Direct preparation of thiazoles, imidazoles, imidazopyridines and thiazolidines from alkenes

Article abstract of DOI:10.1039/c1ob06587d

A range of heterocycles, namely thiazoles, imidazoles, imidazopyridines, thiazolidines and dimethoxyindoles, have been synthesised directly from alkenes via a two-step ketoidoination/cyclisation protocol. The alkene starting materials are themselves readily accessible using many different and well-established approaches, and allow access to a variety of heterocycles with excellent yields and regioselectivity.

Full text of DOI:10.1039/c1ob06587d

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PAPER
Direct preparation of thiazoles, imidazoles, imidazopyridines and
thiazolidines from alkenes†
Timothy J. Donohoe,*a Mikhail A Kabeshov,a Akshat H. Rathi‡a and Ian E. D. Smithb
Received 16th September 2011, Accepted 11th October 2011
DOI: 10.1039/c1ob06587d
A range of heterocycles, namely thiazoles, imidazoles, imidazopyridines, thiazolidines and
dimethoxyindoles, have been synthesised directly from alkenes via a two-step ketoidoination/
cyclisation protocol. The alkene starting materials are themselves readily accessible using many
different and well-established approaches, and allow access to a variety of heterocycles with excellent
yields and regioselectivity.
for the ketoiodination of alkenes in conjunction with iodine11a,12
or NIS.11b
Introduction
A large proportion of modern pharmaceutical chemistry involves
aromatic and non-aromatic heterocyclic compounds which makes
general methods for their rapid and efficient synthesis extremely
valuable. To build heterocyclic compounds a-halo- and tosyloxy-
ketones have proved to be important precursors. For example, the
Hantzsch thiazole synthesis from a-haloketones and thioamides
has been known since the late nineteenth century,1 and alcohols2 as
well as ketones,3 have been converted through a-tosyloxyketones
into a series of thiazoles, imidazoles and imidazopyridines. Simi-
larly, by employing the condensation between a-haloketones and
amidines,4 imidazoles can be obtained. Also, dimethoxyindoles
can be accessed from a-haloketones using Bischler and modified
Bischler methododologies.5
Despite the fact that heterocyclic syntheses employing iodoke-
tones would be expected to occur under mild reaction conditions,
compared to their chloro- and bromo-analogues, they have been
seldom employed as electrophilic partners in aromatic hetero-
cyclic synthesis.6 Iodoketones can be prepared from ketones7 or
their enolates8 by iodination. Alternatively, iodoketones can be
prepared directly from alkenes; this is perhaps a more powerful
and versatile method due to the ready accessibility of alkenes via
a wide variety of well established synthetic methodologies. The
direct ketoiodination of alkenes was first described by Cardillo
et al.9 who used silver(I) chromate and iodine. Later, bis(sym-
collidine)iodine(I) tetrafluoroborate in DMSO was used as a
reagent,10 and latterly IBX has been introduced as an oxidant
Recently we reported an efficient and succinct method for the
synthesis of various heterocycles directly from alkenes using a ke-
toiodination protocol.13 Herein we describe further applications of
the alkene ketoiodination reaction towards the efficient synthesis
of a wider range of heterocyclic compounds such as thiazoles,
imidazoles, imidazopyridines and thiazolidines.
Results and discussion
In our initial experiments, we carried out the ketoiodination of
2-methylstyrene using a procedure described by Moorthy et al.11b
(1.1 eqv. NIS, 2 eqv. IBX, r.t., DMSO). The reaction proceeded
smoothly with t1/2 = 10 min14 and full consumption of the starting
material in 40 min. After the excesses of NIS and IBX were
washed out with aqueous NaHCO3-Na2S2O3, the intermediate
iodoketone 2a15 was treated with thiourea 4a (3 eqv., 25 ◦C,
DMSO-DMF) to afford 5-methyl-4-phenyl-1,3-thiazol-2-amine
3a as the only detectable product in 71% isolated yield and as
a single regioisomer. We subsequently found that replacement
of NIS with I2 (1.1 eqv.) led to a substantial increase of the
reaction rate: (t1/2 = 2 min) with full consumption of the starting
material within 10 min. After condensation of the iodoketone with
thiourea, the corresponding aminothiazole product was isolated
in a similar yield of 74% (Table 1, entry 1). However, when the
pyridyl-substituted alkene 1b was ketoiodinated using the original
conditions (NIS-IBX, in DMSO at 25 ◦C) a markedly slower
reaction was observed with t1/2 = 6 h.14 Consumption of the
starting alkene reached 90% after 20 h, however only traces of
iodoketone were detected by LCMS at this point due to competing
Kornblum oxidation of 2b by DMSO.16 When the ketoiodination
reaction was stopped after 6 h, the subsequent condensation with
thiourea afforded the corresponding thiazole 3b in only 25%
yield. As expected from our earlier results, replacing NIS with
I2 (1.1 eqv.) led to a substantial increase in the reaction rate,
reducing t1/2 from 6 h to 50 min and consequently we managed to
obtain the desired thiazole 3b in 62% yield (Table 1, entry 2). The
aDepartment of Chemistry, University of Oxford, Chemistry Research Labo-
ratory, Mansfield Road, Oxford, UK, OX1 3TA. E-mail: timothy.donohoe@
chem.ox.ac.uk
bGlaxoSmithKline Research and Development Limited, Medicines Research
Centre, Gunnels Wood Road, Stevenage, UK, SG1 2NY. E-mail: ian.e.
smith@gsk.com; Fax: +44 1438764502; Tel: +44 1438762631
† Electronic supplementary information (ESI) available: CCDC reference
numbers 845133–845135. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1ob06587d
‡ The author to whom correspondence regarding the X-ray structures
should be addressed
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Table 1 Synthesis of 2-aminothizolesa
Entry
Alkene
R1
R2
Product
Yield,%b
1
2
3
4
1a
1b
1c
1d
Ph
3-Py
Ph
Me
n-Pr
H
3a
3b
3c
3d
74
62
77
67
n-Pr
5
1e
n-Pr
3e
76
6
7
1f
1g
Ph
-CH2OCH3
H
3f
3g
83
73
8
9
1h
1i
2-Py
H
H
3h
3i
55
62
10
11
1j
H
3j
65
67
1k
H
H
3k
3l
12
13
1l
46
54
1m
a See experimental for conditions. b Isolated yield.
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regiochemistry of the ketoiodination and subsequent heteroarene
formation is that to be expected on mechanistic grounds, vide
infra. A range of solvents other than DMSO (THF, dioxane, water,
DMF, DCM) were trialled in the ketoiodination step but found to
be unsuitable for the ketoiodination reaction.
Our method for heterocycle synthesis was then applied to access
various 2-aminothiazoles (3a–3m, Table 1) utilising a range of
mono- and disubstituted alkenes 1 as starting materials.
The ketoiodination reaction was found to be faster for aromatic
alkenes bearing neutral or electron-rich substituents. However,
the reaction is also tolerant of the presence of a wide range of
functionalities and there was no detrimental effect on the reaction
yield when 2- and 3-substituted pyridines (1b, 1d, 1h), thiazole
(1e), a-methoxymethyl (1f) or a substituted benzene (1i–1m) were
structural parts of the starting alkene 1 (Table 1).17 The same
methodology is also applicable to disubstituted alkenes without
any aryl substituents (Scheme 1).18
Scheme 2 Synthesis of 2-substituted thiazoles.
