A straightforward approach towards 5-substituted thiazolylpeptides via the thio-Ugi-reaction

Article abstract of DOI:10.1039/c0ob00453g

A wide range of 5-substituted thiazoles are easily accessible via cross coupling of thiazolyl triflates. These activated thiazoles can be obtained by Ugi reactions using thioacids (thio-Ugi-reaction) and subsequent cyclisation of the endo thiopeptides for

Full text of DOI:10.1039/c0ob00453g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A straightforward approach towards 5-substituted thiazolylpeptides via the
thio-Ugi-reaction†
Uli Kazmaier* and Andrea Persch
Received 19th July 2010, Accepted 2nd September 2010
DOI: 10.1039/c0ob00453g
A wide range of 5-substituted thiazoles are easily accessible via cross coupling of thiazolyl triflates.
These activated thiazoles can be obtained by Ugi reactions using thioacids (thio-Ugi-reaction) and
subsequent cyclisation of the endo thiopeptides formed with triflic anhydride. In addition, cyclisations
with acyl halides give rise to 5-acyloxysubstituted derivatives.
Introduction
Natural products are an important source not only for pharma-
ceutically relevant compounds such as antibiotics, but also as
lead structures for the development of natural product based
drugs.1 While many classes of natural products can directly be
used as drugs, peptides especially are critical candidates based
on their moderate proteolytic stability. In nature, as well as in
medicinal chemistry this problem can be solved by incorporation
of nonproteinogenic amino acids into the peptides, which are not
accepted by hydrolytic enzymes.2 This explains the wide range of
unusual amino acids found in secondary metabolites and in drugs.1
One interesting option to increase proteolytic stability of a peptide
is the replacement of a peptide bond by a hydrolytically more stable
thioamide bond.3 If such a thioamide is located at the N-terminus
of a serine, subsequent ring closure to the thiazoline4 and oxidation
to the corresponding thiazole amino acid is possible.5 Thiazole
Fig. 1 Thiazolylpeptides as natural products and drugs.
amino acids are also found widespread in nature, especially as
secondary metabolites of marine organisms or bacteria.6 Typical
5-position of unsubstituted thiazoles, but here very strong bases
examples are dolastatin 3,7 the tubulysins8 (Fig. 1) or the large
such as BuLi are required,19 conditions which are not compatible
group of thiopeptides,9 to name only a few.
with peptides.
Biosynthetically, these structures are formed by cyclisation of
Herein, we describe a straightforward protocol towards 5-
cysteine peptides and subsequent oxidation.10 If an enzymatic de-
substituted thiazole peptides based on Ugi-reactions as a key
carboxylation occurs after the oxidation step,11 the corresponding
step. The Ugi-reaction has become an extremely useful tool for
unsubstituted thiazole structure is located at the C-terminus of
the construction of unusual peptides,20 and by using thioacids
the peptide chain, as found in bottromycin (Fig. 1),12 dolastatin
and suitable isonitriles, this multicomponent reaction can also
1013 or the lyngbyabellins.14 The origin of the thiazole moiety from
be used for the synthesis of peptidic thiazole carboxylic acids
cysteine explains why in natural products the 5-position of the
(Scheme 1).21 Very recently, Thompson et al. reported on the
thiazole ring in general is unsubstituted. On the other hand, for
synthesis of 5-aminothiazoles by Ugi-reaction and subsequent
the development of natural product based drugs, modifications at
thionation/cyclisation.22 During our long-term interest in the Ugi-
the 5-position are an interesting issue, and several 5-substituted
reactions and their application,23 we also developed a protocol
thiazole derivatives have made their way into clinical trials, such
suitable for the synthesis of terminal unsubstituted thiazole amino
as BMS-1872515 (Fig. 1) or CP-619700.16
acids.24
For the synthesis of 4-substituted thiazoles, the 4-thiazole
carboxylic acid is a suitable precursor,17 and for the additional
introduction of 5-substituents the corresponding ester can be de-
protonated and subsequently alkylated or acylated.18 In principle,
this approach is also suitable to introduce substituents into the
Institut fu¨r Organische Chemie, Universita¨t des Saarlandes, D-66123
Saarbru¨cken, Germany. E-mail: u.kazmaier@mx.uni-saarland.de; Fax: +49
681 302 2409; Tel: +49 681 302 3409
† Electronic supplementary information (ESI) available: Experimental
procedures and analytical data of compounds 3 to 13 and 1H and 13C
spectra of compounds 1 to 15. See DOI: 10.1039/c0ob00453g
Scheme 1 Thiazolylpeptides via thio-Ugi-reaction.
