rf = 0.62 (Et2O/n-hexane 1:2); 1H NMR (400 MHz, CDCl3): δ = 1.19
(d, 3J = 7.0 Hz, 6H, CH(CH3)2), 2.18 (d, 3H, 4J = 1.5 Hz, CH=CCH3), 4.84
(sept, 3J = 7.0 Hz, 1H, CH(CH3)2), 6.81 (q, 1H, 4J = 1.5 Hz, CH=CCH3),
7.25 (d, J = 7.0 Hz, 2H, arom.), 7.35–7.47 (m, 3H, arom.) ppm; 13C NMR
(100 MHz, CDCl3): δ = 11.78 (q, CH=CCH3), 20.95 (q, CH(CH3)2), 50.62
(d, CH(CH3)2), 120.90 (s, CH=CCH3), 128.26 (d, CHpara), 129.73 (d,
arom.), 130.82 (d, arom.), 135.55 (d, CH=CCH3), 141,62 (s, Cipso),
170.43 (s, N=CS) ppm; IR (CCl4): ṽ = 2975 (m), 1556 (w), 1508 (s), 1303
(m), 1160 (m), 699 (m) cm–1; HRMS (ESI): calcd. for C13H17N2S [M + H]+
233.1107, found 233.1099; [M + Na]+ 255.0926, found 255.0921.
5c: Rf = 0.36 (Et2O/n-hexane 1:2); m.p. 102°C (Et2O/n-hexane); 1H NMR
(400 MHz, CDCl3): δ = 1.19 (d, 3J = 6.5 Hz, 6H, CH(CH3)2), 2.88–3.00
(m, 2H, CH=CCH2), 3.58 (quint, 3J = 7.5 Hz, 1H, CHAr), 4.56 (dd,
2J = 12.5 Hz, 3J = 9.0 Hz, 1H, CH2NO2), 4.62 (dd, 2J = 12.5 Hz,
3J = 6.0 Hz, 1H, CH2NO2), 4.83 (sept, 3J = 7.0 Hz, 1H, CH(CH3)2), 6.82
(s, 1H, CH=CCH2), 7.15 (d, J = 7.5 Hz, 2H, arom.), 7.20–7.38 (m, 5H,
arom.), 7.40–7.50 (m, 3H, arom.) ppm; 13C NMR (100 MHz, CDCl3):
δ = 20.92 (q, CH(CH3)2), 20.96 (q, CH(CH3)2), 31.33 (t, CH=CCH2), 45.44
(d, CHAr), 50.82 (d, CH(CH3)2), 79.28 (t, CH2NO2), 121.38 (s,
CH=CCH2), 127.26 (d, arom.), 127.81 (d, arom.), 128.52 (d, arom.),
128.90 (d, arom.), 129.85 (d, arom.), 130.72 (d, arom.), 137.28 (d,
CH=CCH2), 138.80 (s, Cipso), 141.19 (s, NCipso), 171.14 (s, N=CS) ppm;
2,2,6,6-Tetramethyl-1-[5-(3-nitro-2-phenylpropyl)thiazol-2-
yl]piperidin-4-one (5a): According to GP-1, allenyl isothiocyanate (2a)
(121 mg, 1.25 mmol) was added to a solution of triacetonamine (3a)
(155 mg, 1.00 mmol) and trans-β-nitrostyrene (trans-6) (186 mg,
1.25 mmol) in anhydrous THF (3 mL) and stirred at room temperature for
24 h. Flash chromatography (Et2O/n-hexane 1/2 to 2/1, v/v) gave 5a
(290 mg, 0.72 mmol, 72%) as a yellow, viscous oil, that crystallizes in the
refrigerator. Rf = 0.46 (Et2O/n-hexane 3:1); m.p. 94–95°C; 1H NMR
(400 MHz, CDCl3): δ = 1.23 (s, 12H, C(CH3)2), 2.53 (s, 4H, CH2C(CH3)2),
3.10 (dd, 2J = 14.5 Hz, 3J = 9.0 Hz, 1H, CH=CCH2), 3.21 (dd,
2J = 14.5 Hz, 3J = 6.5 Hz, 1H, CH=CCH2), 3.73 (mC, 1H, CHAr), 4.68 (mC,
2H, CH2NO2), 7.10–7.15 (m, 3H, arom.), 7.25–7.35 (m, 3H, arom.) ppm;
13C NMR (100 MHz, CDCl3): δ = 29.88 (q, C(CH3)2), 31.79 (t, CH=CCH2),
45.78 (d, CHAr), 54.71 (t, CH2C(CH3)2), 58.68 (s, CH2C(CH3)2), 79.35 (t,
CH2NO2), 127.55 (d, CHortho), 128.12 (d, CHpara), 128.99 (d, CHmeta),
132.90 (s, CH=CCH2), 137.24 (d, CH=CCH2), 137.89 (s, Cipso), 167.56 (s,
N=CS), 208.68 (s, CO) ppm, assigned by HMBC; IR (KBr): ṽ = 2968 (s),
2933 (m), 1704 (s), 1552 (m) cm–1; C21H27N3O3S (401.52): calcd. C
62.82, H 6.78, N 10.47, S 7.99; found C 62.15, H 6.60, N 10.13, S
7.70%.
IR (CCl4): ṽ = 2976 (m), 2920 (w), 1550 (s), 1504 (s), 700 (m) cm–1
;
C21H23N3O2S (381.49): calcd. C 66.12, H 6.08, N 11.01, S 8.41; found C
65.71, H 6.04, N 10.91, S 8.54%.
N,N-Diisopropyl-5-(3-nitro-2-phenylpropyl)thiazol-2-amine
(5d):
According to GP-1, diisopropylamine (3d) (101 mg, 1.00 mmol) and
trans-β-nitrostyrene (trans-6) (224 mg, 1.50 mmol) were reacted with
allene 2a (146 mg, 1.50 mmol) in anhydrous THF (3 mL) for 10 min at
0°C. Flash chromatography (Et2O/n-hexane 1/20 to 1/2, v/v) gave 5d
(214 mg, 0.62 mmol, 62%) as a yellow, viscous oil, that crystallizes
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800701
European Journal of Organic Chemistry
FULL PAPER
slowly and N,N-diisopropyl-5-methylthiazol-2-amine (4d) (18 mg,
0.09 mmol, 9%) as a pale yellow oil.
4f: Rf = 0.48 (Et2O/n-hexane 1:2); 1H NMR (400 MHz, CDCl3): δ = 1.16
(d, 3J = 7.0 Hz, 6H, CH(CH3)2), 2.17 (d, 3H, 4J = 1.5 Hz, CH=CCH3), 3.84
(s, 3H, OMe), 4.81 (sept, 3J = 7.0 Hz, 1H, CH(CH3)2), 6.79 (q, 1H,
4J = 1.5 Hz, CH=CCH3), 6.96 (d, J = 6.5 Hz, 2H, arom.), 7.16 (d,
J = 6.5 Hz, 2H, arom.) ppm; 13C NMR (100 MHz, CDCl3): δ = 11.79 (q,
CH=CCH3), 20.92 (q, CH(CH3)2), 50.30 (d, CH(CH3)2), 55.39 (q, OCH3),
114.84 (d, arom.), 120.72 (s, CH=CCH3), 132.08 (d, arom.), 134.15 (s,
Cipso), 135.71 (d, CH=CCH3), 159.29 (s, COCH3), 171.10 (s, N=CS) ppm;
IR (CCl4): ṽ = 2974 (m), 1608 (w), 1508 (s), 1303 (m), 1246 (m), 1169
(m), 1040 (m) cm–1; HRMS (ESI): calcd. for C14H19N2OS [M + H]+
263.1213, found 263.1211; [M + Na]+ 285.1032, found 285.1030.