Scheme
1
Dialkyl-2-aminothiazoles (IBX/I2 then thiourea, see
Experimental).
Both symmetrical and unsymmetrical dialkyl alkenes were
converted to the corresponding 2-aminothiazoles (3n and 3o,
Scheme 1). The aminothiazole 3o was isolated as a single
regioisomer,19 probably due to steric effects (see mechanism in
Scheme 7 and discussion). The structures of the thiazole products
were supported by correlation with literature data for 3a, 3c, 3h, 3j,
3k, 3l, 3m, 3o. In addition, HMBC experiments were undertaken
to prove the structure of 3o, and X-ray diffraction data has been
collected for compounds 3m and 3o (see Table 1 and Scheme 1). We
have previously reported X-ray diffraction data for compounds 3b
and 3f.13 The remaining compounds were assigned by analogy.
In addition to thiourea, we showed that N-substituted thioureas
(R1 = NHPy, 5a, Scheme 2), alkyl thioamides (R1 = t-Bu, 5c,
Scheme 2) or aryl thioamides (R1 = 3-Py, 5b, Scheme 2) can also
be used as nucleophiles in this sequence, in so doing extending the
scope of the product substitution. The structures of products 5b
and 5c were assigned by correlation with literature data.13
By employing amidines, or their salts, as nucleophiles, one can
access the corresponding imidazoles 6a–6e (Scheme 3). Thus,
the method is applicable to the use of alkyl amidines (6a, 6d),
aryl amidines (6b, 6e), mono N-substituted amidines (6d) and
S-alkylated pseudothioureas (6c), in partnership with mono- (6a–
d) or disubstituted (6e) alkenes. The structures of products 6a,
6b, 6c, 6d were proven by correlation with literature data and,
additionally, HMBC experiments supported the structure of 6d.
In a manner similar to that shown above for imidazoles, imida-
zopyridines 7a, 7b, 7c can be synthesised from the corresponding
alkene 1 and a substituted 2-aminopyridine. The more nucleophilic
2-aminopyridine precursors would be expected to react faster with
Scheme 3 Synthesis of imidazoles.
the corresponding iodoketones which in turn could explain the
trend in isolated yields of the final products (compare 7b and
7c, Scheme 4). The structure of 7a was proven by correlation
with literature data, and X-ray diffraction data has been collected
for compound 7c (Scheme 4); the structure of compound 7b was
assigned by analogy.
When N,N¢-disubstituted thioureas were used as nucleophiles,
thiazolidines (8a, 8b) were synthesised from the corresponding
alkene (Scheme 5) with good yields. It is interesting to note that
compound 8b was obtained as a single regioisomer as determined
by HMBC NMR.
Finally, the dimethoxyindole (9) was synthesised using 3,5-
dimethoxyaniline as the nucleophile by a Bischler-type method
(Scheme 6).5 Unfortunately, the scope of this reaction is limited
because the use of a symmetrical and electron-rich aniline is
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Scheme 4 Synthesis of imidazopyridines.
Scheme 7 The proposed mechanism of ketoiodination.
10 giving the corresponding regioisomer of the iodoketone 2 (see
3o, Scheme 1). Finally, the corresponding iodoketone 2 is formed
from the intermediate 13 via an elimination step. In the second
step to form the aromatic heterocycle, the regiochemistry of the
iodoketone is translated into the regiochemistry of the heteroarene
product. Thus, during this step the most nucleophilic atom of
the corresponding reagent (e.g., thiourea, thioamide, amidine,
aminopyridine) initially substitutes iodide and then a cyclisation-
dehydration step follows.
Conclusions
In summary, we have demonstrated that a series of aromatic
heterocycles, here thiazoles, imidazoles, imidazopyridines, thi-
azolidines and indoles, can be synthesised directly from the
corresponding alkenes using an efficient and succinct method.
This methodology enables the preparation of heterocycles having
multiple points of diversity whilst controlling the regiochemistry
of many unsymmetrical heterocyclic products especially those
derived from aryl/alkyl alkenes. The method should become a
useful tool for medicinal chemistry enabling the synthesis of
suitable heterocyclic compounds either individually or in parallel
as multidimensional arrays.
Scheme 5 Synthesis of thiazolidines.
Scheme 6 Synthesis of dimethoxyindole 9.
required. Thus, only traces of the corresponding indole products
were detected when p-methylaniline or p-bromoaniline were used
as nucleophiles. The structure of 9 was proven by correlation with
literature data.
Experimental
General
The following mechanism of the ketoiodination has been
proposed (Scheme 7).11b The alkene 1 reacts reversibly with I2
to form the iodonium ion 10,20 which can be attacked by IBX
11 acting as a nucleophile. However, it has been demonstrated21
that IBX (11) forms a complex 12 with DMSO which enhances
its nucleophilicity, and formation of this activated IBX-DMSO
complex 12 may explain why ketoiodination proceeds significantly
better in DMSO than in other solvents.22 The regioselectivity
of the nucleophilic substitution reaction between intermediates
10 and 12, which ultimately leads to that of the iodoketone (2)
when R1 = aryl and R2 = H or alkyl, can be easily explained
by a faster SN2 reaction at a benzylic centre. When both R1
and R2 are alkyl groups, complex 12 would be expected to react
preferentially with the least hindered end of the iodonium ion
All solvents and reagents were used as received from commercial
sources. Alkenes 1b, 1d, 1e, 1f were prepared employing stan-
dard methods for Suzuki coupling23 from commercially available
precursors. Proton nuclear magnetic resonance spectra (NMR)
were recorded at 400 MHz. 13C NMR spectra were recorded at
100 MHz. The LCMS analysis was conducted on an Acquity
UPLC BEH C18 column (50 mm ¥ 2.1 mm internal diameter 1.7
mm packing diameter) at 40 ◦C employing gradient CH3CN–H2O
with 0.1% formic acid or on an XBridge C18 column (50 mm ¥
4.6 mm internal diameter 3.5 mm packing diameter) at 30 ◦C
employing gradient CH3CN-H2O with 10 mM NH4HCO3. Mass-
Directed Autopreparative HPLC analysis (MDAP) was conducted
on an XBridge C18 column (150 mm ¥ 30 mm internal diameter,
5 mm packing diameter) at ambient temperature employing
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gradient CH3CN–H2O with 10 mM NH4HCO3. Accurate mass
spectra under the conditions of electrospray ionisation (ESI) were
recorded on Bruker Apex IV. Infrared spectra (IR) were recorded
as evaporated films. Melting points were obtained using a Leica
VMTG heated-stage microscope and are uncorrected.
