Trimethylsilyl chloride as a promoter for the groebke-blackburn reaction: Preparation of imidazo[2,1-b][1,3]benzothiazoles

Article abstract of DOI:10.1080/00397910902953331

2-Amino[1,3]benzothiazoles can be efficiently used as substrates for the Groebke-Blackburn (GB) reaction using equimolar trimethylsilyl chloride (TMSCl) as a promoter. This finding extends the utility of TMSCl in isocyanide-based multicomponent reactions (MCRs) and expands the scope of reactive 2-aminoazole participants for the GBMCR.

Full text of DOI:10.1080/00397910902953331

This article was downloaded by: [University of Virginia, Charlottesville]
On: 19 August 2012, At: 18:30
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Trimethylsilyl Chloride as a Promoter
for the Groebke–Blackburn Reaction:
Preparation of Imidazo[2,1-b]
[1,3]Benzothiazoles
Sergey Tsirulnikov a b , Volodymyr Kysil c , Alexandre Ivachtchenko c
& Mikhail Krasavin a
a Chemical Diversity Research Institute, Moscow, Russia
b Department of Organic and Biological Chemistry, L. N. Tolstoy
State Pedagogical University, Tula, Russia
c ChemDiv, Inc., San Diego, California, USA
Version of record first published: 09 Dec 2009
To cite this article: Sergey Tsirulnikov, Volodymyr Kysil, Alexandre Ivachtchenko & Mikhail Krasavin
(2009): Trimethylsilyl Chloride as a Promoter for the Groebke–Blackburn Reaction: Preparation of
Imidazo[2,1-b][1,3]Benzothiazoles, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:1, 111-119
To link to this article: http://dx.doi.org/10.1080/00397910902953331
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,

demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 40: 111–119, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902953331
TRIMETHYLSILYL CHLORIDE AS A PROMOTER FOR
THE GROEBKE–BLACKBURN REACTION: PREPARATION
OF IMIDAZO[2,1-b][1,3]BENZOTHIAZOLES
Sergey Tsirulnikov,1,2 Volodymyr Kysil,3
Alexandre Ivachtchenko,3 and Mikhail Krasavin1
1Chemical Diversity Research Institute, Moscow, Russia
2Department of Organic and Biological Chemistry, L. N. Tolstoy State
Pedagogical University, Tula, Russia
3ChemDiv, Inc., San Diego, California, USA
2-Amino[1,3]benzothiazoles can be efficiently used as substrates for the Groebke–
Blackburn (GB) reaction using equimolar trimethylsilyl chloride (TMSCl) as a promoter.
This finding extends the utility of TMSCl in isocyanide-based multicomponent reactions
(MCRs) and expands the scope of reactive 2-aminoazole participants for the GBMCR.
Keywords: Groebke–Blackburn reaction; imidazo[1,2-x]azoles; isocyanide-based multicomponent reactions;
trimethylsilyl chloride
A three-component reaction of 2-aminoazines and -azoles (1) with aldehydes
(2) and isocyanides (3), leading to imidazo[1,2-x]azines and -azoles (4), respectively,
was discovered just more than a decade ago by three independently research
groups[1] and is frequently referred to as the Groebke–Blackburn multicomponent
reaction (GBMCR, Scheme 1).[2] The value of the new imidazo-fused molecular scaf-
folds 4 for the discovery of novel biological activities associated with them has been
demonstrated by numerous reports in the literature. For instance, this new chemical
class now includes modulators of sodium channels,[3] ubiquitin ligase inhibitors,[4]
hystone deacetylase inhibitors,[5] and G-protein coupled receptor ligands,[6] which
render the GB core as a privileged structure for bioactive compound design.[7]
In our ongoing program aimed at synthesis of combinatorial libraries for
biological screening, we have been focusing on addressing novel 2-aminoazines
and -azoles 1 as partners in the GBMCR. Although the substrate scope was quite
[1c]
´
widely surveyed in the pioneering work of Bienayme and Bouzid, we found that
a number of substrates and methods (including Brønsted[1c] or Lewis acid[1b] cataly-
sis) were not applicable to synthesis of larger compound arrays in combinatorial
fashion. Not only did some of the substrates react poorly under the traditional (vide
Received March 25, 2009.