5d: Rf = 0.31 (Et2O/n-hexane 1:2); m.p. 78°C; 1H NMR (400 MHz,
CDCl3): δ = 1.32 (d, 3J = 7.0 Hz, 6H, CH(CH3)2), 1.33 (d, 3J = 7.0 Hz, 6H,
CH(CH3)2), 2.98–3.08 (m, 2H, CH=CCH2), 3.68 (mC, 1H, CHAr), 3.86
(sept, 3J = 7.0 Hz, 2H, CH(CH3)2), 4.61 (dd, 2J = 13.0 Hz, 3J = 9.0 Hz, 1H,
2
CH2NO2), 4.69 (dd, J = 13.0 Hz, 3J = 6.0 Hz, 1H, CH2NO2), 6.79 (s, 1H,
CH=CCH2), 7.22 (d, J = 8.0 Hz, 2H, arom.), 7.26–7.39 (m, 3H, arom.)
ppm; 13C NMR (100 MHz, CDCl3): δ = 20.06 (q, CH(CH3)2), 20.12 (q,
CH(CH3)2), 31.36 (t, CH=CCH2), 45.58 (d, CHAr), 50.30 (d, CH(CH3)2),
79.43 (t, CH2NO2), 119.25 (s, CH=CCH2), 127.40 (d, CHortho), 127.86 (d,
CHpara), 128.94 (d, CHmeta), 137.39 (s, Cipso), 139.02 (d, CH=CCH2),
167.85 (s, N=CS) ppm, assignment by comparison; IR (KBr): ṽ = 2994
(m), 2970 (m), 2930 (w), 1531 (s), 1380 (m), 1366 (m), 1222 (m), 1124
(m), 762 (m), 704 (m) cm–1; C18H25N3O2S (347.48): calcd. C 62.22, H
7.25, N 12.09, S 9.23; found C 61.92, H 7.15, N 12.00, S 9.38%.
1
5f: Rf = 0.26 (Et2O/n-hexane 1:2); m.p. 140°C (Et2O/n-hexane); H NMR
(400 MHz, CDCl3): δ = 1.16 (d, 3J = 7.0 Hz, 6H, CH(CH3)2), 2.80–2.95
(m, 2H, CH=CCH2), 3.57 (mC, 1H, CHAr), 3.86 (s, 3H, OMe), 4.56 (dd,
2J = 12.5 Hz, 3J = 9.0 Hz, 1H, CH2NO2), 4.62 (dd, 2J = 12.5 Hz,
3J = 5.5 Hz, 1H, CH2NO2), 4.80 (sept, 3J = 7.0 Hz, 1H, CH(CH3)2), 6.80
(s, 1H, CH=CCH2), 6.97 (d, J = 8.5 Hz, 2H, arom.), 7.15 (d, J = 8.5 Hz,
4H, arom.), 7.20–7.35 (m, 3H, arom.) ppm; 13C NMR (100 MHz, CDCl3):
δ = 20.91 (q, CH(CH3)2), 20.94 (q, CH(CH3)2), 31.41 (t, CH=CCH2), 45.48
(d, CHAr), 50.59 (d, CH(CH3)2), 55.43 (q, OCH3), 79.32 (t, CH2NO2),
114.99 (d, arom.), 121.29 (s, CH=CCH2), 127.27 (d, arom.), 127.84 (d,
CHpara), 128.94 (d, arom), 131.95 (d, arom), 133.74 (s, Cipso), 137.41 (d,
CH=CCH2), 138.89 (s, Cipso), 159.48 (s, COCH3), 171.83 (s, N=CS) ppm;
IR (KBr): ṽ = 2967 (m), 2839 (s), 1606 (w), 1549 (s), 1510 (s), 1298 (m),
1249 (m), 1171 (m), 820 (m), 761 (m), 701 (m) cm–1; HRMS (ESI): calcd.
for C22H25N3NaO3S [M + Na]+ 434.1509; found 434.1497.
N-Isopropyl-5-(3-nitro-2-phenylpropyl)-N-(p-tolyl)thiazol-2-amine
(5e): According to GP-1, N-isopropyl-4-methyaniline (3e) (149 mg,
1.00 mmol) and trans-β-nitrostyrene (trans-6) (224 mg, 1.50 mmol) were
reacted with allene 2a (146 mg, 1.50 mmol) in anhydrous THF (3 mL) for
10 min at 0°C. The crude product was purified by flash chromatography
(Et2O/n-hexane 1/5 to 1/2, v/v) to give 5e (243 mg, 0.61 mmol, 61%) as a
colorless solid and N-isopropyl-5-methyl-N-p-tolylthiazol-2-amine (4e)
(81 mg, 0.33 mmol, 33%) as a yellow oil.
4e: Rf = 0.40 (Et2O/n-hexane 1:2); 1H NMR (400 MHz, CDCl3): δ = 1.18
3
4
(d, J = 7.5 Hz, 6H, CH(CH3)2), 2.17 (d, J = 1.5 Hz, 3H, 5-CH3), 2.40 (s,
3
4
3H, 4’-CH3), 4.82 (sept, J = 7.0 Hz, 1H, CH(CH3)2), 6.80 (q, J = 1.5 Hz,
3H, 4-H), 7.25 (d, J = 9.0 Hz, 2H, arom.), 7.46 (d, J = 9.0 Hz, 2H, arom.)
ppm; 13C NMR (100 MHz, CDCl3): δ = 11.77 (q, 5-CH3), 20.95 (q,
CH(CH3)2), 21.20 (q, 4’-CH3), 50.46 (d, CH(CH3)2), 120.70 (s, C-5),
130.40 (d, CH arom.), 130.61 (d, CH arom.), 135.58 (d, 4-CH), 138.26 (s,
C-1’/4’), 138.92 (s, C-1’/4’), 170.70 (s, N=CS) ppm; IR (CCl4): ṽ = 2975
(m), 2920 (m), 1509 (s), 1303 (m), 1161 (m) cm–1; HRMS (ESI): calcd. for
C14H19N2S [M + H]+ 247.1263, found 247.1282; [M + Na]+: 269.1083;
found 269.1099.
N-Methyl-5-(3-nitro-2-phenylpropyl)-N-phenylthiazol-2-amine
(5g):
According to GP-1, N-methylaniline (3g) (107 mg, 1.00 mmol) and trans-
β-nitrostyrene (trans-6) (224 mg, 1.50 mmol) were reacted with allene 2a
(146 mg, 1.50 mmol) in anhydrous THF (3 mL) for 10 min at 0°C. Column
chromatography (Et2O/n-hexane 1/3 to 1/1, v/v) gave 5g (203 mg,
0.58 mmol, 58%) and 4g (19%, NMR yield)[19] as yellow oils.
1
5g: Rf = 0.19 (Et2O/n-hexane 2:1); H NMR (400 MHz, CDCl3): δ = 3.00
(d, 3J = 7.5 Hz, 2H, CH=CCH2), 3.47 (s, 3H, NCH3), 3.63 (mC, 1H, CHAr),
2
2
4.58 (dd, J = 12.5 Hz, 3J = 8.5 Hz, 1H, CH2NO2), 4.63 (dd, J = 12.5 Hz,
3J = 6.5 Hz, 1H, CH2NO2), 6.84 (s, 1H, CH=CCH2), 7.15–7.18 (m, 2H,
arom.), 7.23–7.45 (m, 8H, arom.) ppm; 13C NMR (100 MHz, CDCl3):
δ = 31.21 (t, CH=CCH2), 39.98 (q, NCH3), 45.51 (d, CHAr), 79.30 (t,
CH2NO2), 122.26 (s, CH=CCH2), 124.78 (d, NCHortho), 126.34 (d,
NCHpara), 127.33 (d, CHortho), 127.88 (d, CHpara), 128.94 (d, CHmeta),
129.65 (d, NCHmeta), 137.53 (d, CH=CCH2), 138.54 (s, Cipso), 146.19 (s,
NCipso), 169.48 (s, N=CS) ppm; IR (CCl4): ṽ = 3034 (m), 1599 (w), 1557
(m), 1513 (s), 1496 (s), 1376 (m), 1164 (m), 697 (s) cm–1; HRMS (ESI):
calcd. for C19H20N3O2S [M + H]+ 354.1274; found 354.1271.