J = 7.0 Hz, 2 H, Ph), 7.78 (d, J = 7.0 Hz, 2 H, Ph); 13C NMR (101
MHz, CDCl3) d (ppm) 102.9 (CH-S), 126.0 (CH), 127.7 (CH),
128.6 (CH), 134.6 (C), 151.3 (C-N), 167.1 (N = C-S). NMR data
matched that reported in the literature.25
5-(2-Amino-5-propyl-1,3-thiazol-4-yl)-N,N-dimethyl-2-
General procedure A
pyridinamine (3d)
To a solution of IBX (2 eqv., 45% stabilized with benzoic and
isophthalic acids) and iodine (1.1 eqv.) in dry dimethyl sulfoxide
(0.25 M) stirred at room temperature was added the corresponding
alkene (1 eqv.) in one charge. The reaction mixture was stirred at
room temperature until full consumption of the starting alkene
(monitored by LCMS). Then it was diluted with DCM (30 mL for
~0.5 mmol scale) and washed with saturated aqueous NaHCO3–
Na2S2O3. The aqueous layer was extracted with DCM (2 ¥ 20 mL
for ~0.5 mmol scale); the combined organic layers were dried over
Na2SO4 and filtered. The corresponding nucleophile (3 eqv.) and
dry N,N-dimethylformamide (0.15 M) were added to the DCM
solution and its volume was reduced down to ~2 mL (for ~0.5
mmol scale) under vacuum. The reaction mixture was stirred
at room temperature for 12 h. The corresponding product was
isolated by MDAP using a gradient CH3CN-H2O solvent mixture
unless otherwise stated.
Using N,N-dimethyl-5-[(1E)-1-penten-1-yl]-2-pyridinamine (1d,
60 mg, 0.32 mmol) and thiourea (4a, 72 mg, 0.95 mmol) as the
nucleophile, the produ◦ct was obtained as a yellow solid (55 mg,
67% yield). M.p. > 110 C (decomp.); 1H NMR (400 MHz, CDCl3)
d (ppm) 0.96 (t, J = 7.5 Hz, 3 H, CH3CH2), 1.63 (sxt, J = 7.5 Hz,
2 H, CH2), 2.71 (t, J = 7.5 Hz, 2 H, CH2), 3.12 (s, 6 H, CH3N),
4.96 (br. s, 2 H, NH2), 6.56 (d, J = 8.5 Hz, 1 H, Ar), 7.68 (dd, J =
8.5, 2.5 Hz, 1 H, Ar), 8.30 (d, J = 2.5 Hz, 1 H, Ar); 13C NMR
(101 MHz, CDCl3) d (ppm) 13.8 (CH3), 25.5 (CH2), 29.1 (CH2),
38.2 (CH3N), 105.4 (CH), 119.3 (C), 123.1 (C), 137.5 (CH), 143.6
(C); 147.2 (CH), 158.2 (C), 164.0 (C); IR u cm-1 3178, 2958, 2928,
1610, 1567, 1542, 1512, 1392, 1317, 1215, 956, 813; HRMS (ES+)
m/z 263.1324 (M+H; C13H19N4S requires 263.1330).
5-Propyl-4,5¢-bi-1,3-thiazol-2-amine (3e)
Using 5-propyl-4,5¢-bi-1,3-thiazol-2-amine (1e, 70 mg, 0.46 mmol)
and thiourea (4a, 104 mg, 1.37 mmol) as the nucleophile, the
product was o◦btained as a pale yellow solid (78 mg, 76% yield).
M.p. 133–134 C [CHCl3]; 1H NMR (400 MHz, CDCl3) d (ppm)
1.01 (t, J = 7.4 Hz, 3 H, CH3), 1.67 (sxt, J = 7.4 Hz, 2 H, CH2),
2.79 (t, J = 7.4 Hz, 2 H, CH2), 5.37 (br. s, 2 H, NH2), 8.01 (s, 1
H, Ar), 8.73 (s, 1 H, Ar); 13C NMR (101 MHz, CDCl3) d (ppm)
13.8 (CH3), 24.5 (CH2), 29.1 (CH2), 125.5 (C), 133.3 (C), 136.4
(C), 140.1 (CH), 151.8 (CH), 164.5 (N = C-S); IR u cm-1 3300,
3134, 2957, 2905, 1640, 1559, 1537, 1501, 1318, 1262, 1105, 1016,
884, 804, 775, 674; HRMS (ES+) m/z 226.0466 (M+H; C9H12N3S2
requires 226.0473).
5-Methyl-4-phenyl-1,3-thiazole-2-amine (3a)
Using b-methylstyrene (1a, 0.055 mL, 0.42 mmol) and thiourea
(4a, 97 mg, 1.3 mmol) as the nucleophile, the product was obtained
as a yellow solid (60 mg, 74% yield). M.p. 118–121 ◦C [CHCl3; lit.24
115–116 ◦C]; 1H NMR (400 MHz, CDCl3) d (ppm) 2.39 (s, 3 H,
CH3), 5.28 (br. s., 2 H, NH2), 7.32 (t, J = 7.5 Hz, 1 H, Ph), 7.40
(t, J = 7.5 Hz, 2 H, Ph), 7.56 (d, J = 7.5 Hz, 2 H, Ph); 13C NMR
(101 MHz, CDCl3) d (ppm) 12.3 (CH3), 117.4 (C-S), 127.1 (CH),
128.2 (CH), 128.3 (CH), 135.1 (C), 146.0 (C-N), 164.0 (C-NH2).
NMR data matched that reported in the literature.25
5-Propyl-4-(3-pyridinyl)-1,3-thiazol-2-amine (3b)
5-[(Methoxy)methyl]-4-phenyl-1,3-thiazol-2-amine (3f)
Using 3-[(1E)-1-penten-1-yl]pyridine (1b, 60 mg, 0.41 mmol) and
thiourea (4a, 93 mg, 1.2 mmol) as the nucleophile, the product was
obtained as a pale yellow solid (55 mg, 62% yield). M.p. 61–62 ◦C
[CHCl3]; 1H NMR (400 MHz, CDCl3) d (ppm) 0.97 (t, J = 7.5 Hz,
3 H, CH3), 1.66 (sxt, J = 7.5 Hz, 2 H, CH2), 2.75 (t, J = 7.5 Hz, 2
H, CH2), 5.02 (br. s, 2 H, NH2), 7.33 (dd, J = 8.0, 5.0 Hz, 1 H, Ar),
7.86 (d, J = 8.0 Hz, 1 H, Ar), 8.55 (d, J = 5.0 Hz, 1 H, Ar), 8.78 (s,
1 H, Ar); 13C NMR (101 MHz, CDCl3) d (ppm) 13.7 (CH3), 25.4
(CH2), 29.0 (CH2), 123.2 (CH), 126.1 (C), 131.3 (C), 135.8 (CH),
142.7 (C-N), 148.3 (CH), 149.3 (CH), 164.5 (N = C-S); IR u cm-1
3290, 3130, 2959, 2930, 1628, 1535, 1340, 1320, 1180, 1100, 1024,
813, 710; HRMS (ES+) m/z 220.0905 (M+H; C11H14N3S requires
220.0908).
Using methyl (2E)-3-phenyl-2-propen-1-yl ether (1f, 50 mg, 0.34
mmol) and thiourea (4a, 77 mg, 1.0 mmol) as the nucleophile, the
product was o◦btained as a pale yellow solid (62 mg, 83% yield).
M.p. 127–128 C [CHCl3]; 1H NMR (400 MHz, CDCl3) d (ppm)
3.39 (s, 3 H, CH3), 4.49 (s, 2 H, CH2), 5.31 (br. s, 2 H, NH2),
7.32–7.38 (m, 1 H, Ph), 7.39–7.45 (m, 2 H, Ph), 7.58 (d, J = 7.5 Hz,
2 H, Ph); 13C NMR (101 MHz, CDCl3) d (ppm) 57.7 (CH3), 66.4
(CH2), 119.0 (C-S), 127.9 (CH), 128.3 (CH), 128.5 (CH), 134.5
(C), 149.6 (C–N), 166.2 (N = C–S); IR u cm-1 3330, 3297, 3123,
2928, 2867, 1625, 1527, 1487, 1336, 1190, 1071, 775, 701; HRMS
(ES+) m/z 221.0741 (M+H; C11H13N2OS requires 221.0749).