Address correspondence to Mikhail Krasavin, Chemical Diversity Research Institute, 2a
Rabochaya Street, Khimki, Moscow Reg. 114401, Russia. E-mail: myk@chemdiv.com
111

112
S. TSIRULNIKOV ET AL.
Scheme 1.
supra) conditions, the desired products 4 are often accompanied by their regioiso-
meric counterparts 40 as was first established by Mandair et al. (Scheme 1).[8] The
latter hurdle can be alleviated by using ammonium chloride in toluene as demon-
strated by us[9] and verified by others.[10] However, these conditions do not solve
the problem of poor reactivity of some substrates.
We have recently discovered that trimethylsilyl chloride (TMSCl), when used
in equimolar amounts in acetonitrile (with or without methanol as cosolvent), effec-
tively promotes the GBMCR of 2-aminoazoles that are otherwise unreactive.[11]
Encouraged by these findings and also by the known utility of TMSCl as promoter
of other isocyanide-based MCRs,[12] we continued to test other poorly reactive sub-
strates under the newly discovered conditions. Herein we report on the applicability
of these conditions to 2-amino[1,3]benzothiazoles. Although positive results on these
2-aminoazoles as participants in the GBMCR have been reported on solid phase[13]
and in solution,[14] unfortunately, in our laboratories, we continued to find these
reactions’ outcomes discouraging in terms of efficient combinatorial synthesis.
TMSCl appears to solve this problem, as described here.
A series of 2-amino[1,3]benzothiazoles 1 was reacted with aldehydes 2 and iso-
cyanides 3 in acetonitrile in the presence of an equimolar amount of TMSCl
(Scheme 2).
Simple mixing of all three components with the promoter and heating the
reaction mixture at 70ꢀC gave inferior results in terms of yield and ease of product iso-
lation compared to the procedure that involved preformation of an imine 5 intermedi-
ate prior to addition of the isocyanide and the promoter (see the Experimental section).
Scheme 2.

TMSCL-PROMOTED GROEBKE–BLACKBURN REACTION
113
Table 1. Imidazo[2,1-b][1,3]benzothiazoles 4a–n prepared in this work (Scheme 2)
Product
R1
R2
R3
Isolated yield (%)a
4a
H
87 (72)
4b
H
82 (77)
4c
4d
4e
H
H
96 (84)
78 (69)
66 (62)
Me
4f
Me
Me
90 (77)
99 (81)
71 (58)
4g
4h
MeO
4i
MeO
EtO
EtO
83 (73)
74 (62)
97 (86)
4j
4k
4l
EtO
Cl
75 (61)
88 (73)
4m
4n
Cl
85 (64)
aThe number in parentheses indicates the yield after crystallization.

114
S. TSIRULNIKOV ET AL.
Figure 1.
Although the reasons for that were not studied in detail, one can speculate that in the
latter case, the reaction’s regiochemical course is swayed away from the formation of
intermediate 50, which would ultimately lead to isomeric products (like 40). This was
confirmed by liquid chromatographic–mass spectrographic (LCMS) analysis of the
reaction mixture resulting from such ‘‘mix-all’’ experiments where additional peaks
with the desired m=z value were detected.
The products 4a–n of at least 85% purity were isolated in good yields (Table 1)
by simple filtration. Better purities were achieved by crystallization from an appro-
1
priate solvent. The product identity in each case was confirmed by H NMR, 13C
NMR, and LCMS. To confirm that the desired regioisomer was obtained, nuclear
Overhauser effect spectroscopic (NOESY) spectrum of a representative compound
(4g) was examined to reveal the presence of through-space interactions expected only
for the target regioisomer (Fig. 1).
EXPERIMENTAL
All reactions were run in oven-dried glassware in an ambient atmosphere.
Melting points were measured with a Buchi B-520 melting-point apparatus and were
not corrected. Analytical thin-layer chromatography (TLC) was carried out on EM
Separations Technology F254 silica-gel plates. Compounds were visualized with
short-wavelength ultraviolet (UV) light. 1H NMR and 13C NMR spectra were
recorded on Bruker DPX-300 spectrometers in dimethylsulfoxide (DMSO-d6) using
tetramethylsilane (TMS) as an internal standard. Mass-spectral (MS) analyses were
obtained on a PE SCIEX API 150EX mass spectrometer. All solvents and reagents
were obtained from commercial sources and used without purification.