5e: Rf = 0.17 (Et2O/n-hexane 1:2); m.p. 135°C (Et2O/n-hexane), 1H NMR
(400 MHz, CDCl3, TMS): δ = 1.17 (d, 3J = 7.0 Hz, 3H, CHCH3), 1.18 (d,
3J = 7.0 Hz, 3H, CHCH3), 2.42 (s, 3H, C6H4CH3), 2.94 – 2.99 (m, 2H,
CH=CCH2), 3.57 (mC, 1H, CHAr), 4.55 (dd, 2J = 12.5 Hz, 3J = 9.5 Hz, 1H,
2
CHHNO2), 4.62 (dd, J = 12.5 Hz, 3J = 6.0 Hz, 1H, CHHNO2), 4.82 (sept,
3J = 7.0 Hz, 1H, CH(CH3)2), 6.80 (s, 1H, CH=CCH2), 7.10–7.16 (m, 4H,
arom.), 7.22–7.32 (m, 5H, arom.) ppm; 13C NMR (100 MHz, CDCl3):
δ = 20.91 (q, CHCH3), 20.94 (q, CHCH3), 21.22 (q, ArCH3), 31.35 (t,
CH=CCH2), 45.43 (d, CHAr), 50.73 (d, CH(CH3)2), 79.27 (t, CH2NO2),
121.21 (s, CH=CCH2), 127.26 (d, arom.), 127.81 (d, CHpara), 128.90 (d,
arom.), 130.42 (d, arom.), 130.55 (d, arom.), 137.08 (d, CH=CCH2),
138.37 (s, arom), 138.63 (s, arom), 138.82 (s, arom), 171.37 (s, N=CS)
ppm; IR (CCl4): ṽ = 3033 (w), 2976 (w), 2931 (w), 1557 (s), 1508 (s) cm–
1; HRMS (ESI): calcd. for: C22H26N3O2S [M + H]+ 396.1740, found
396.1720; [M + Na]+ 418.1560, found 418.1537.
N,N-Diisopropyl-4-methoxymethyl-5-(3-nitro-2-phenylpropyl)-thiazol-
2-amine (5h): 3-Isothiocyanato-4-methoxybuta-1,2-diene (2b) (141 mg,
1.0 mmol) was added dropwise to
diisopropylamine (3d) (101 mg; 1.0 mmol)
a
solution of N,N-
and trans-
β-nitrostyrene (trans-6) (149 mg; 1.0 mmol) in anhydrous THF (5 mL) at
room temperature. After completion of the reaction (about 1 h, TLC) the
mixture was concentrated in vacuo. Column chromatography (Et2O/n-
hexane 1/2, v/v) gave 5h (268 mg, 0.684 mmol, 68%) as a yellow solid
after crystallization was induced; m.p. 84−86°C; 1H NMR (400 MHz;
CDCl3): δ = 1.31 (d, 3J = 6.8 Hz, 6H, CH(CH3)2), 1.32 (d, 3J = 6.8 Hz, 6H,
CH(CH3)2), 3.01 (dd, 2J = 15.0 Hz, 3J = 6.4 Hz, 1H, C=CCH2CH), 3.12
(dd, 2J = 15.0 Hz, 3J = 8.9 Hz, 1H, C=CCH2CH), 3.40 (s, 3H, OCH3), 3.68
(m, 1H, CHPh), 3.87 (m, 2H, CH(CH3)2), 4.23 (m, 2H, CH3OCH2), 4.63
(dd, 2J = 12.9 Hz, 3J = 9.3 Hz, 1H, CH2NO2), 4.70 (dd, 2J = 12.9 Hz, 3J =
5.9 Hz, 1H, CH2NO2), 7.22 (m, 2H, o-Ph), 7.27 (m, 1H, p-Ph), 7.36 (m,
2H, m-Ph); 13C NMR (100.60 MHz; CDCl3): δ = 20.05 (q, CH(CH3)2),
20.11 (q, CH(CH3)2), 30.48 (t, C=CCH2CH), 46.01 (d, CHPh), 50.11 (d
N-Isopropyl-N-(4-methoxyphenyl)-5-(3-nitro-2-phenylpropyl)thiazol-
2-amine (5f): According to GP-1, N-isopropyl-p-anisidine (3f) (165 mg,
1.00 mmol) and trans-β-nitrostyrene (trans-6) (224 mg, 1.50 mmol) were
reacted with allene 2a (146 mg, 1.50 mmol) in anhydrous THF (3 mL) for
10 min at 0°C. Column chromatography (Et2O/n-hexane 1/1 to 3/1, v/v)
gave 5f (249 mg, 0.61 mmol, 61%) as a colorless, crystalline solid and N-
isopropyl-N-(4-methoxyphenyl)-5-methylthiazol-2-amine (4f) (70 mg,
0.27 mmol, 27%) as a yellow oil.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800701
European Journal of Organic Chemistry
FULL PAPER
CH(CH3)2), 58.27 (q, OCH3), 68.33 (t, CH3OCH2), 79.22 (t, CH2NO2),
117.22 (s, C=CCH2CH), 127.38 (d, o-Ph), 127.77 (d, p-Ph), 128.88 (d, m-
Ph), 139.29 (s, i-Ph), 146.12 (s, C=CCH2CH), 165.19 (s, N=CS). IR
(CCl4): ṽ = 2972 (m), 2929 (m), 1556 (s), 1530 (s), 1378 (m), 1367 (m),
1286 (m), 1258 (m), 1210 (m), 1101 (m) cm–1; HRMS (ESI): calcd. for
C20H30N3O3S [M + H]+ 392.2002, found 392.1996; [M + Na]+ 414.1822,
found 414.1812.
CH=CH2), 128.12 (d, arom.), 129.07 (d, Cpara), 129.11 (d, arom.), 135.66
(s, Cipso), 136.57 (d, CH=CH2), 147.11 (s, N=CS) ppm, assigned by
HMBC and HSQC; IR (CCl4): ṽ = 2973 (m), 2932 (w), 1603 (s), 1554 (s)
cm–1; HRMS (ESI): calcd. for C18H26N3O2S [M + H]+ 348.1740, found
348.1780.
N,N-Diisopropyl-6-nitro-5-phenyl-4,5,6,7-tetrahydrobenzo[d]-thiazol-
2-amine (9): 4-Acetoxy-3-isothiocyanatobuta-1,2-diene (2d) (84.60 mg;
0.50 mmol) was added slowly and dropwise to a solution of N,N-
2-(1H-Imidazol-1-yl)-5-(3-nitro-2-phenylpropyl)thiazole (5i): According
to GP-1, allenyl isothiocyanate (2a) (97 mg, 1.00 mmol) was added to a
solution of 1H-imidazole (68 mg, 1.00 mmol) and trans-
β-nitrostyrene (trans-6) (150 mg, 1.00 mmol) in anhydrous THF (3 mL)
and stirred at room temperature for 3 h. Flash chromatography (Et2O/n-
hexane 3/1 to EtOAc) gave 5i (74 mg, 0.24 mmol, 24%) as a pale yellow
solid. m.p. 143−145°C; 1H NMR (400 MHz, CDCl3): δ = 3.20 (dd,
2J = 15.0 Hz, 3J = 9.3 Hz, 1H, CH2CHPh), 3.30 (dd, 2J = 15.0 Hz,
3J = 5.5 Hz, 1H, CH2CHPh), 3.74 (m, 1H, CHPh), 4.68 (m, 2H, CH2NO2),
7.14 – 7.19 (m, 4H, CH), 7.33 – 7.38 (m, 4H, CH), 8.05 (s, 1H, CH-2')
ppm; 13C NMR (100 MHz, CDCl3): δ = 30.83 (t, CH2CHPh), 45.49 (d,
CHPh), 79.35 (t, CH2NO2), 117.47 (d, C-5'), 127.59 (d, Cortho), 128.57 (d,
Cpara), 129.34 (d, Cmeta), 130.61 (d, C-4), 131.26 (s, C-5), 135.21 (d, C-
2'), 137.13 (s, Cipso), 138.84 (d, C-4'), 156.29 (s, N=CS) ppm, assigned
by HMBC and HSQC; IR (CCl4): ṽ = 3033 (w), 2923 (w), 2235 (w), 1556
(s), 1508 (s) cm–1; C15H14N4O2S (314.36): calcd. C 57.31, H 4.49, N
17.82, S 10.20; found C 56.74, H 4.47, N 17.27, S 10.60%.