1-(3-(2-Aminothiazol-4-yl)phenyl)ethanone (3g)
Using 1-(3-vinylphenyl)ethanone (1g, 80 mg, 0.55 mmol) and
thiourea (4a, 125 mg, 1.64 mmol) as the nucleophile, the product
was◦obtained as a pale yellow solid (87 mg, 73% yield). M.p. 148–
150 C [CH3CN]; 1H NMR (400 MHz, CDCl3 + MeOH-d4 (1 : 1))
d (ppm) 2.67 (s, 3 H, CH3), 6.84 (s, 1 H, CH), 7.50 (t, J = 8.0 Hz, 1
H, CH), 7.86–7.92 (m, 1 H, CH), 7.95–7.99 (m, 1 H, CH), 8.35 (t,
J = 1.5 Hz, 1 H, CH); 13C NMR (101 MHz, CDCl3 + MeOH-d4
4-Phenyl-1,3-thiazol-2-amine (3c)
Using styrene (1c, 0.055 mL, 0.48 mmol) and thiourea (4a, 110 mg,
1.44 mmol) as the nucleophile, the product was o◦btained as a pale
yellow solid (65 mg, 77% yield). M.p. 146–150 C [CHCl3; lit.24
150–151 ◦C]; 1H NMR (400 MHz, CDCl3) d (ppm) 5.24 (br. s, 2
H, NH2), 6.73 (s, 1 H, CH-S), 7.31 (t, J = 7.0 Hz, 1 H, Ph), 7.39 (t,
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(1 : 1)) 27.0 (CH3), 103.8 (CH), 126.6 (CH), 128.1 (CH), 129.6
(CH), 131.3 (CH), 136.0 (C), 138.0 (C), 150.1 (C), 170.6 (C), 200.2
(CO); IR u cm-1 3345, 1677, 1540, 1418, 1358, 1254, 714; HRMS
(ES+) m/z 219.0588 (M+H; C11H11N2OS requires 219.0592).
4-(4-Methoxyphenyl)thiazol-2-amine (3l)
Using 1-methoxy-4-vinylbenzene (1l, 50 mg, 0.37 mmol) and
thiourea (4a, 85 mg, 1.1 mmol) as the nucleophile. The product was
obtained as a pale yellow solid (35 mg, 46% yield). M.p. 205–207
◦C [CH3CN; lit.29 204–205 ◦C]; 1H NMR (400 MHz, DMSO-d6)
d (ppm) 3.76 (s, 3 H, CH3), 6.83 (s, 1 H, CH), 6.92 (d, J = 8.5 Hz,
1 H, CH), 7.01 (br. s, 2 H, NH2), 7.72 (d, J = 8.5 Hz, 1 H, CH);
13C NMR (101 MHz, DMSO-d6) 55.1 (CH3), 99.3 (CH), 113.8
(CH), 126.8 (CH), 127.8 (C), 149.7 (C), 158.5 (C), 168.0 (C); IR
u cm-1 3440, 3270, 3117, 1626, 1538, 1493, 1246, 1179, 1037, 836,
738; HRMS (ES+) m/z 207.0591 (M+H; C10H11N2OS requires
207.0592). NMR data matched that reported in the literature.30
4-(2-Pyridinyl)-1,3-thiazol-2-amine (3h)
Using 2-vinylpyridine (1h, 60 mg, 0.57 mmol) and thiourea (4a,
130 mg, 1.71 mmol) as the nucleophile, the product was obtained
as a pale yellow solid (56 mg, 55% yield). M.p. 170–172 ◦C [CHCl3;
lit.26 173–175 ◦C]; 1H NMR (400 MHz, MeOH-d4) d (ppm) 7.23
(s, 1 H, CH-S), 7.24–7.30 (m, 2 H, CH), 7.78–7.90 (m, 2 H, CH),
8.50–8.52 (m, 1 H, CH); 13C NMR (101 MHz, MeOH-d4) 106.3
(CH), 121.3 (CH), 122.7 (CH), 137.8 (CH), 148.9 (CH), 149.9 (C),
152.8 (C), 170.2 (C); IR u cm-1 3291, 3128, 1590, 1535, 1423, 1344,
1056, 793, 746, 710; HRMS (ES+) m/z 178.0436 (M+H; C8H8N3S
4,5-Dihydronaphtho[1,2-d]thiazol-2-amine (3m)
Using 1,2-dihydronaphthalene (1m, 50 mg, 0.38 mmol) and
thiourea (4a, 88 mg, 1.2 mmol) as the nucleophile, the product
was ◦obtained as a pale yellow solid (42 mg, 54% yield). M.p. 132–
134 C [CH3CN; lit.29 133–134 ◦C]; 1H NMR (400 MHz, CDCl3)
d (ppm) 2.82–2.90 (m, 2 H, CH2), 2.97–3.07 (m, 2 H, CH2), 5.01
(br. s, 2 H, NH2), 7.12–7.27 (m, 3 H, CH), 7.68 (d, J = 7.5 Hz, 1 H,
CH); 13C NMR (101 MHz, CDCl3) 21.7 (CH2), 29.1 (CH2), 120.3
(C), 122.7 (CH), 126.2 (CH), 126.7 (CH), 127.7 (CH), 131.5 (C),
134.4 (C), 145.2, (C), 165.5 (C); IR u cm-1 3283, 3124, 2934, 1606,
1527, 1364, 1293, 1062, 766. 718; HRMS (ES+) m/z 203.0643
(M+H; C11H11N2S requires 203.0643). NMR data matched that
reported in the literature.31
1
requires 178.0439). H NMR data matched that reported in the
literature.27
Ethyl 3-(2-amino-1,3-thiazol-4-yl)benzoate (3i)
Using 3-vinylbenzoic acid ethyl ester (1i, 70 mg, 0.40 mmol) and
thiourea (4a, 91 mg, 1.2 mmol) as the nucleophile, the product was
obtained as a pale yellow solid (61 mg, 62% yield). M.p. 112–114
◦C [CHCl3]; 1H NMR (400 MHz, CDCl3) d (ppm) 1.41 (t, J = 7.0
Hz, 3 H, CH3), 4.40 (q, J = 7.0 Hz, 2 H, CH2), 5.20 (br. s, 2 H,
NH2), 6.82 (s, 1 H, CH), 7.45 (t, J = 8.0 Hz, 1 H, CH), 7.94–8.00
(m, 2 H, CH), 8.42 (t, J = 2.0 Hz, 1 H, CH); 13C NMR (101
MHz, CDCl3) 14.4 (CH3), 61.1 (CH2), 103.7 (CH), 127.0 (CH),
128.6 (CH), 128.7 (CH), 130.3 (CH), 130.9 (C), 134.9 (C), 150.3
(C), 166.6 (C), 167.4 (C); IR u cm-1 3344, 3119, 2981, 1706, 1609,
1534, 1338, 1256, 1197, 1106, 1021, 762, 710; HRMS (ES+) m/z
249.0695 (M+H; C12H13N2O2S requires 249.0698).