General Procedure: Preparation of Imidazo[2,1-b][1,3]benzothiazoles
4a–n
A solution (or suspension) of the starting 2-amino[1,3]benzothiazole 1
(1 mmol) and an aldehyde 2 (1 mmol) in acetonitrile (15 mL) was heated at reflux
for 2 h (or until the suspension cleared). The reaction mixture was cooled down to
room temperature, and evaporated to dryness, and the solid residue was suspended

TMSCL-PROMOTED GROEBKE–BLACKBURN REACTION
115
in toluene and evaporated to dryness on a rotary evaporator to ensure complete
removal of water. The residues was dissolved (or suspended) in acetonitrile
(10 mL) and treated with a solution of TMSCl (1 mmol) in a minimum volume
(0.5–1.0 mL) of DCM. The mixture was stirred at ambient temperature for 30 min
(in most cases, the suspension cleared) and then treated with a solution of isocyanide
3 (1 mmol) in acetonitrile (5 mL). The reaction mixture was heated at 70ꢀC overnight
and cooled down to rt. The resulting precipitates were collected by filtration, care-
fully washed with water and ice-cold acetonitrile, and air-dried. In all cases, the
crude products were at least 85% pure by LCMS analyses. Crystallization from
either isopropanol, methanol, or acetonitrile afforded analytically pure compounds
without significant drop in the yield (Table 1).
N-(1H-1,2,3-Benzotriazol-5-ylmethyl)-N-phenylamine, 4a
Mp 165–168ꢀC (MeOH); 1H NMR (300 MHz, d6-DMSO) d 8.32 (d, J ¼ 8.0 Hz,
1H), 8.09 (d, J ¼ 8.0 Hz, 1H), 7.94 (d, J ¼ 8.4 Hz, 2H), 7.61 (t, J ¼ 7.7 Hz, 1H), 7.49
(t, J ¼ 7.7 Hz, 1H), 7.15 (d, J ¼ 8.4 Hz, 2H), 3.44 (t, J ¼ 5.2 Hz, 2H), 3.14 (s, 3H), 2.74
(s, 6H), 3.14 (m, 2H); 13C NMR (75 MHz, d6-DMSO) d 147.0, 142.0, 132.2, 130.1,
129.1, 126.8, 125.5, 124.8, 115.0, 114.7, 71.3, 57.9, 47.7, 41.8; MS MHþ ¼ 367;
HRMS (EI) m=z calcd. for C20H23N4OS (MHþ) 367.4965; found 367.4972.
4-{3-[(3-Isopropoxypropyl)amino]imidazo[2,1-b][1,3]benzothiazol-2-yl}-
2-methoxyphenol, 4b
Mp 175ꢀC (MeCN, decomp.); 1H NMR (300 MHz, d6-DMSO) d 8.19 (d,
J ¼ 8.0 Hz, 1H), 8.06 (d, J ¼ 8.0 Hz, 1H), 7.55–7.62 (m, 2H), 7.38–7.49 (m, 2H),
6.85 (d, J ¼ 8.2 Hz, 1H), 3.84 (s, 3H), 3.39–3.50 (m, 3H), 3.07 (t, J ¼ 6.6 Hz, 2H),
1.72–1.82 (m, 2H), 1.02 (d, J ¼ 6.6 Hz, 6H); 13C NMR (75 MHz, d6-DMSO) d
147.6, 146.2, 141.8, 133.8, 132.4, 130.0, 129.2, 126.6, 125.2, 124.8, 123.4, 118.8,
115.6, 114.2, 110.4, 70.6, 64.9, 55.6, 45.8, 30.4, 22.0; MS MHþ ¼ 412; HRMS (EI)
m=z calcd. for C22H26N3O3S (MHþ) 412.5348; found 412.5355.