diisopropylamine (3d)
(51 mg;
0.50 mmol)
and
trans-
β-nitrostyrene (trans-6) (75 mg; 0.50 mmol) in anhydrous THF (3 mL) at
room temperature. After completion of the reaction (about 15 h, TLC) the
mixture was concentrated in vacuo, and flash column chromatography
(Et2O/n-hexane 1:1) gave the title compound 9 as bright yellow crystals
(68 mg, 0.189 mmol, 61%); m.p.: 199−201°C; 1H NMR (400 MHz;
CDCl3): δ = 1.36 (d, 3J = 7.0 Hz, 12H, CH(CH3)2), 2.90 (dd, 2J = 17.0 Hz,
3J = 11.0 Hz, 1H, CH2CHPh), 3.10 (dd, 2J = 17.0 Hz, 3J = 6.0 Hz, 1H,
CH2CHPh), 3.28−3.40 (m, 2H, CH2CHNO2), 3.68 (ddd, 3J = 11.0 Hz, 3J =
3
3
11.0 Hz, J = 6.0 Hz 1H, CHPh) 3.88 (sept, J = 7.0 Hz, 2H, CH(CH3)2),
5.12 (ddd, 3J = 11.0 Hz, 3J = 10.0 Hz, 3J = 6.0 Hz, 1H, CHNO2),
7.25−7.29 (m, 3H, Ph), 7.32−7.35 (m, 2H, Ph), NO2 and Ph in trans
configuration, assigned by Double Resonance experiments, structure
determined by COSY and HMBC; 13C NMR (100.60 MHz; CDCl3): δ =
20.01 (q, CH(CH3)2), 20.05 (q, CH(CH3)2), 28.88 (t, CH2CHNO2), 33.96 (t,
CH2CHPh), 45.12 (d, CHPh), 50.47 (d, CH(CH3)2), 87.67 (d, CHNO2),
108.20 (s, =C−S), 127.43 (d, m-Ph), 127.71 (d, p-Ph), 128.84 (d, o-Ph),
139.35 (s), 144.67 (s, =C−N), 166.64 (s, NCS); IR (CCl4): ṽ = 2972 (w),
1555 (m), 1534 (m) cm–1; C19H25N3O2S (359.49): C 63.48, H 7.01, N
11.69, S 8.92; found: C 63.22, H 7.04, N 11.26, S 9.17.
2-(1H-Imidazol-1-yl)-4-methoxymethyl-5-(3-nitro-2-phenylpropyl)-
thiazole (5j): According to GP-1, 3-isothiocyanato-4-methoxybuta-1,2-
diene (2b) (141 mg, 1.00 mmol) was added to a solution of 1H-imidazole
(68 mg, 1.00 mmol) and trans-β-nitrostyrene (trans-6) (150 mg, 1.00
mmol) in anhydrous THF (3 mL) and stirred at room temperature for 4
days. Flash chromatography (EtOAc/MeOH 10/1) gave 5j (48 mg, 0.13
mmol, 13%) and 4j (69 mg, 0.33 mmol, 33%) as yellow oils.
Similar experiments with cis-6 instead of trans-6 or 2c instead of 2d
produced also 9, however, in lower yields.
1-{5-[2-Hydroxy-2-(4-nitrophenyl)ethyl]thiazol-2-yl}-2,2,6,6-
5j: 1H NMR (400 MHz, CDCl3): δ = 3.16 (dd, 2J = 15.0 Hz, 3J = 9.3 Hz,
tetramethylpiperidin-4-one (11a): According to GP-1, allenyl
isothiocyanate (2a) (49 mg, 0.50 mmol) was added to a solution of
triacetonamine (3a) (62 mg, 0.40 mmol) and 4-nitrobenzaldehyde (10a)
(76 mg, 0.50 mmol) in anhydrous THF (2 mL) and stirred at room
temperature for 24 h. Flash chromatography (Et2O/n-hexane 1/3 to 1/1,
v/v) gave 11a (120 mg, 0.30 mmol, 74%) as a pale yellow, crystalline
solid. Rf = 0.20 (Et2O/n-hexane 3:1); m.p. 153–155°C (Et2O/n-hexane);
1H NMR (400 MHz, CDCl3): δ = 1.27 (s, 12H, C(CH3)2), 2.46 (s, 1H, OH),
2
3
1H, CH2CHPh), 3.37 (dd, J = 15.0 Hz, J = 5.5 Hz, 1H, CH2CHPh), 3.40
(s, 3H, OCH3), 3.74 (m, 1H, CHPh), 4.32 (s, 2H, CH3OCH2), 4.68 (m, 2H,
CH2NO2), 7.11 (s, 1H, CH-4'), 7.15 – 7.17 (m, 2H, Ph), 7.30 – 7.34 (m,
3H, Ph), 7.36 (s, 1H, CH-5'), 8.05 (s, 1H, CH-2') ppm; 13C NMR
(100 MHz, CDCl3): δ = 30.07 (t, CH2CHPh), 45.70 (d, CHPh), 58.55 (q,
OCH3), 67.75 (t, CH3OCH2), 79.12 (t, CH2NO2), 117.44 (d, C-5'), 127.56
(d, Cortho), 128.43 (d, Cpara), 129.13 (s, C-5), 129.23 (d, Cmeta), 130.49 (d,
C-4'), 135.25 (d, C-2'), 137.34 (s, Cipso), 147.66 (s, C-4), 154.47 (s,
N=CS) ppm, assigned by HMBC and HSQC; IR (CCl4): ṽ = 3032 (w),
2990 (w) 2925 (w), 1557 (s), 1528 (s), 1510 (s), 1102 (m) cm–1; HRMS
(ESI): calcd. for C17H19N4O3S [M + H]+ 359.1172, found 359.1223; [M +
Na]+ 381.0992, found 381.1000.
3
2.56 (s, 4H, CH2C(CH3)2), 3.19 (d, J = 6.0 Hz, 2H, CH=CCH2), 5.07 (td,
3J = 6.0 Hz, 3J = 3.0 Hz, 1H, CHAr), 7.19 (s, 1H, CH=CCH2), 7.50 (d,
J = 8.5 Hz, 2H, H-2’’,6’’), 8.19 (d, J = 8.5 Hz, 2H, H-3’’,5’’) ppm; 13C NMR
(100 MHz, CDCl3): δ = 29.96 (q, C(CH3)2), 37.56 (t, CH=CCH2), 54.69 (t,
CH2C(CH3)2), 58.70 (s, CH2C(CH3)2), 73.34 (d, CHAr), 123.66 (d, C-
2’’,6’’), 126.67 (d, C-3’’,5’’), 131.47 (s, CH=CCH2), 137.54 (d, CH=CCH2),
147.49 (s, C-4’’), 150.10 (s, C-1’’), 167.94 (s, N=CS), 208.73 (s, CO)
ppm, assigned by HMBC; IR (KBr): ṽ = 3413 (s), 2972 (m), 2912 (m),
1698 (s), 1519 (m) cm–1; C20H25N3O4S (403.50): calcd. C 59.53, H 6.25,
N 10.41, S 7.95; found C 59.44, H 6.25, N 10.34, S 7.93%.