4,5-Dibutyl-1,3-thiazol-2-amine (3n)
Using 5-decene (1n, 0.095 mL, 0.50 mmol) and thiourea (4a, 77
mg, 1.0 mmol) as the nucleophile, the product was obtained as a
1
colorless oil (82 mg, 77% yield). H NMR (400 MHz, CDCl3) d
(ppm) 0.92 (t, J = 7.3 Hz, 6 H, CH3), 1.25–1.40 (m, 4 H, CH2),
1.44–1.63 (m, 4 H, CH2), 2.36–2.48 (m, 2 H, CH2), 2.56 (t, J =
7.5 Hz, 2 H, CH2), 4.90 (br. s, 2 H, NH2); 13C NMR (101 MHz,
CDCl3) d (ppm) 13.8 (CH3), 14.0 (CH3), 22.1 (CH2), 22.5 (CH2),
25.8 (CH2), 28.7 (CH2), 31.8 (CH2), 34.1 (CH2), 121.9 (C-S), 147.1
(C-N), 164.0 (S-C = N); IR u cm-1 3283, 3122, 2954, 2927, 2857,
1609, 1523, 1461, 1317, 1127, 1064, 748, 705; HRMS (ES+) m/z
213.1423 (M+H; C11H21N2S requires 213.1425).
Methyl 4-(2-amino-1,3-thiazol-4-yl)benzoate (3j)
Using methyl 4-ethenylbenzoate (1j, 150 mg, 0.92 mmol) and
thiourea (4a, 211 mg, 2.77 mmol) as the nucleophile, the product
was obtained as a pale yellow solid (140 mg, 65% yield). M.p.
233–235 ◦C [CH3CN]; 1H NMR (400 MHz, DMSO-d6) d (ppm)
3.85 (s, 3 H, CH3), 7.16 (br. s, 2 H, NH2), 7.25 (s, 1 H, CH), 7.91–
8.00 (m, 4 H, Ar); 13C NMR (101 MHz, acetone-d6) d (ppm) 51.3
(CH3), 104.5 (CH), 125.6 (CH), 128.6 (C), 129.5 (CH), 139.5 (C),
149.7 (C), 166.1 (C), 168.2 (C); IR u cm-1 1694, 1606, 1556, 1282,
1112, 859, 718; HRMS (ES+) m/z 235.0541 (M+H; C11H11N2O2S
5-Isopropyl-4-methylthiazol-2-amine (3o)
Using 4-methylpent-2-ene (1o, 0.073 mL, 0.60 mmol) and thiourea
(4a, 136 mg, 1.78 mmol) as the nucleophile, the product was
obtained as a colorless oil (51 mg, 55% yield). M.p. 64–66 ◦C
[CHCl3; lit.32 65–67 ◦C]; 1H NMR (400 MHz, CDCl3) d (ppm) 1.20
(d, J = 7.0 Hz, 6 H, CH3CH), 2.13 (s, 3 H, CH3), 3.07 (sept, J = 7.0
Hz, 1 H, CH3CH), 4.65 (br. s, 2 H, NH2); 13C NMR (101 MHz,
CDCl3) 14.6 (CH3), 24.8 (CH3CH), 27.1 (CH3CH), 129.6 (C),
140.3 (C), 163.7 (C); IR u cm-1 3292, 3176, 2959, 1610, 1521, 1460,
1382, 1310, 1108; HRMS (ES+) m/z 157.0806 (M+H; C7H13N2S
1
requires 235.0541). H NMR data matched that reported in the
literature.28
4-(2-Methylphenyl)-1,3-thiazol-2-amine (3k)
Using 2-methylstyrene (1k, 50 mg, 0.42 mmol) and thiourea (4a,
97 mg, 1.3 mmol) as the nucleophile, the product was obtained
as a pale yellow solid (54 mg, 67% yield). M.p. 80–82 ◦C [CHCl3;
◦
1
lit.29 81–82 C]; H NMR (400 MHz, CDCl3) d (ppm) 2.44 (s, 3
H, CH3), 5.18 (br. s, 2 H, NH2), 6.45 (s, 1 H, CH), 7.18–7.26 (m,
3 H, CH), 7.51–7.54 (m, 1 H, CH); 13C NMR (101 MHz, CDCl3)
21.0 (CH3), 105.7 (CH), 125.7 (CH), 127.8 (CH), 129.5 (CH),
130.7 (CH), 134.9 (C), 136.0 (C), 151.3 (C), 166.4 (C); IR u cm-1
3285, 3119, 1622, 1523, 1329, 1032, 767, 730; HRMS (ES+) m/z
191.0638 (M+H; C10H11N2S requires 191.0643).
1
requires 157.0799). H NMR data matched that reported in the
literature.33
N-(4-Phenyl-1,3-thiazol-2-yl)-2-pyridinamine (5a)
Using styrene (1c, 0.055 mL, 0.48 mmol) and 2-pyridylthiourea
(4b, 221 mg, 1.44 mmol) as the nucleophile, the product was
1098 | Org. Biomol. Chem., 2012, 10, 1093–1101
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◦
obtained as a colorless oil (75 mg, 62% yield). M.p. 164–166 C
4(5)-Phenyl-2-propyl-1H-imidazole (6a)
[CH3CN]; 1H NMR (400 MHz, CDCl3) d (ppm) 6.42 (d, J = 8.0
Hz, 1 H, CH), 6.73 (dd, J = 7.0 Hz, J = 5.0 Hz, 1 H, CH), 6.98 (s,
1 H, CH), 7.15–7.35 (m, 4 H, CH), 7.81–7.84 (m, 2 H, Ph), 8.25
(d, J = 5.0 Hz, 1 H, CH), 10.15 (br. s, 1 H, NH); 13C NMR (101
MHz, CDCl3) 105.7 (CH), 110.6 (CH), 116.2 (CH), 126.1 (CH),
127.8 (CH), 128.7 (CH), 134.7 (C), 137.4 (CH), 146.6 (CH), 149.3
(C), 151.3 (C), 161.1 (C); IR u cm-1 3176, 3053, 2950, 1605, 1542,
1478, 1408, 1328, 770, 715; HRMS (ES+) m/z 254.0752 (M+H;
C14H12N3S requires 254.0752).
Using styrene (1c, 0.050 mL, 0.42 mmol) and butyramidine
hydrochloride (4e, 156 mg, 1.27 mmol) as the nucleophile, the
product was obtained as a pale yellow◦solid (57 mg, 72% yield).
◦
M.p. 130–132 C [aq. EtOH; lit36 136 C]. H NMR (400 MHz,
CDCl3) d (ppm) 0.95 (t, J = 7.5 Hz, 3 H, CH3), 1.75 (sxt, J = 7.5
Hz, 2 H, CH2), 2.72 (t, J = 7.5 Hz, 2 H, CH2), 7.18–7.26 (m, 2 H,
Ph + CH-NH), 7.36 (t, J = 7.5 Hz, 2 H, Ph), 7.69 (d, J = 7.5 Hz,
2 H, Ph); 13C NMR (101 MHz, CDCl3) d (ppm) 13.7 (CH3), 22.0
(CH2), 30.3 (CH2), 115.1 (CH-N), 124.8 (CH), 126.8 (CH), 128.7
(CH), 132.6 (C), 137.4 (C-N), 149.4 (N = C-NH); IR u cm-1 3033,
2961, 2930, 2871, 1607, 1539, 1514, 1455, 1426, 1260, 1134, 1094,
1069, 1014, 801, 748, 692; HRMS (ES+) m/z 187.1232 (M+H;
C12H15N2 requires 187.1235).