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Table 1 Thio-Ugi-reactions and applications
In the reaction of the acetal of isocyanoacetaldehyde in
combination with thioacids the corresponding endothiopeptide
acetals are obtained, which undergo cyclisation under Lewis acidic
conditions (Scheme 1).
Results and discussion
Based on this protocol, we developed a route towards 5-substituted
thiazole peptides. As a standard thiobenzoic acid was used in
combination with isocyanoacetates. As aldehydes we used the
sterically demanding isobutyraldehyde (providing valine peptides)
and pivaldehyde (tert-leucine peptides). As amine component we
used benzylamine as a representative for the synthesis of N-
alkylated peptides and ammonia, or ammonium hydroxide respec-
tively, for the unsubstituted peptides. Although Ugi-reactions with
ammonia are critical candidates because of several possible side
reactions,25 the yields obtained were good in all cases (Table 1).
It is recommended to use CF3CH2OH as solvent in the ammonia
reactions to avoid participation of the solvent in the Ugi-reaction,
as is observed in CH3OH as solvent.25 In some reactions we
observed the formation of the 5-thiazolone 2 as side product from
nucleophilic attack of the thiocarbonyl group on the ester moiety.
In principle, this thiazolone should be a good precursor for the
synthesis of 5-substituted thiazoles. Unfortunately, all attempts
to cyclise the thiopeptides 1 directly to the thiazolone 2 e.g. by
refluxing overnight, gave no synthetically useful yields. Therefore,
we decided to saponify the ester to obtain the thiazolones via
activation/cyclisation. The free peptide acids 3 were obtained
quantitatively in all cases. And indeed, on addition of DCC the cor-
responding thiazolones 2 were formed in good to excellent yields.
Interestingly, a complete different reaction behavior was ob-
served if the peptide acids were activated as mixed anhydrides
(Table 2). With one equivalent of acetyl chloride around 50%
conversion was observed, but not towards the corresponding
thiazolone 2, but the acylated thiazole derivatives 4. Probably,
the thiazolone was formed as an intermediate, and under the basic
conditions used, the deprotonated thiazolone reacts faster with
the acyl halide than the peptide acid.26
R1
R2
1
Yield (%)
3
Yield (%)
2
Yield (%)
H
H
Bn
Bn
iPr
1a
1b
1c
1d
69
60
75
80
3a
3b
3c
3d
99
99
99
99
2a
2b
n.i.
n.i.
65
97
tBu
iPr
tBu
n.i.: not investigated.
Therefore, unreacted peptide could be recovered. But by using
two equivalents of acyl halide the corresponding acylated hydroxy
thiazoles were formed in excellent yield, independent of the halide
used. Both, acyl halides (entries 1 and 2) as well as chloroformates
(entries 3 to 7) can be used with comparable success. Even with
inorganic halides such as phosphoryl chlorides (entry 8) the
corresponding thiazolylphosphate 8 was obtained, although the
yield was somewhat lower in this case. This forced us to investigate
the synthesis of thiazolyl triflates directly from the peptide acids by
using triflic anhydrides. This would be a straightforward approach
towards a wide range of thiazole derivatives via subsequent cross
coupling. With triflic anhydride the reaction behaved slightly
different compared to the other acyl halides investigated. In THF
as a solvent, the yields were only moderate (10–15%), and therefore
we had to switch to other solvents, such as CH2Cl2.
Table 2 Synthesis of 5-substituted thiazoles
Entry
Peptide
R1
R2
R3X (equiv)
Base (equiv)
Solvent
Product
Yield (%)
1
2
3
4
5
6
7
8
3d
3d
3b
3d
3b
3c
3d
3b
3c
3d
3d
2a
2b
Bn
Bn
H
Bn
H
Bn
Bn
H
Bn
Bn
Bn
H
tBu
tBu
tBu
tBu
tBu
iPr
tBu
tBu
iPr
MeCOCl (2.0)
PhCOCl (2.0)
NEt3 (3.0)
NEt3 (3.0)
NEt3 (3.0)
NEt3 (3.0)
NEt3 (3.0)
NEt3 (3.0)
NEt3 (3.0)
NEt3 (3.0)
NMM (2.0)
NMM (2.0)
NMM (2.0)
—
THF
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
4d
5d
6b
6d
7b
7c
7d
8b
9c
9d
2d
9a
9b
92
93
91
94
95
92
98
69
50
48
68
55
60
EtOCOCl (2.0)
EtOCOCl (2.0)
iBuOCOCl (2.0)
iBuOCOCl (2.0)
iBuOCOCl (2.0)
(EtO)2POCl (2.0)
(CF3SO2)2O (2.0)
(CF3SO2)2O (2.0)
(CF3SO2)2O (1.0)
(CF3SO2)2O (1.0)
(CF3SO2)2O (1.0)
9
10
11
12
13
tBu
tBu
iPr
H
tBu
—
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Table 3 Cross coupling reactions of thiazolyltriflates 9
In this solvent the yields could be increased to 50% and 48%
respectively (entries 9 and 10). Although this is not outstanding,
the short reaction sequence still makes this approach attractive.