N,N-Diisopropyl-5-nitro-6-phenyl-4-vinyl-5,6-dihydro-4H-1,3-thiazin-
2-amine (7): To a solution of diisopropylamine (3d) (202 mg, 2.00 mmol)
and trans-β-nitrostyrene (trans-6) (448 mg, 3.00 mmol) in anhydrous THF
(6 mL) was added allene 2a (292 mg, 3.00 mmol) at –30°C. After 20 min
of stirring, the solvent was removed under reduced pressure. The crude
product was purified by flash chromatography (Et2O/n-hexane 1/20 to 1/2,
v/v) to give 5d (226 mg, 0.66 mmol, 33%) as a colorless solid and 7
(25 mg, 0.07 mmol, 4%) as a colorless, crystalline solid. m.p. 118°C
(Et2O/n-hexane); 1H NMR (400 MHz, CDCl3): δ = 1.29 (d, 3J = 7.0 Hz,
1-{5-[2-Hydroxy-2-(perfluorophenyl)ethyl]thiazol-2-yl}-2,2,6,6-
tetramethylpiperidin-4-one (11b): According to GP-1, allenyl
isothiocyanate (2a) (49 mg, 0.50 mmol) was added to a solution of
triacetonamine (3a)
flourobenzaldehyde (10b) (0.06 mL, 98 mg, 0.50 mmol) in anhydrous
THF (2 mL) and stirred at room temperature for days. Flash
(62 mg,
0.40 mmol)
and
penta-
3
6H, CH(CH3)2), 1.30 (d, J = 7.0 Hz, 6H, CH(CH3)2), 3.80 – 3.96 (m, 2H,
CH(CH3)2), 4.52 (dd, 3J = 10.0 Hz, 3J = 7.0 Hz, 1H, CHCH=CH2), 4.75
(dd, 3J = 10.5 Hz, 3J = 10.0 Hz, 1H, CHNO2), 4.92 (d, 3J = 10.5 Hz, 1H,
CHPh), 5.20 (d, 3J = 10.0 Hz, 1H, C=CHH), 5.36 (d, 3J = 17.0 Hz, 1H,
C=CHH), 5.83 (ddd, 3J = 17.0 Hz, 3J = 10.0 Hz, 3J = 7.0 Hz, 1H,
CHCH=CH2), 7.27 – 7.40 (m, 5H, Ph) ppm; 13C NMR (100 MHz, CDCl3):
δ = 20.87 (q, CH(CH3)2), 21.12 (q, CH(CH3)2), 47.88 (d, CHPh), 48.54 (d,
CH(CH3)2), 64.13 (d, CHCH=CH2), 91.22 (d, CHNO2), 117.73 (t,
4
chromatography (Et2O/n-hexane 1/2 to 2/1, v/v) gave 11b (122 mg,
0.27 mmol, 68%) as a colorless, crystalline solid. Rf = 0.46 (Et2O/n-
hexane 3:1); m.p. 125–126°C (Et2O/n-hexane); 1H NMR (400 MHz,
CDCl3): δ = 1.25 (s, 12H, C(CH3)2), 2.55 (s, 4H, CH2C(CH3)2), 2.72 (s,
1H, OH), 3.30 (dd, 2J = 14.5 Hz, 3J = 7.0 Hz, 1H, CH=CCH2), 3.46 (dd,
2J = 14.5 Hz, 3J = 7.0 Hz, 1H, CH=CCH2), 5.27 (mC, 1H, CHAr), 7.22 (s,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800701
European Journal of Organic Chemistry
FULL PAPER
1H, CH=CCH2) ppm; 13C NMR (100 MHz, CDCl3): δ = 29.84 (q, C(CH3)2),
34.99 (t, CH=CCH2), 54.68 (t, CH2C(CH3)2), 58.73 (s, CH2C(CH3)2),
67.02 (d, CHAr), 131.07 (s, CH=CCH2), 137.46 (d, CH=CCH2), 168.08 (s,
N=CS), 208.72 (s, CO) ppm, C6F5-signals absent, assignment by
comparison; IR (KBr): ṽ = 3210 (br), 2983 (m), 2930 (m), 1723 (s),
1525 (s), 1501 (s), 1447 (s) cm–1; HRMS (ESI): calcd. for C20H22F5N2O2S
[M + H]+ 449.1322; found 449.1294.
CHAr), 125.82 (d, CHortho), 127.93 (d, CHpara), 128.43 (d, CHmeta), 133.23
(s, CH=CCH2), 136.93 (d, CH=CCH2), 143.00 (s, Cipso), 167.35 (s,
N=CS), 209.17 (s, CO) ppm, assigned by HMBC; IR (KBr): ṽ = 3263 (br),
2970 (m), 2907 (m), 1726 (s), 1712 (s), 1426 (s), 754 (w), 705 (s) cm–1;
HRMS (ESI): calcd. for C20H27N2O2S [M + H]+ 359.1788; found 359.1764.
N,N-Diisopropyl-5-[2-hydroxy-2-(4-nitrophenyl)-ethyl]-thiazol-2-
amine (11f): Isothiocyanatopropadiene (2a) (97 mg; 1.00 mmol) was
added dropwise to a solution of N,N-diisopropylamine (3d) (101 mg;
1.00 mmol) and 4-nitrobenzaldehyde (10a) (151 mg; 1.00 mmol) in
anhydrous THF (5 mL) at room temperature. After completion of the
reaction (about 1 h, TLC) the mixture was concentrated in vacuo and the
crude product was purified by flash chromatography (Et2O/n-hexane 1:1)
to give the title compound 11f as yellow crystals (170 mg, 0.486 mmol,
1-{5-[2-(4-Chlorophenyl)-2-hydroxyethyl]thiazol-2-yl}-2,2,6,6-
tetramethylpiperidin-4-one (11c): According to GP-1, allenyl
isothiocyanate (2a) (49 mg, 0.50 mmol) was added to a solution of
triacetonamine (3a) (62 mg, 0.40 mmol) and 4-chlorobenzaldehyde (10c)
(70 mg, 0.50 mmol) in anhydrous THF (2 mL) and stirred at room
temperature for 4 days. Flash chromatography (Et2O/n-hexane 2/1 to 4/1,
v/v) gave 11c (88 mg, 0.22 mmol, 56%) as a colorless, crystalline solid.
Rf = 0.30 (Et2O/n-hexane 3:1); m.p. 165–166°C (Et2O/n-hexane); 1H
NMR (400 MHz, CDCl3): δ = 1.26 (s, 12H, C(CH3)2), 2.45 (br s), 1H, OH),
2.54 (s, 4H, CH2C(CH3)2), 3.14 (mC, 2H, CH=CCH2), 4.90 (t, 3J = 6.0 Hz,
1H, CHAr), 7.18 (s, 1H, CH=CCH2), 7.23 (d, J = 6.5 Hz, 2H, H-3’’,5’’),
7.29 (d, J = 6.5 Hz, 2H, H-2’’,6’’) ppm; 13C NMR (100 MHz, CDCl3):
δ = 29.92 (q, C(CH3)2), 37.55 (t, CH=CCH2), 54.77 (t, CH2C(CH3)2),
58.68 (s, CH2C(CH3)2), 73.74 (d, CHAr), 127.23 (d, 3’’,5’’-CH), 128.59 (d,
2’’,6’’-CH), 132.47 (s, C-4’’), 133.61 (s, CH=CCH2), 137.54 (d,
CH=CCH2), 141.44 (s, C-1’’), 167.60 (s, N=CS), 208.89 (s, CO) ppm,
assigned by HMBC; IR (KBr): ṽ = 3520 (br), 2968 (m), 1699 (s), 837 (m),
815 (m) cm–1; HRMS (ESI): calcd. for C20H26ClN2O2S [M + H]+ 393.1404;
found 393.1382.
3
50%); m.p. 143−145°C; 1H NMR (400 MHz; CDCl3): δ = 1.34 (d, J = 6.8
2
3
Hz, 12H, CH(CH3)2), 2.38 (bs, 1H, OH), 2.96 (dd, J = 15.2 Hz, J = 8.6
Hz, 1H, CH2CHOH), 3.09 (dd, 2J = 15.2 Hz, 3J = 4.0 Hz, 1H, CH2CHOH),
3.88 (sept, 3J = 6.8 Hz, 2H, CH(CH3)2), 4.92 (dd, 3J = 8.6 Hz, 3J = 4.0 Hz,
1H, CHOH), 6.89 (s, 1H, CH=CCH2CHOH), 7.56 (d, J = 8.6 Hz, 2H,
C6H4), 8.21 (d, J = 8.6 Hz, 2H, C6H4); 13C NMR (100.6 MHz; CDCl3): δ =
20.04 (q, CH(CH3)2), 20.11 (q, CH(CH3)2), 37.51 (t, CH2CHOH), 50.35 (d,
CH(CH3)2), 73.22 (d, CHOH), 117.69 (s, =CCH2CHOH), 123.64 (d, C-
2'',6''), 126.60 (d, C-3'',5''), 138.06 (d, CHC=), 147.31 (s, C-4''), 150.54 (s,
C-1''), 168.33 (s, NCS); Assignment according to 11a; IR (CHCl3): ṽ =
3601 (w), 2974 (w), 2934 (w), 2040 (w) cm–1; C17H23N3O3S (349.45):
calcd. C 58.43, H 6.63, N 12.02, S 9.17; found: C 58.07, H 6.71, N 11.21,
S 9.43.