N-(1H-1,2,3-Benzotriazol-5-ylmethyl)-N-(3-methoxypropyl)amine
dihydrochloride, 4c
Mp 137–138ꢀC (MeOH); 1H NMR (300 MHz, d6-DMSO) d 8.42 (d, J ¼ 8.0 Hz,
1H); 8.21 (d, J ¼ 8.2 Hz, 2H); 8.01 (d, J ¼ 8.0 Hz, 1H); 7.82 (d, J ¼ 8.2 Hz, 2H); 7.56
(t, J ¼ 7.3 Hz, 1H); 7.41 (t, J ¼ 7.3 Hz, 1H); 1.01 (s, 9H); 13C NMR (75 MHz, d6-
DMSO) d 143.8, 138.6, 137.1, 132.7, 132.0, 130.2, 129.2, 127.6, 126.2, 125.2, 124.8,
118.9, 115.0, 109.0, 56.2, 29.6; MS MHþ ¼ 347; HRMS (EI) m=z calcd. for
C20H18N4S (MHþ) 347.4652; found 347.4641.
N-(tert-Butyl)-2-(2-fluorophenyl)imidazo[2,1-b][1,3]benzothiazol-
3-amine, 4d
Mp 173–175ꢀC (iPrOH); 1H NMR (300 MHz, d6-DMSO) d 8.42 (d, J ¼ 8.0 Hz,
1H), 8.01 (d, J ¼ 8.0 Hz, 1H), 7.77 (t, J ¼ 7.6 Hz, 1H), 7.56 (t, J ¼ 7.6 Hz, 1H), 7.40

116
S. TSIRULNIKOV ET AL.
(m, 2H), 7.27 (m, 2H), 4.02 (m, 1H), 0.93 (s, 9H); 13C NMR (75 MHz, d6-DMSO) d
159.1 (d, JCꢁF ¼ 244.4 Hz), 142.9, 134.9 (d, JCꢁF ¼ 2.4 Hz), 131.3 (d, JCꢁF ¼ 3.7 Hz),
130.1, 129.4 (d, JCꢁF ¼ 8.6 Hz), 129.2, 125.9, 124.7, 124.3 (d, JCꢁF ¼ 3.1 Hz), 122.6
(d, JCꢁF ¼ 14.1 Hz), 121.8 (d, JCꢁF ¼ 32.5 Hz), 115.6 (d, JCꢁF ¼ 22.7 Hz), 114.4;
MS MHþ ¼ 340; HRMS (EI) m=z calcd. for C19H19FN3S (MHþ) 340.4458; found
340.4464.
2-[4-(Dimethylamino)phenyl]-N-(2-methoxyethyl)-7-
methylimidazo[2,1-b][1,3]benzothiazol-3-amine, 4e
Mp 167ꢀC (MeCN, decomp.); 1H NMR (300 MHz, d6-DMSO) d 8.19 (d,
J ¼ 8.0 Hz, 1H), 7.88 (d, J ¼ 8.8 Hz, 2H), 7.83 (s, 1H), 7.41 (d, J ¼ 8.0 Hz, 1H),
7.03 (d, J ¼ 8.8 Hz, 2H), 3.48 (t, J ¼ 5.6 Hz, 2H), 3.20 (s, 3H), 3.18 (t, J ¼ 5.6 Hz,
2H), 3.01 (s, 6H); 13C NMR (75 MHz, d6-DMSO) d 148.2, 141.6, 135.2, 130.3,
129.8, 129.2, 127.6, 127.1, 124.4, 114.3, 114.0, 71.5, 57.9, 47.8, 20.7; MS MHþ ¼ 381;
381; HRMS (EI) m=z calcd. for C21H25N4OS (MHþ) 381.5236; found 381.5249.