Interestingly, if only one equivalent of Tf2O was used, the
formation of the thiazolyl triflate 9 was not observed, but
thiazolone 2 was formed (entry 11). This clearly supports the idea,
that 2 is the intermediate in this domino cyclisation/acylation
process. Unfortunately, this direct interconversion of 3 into the
triflates 9 works only with the N-substituted peptides 3c and 3d,
because 3a and 3b are insoluble in CH2Cl2. But in this case the
thiazolones 2a and 2b obtained by the DCC-coupling can be used
as substrates (entries 12 and 13). This reaction does not require
N-methylmorpholine (NMM) as an additional base and makes
the triflates of all different substituted thiazoles accessible.
With these thiazolyl triflates in hand we next investigated a
range of cross coupling reactions, starting with Suzuki couplings
(Scheme 2). To evaluate the scope and limitations of this protocol
we subjected all four triflates 9 to a coupling with phenylboronic
acid. The reactions were carried out under microwave irradiation.27
After 20 min all reactions were complete and the coupling products
10 were obtained in 73–76% yields, independent of the substitution
pattern of the thiazoles 9 (Table 3, entries 1–4). With another p-
methoxyphenyl boronic acid the yield was even better under the
same reaction conditions (entry 5).
Entry
Triflate
R1
R2
Product
R3
Yield (%)
1
2
3
4
5
6
7
8
9
9a
9b
9c
9d
9a
9b
9c
9c
9c
9a
H
H
Bn
Bn
H
iPr
tBu
iPr
tBu
iPr
tBu
iPr
iPr
iPr
iPr
10a
10b
10c
10d
11a
12b
12c
13c
14c
15a
Ph
Ph
Ph
Ph
p-MeOPh
Ph
Ph
CH2OH
allyl
H
73
73
76
76
85
95
95
58
51
94
H
Bn
Bn
Bn
H
10
obtained in a Pd-catalyzed hydride transfer using formic acid as
reducing agent.30
Conclusion
In conclusion, we have shown that thio Ugi reactions are a
straightforward approach towards 5-substituted thiazolyl pep-
tides. The primarily formed endo thiopeptides can be cyclised
with a wide range of organic and inorganic acid chlorides and
anhydrides. The especially interesting thiazolyl triflates can be
obtained either from the peptide acid or from the corresponding
thiazolone, and they are excellent substrates for subsequent
cross couplings or reductions. Further investigations concerning
synthetic applications are currently in progress.
Experimental
General remarks
All reactions were carried out in oven-dried glassware (100 ◦C) un-
der nitrogen. All solvents were dried before use: THF was distilled
from LiAlH4 and CH2Cl2 from CaH2. The products were purified
by flash chromatography on silica gel (0.063–0.2 mm). Mixtures of
ethyl acetate and hexanes were generally used as eluents. Analysis
by TLC was carried out on commercially precoated Polygram
SIL-G/UV 254 plates (Machery-Nagel, Dueren). Visualization
was accomplished with UV light, KMnO4 solution or iodine.
1H- and 13C-NMR spectroscopic analysis was performed on a
Bruker Avence II 400 MHz spectrometer. Chemical shifts are
reported on the d (ppm) scale and the coupling constants are
given in Hz. HRMS were measured with Finnigan MAT 95S
mass spectrometer. Elemental analyses were carried out at the
Department of Chemistry at Saarland University.
2-[1-(N-Benzoylamino)-2-methylpropyl]-4H-5-thiazolone (2a).
Carboxylic acid 3a31 (100 mg, 0.34 mmol) was dissolved in THF
(3 mL) before a solution of DCC (70 mg, 0.34 mmol) in THF
(3 mL) was added. After stirring for 30 min at room temperature
the solvent was removed in vacuo. The residue was dissolved
in ether and filtered. After evaporation of the solvent 2a was
obtained as pale brown solid (60 mg, 0.22 mmol,◦ 65%), which
Scheme 2 Cross coupling reactions of thiazolyl triflates 9.