1
3-(4-Phenyl-1,3-thiazol-2-yl)pyridine (5b)
Using styrene (1c, 0.050 mL, 0.42 mmol) and thionicotinamide (4c,
175 mg, 1.27 mmol) as the nucleophile, the product was obtained
as a pale yellow solid (71 mg, 68% yield). M.p. 64–65 ◦C [CHCl3;
3-(4(5)-Phenyl-1H-imidazol-2-yl)pyridine (6b)
◦
1
lit34 67–68 C]; H NMR (400 MHz, CDCl3) d (ppm) 7.35–7.52
(m, 4 H, Ar), 7.55 (s, 1 H, CH-S), 8.01 (d, J = 7.5 Hz, 2 H, Ar),
8.34 (br. d, J = 8.0 Hz, 1 H, Ar), 8.68 (br. d, J = 3.5 Hz, 1 H,
Ar), 9.26 (br. s, 1 H, Ar); 13C NMR (101 MHz, CDCl3) d (ppm)
113.2 (CH-S), 123.7 (CH), 126.4 (CH), 128.4 (CH), 128.8 (CH),
129.7 (C), 133.6 (CH), 134.0 (C), 147.7 (CH), 150.8 (CH), 156.7
(C), 164.3 (C); IR u cm-1 3062, 2987, 1569, 1495, 1474, 1444, 1417,
1408, 1330, 1254, 1189, 1072, 1024, 976, 808, 730, 702, 679; HRMS
(ES+) m/z 239.0638 (M+H; C14H11N2S requires 239.0643).
Using styrene (1c, 0.050 mL, 0.42 mmol) and 3-amidinopyridine
hydrochloride (4f, 200 mg, 1.27 mmol) as the nucleophile, the
product was obtained as a pale yellow solid ◦(62 mg, 67% yield).
◦
1
M.p. 192–194 C [aq. EtOH; lit.37 201–203 C]. H NMR (400
MHz, MeOD) d (ppm) 7.26 (t, J = 7.5 Hz, 1 H, Ar), 7.40 (t, J =
7.5 Hz, 2 H, Ar), 7.49–7.60 (m, 2 H, Ar + CHNH), 7.78 (d, J = 7.5
Hz, 2 H, Ar), 8.35 (d, J = 8.5 Hz, 1 H, Ar), 8.54 (d, J = 3.5 Hz, 1 H,
Ar), 9.12 (s, 1 H, Ar); 13C NMR (125 MHz, CDCl3 + 5% MeOD) d
(ppm) 118.4 (CH-NH), 124.2 (CH), 125.0 (CH), 126.6 (C), 127.4
(CH), 128.7 (CH), 131.8 (C), 134.0 (CH), 139.4 (C), 143.7 (C),
145.6 (CH), 148.4 (CH); IR u cm-1 3100, 3056, 2980, 2950, 1660,
1606, 1576, 1484, 1464, 1436, 1148, 1087, 1026, 950, 811, 757, 695;
HRMS (ES+) m/z 222.1028 (M+H; C14H12N3 requires 222.1031).
1H NMR of 6b·2HCl (400 MHz, DMSO-d6) d (ppm) 7.45 (t, J =
7.5 Hz, 1 H), 7.55 (t, J = 7.5 Hz, 2H), 7.81 (dd, J = 8.5 Hz, J =
5.5 Hz, 1H), 8.02 (d, J = 7.5 Hz, 2H), 8.29 (s, 1H), 8.75 (d, J = 8.5
Hz, 1H), 8.83 (dd, J = 5.5 Hz, J = 1.5 Hz, 1H), 9.42 (d, J = 1.5 Hz,
1H) identical to that reported in the literature.38
2-(1,1-Dimethylethyl)-4-phenyl-1,3-thiazole (5c)
Using styrene (1c, 0.050 mL, 0.42 mmol) and 2,2-
dimethylthiopropioamide (4d, 149 mg, 1.27 mmol) as the nucle-
ophile, the product was obtained as a yellow oil (62 mg, 67%
yield). 1H NMR (400 MHz, CDCl3) d (ppm) 1.51 (s, 9 H, CH3),
7.29–7.37 (m, 2 H, Ph + CH-S), 7.43 (t, J = 7.5 Hz, 2 H, Ph),
7.94 (d, J = 7.5 Hz, 2 H, Ph); 13C NMR (101 MHz, DMSO-d6) d
(ppm) 30.6 (CH3), 37.3 (CH3C), 112.9 (CH-S), 126.0 (CH), 127.8
(CH), 128.7 (CH), 134.3 (C), 153.5 (C-N), 180.2 (S-C = N); IR u
cm-1 2962, 2927, 1494, 1475, 1460, 1445, 1363, 1223, 1066, 1015,
727, 689; HRMS (ES+) m/z 218.1000 (M+H; C13H16NS requires
218.1003). 13C NMR data matched that reported in the literature.35
2-(Ethylthio)-4(5)-phenyl-1H-imidazole (6c)
Using styrene (1c, 0.050 mL, 0.42 mmol) and 2-ethylisothiourea,
hydrobromide (4g, 235 mg, 1.27 mmol) as the nucleophile, the
product was obtained as a white solid◦(62 mg, 72% yield). M.p.
◦
1
130–132 C [aq. EtOH; lit.39 129–130 C]; H NMR (400 MHz,
CDCl3) d (ppm) 1.31 (t, J = 7.2 Hz, 3 H, CH3), 3.04 (q, J = 7.2
Hz, 2 H, CH2), 7.23–7.29 (m, 1 H, Ph), 7.33–7.42 (m, 3 H, Ph
+ CH-N), 7.70 (d, J = 7.5 Hz, 2 H, Ph); 13C NMR (101 MHz,
CDCl3) d (ppm) 15.3 (CH3), 29.5 (CH2), 117.6 (CH-N), 124.8
(CH), 127.1 (CH), 128.7 (CH), 132.3 (C), 139.9 (C-N), 140.6 (N-
C-S); IR u cm-1 3059, 2965, 2925, 2867, 1606, 1495, 1449, 1389,
1261, 1129, 1082, 986, 801, 756, 692; HRMS (ES+) m/z 205.0797
(M+H; C11H13N2S requires 205.0799).
General procedure B
To a solution of IBX (2 eqv., 45% stabilized with benzoic and
isophthalic acids) and iodine (1.1 mmol) in dry dimethyl sulfoxide
(0.25 M) stirred at room temperature was added the corresponding
alkene (1 eqv.) in one charge. The reaction mixture was stirred at
room temperature until full consumption of the starting alkene
(monitored by LCMS). Then it was diluted with DCM (30 mL for
~0.5 mmol scale) and washed with saturated aqueous NaHCO3–
Na2S2O3. The aqueous layer was extracted with DCM (2 ¥ 20
mL for ~0.5 mmol scale); the combined organic layers were dried
over Na2SO4 and filtered. The corresponding nucleophile (3 eqv.),
potassium carbonate (2 eqv.) and dry N,N-dimethylformamide
(0.15 M) were added to the DCM solution and the volume was
reduced down to ~2 mL (for ~0.5 mmol scale) under vacuum.
The reaction mixture was stirred at room temperature for 12 h.
The corresponding product was isolated by MDAP using gradient
CH3CN–H2O solvent mixture unless otherwise stated.