2-Methoxy-4-{3-[(3-methoxypropyl)amino]-7-methylimidazo[2,1-
b][1,3]benzothiazol-2-yl}phenol, 4f
Mp 110–112ꢀC (MeOH); 1H NMR (300 MHz, d6-DMSO) d 8.19 (d, J ¼ 8.4 Hz,
1H), 7.97 (s, 1H), 7.55 (s, 1H), 7.47 (d, J ¼ 8.4 Hz, 1H), 7.38 (dd, J ¼ 8.4, 2.1 Hz, 1H),
6.92 (d, J ¼ 8.4 Hz, 1H), 3.88 (s, 3H), 3.38 (t, J ¼ 6.2 Hz, 2H), 3.20 (s, 3H), 3.07 (t,
J ¼ 7.0 Hz, 2H), 2.45 (s, 3H), 1.78 (m, 2H); 13C NMR (75 MHz, d6-DMSO) d
147.6, 146.8, 141.7, 135.9, 130.4, 130.0, 129.8, 129.3, 128.3, 128.1, 124.8, 119.2,
115.6, 114.6, 110.4, 69.6, 57.6, 55.6, 45.4, 29.6, 20.8; MS MHþ ¼ 398; HRMS (EI)
m=z calcd. for C21H24N3O3S (MHþ) 398.5077; found 398.5083.
4-{3-[(3-Isopropoxypropyl)amino]-7-methylimidazo[2,1-
b][1,3]benzothiazol-2-yl}benzonitrile, 4g
Mp 156–158ꢀC (iPrOH); 1H NMR (300 MHz, d6-DMSO) d 8.19 (d, J ¼ 8.4 Hz,
2H), 8.00 (d, J ¼ 8.4 Hz, 1H), 7.88 (d, J ¼ 8.4 Hz, 2H), 7.83 (s, 1H), 7.34 (d,
J ¼ 8.4 Hz, 1H), 5.04 (bt, 1H), 3.37–3.47 (m, 3H), 3.07 (t, J ¼ 7.0 Hz, 2H), 2.45 (s,
3H), 1.78 (m, 2H), 1.02 (d, J ¼ 6.2 Hz, 6H); 13C NMR (75 MHz, d6-DMSO) d
142.8, 138.8, 134.7, 133.8, 133.2, 132.2, 130.1, 129.3, 127.3, 125.8, 124.6, 119.2,
113.6, 108.0, 70.6, 64.9, 55.6, 45.8, 30.4, 22.0, 20.8; MS MHþ ¼ 405; HRMS (EI)
m=z calcd. for C23H25N4OS (MHþ) 405.5459; found 405.5455.
4-[3-(tert-Butylamino)-7-methoxyimidazo[2,1-
b][1,3]benzothiazol-2-yl]-2-methoxyphenol, 4h
Mp 176ꢀC (decomp., MeCN); 1H NMR (300 MHz, d6-DMSO) d 8.42 (d,
J ¼ 8.4 Hz, 1H), 7.80 (s, 1H), 7.52 (s, 1H), 7.38 (d, J ¼ 8.4 Hz, 1H), 7.28 (dd,
J ¼ 8.4, 2.1 Hz, 1H), 6.92 (d, J ¼ 8.4 Hz, 1H), 5.02 (bm, 1H), 3.88 (s, 6H), 0.99 (s,
9H); 13C NMR (75 MHz, d6-DMSO) d 157.4, 147.5, 147.2, 141.5, 133.8, 130.9,
127.6, 126.4, 120.7, 116.4, 115.4, 115.0, 114.3, 112.0, 109.2, 56.0, 55.9, 55.8, 29.6;

TMSCL-PROMOTED GROEBKE–BLACKBURN REACTION
117
MS MHþ ¼ 398; HRMS (EI) m=z calcd. for C21H24N3O3S (MHþ) 398.5077; found
398.5089.
N-(tert-Butyl)-2-(4-fluorophenyl)-7-methoxyimidazo[2,1-
b][1,3]benzothiazol-3-amine, 4i
Mp 147–149ꢀC (MeOH); 1H NMR (300 MHz, d6-DMSO) d 8.37 (d, J ¼ 9.1 Hz,
1H), 8.02 (m, 2H), 7.77 (d, J ¼ 2.4 Hz, 1H), 7.30 (t, J ¼ 8.8 Hz, 2H), 7.22 (dd, J ¼ 9.1,
2.4 Hz, 1H), 3.85 (s, 3H), 0.99 (s, 9H); 13C NMR (75 MHz, d6-DMSO) d 161.7 (d,
JCꢁF ¼ 243.8 Hz), 157.1, 142.2, 134.0, 130.8, 129.6 (d, JCꢁF ¼ 8.0 Hz), 128.4, 127.7,
126.5, 116.1, 115.2 (d, JCꢁF ¼ 21.5 Hz), 113.9, 109.1, 55.8, 55.6, 29.5; MS
MHþ ¼ 370; HRMS (EI) m=z calcd. for C20H21FN3OS (MHþ) 370.4723; found
370.4734.