1-{5-[2-(2,4-Dinitrophenyl)-2-hydroxyethyl]thiazol-2-yl}-2,2,6,6-
tetramethylpiperidin-4-one (11d): According to GP-1, allenyl
isothiocyanate (2a) (49 mg, 0.50 mmol) was added to a solution of
N,N-Diisopropyl-5-[2-hydroxy-2-(4-nitrophenyl)-ethyl]-4-
methoxymethyl-thiazol-2-amine
(11g):
3-Isothiocyanato-4-
methoxybuta-1,2-diene (2b) (141 mg; 1.00 mmol) was added dropwise to
a solution of N,N-diisopropylamine (3d) (101 mg; 1.00 mmol) and 4-
nitrobenzaldehyde (10a) (151 mg; 1.00 mmol) in anhydrous THF (5 mL)
at room temperature. After completion of the reaction (about 1 h, TLC)
the mixture was concentrated in vacuo and the crude product was
recyrstallized from Et2O/n-hexane (1:1, v/v) to give the title compound
11g as orange crystals (320 mg, 0.813 mmol, 81%); m.p. 84−87°C; 1H
triacetonamine (3a)
(62 mg,
0.40 mmol)
and
2,4-
dinitrobenzaldehyde (10d) (98 mg, 0.50 mmol) in anhydrous THF (2 mL)
and stirred at room temperature for 2 days. Flash chromatography
(Et2O/n-hexane 1/1 to 3/1, v/v) gave 11d (77 mg, 0.17 mmol, 43%) as a
dark yellow, crystalline solid. Rf = 0.46 (Et2O/n-hexane 3:1); m.p. 146–
147°C (Et2O/n-hexane); 1H NMR (400 MHz, CDCl3): δ = 1.28 (s, 12H,
C(CH3)2), 2.56 (s, 4H, CH2C(CH3)2), 3.11 (dd, 2J = 15.0 Hz, 3J = 8.0 Hz,
1H, CH=CCH2), 2.80 (br s, 1H, OH), 3.37 (dd, 2J = 15.0 Hz, 3J = 3.0 Hz,
3
NMR (400 MHz; CDCl3): δ = 1.31 (d, J = 6.8 Hz, 12H, CH(CH3)2), 2.96
(dd, 2J = 15.2 Hz, 3J = 8.3 Hz, 1H, CH2CHOH), 3.11 (dd, 2J = 15.2 Hz, 3J
= 3.1 Hz, 1H, CH2CHOH), 3.49 (s, 3H, OCH3), 3.84 (sept, 3J = 6.8 Hz, 2H,
CH(CH3)2), 4.35 (s, 2H, CH3OCH2), 4.90 (dd, 3J = 8.3 Hz, 3J = 3.1 Hz, 1H,
CHOH), 7.56 (d, J = 8.8 Hz, 2H, C6H4), 8.20 (d, J = 8.8 Hz, 2H, C6H4),
OH was not found. 13C NMR (100.6 MHz; CDCl3): δ = 20.04 (q,
CH(CH3)2), 36.55 (t, CH2CHOH), 50.16 (d, CH(CH3)2), 58.39 (q, OCH3),
68.51 (t, CH3OCH2), 72.87 (d, CHOH), 116.17 (s, =CCH2CHOH), 123.55
(d, C-2'',C-6''), 126.53 (d, C-3'',C-5''), 146.73 (s, OCH2C=), 147.11 (s, C-
4''), 151.66 (s, C-1''), 165.49 (s, NCS); Assignment according to 11a; IR
(CCl4): ṽ = 3420 (br), 2970 (m), 2930 (m), 2140 (w) cm–1; C19H27N3O4S
(393.50): calcd. C 57.99, H 6.92, N 10.68, S 8.15; found: C 58.15, H 7.16,
N 10.39, S 8.13.
3
1H, CH=CCH2), 5.64 (dd, 3J = 8.0 Hz, J = 3.0 Hz, 1H, CHAr), 7.24 (s,
1H, CH=CCH2), 8.09 (d, 3J = 9.0 Hz, 1H, H-6’’), 8.43 (dd, 3J = 9.0 Hz,
4J = 2.5 Hz, 1H, H-5’’), 8.83 (d, 4J = 2.5 Hz, 1H, H-3’’) ppm; 13C NMR
(100 MHz, CDCl3): δ = 29.95 (q, C(CH3)2), 36.77 (t, CH=CCH2), 54.66 (t,
CH2C(CH3)2), 58.71 (s, CH2C(CH3)2), 69.34 (d, CHAr), 120.11 (d, C-3’’),
127.49 (d, C-5’’), 130.19 (d, C-6’’), 131.45 (s, CH=CCH2), 137.54 (d,
CH=CCH2), 145.51 (s, C-1’’), 147.13 (s, CNO2), 147.14 (s, CNO2),
168.16 (s, N=CS), 208.80 (s, CO) ppm, assigned by HMBC; IR (KBr): ṽ =
3331 (br), 3117 (w), 2973 (m), 1722 (m), 1690 (s), 1607 (m), 1537 (s),
1437 (m), 1345 (s), 910 (m), 846 (m), 726 (m) cm–1; HRMS (ESI): calcd.
for C20H25N4O6S [M + H]+ 449.1489; found 449.1469.
1-[5-(2-Hydroxy-2-phenylethyl)thiazol-2-yl]-2,2,6,6-tetramethyl-
piperidin-4-one (11e): According to GP-1 allenyl isothiocyanate (2a)
(49 mg, 0.50 mmol) was added to a solution of triacetonamine (3a)
(62 mg, 0.40 mmol) and benzaldehyde (10e) (0.05 mL, 53 mg,
0.50 mmol) in anhydrous THF (2 mL) and stirred at room temperature for
2 days. Flash chromatography (Et2O/n-hexane 1/1 to 3/1, v/v) gave 11e
(61 mg, 0.17 mmol, 43%) as a pale yellow, viscous oil, that crystallizes in
the refrigerator. Rf = 0.31 (Et2O/n-hexane 3:1); m.p. 121–122°C; 1H NMR
(400 MHz, CDCl3): δ = 1.24 (s, 12H, C(CH3)2), 2.53 (s, 4H, CH2C(CH3)2),
3.10–3.22 (m, 2H, CH=CCH2), 4.90 (dd, 3J = 7.5 Hz, 3J = 5.5 Hz, 1H,
CHAr), 7.20 (s, 1H, CH=CCH2), 7.25–7.35 (m, 5H, arom.) ppm, OH
missing; 13C NMR (100 MHz, CDCl3): δ = 29.84 (q, C(CH3)2), 37.56 (t,
CH=CCH2), 54.78 (t, CH2C(CH3)2), 58.67 (s, CH2C(CH3)2), 74.40 (d,
5-[2-Hydroxy-2-(4-nitrophenyl)ethyl]-2-(1H-imidazol-1-yl)-thiazole
(11h): According to GP-1, allenyl isothiocyanate (2a) (97 mg, 1.00 mmol)
was added to a solution of 1H-imidazole (68 mg, 1.00 mmol) and 4-
nitrobenzaldehyde (10a) (151 mg, 1.00 mmol) in anhydrous THF (3 mL)
and stirred at room temperature for 4 hours. Flash chromatography
(Et2O/n-hexane 3/1 to EtOAc) gave 11h (85 mg, 0.27 mmol, 27%) as a
yellow solid; m.p. 197−199°C ; 1H NMR (400 MHz, DMSO-d6): δ = 3.13
(dd, 2J = 15.0 Hz, 3J = 7.2 Hz, 1H, CH2CHPh), 3.28 (dd, 2J = 15.0 Hz,
3J = 3.9 Hz, 1H, CH2CHPh), 4.99 (dt, 3J = 7.3 Hz, 3J = 4.0 Hz, 1H,
CHOH), 6.17 (d, 3J = 4.4 Hz, 1H, OH), 7.12 (s, 1H, CH-4), 7.30 (s, 1H,
CH-4'), 7.65 (d, J = 8.7 Hz, 2H, CH-2'', CH-6''), 7.76 (s, 1H, CH-5'), 8.18
(d, J = 8.8 Hz, 2H, CH-3'', CH-5''), 8.33 (s, 1H, CH-2') ppm; 13C NMR
(100 MHz, DMSO-d6): δ = 36.06 (t, CH2CHPh), 70.85 (d, CHOH), 118.05
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800701
European Journal of Organic Chemistry
FULL PAPER
(d, C-5'), 123.25 (d, C-3'', C-5''), 127.11 (d, C-2'', C-6''), 130.30 (d, C-4),
131.63 (s, C-5), 135.61 (d, C-2'), 138.30 (d, C-4'), 146.46 (s, C-4''),
152.14 (s, C-1''), 156.20 (s, N=CS) ppm, assigned by HMBC and HSQC;
IR (KBr): ṽ = 3223 (br), 3091 (w), 2940 (w), 1597 (m), 1546 (s), 1512 (s)
cm–1; C14H12N4O3S (316.34): calcd. C 53.16, H 3.82, N 17.71, S 10.13;
found C 52.63, H 3.83, N 16.70, S 10.29%.