2-Phenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyridine (6d)
Using styrene (1c, 0.050 mL, 0.42 mmol) and 2-iminopiperidine
hydrochloride (4h, 171 mg, 1.27 mmol) as the nucleophile, the
product was◦obtained as a pale yellow solid (60 mg, 71% yield).
◦
1
M.p. 93–95 C [CHCl3; lit40 98–100 C]. H NMR (400 MHz,
CDCl3) d (ppm) 1.92–2.04 (m, 4 H, CH2), 2.94 (t, J = 6.0 Hz, 2 H,
CH2), 3.98 (t, J = 6.0 Hz, 2 H, CH2N), 7.07 (s, 1 H, CH-N), 7.21
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(t, J = 7.5 Hz, 1 H, Ph), 7.35 (t, J = 7.5 Hz, 2 H, Ph), 7.75 (d, J = 7.5
Hz, 2 H, Ph); 13C NMR (101 MHz, CDCl3) d (ppm) 21.1 (CH2),
23.0 (CH2), 24.6 (CH2), 44.8 (CH2N), 113.8 (CH-N), 124.6 (CH),
126.4 (CH), 128.4 (CH), 134.4 (C), 140.5 (C), 145.2 (N-C = N);
IR u cm-1 2947, 2862, 1604, 1516, 1446, 1425, 1377, 1319, 1193,
1076, 951, 744, 696; HRMS (ES+) m/z 199.1234 (M+H; C13H15N2
requires 199.1235).
Ph), 7.42–7.48 (m, 2 H, Ph), 7.54 (d, J = 9.5 Hz, 1 H, CH), 7.84
(br. s, 1 H, CH-N), 7.92–7.96 (m, 2 H, Ph), 8.28 (dd, J = 2.0 Hz,
J = 1.0 Hz, 1 H, CH); 13C NMR (101 MHz, CDCl3) 107.0 (C),
108.3 (CH), 118.1 (CH), 125.5 (CH), 126.1 (CH), 128.1 (CH),
128.3 (CH), 128.8 (CH), 133.2 (C), 144.1 (C), 146.7 (C); IR u
cm-1 1565, 1481, 1380, 1230, 808, 774, 718, 689; HRMS (ES+)
m/z 273.0030 (M+H; C13H10N2Br requires 273.0027).
3-{4(5)-[(Methoxy)methyl]-5(4)-phenyl-1H-imidazol-2-
yl}pyridine (6e)
General procedure C
To a solution of IBX (2 eqv., 45% stabilized with benzoic and
isophthalic acids) and iodine (1.1 mmol) in dry dimethyl sulfoxide
(0.25 M) stirred at room temperature was added the corresponding
alkene (1 eqv.) in one charge. The reaction mixture was stirred at
room temperature until full consumption of the starting alkene
(monitored by LCMS). Then it was diluted with DCM (30 mL for
~0.5 mmol scale) and washed with saturated aqueous NaHCO3–
Na2S2O3. The aqueous layer was extracted with DCM (2 ¥ 20 mL
for ~0.5 mmol scale); the combined organic layers were dried over
Na2SO4 and filtered. The corresponding nucleophile (3 eqv.) and
dry N,N-dimethylformamide (0.15 M) were added to the DCM
solution and the volume was reduced down to ~2 mL (for ~0.5
mmol scale) under vacuum. The reaction mixture was stirred at
room temperature for 15 min and then at 80 ◦C for 2 h. The
corresponding product was isolated by MDAP using gradient
CH3CN–H2O solvent mixture unless otherwise stated.
Using (2E)-3-phenyl-2-propen-1-yl ether (1f, 70 mg, 0.47 mmol)
and benzamidine (4i, 170 mg, 1.27 mmol) as the nucleophile, the
product was obtained as a pale yellow oil (87 mg, 70% yield).
1H NMR (400 MHz, CDCl3) d (ppm) 3.41 (s, 3 H, CH3), 4.57
(s, 2 H, CH2), 7.28–7.45 (m, 6 H, Ph), 7.61 (d, J = 7.0 Hz, 2 H,
Ph), 7.87 (d, J = 7.0 Hz, 2 H, Ph); 13C NMR (101 MHz, CDCl3)
d (ppm) 58.0 (CH3), 66.0 (CH2), 125.5 (CH), 127.3 (CH), 127.4
(CH), 128.6 (CH), 128.7 (CH), 128.8 (CH), 129.4 (C), 129.6 (C),
131.7 (C), 135.5 (C), 145.9 (N = C-N); IR u cm-1 3059, 2923, 1589,
1494, 1461, 1402, 1189, 1087, 912, 773, 696; HRMS (ES+) m/z
265.1346 (M+H; C17H17N2O requires 265.1341).
2-Phenylimidazo[1,2-a]pyridine (7a)
Using styrene (1c, 50 mg, 0.48 mmol) and 2-aminopyridine (4j, 136
mg, 1.44 mmol) as the nucleophile, the product was obtained as a
pale yellow solid (64 mg, 69% yield). M.p. 132–134 ◦C [CH3CN;
lit.41 133–133.5 ◦C]; 1H NMR (400 MHz, CDCl3) d (ppm) 6.78 (t,
J = 7.0 Hz, 1 H, CH), 7.15–7.22 (m, 1 H, CH), 7.33 (t, J = 7.0 Hz,
1 H, Ph), 7.44 (t, J = 7.0 Hz, 2 H, CH), 7.66 (d, J = 9.0 Hz, 1 H,
CH), 7.86 (s, 1 H, CH), 7.94–7.98 (m, 2 H, Ph), 8.12 (d, J = 7.0
Hz, 1 H, CH); 13C NMR (101 MHz, CDCl3) d (ppm) 108.1 (CH),
112.6 (CH), 117.4 (CH), 119.5 (C), 124.9 (CH), 125.6 (CH), 126.1
(CH), 128.1 (CH), 128.7 (CH), 133.4 (C), 145.5 (C); IR u cm-1
1561, 1476, 1371, 1229, 742, 722; HRMS (ES+) m/z 195.0919
(M+H; C13H11N2 requires 195.0922). NMR data matched that
reported in the literature.42
N-(3-Isopropyl-4-(o-tolyl)thiazol-2(3H)-ylidene)propan-2-amine
(8a)
Using 1-methyl-2-vinylbenzene (1k, 50 mg, 0.42 mmol) and 1,3-
diisopropylthiourea (4m, 203 mg, 1.27 mmol) as the nucleophile,
the product was obtained as a pale yellow solid (68 mg, 59% yield).
◦
1
M.p. 65–67 C [CHCl3]; H NMR (400 MHz, CDCl3) d (ppm)
1.15–1.22 (m, 6 H, CH3), 1.28 (d, J = 7.0 Hz, 3 H, CH3), 1.46 (d,
J = 7.0 Hz, 3 H, CH3), 2.28 (s, 3 H, CH3Ar), 3.06 (sept, J = 7.0
Hz, 1 H, CH), 3.73 (sept, J = 7.0 Hz, 1 H, CH), 5.50 (s, 1 H, CH),
7.18–7.35 (m, 4 H, Ar); 13C NMR (101 MHz, CDCl3) d (ppm)
18.7 (CH3), 19.5 (CH3), 19.8 (CH3), 23.5 (CH3), 23.5 (CH3), 49.7
(CH-N), 56.6 (CH-N), 93.5 (CH), 125.6 (CH), 129.0 (CH), 130.1
(CH), 130.5 (CH), 133.1 (C), 138.1 (C), 139.5 (C), 154.2 (C); IR u
cm-1 2965, 2928, 1622, 1377, 1338, 1251, 760, 693; HRMS (ES+)
m/z 275.1573 (M+H; C16H23N2S requires 275.1582).