4-[3-(tert-Butylamino)-7-ethoxyimidazo[2,1-b][1,3]benzothiazol-
2-yl]phenol, 4j
1
Mp 134–136ꢀC (MeCN); H NMR (300 MHz, d6-DMSO) d 9.50 (br s, 1H),
8.27 (d, J ¼ 9.1 Hz, 1H), 7.76 (d, J ¼ 8.6 Hz, 2H), 7.63 (d, J ¼ 2.4 Hz, 1H), 7.13
(dd, J ¼ 9.1, 2.4 Hz, 1H), 6.78 (d, J ¼ 8.6 Hz, 2H), 4.75 (m, 1H), 4.09 (m, 2H), 1.37
(t, J ¼ 6.9 Hz, 3H), 1.01 (s, 9H); 13C NMR (75 MHz, d6-DMSO) d 156.7, 155.8,
141.5, 137.6, 130.5, 128.8, 127.4, 126.8, 124.0, 115.4, 114.8, 113.7, 109.5, 63.8,
55.5, 29.6, 14.6; MS MHþ ¼ 382; HRMS (EI) m=z calcd. for C21H24N3O2S (MHþ)
382.5083; found 382.5091.
4-{7-Ethoxy-3-[(3-isopropoxypropyl)amino]imidazo[2,1-
b][1,3]benzothiazol-2-yl}benzonitrile, 4k
Mp 144–145ꢀC (MeOH); 1H NMR (300 MHz, d6-DMSO) d 8.20 (d, J ¼ 8.6 Hz,
2H), 8.00 (d, J ¼ 8.8 Hz, 1H), 7.80 (d, J ¼ 8.6 Hz, 2H), 7.62 (d, J ¼ 2.4 Hz, 1H), 7.10
(dd, J ¼ 8.8, 2.4 Hz, 1H), 5.04 (br t, 1H), 4.07 (m, 2H), 3.37–3.47 (m, 3H), 3.07 (t,
J ¼ 7.0 Hz, 2H), 1.78 (m, 2H), 1.35 (t, J ¼ 6.9 Hz, 3H), 1.02 (d, J ¼ 6.2 Hz, 6H);
13C NMR (75 MHz, d6-DMSO) d 155.9, 142.6, 139.0, 133.4, 132.9, 132.2, 130.6,
126.1, 125.7, 119.2, 114.5, 113.7, 109.7, 108.0, 70.4, 64.9, 63.8, 45.8, 30.4, 22.0,
14.6; MS MHþ ¼ 435; HRMS (EI) m=z calcd. for C24H27N4O2S (MHþ) 435.5724;
found 435.5733.
5-[3-(tert-Butylamino)-7-ethoxyimidazo[2,1-b][1,3]benzothiazol-2-yl]-2-
methoxyphenol, 4l
1
Mp 173ꢀC (MeOH, decomp.); H NMR (300 MHz, d6-DMSO) d 8.95 (br s,
1H), 8.29 (d, J ¼ 8.8 Hz, 1H), 7.64 (m, 1H), 7.37 (s, 1H), 7.35 (d, J ¼ 8.8 Hz, 1H),
7.12 (dd, J ¼ 1.5, 8.4 Hz, 1H), 6.92 (d, J ¼ 8.4 Hz, 2H), 4.73 (br s, 1H), 4.08 (q,
J ¼ 6.8 Hz, 2H), 3.79 (s, 3H), 1.36 (t, J ¼ 6.8 Hz, 3H), 0.99 (s, 9H); 13C NMR
(75 MHz, d6-DMSO) d 155.8, 147.0, 146.0, 141.6, 137.2, 130.5, 127.6, 126.8, 125.9,
118.7, 115.5, 114.9, 113.7, 111.5, 109.5, 63.7, 55.5, 29.6, 14.5; MS MHþ ¼ 412;
HRMS (EI) m=z calcd. for C22H26N3O3S (MHþ) 412.5348; found 412.5355.