Acknowledgements
We thank Dr. Manfred Hagedorn for his assistance with NMR
measurements and Dr. Andreas Ihle for his help in connection
with the manuscript.
N-{1-Phenyl-2-[2-(2,2,6,6-tetramethyl-4-oxopiperidin-1-yl)thiazol-5-
yl]-ethyl}benzenesulfonamide (13a): According to GP-1 allene 2a
(291 mg, 3.00 mmol) was added to a solution of triacetonamine (3a)
(310 mg, 2.00 mmol) and imide 12 (736 mg, 3.00 mmol) in anhydrous
THF (10 mL) and stirred at room temperature for 24 h. The white
precipitate was filtered off and washed with a few milliliters of Et2O to
give 13a (808 mg, 1.62 mmol, 81%) as a colorless, crystalline solid,
which was recrystallized from CHCl3 to give colorless rod-like crystals;
m.p. 197°C (CHCl3); 1H NMR (400 MHz, CDCl3): δ = 1.21 (s, 6H, CCH3),
1.22 (s, 6H, CCH3), 2.53 (s, 4H, CH2C=O), 3.14 (dd, 2J = 15.0 Hz,
3J = 7.0 Hz, 1H, CH=CCHH), 3.29 (dd, 2J = 15.0 Hz, 3J = 6.0 Hz, 1H,
CH=CCHH), 4.54 (ddd, 3J = 6.0 Hz, 3J = 7.0 Hz, 3J = 7.0 Hz, 1H, CHNH),
5.21 (d, br, 3J = 7.0 Hz, 1H, NH), 6.95 (d, J = 7.5 Hz, 2H, arom.), 7.08 (s,
1H, CH=CCH2), 7.09–7.18 (m, 3H, arom), 7.34 (t, J = 7.5 Hz, 2H, arom.),
7.46 (t, J = 7.5 Hz, 1H, arom.), 7.68 (d, J = 7.5 Hz, 2H, arom.) ppm; 13C
NMR (100 MHz, CDCl3): δ = 29.90 (q, CCH3), 35.94 (t, CH=CCH2), 54.73
(t, CH2C=O), 58.69 (d, CH-NH), 58.89 (s, CCH3), 126.58 (d, arom.),
126.99 (d, arom.), 128.02 (d, Cpara), 128.54 (d, arom.), 128.85 (d, arom.),
131.45 (s, CH=CCH2), 132.53 (d, Cpara), 137.61 (s, Cipso), 138.82 (d,
CH=CCH2), 140.18 (s, Cipso), 167.83 (s, N=CS), 208.69 (s, C=O) ppm,
assigned by HSQC; IR (KBr): ṽ = 3359 (m), 3148 (w), 2971 (m), 2935 (w),
1695 (s) cm–1; HRMS (ESI): calcd. for C26H32N3O3S2 [M + H]+ 498.1880,
found 498.1849; [M + Na]+ 520.1699, found 520.1657.
Keywords: C−C coupling • Cyclization • Heterocycles •
Multicomponent reactions • Thiazoles
[1]
[2]
D. Das, P. Sikdar, M. Bairagi, Eur. J. Med. Chem. 2016, 109, 89–98.
a) S. Ghaemmaghami, B. C. H. May, A. R. Renslo, S. B. Prusiner, J.
Virol. 2010, 84, 3408–3412; b) A. Gallardo-Godoy, J. Gever, K. L. Fife,
B. M. Silber, S. B. Prusiner, A. R. Renslo, J. Med. Chem. 2011, 54,
1010–1021; c) J. Das, P. Chen, D. Norris, R. Padmanabha, J. Lin, R. V.
Moquin, Z. Shen, L. S. Cook, A. M. Doweyko, S. Pitt, S. Pang, D. R.
Shen, Q. Fang, H. F. de Fex, K. W. McIntyre, D. J. Shuster, K. M.
Gillooly, K. Behnia, G. L. Schieven, J. Wityak, J. C. Barrish, J. Med.
Chem. 2006, 49, 6819–6832; d) J. Araujo, C. Logothetis, Cancer Treat.
Rev. 2010, 36, 492–500; e) B.-C. Chen, R. Zhao, B. Wang, R. Droghini,
J. Lajeunesse, P. Sirard, M. Endo, B. Balasubramanian, J. C. Barrish,
ARKIVOC 2010, (vi), 32–38.
[3]
[4]
a) S. Mitra, A. Chakraborty, S. Mishra, A. Majee, A. Hajra, Org. Lett.
2014, 16, 5652–5655; b) A. Sarkar, S. Santra, S. Kumar Kundu, A.
Hajra, G. V. Zyryanov, O. N. Chupakhin, V. N. Charushin, A. Majee,
Green Chem. 2016, 18, 4475–4525.
a) M. Pieroni, B. Wan, S. Cho, S. G. Franzblau, G. Costantino, Eur. J.
Med. Chem. 2014, 72, 26–34; b) E. A. Kesicki, M. A. Bailey, Y.
Ovechkina, J. V. Early, T. Alling, J. Bowman, E. S. Zuniga, S. Dalai,
N. Kumar, T. Masquelin, P. A. Hipskind, J. O. Odingo, T. Parish,
PLOS ONE 2016, 11, e0155209; c) S. B. M. Kretschmer, S.
Woltersdorf, C. B. Rödl, D. Vogt, A.-K. Häfner, D. Steinhilber, H. Stark,
B. Hofmann, Future Med. Chem. 2016, 8, 149–164; d) S. B. M.
Kretschmer, S. Woltersdorf, D. Vogt, F. F. Lillich, M. Rühl, M. Karas, I.
V. Maucher, J. Roos, A.-K. Häfner, A. Kaiser, M. Wurglics, M.
Schubert-Zsilavecz, C. Angioni, G. Geisslinger, H. Stark, D. Steinhilber,
B. Hofmann, Biochem. Pharmacol. 2017, 123, 52–62; e) A. S. Al-Ayed,
Asian J. Chem. 2015, 27, 4081–4084; f) K. S. Kim, S. D. Kimball, R. N.
Misra, D. B. Rawlins, J. T. Hunt, H.-Y. Xiao, S. Lu, L. Qian, W.-C. Han,
W. Shan, T. Mitt, Z.-W. Cai, M. A. Poss, H. Zhu, J. S. Sack, J. S.
Tokarski, C. Y. Chang, N. Pavletich, A. Kamath, W. G. Humphreys, P.
Marathe, I. Bursuker, K. A. Kellar, U. Roongta, R. Batorsky, J. G.
Mulheron, D. Bol, C. R. Fairchild, F. Y. Lee, K. R. Webster, J. Med.
Chem. 2002, 45, 3905–3927; g) R. N. Misra, H.-Y. Xiao, K. S. Kim, S.
Lu, W.-C. Han, S. A. Barbosa, J. T. Hunt, D. B. Rawlins, W. Shan, S. Z.
Ahmed, L. Qian, B.-C. Chen, R. Zhao, M. S. Bednarz, K. A. Kellar, J. G.
Mulheron, R. Batorsky, U. Roongta, A. Kamath, P. Marathe, S. A.
Ranadive, J. S. Sack, J. S. Tokarski, N. P. Pavletich, F. Y. F. Lee, K. R.
Webster, S. D. Kimball, J. Med. Chem. 2004, 47, 1719–1728; h) R. M.
Borzilleri, R. S. Bhide, J. C. Barrish, C. J. D'Arienzo, G. M. Derbin, J.
Fargnoli, J. T. Hunt, R. Jeyaseelan, A. Kamath, D. W. Kukral, P.
Marathe, S. Mortillo, L. Qian, J. S. Tokarski, B. S. Wautlet, X. Zheng, L.