2-Phenylimidazo[1,2-a]pyridin-7-amine (7b)
Using styrene (1c, 50 mg, 0.48mmol)and 2,4-diaminopyridine (4k,
157 mg, 1.44 mmol) as the nucleophile, the product was obtained
as a pale yellow solid (71 mg, 71% yield). M.p. 215 ◦C [decomp.,
CH3CN]; 1H NMR (400 MHz, MeOH-d4) d (ppm) 6.44 (dd, J =
7.0 Hz, J = 2.0 Hz, 1 H, CH), 6.53 (d, J = 2.0 Hz, 1 H, CH),
7.25–7.30 (m, 1 H, Ph), 7.35–7.42 (m, 2 H, Ph), 7.75–7.85 (m, 3 H,
Ph + CH), 8.03 (d, J = 7.0 Hz, 1 H, CH); 13C NMR (101 MHz,
MeOH-d4) 93.7 (CH), 108.1 (CH), 108.4 (CH), 126.8 (CH), 127.9
(CH), 128.65 (CH), 129.8 (CH), 135.4 (CH), 145.0 (CH), 149.2
(C), 149.9 (C); IR u cm-1 3380, 3204, 1657, 1484, 1373, 1227, 710;
HRMS (ES+) m/z 210.1029 (M+H; C13H12N3 requires 210.1031).
4-Fluoro-N-(3-methyl-4-(o-tolyl)thiazol-2(3H)-ylidene)aniline (8b)
Using 1-methyl-2-vinylbenzene (1k, 50 mg, 0.42 mmol) and 1-(4-
fluorophenyl)-3-methylthiourea (4n, 234 mg, 1.27 mmol) as the
nucleophile, the product was o◦btained as a pale yellow solid (79
1
mg, 63% yield). M.p. 104–106 C [CHCl3]; H NMR (400 MHz,
CDCl3) d (ppm) 2.27 (s, 3 H, CH3C), 3.13 (s, 3 H, CH3N), 5.71
(s, 1 H, CH), 7.00–7.10 (m, 4 H, Ar), 7.20–7.40 (m, 4 H, Ar); 13
C
NMR (101 MHz, CDCl3) 19.6 (CH3C), 32.1 (CH3N), 94.6 (CH),
116.0 (d, J = 22.0 Hz, CH), 122.0 (d, J = 8.0 Hz, CH), 126.1 (CH),
129.6 (CH), 130.3 (CH), 130.4 (CH), 131.1 (C), 137.8 (C), 139.3
(C), 147.8 (d, J = 2.5 Hz, C), 157.4 (d, J = 241.0 Hz, C), 160.3
(d, J = 1.5 Hz, C); IR u cm-1 2917, 1601, 1578, 1500, 1363, 1204,
837, 766, 743; HRMS (ES+) m/z 299.1018 (M+H; C17H16N2FS
requires 299.1018).
6-Bromo-2-phenylimidazo[1,2-a]pyridine (7c)
Using styrene (1c, 50 mg, 0.48 mmol) and 5-bromo-2-
aminopyridine (4l, 249 mg, 1.44 mmol) as the nucleophile, the
product was obtained as a pale yellow solid (72 mg, 55% yield).
M.p. 193–196 ◦C [CH3CN]; 1H NMR (400 MHz, CDCl3) d (ppm)
7.24 (dd, J = 9.5 Hz, J = 2.0 Hz, 1 H, CH), 7.33–7.38 (m, 1 H,
1100 | Org. Biomol. Chem., 2012, 10, 1093–1101
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4,6-Bis(methoxy)-2-phenyl-1H-indole (9)
15 1H NMR of the crude 2-Iodo-1-phenyl-1-propanone, d (ppm): 2.04 (d,
3
3JCH
= 7.0 Hz, 3 H, CH3), 5.47 (q, JCH
= 7.0 Hz, 1 H, CH-I),
3 ,CH
3 ,CH
7.40–7.46 (m, 2 H, Ph), 7.50–7.56 (m, 1 H), 7.92–7.98 (m, 2 H, Ph);
1H NMR of the crude 2-iodo-1-phenyl-1-ethanone (prepared by the
same procedure), d (ppm): 4.30 (s, 2 H, CH2), 7.40–7.48 (m, 2 H, Ph),
7.52–7.60 (m, 2 H, Ph), 7.90–7.98 (m, 2 H, Ph) in agreement with the
Using styrene (1c, 50 mg, 0.42 mmol) and 3.5-bis(methoxy)aniline
(4o, 234 mg, 1.27 mmol) as the nucleophile, the product was
obtained as a greenish oil (67 mg, 63% yield). H NMR (400
1
literature11a
.
MHz, CDCl3) d (ppm) 3.87 (s, 3 H, CH3O), 3.95 (s, 3 H, CH3O),
6.25 (s, 1 H, CO-CH-CO), 6.53 (s, 1 H, CO-CH-CN), 6.87 (s,
1 H, CH = C-NH), 7.24–7.32 (m, 1 H, Ph), 7.42 (t, J = 7.5
Hz, 2 H, Ph), 7.61 (d, J = 7.5 Hz, 2 H, Ph), 8.26 (br. s, 1 H,
NH); 13C NMR (101 MHz, CDCl3) d (ppm) 55.4 (CH3), 55.7
(CH3), 86.7 (CO-CH-CN), 91.9 (CO-CH-CO), 97.1 (CH C–
NH), 114.5 (CO-C-C-NH), 124.4 (Ph, CH), 127.0 (Ph, CH),
129.0 (Ph, CH), 132.5 (Ph, C), 135.1 (CN), 138.1 (C-N), 153.7
(C-O), 157.8 (C-O); IR u cm-1 3419, 2935, 2838, 1624, 1600, 1511,
1453, 1373, 1345, 1277, 1216, 1199, 1148, 1127, 1043, 803, 761,
738, 692; HRMS (ES+) m/z 254.1171 (M+H; C16H16NO2 requires
16 (a) N. Kornblum, J. W. Jones and G. J. Anderson, J. Am. Chem. Soc.,
1959, 81, 4113; (b) P. Dave, H. S. Byun and R. Engel, Synth. Commun.,
1986, 16, 1343.
17 Reaction with an alkene with R1 = p-NO2Ph, R2 = H (Table 1) gave no
desired product 3.
18 The reaction with stilbenes usually gives traces of the corresponding
products due to rapid Kornblum oxidation of the intermediate iodoke-
tone to the corresponding diketone.
1
19 The ratio of the regioisomers was detected as >25 : 1 by H NMR of
the crude iodoketone.
20 The simplest explanation of the mechanism involves an iodonium ion;
for more details see: R. S. Brown, R. W. Nagorski, A. J. Bennet, R.
E. D. McClung, G. H. M. Aarts, M. Klobukowski, R. McDonald and
B. D. Santarsiero, J. Am. Chem. Soc., 1994, 116, 2448 and references
therein.
21 K. C. Nicolaou, T. Montagnon and P. S. Baran, Angew. Chem., Int.
Ed., 2002, 41, 993.
22 Compare references 9a and 9b.
1
254.1181). H NMR data was identical to that reported in the
literature.43
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