118
S. TSIRULNIKOV ET AL.
7-Chloro-2-[4-(dimethylamino)phenyl]-N-(3-methoxypropyl)-
imidazo[2,1-b][1,3]benzothiazol-3-amine, 4m
Mp 177ꢀC (iPrOH, decomp.); 1H NMR (300 MHz, d6-DMSO) d 8.15 (d,
J ¼ 8.6 Hz, 2H), 7.87 (d, J ¼ 8.8 Hz, 2H), 7.62 (dd, J ¼ 8.6, 2.1 Hz, 1H), 7.07 (d,
J ¼ 8.8 Hz, 2H), 3.88 (s, 3H), 3.38 (t, J ¼ 6.2 Hz, 2H), 3.22 (s, 3H), 3.07 (t, J ¼ 7.0 Hz,
Hz, 2H), 3.02 (s, 6H), 1.78 (m, 2H); 13C NMR (75 MHz, d6-DMSO) d 147.8, 142.1,
134.4, 131.4, 131.2, 130.3, 129.2, 127.2, 126.7, 124.4, 121.1, 115.1, 114.4, 69.8, 57.6,
45.8, 41.4, 29.8; MS MHþ ¼ 416; HRMS (EI) m=z calcd. for C21H23ClN4OS (MHþ)
415.9686; found 415.9699.
7-Chloro-2-[4-(dimethylamino)phenyl]-N-(2-methoxyethyl)imidazo[2,1-
b][1,3]benzothiazol-3-amine, 4n
Mp 158–160ꢀC (MeCN); 1H NMR (300 MHz, d6-DMSO) d 8.26 (d, J ¼ 8.8 Hz,
1H), 8.13 (d, J ¼ 1.9 Hz, 1H), 7.90 (d, J ¼ 8.8 Hz, 2H), 7.58 (dd, J ¼ 8.8, 1.9 Hz, 1H),
7.05 (d, J ¼ 8.8 Hz, 2H), 3.48 (t, J ¼ 5.6 Hz, 2H), 3.20 (s, 3H), 3.18 (t, J ¼ 5.6 Hz, 2H),
3.01 (s, 6H); 13C NMR (75 MHz, d6-DMSO) d 131.5, 131.1, 127.1, 126.5, 124.2,
115.3, 114.2, 114.0, 71.5, 57.9, 47.9, 41.2; MS MHþ ¼ 402; HRMS (EI) m=z calcd.
for C20H22ClN4OS (MHþ) 401.9415; found 401.9407.
REFERENCES
1. (a) Groebke, K.; Weber, L.; Mehlin, F. Synthesis of imidazo[1,2-a] annulated pyridines,
pyrazines and pyrimidines by a novel three-component condensation. Synlett 1998,
661–663; (b) Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai, S. Parallel synthesis
of 3-aminoimidazo[1,2-a]pyridines and pyrazines by a new three-component con-
densation. Tetrahedron Lett. 1998, 39, 3635–3638; (c) Bienayme, H.; Bouzid, K. A new
´
heterocyclic multicomponent reaction for the combinatorial synthesis of fused 3-amino-
imidazoles. Angew. Chem. Int. Ed. 1998, 37, 2234–2237.
2. (a) Sandulenko, Y.; Komarov, A.; Rufanov, K.; Krasavin, M. Greater variety in
Groebke–Blackburn-type 3-arylaminoimidazo[1,2-a]azines accessed via Pd-catalyzed ary-
lation of a primary amine precursor. Tetrahedron Lett. 2008, 49, 5990–5993; (b) Krasavin,
M.; Tsirulnikov, S.; Nikulnikov, M.; Sandulenko, Y.; Bukhryakov, K. tert-Butyl isocya-
nide revisited as a convertible reagent in the Groebke–Blackburn reaction. Tetrahedron
Lett. 2008, 49, 7318–7321.
3. Fraser, R.; Fu, J.; Kamboj, R.; Liu, S. Methods of using bicyclic compounds in treating
sodium channel-mediated diseases. PCT Int. Appl. WO2008134553, April 25, 2008; Chem.