J. Lombardo, J. Med. Chem. 2006, 49, 3766–3769.
N-{2-[2-(N-Isopropyl-N-p-tolylamino)thiazol-5-yl]-1-phenylethyl}-
benzenesulfonamide (13e): According to GP-1 allene 2a (291 mg,
3.00 mmol) was added to a solution of N-isopropyl-4-methylaniline (3e)
(299 mg, 2.00 mmol) and imide 12 (736 mg, 3.00 mmol) in anhydrous
THF (10 mL) at 0°C and stirred for 20 min. Flash chromatography
(Et2O/n-hexane 1/5 to 1/3, v/v) gave 13e (685 mg, 1.39 mmol, 70%) as a
colorless, crystalline solid, which was recrystallized from toluene to give
colorless, prism-like crystals. Rf = 0.17 (Et2O/n-hexane 3:1); m.p. 158°C
1
3
(toluene); H NMR (400 MHz, CDCl3, TMS): δ = 1.16 (d, J = 7.5 Hz, 3H,
3
CHCH3), 1.18 (d, J = 7.0 Hz, 3H, CHCH3), 2.40 (s, 3H, CaromCH3), 2.87
(dd, 2J = 15.0 Hz, 3J = 6.0 Hz, 1H, CH=CCHH), 2.93 (dd, 2J = 15.0 Hz,
3J = 7.5 Hz, 1H, CH=CCHH), 4.35 (dt, 3J = 6.0 Hz, 3J = 7.5 Hz, 1H,
CHNH), 4.76 (sept, 3J = 6.5 Hz, 1H, CH(CH3)2), 5.00 (s, br, 1H, NH), 6.71
(s, 1H, CH=CCH2), 7.00–7.05 (m, 2H, arom.), 7.07 (d, J = 8.0 Hz, 2H,
arom.), 7.10–7.17 (m, 3H, arom), 7.25 (d, J = 8.0 Hz, 2H, arom.), 7.31 (t,
J = 7.5 Hz, 2H, arom.), 7.44 (t, J = 7.0 Hz, 1H, arom.), 7.59 (d,
J = 7.5 Hz, 2H, arom.) ppm; 13C NMR (100 MHz, CDCl3, TMS): δ = 20.91
(q, CHCH3), 21.02 (q, CHCH3), 21.24 (q, CaromCH3), 35.48 (t, CH=CCH2),
50.82 (d, CH(CH3)2), 58.47 (d, CH-NH), 119.51 (s, CH=CCH2), 126.67 (d,
arom.), 127.09 (d, arom.), 127.70 (d, arom.), 128.42 (d, arom.), 128.68
(d, arom.), 130.42 (d, arom.), 130.50 (d, arom.), 132.28 (d, arom.),
137.98 (d, arom.), 138.46 (s, arom.), 138.52 (s, arom.), 139.71 (s, arom.),
140.16 (s, arom.), 171.71 (s, N=CS) ppm; IR (KBr): ṽ = 3168 (m, br),
3056 (m), 2964 (m), 1500 (s), 1447 (m) cm–1; HRMS (ESI): calcd. for
C27H30N3O2S2 [M + H]+ 492.1774, found 492.1752; [M + Na]+ 514.1599,
found 514.1548.
[5]
[6]
a) M. T. Chhabria, S. Patel, P. Modi, P. S. Brahmkshatriya, Curr. Top.
Med. Chem. 2016, 16, 2841–2862; b) V. Gupta, V. Kant, Sci. Int. 2013,
1, 253–260.
A. Hantzsch, J. H. Weber, Ber. Dtsch. Chem. Ges. 1887, 20, 3118–
3132.
[7]
[8]
A. Hantzsch, Ber. Dtsch. Chem. Ges. 1928, 61, 1776–1788.
R. L. P. de Jong, J. Meijer, R. S. Sukhai, L. Brandsma, Recl. Trav.
Chim. Pays-Bas 1982, 101, 310–313.
[9]
a) V. Golubev, F. Zubkov, M. Krasavin, Tetrahedron Lett. 2013, 54,
4844–4847; b) H. Zheng, Y.-J. Mei, K. Du, X.-T. Cao, P.-F. Zhang,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800701
European Journal of Organic Chemistry
FULL PAPER
Molecules 2013, 18, 13425–13433; c) H. B. Jalani, A. N. Pandya, D. H.
Pandya, J. A. Sharma, V. Sudarsanam, K. K. Vasu, Tetrahedron Lett.
2013, 54, 5403–5406.
Ann./Recueil 1997, 2005–2018; c) K. Banert, S. Groth, H. Hückstädt, J.
Lehmann, J. Schlott, K. Vrobel, Synthesis 2002, 1423–1433; d) K.
Banert, B. Jawabrah Al-Hourani, S. Groth, K. Vrobel, Synthesis 2005,
2920–2926; e) B. Jawabrah Al-Hourani, K. Banert, T. Rüffer, B. Walfort,
H. Lang, Heterocycles 2008, 75, 2667–2679; f) B. Jawabrah Al-Hourani,
K. Banert, N. Gomaa, K. Vrobel, Tetrahedron 2008, 64, 5590–5597.
[15] K. Banert, K. Fink, M. Hagedorn, F. Richter, ARKIVOC 2012, (III), 379–
390.
[10] a) C. Vaxelaire, P. Winter, M. Christmann, Angew. Chem. 2011, 123,
3685–3687; Angew. Chem. Int. Ed. 2011, 50, 3605–3607; b) Y.
Hayashi, Chem. Sci. 2016, 7, 866–880.
[11] a) L. F. Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137–170; Angew.
Chem. Int. Ed. Engl. 1993, 32, 131–163; b) L. F. Tietze, Chem. Rev.
1996, 96, 115–136.
[16] K. Banert, F. Richter, M. Hagedorn, Org. Process Res. Dev. 2015, 19,
1068–1070.
[12] a) G. Balme, D. Bouyssi, N. Monteiro in Multicomponent Reactions,
(Eds.: J. Zhu, H. Bienaymé), Wiley-VCH, Weinheim, 2005, p. 224; b) A.
Dömling, W. Wang, K. Wang, Chem. Rev. 2012, 112, 3083−3135; c) C.
de Graaff, E. Ruijter, R. V. A. Orru, Chem. Soc. Rev. 2012, 41, 3969–
4009; d) I. Ugi, Pure Appl. Chem. 2001, 73, 187–191; e) A. Dömling, I.
Ugi, Angew. Chem. 2000, 112, 3300–3344; Angew. Chem. Int. Ed.
2000, 39, 3168–3210; f) R. W. Armstrong, A. P. Combs, P. A. Tempest,
S. D. Brown, T. A. Keating, Acc. Chem. Res. 1996, 29, 123–131; g) I.
Ugi, A. Dömling, W. Hörl, Endeavour 1994, 18, 115–122.
[17] M. Vuagnoux-d'Augustin, A. Alexakis, Eur. J. Org. Chem. 2007, 5852–
5860.
[18] a) M. Manoharan, F. De Proft, P. Geerlings, J. Org. Chem. 2000, 65,
7971–7976; b) M. Manoharan, F. De Proft, P. Geerlings, J. Chem. Soc.,
Perkin Trans. 2 2000, 1767–1773; c) T.-S. Chou, C.-Y. Tsai, Youji
Huaxue 1993, 13, 307–308; d) P. M. S. Chauhan, A. P. A. Crew, G.
Jenkins, R. C. Storr, S. M. Walker, M. Yelland, Tetrahedron Lett. 1990,
31, 1487–1490.
[13] a) I. Ugi, J. Prakt. Chem. 1997, 399, 499–516; b) H. Bienaymé, C.
Hulme, G. Oddon, P. Schmitt, Chem. Eur. J. 2000, 6, 3321–3329.
[14] a) K. Banert, H. Hückstädt, K. Vrobel, Angew. Chem. 1992, 104, 72–74;
Angew. Chem. Int. Ed. Engl. 1992, 31, 90–92; b) K. Banert, Liebigs
[19] F. Eloy, A. Deryckere, Chim. Thera. 1973, 8, 437–446.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800701
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
The product of a three-component
reaction (3CR) is formed only if all
reagents, the allenyl
2-Aminothiazoles
Frank Richter, Jennifer Seifert,
Marcus Korb, Heinrich Lang, and
Klaus Banert*
isothiocyanate, the nucleophile
NuH (sec. amine), and the
electrophile E+ (Michael acceptor,
aldehyde, etc.) are present at the
same time; otherwise a simple
thiazole is generated by
Page No. – Page No.
Real Multicomponent Reactions:
Syntheses of Highly Substituted
2-Aminothiazoles
tautomerism (~ H+).
This article is protected by copyright. All rights reserved.