Abstr. 2008, 1339336.
4. Singh, R.; Ramesh, U.; Huang, J.; Issakani, S. D.; Tsvetkov, L.; Petroski, M. D. Ubiqui-
tin ligase inhibitors. PCT Int. Appl. WO2008115259, August 8, 2007; Chem. Abstr. 2008,
1158545.
5. Lee, K. C.; Sun, E. T.; Wang, H. Imidazo[1,2-a]pyridine derivatives: Preparation and phar-
maceutical applications. U.S. Pat. Appl. Publ. 2008=085896, September 19, 2007; Chem.
Abstr. 2008, 449628.
6. Hembrough, T. A.; Agoston, G. E.; Treston, A. M.; Hanson, A. D. Compositions and
methods comprising proteinase activated receptor antagonists. PCT Int. Appl.
WO2007076055, December 21, 2006; Chem. Abstr. 2007, 729396.
7. Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter, W. L.;
Lundell, G. F.; Veber, D. F.; Anderson, P. S. Methods for drug discovery: Development

TMSCL-PROMOTED GROEBKE–BLACKBURN REACTION
119
of potent, selective, orally effective cholecyctokinin antagonists. J. Med. Chem. 1988, 31,
2235–2246.
8. Mandair, G. S.; Light, M.; Russell, A.; Hursthouse, M.; Bradley, M. Re-evaluation of the
outcome of a multiple component reaction—2- and 3-aminoimidazo[1,2-a]pyrimidines?
Tetrahedron Lett. 2002, 43, 4267–4269.
9. Parchinsky, V. Z.; Shuvalova, O.; Ushakova, O.; Kravchenko, D. V.; Krasavin, M.
Multi-component reactions between 2-aminopyrimidine, aldehydes, and isonitriles: The
use of nonpolar solvent suppresses formation of multiple products. Tetrahedron Lett.
2006, 47, 947–951.
10. (a) Craballares, S.; Cifuentes, M. M.; Stephenson, G. A. Regioselective two-step synthesis
of 3-substituted 2-aminoimidazo[1,2-a]pyrimidines. Tetrahedron Lett. 2007, 48, 2041–
2045; (b) Lacerda, R. B.; de Lima, C. K. F.; da Silva, L. L.; Romeiro, N. C.; Miranda,
A. L. P.; Barreiro, E. J.; Fraga, C. A. M. Discovery of novel analgesic and
anti-inflammatory 3-arylamine-imidazo[1,2-a]pyridine symbiotic prototypes. Bioorg.
Med. Chem. 2009, 12, 74–84; (c) Nenajdenko, V. G.; Reznichenko, A. L.; Balenkova,
E. S. The synthesis of aminoimidazo[1,2-a]azinecarboxylic acid esters from ethyl
glyoxylate. Russ. Chem. Bull. Int. Ed. 2007, 56, 560–562.
11. Krasavin, M.; Tsirulnikov, S.; Nikulnikov, M.; Kysil, V.; Ivachtchenko, A. Poorly
reactive 5-piperazin-1-yl-1,3,4-thidiazol-2-amines rendered as valid substrates for
Groebke–Blackburn-type multi-component reaction with aldehydes and isocyanides using
TMSCl as a promoter. Tetrahedron Lett. 2008, 49, 5241–5243.
12. Kysil, V.; Tkachenko, S.; Khvat, A.; Williams, C.; Tsirulnikov, S.; Churakova, M.;
Ivachtchenko, A. TMSCl-promoted isocyanide-based MCR of ethylenediamines: An
efficient assembling of 2-aminopyrazine core. Tetrahedron Lett. 2007, 48, 6239–6244.
13. Yang, K.; Lou, B. a-Isocyanocarboxylate solid support templates, methods of preparation
and for using the same. U.S. Pat. Appl. Publ. US2004=0127719, March 8, 2002; Chem.
Abstr. 2004, 532969.
14. Sun, C.; Ji, S.-J.; Liu, Y. A novel, simple, and efficient synthesis of 2-amino-benzo
[d]imidazo[2,1-b]thiazole derivatives via a multicomponent procedure. J. Chinese Chem.
Soc. 2008, 55, 292–296.