With phenylacetylene we were able to get excellent yields in the
corresponding Sonogashira coupling with both types of thiazolyl
peptides (entries 6 and 7). Even unprotected propargylic alcohol
could be coupled under the same reactions conditions,28 although
the yield was lower in this case (entry 8). A similar result was
also obtained in a Stille coupling using allylstannane (entry 9).29
Last, but not least, we investigated the direct reduction of the
triflate towards the unsubstituted thiazole. An excellent yield was
1
was crystallized from CH2Cl2–Et2O, mp. 110–111 C; H-NMR
(400 MHz, CDCl3): d = 1.02 (d, J = 6.8 Hz, 3H), 1.10 (d, J =
6.8 Hz, 3H), 2.32 (dqq, J = 6.8, 6.8, 6.8 Hz, 1H), 4.61 (dd, J =
23.6, 2.0 Hz, 1H), 4.67 (dd, J = 23.6, 2.0 Hz, 1H), 5.15 (m, 1H),
6.88 (d, J = 8.0 Hz, 1H), 7.45 (m, 2H), 7.52 (m, 1H), 7.81 (m, 2H);
13C-NMR (100 MHz, CDCl3): d = 17.0, 19.5, 31.6, 58.5, 71.7,
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127.0, 128.6, 131.9, 133.9, 167.4, 171.6, 205.6; HRMS (CI) calcd
for C14H17N2O2S [M + H]+: 277.1011. Found; 277.0997.
2-[1-(N-Benzoylamino)-2-methylpropyl]-5-thiazolyl triflate (9a).
Triflic anhydride (69 mg, 0.24 mmol) was added to a solution of
thiazolone 2a (60 mg, 0.22 mmol) in CH2Cl2 (3 mL) under N2.
After stirring for 30 min at room temperature the solvent was
removed in vacuo and the crude product was purified by flash
chromatography (silica, hexanes–EtOAc, 7 : 3) to give 9a ◦in 55%
yield (50 mg, 0.12 mmol) as an orange solid, mp. 119–121 C. 1H-
NMR (400 MHz, CDCl3): d = 1.03 (d, J = 6.4 Hz, 6H), 2.44 (m,
1H), 5.32 (m, 1H), 6.89 (d, 3JNH,6 = 8.0 Hz, 1H), 7.44–7.57 (m, 4H),
7.82 (d, J = 7.6 Hz, 2H); 13C-NMR (100 MHz, CDCl3): d = 17.8,
19.3, 33.3, 57.0, 118.6 (q, JC,F = 320 Hz), 127.1, 128.7, 132.0, 133.2,
133.8, 145.8, 167.0, 167.1. HRMS (CI) calcd for C15H16N2O4F3S2
[M + H]+: 409.0504. Found; 409.0502.
2-[1-(N -Benzoylamino)-2,2-dimethylpropyl]-4H-5-thiazolone
(2b). Thiazolone 2b was obtained according to 2a from acid
3b31 (500 mg, 1.62 mmol) and DCC (334 mg, 1.62 mmol) as a pale
yellow solid (457 mg, 1.57 mmol, 97%), mp. 106–109 ◦C; 1H-NMR
(400 MHz, CDCl3): d = 1.12 (s, 9H), 4.61 (d, J = 23.8 Hz, 1H), 4.68
(d, J = 23.8 Hz, 1H), 5.02 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.8 Hz,
1H), 7.44 (m, 2H), 7.52 (m, 1H), 7.79 (d, J = 7.2 Hz, 2H); 13C-NMR
(100 MHz, CDCl3): d = 26.9, 35.5, 61.3, 71.9, 127.0, 128.7, 131.8,
133.9, 167.0, 170.8, 205.7. Anal. calcd for C15H18N2O2S (290.38):
C, 62.05; H, 6.25; N, 9.66. Found: C, 62.13; H, 6.32; N, 9.53%.
2-[1-(N-Benzoylamino)-2,2dimethylpropyl]-5-thiazolyl triflate
(9b). According to triflate 9a, 9b was obtained from thiazolone
2b (88 mg, 0.30 mmol) and triflic anhydride (95 mg, 0.33 mmol)
as a pale orange solid (76 mg, 0.18 mmol, 60%), mp. 82–84 ◦C
2-[1-(N -Benzoyl-N -benzylamino)-2,2-dimethylpropyl]-4H-5-
thiazolone (2d). Carboxylic acid 3d31 (100 mg, 0.25 mmol) was
dissolved in CH2Cl2 (5 mL) under Ar before 2,6-di-tert-butyl-4-
methyl-pyridine (103 mg, 0.50 mmol) and triflic anhydride (72 mg,
0.25 mmol) was added slowly. After stirring for 4 h at room
temperature, the solvent was removed in vacuo and the residue was
purified by flash chromatography (silica, hexanes/EtOAc, 7 : 3) to
give 2d in 68% yield (65 mg, 0.17 mmol) as an orange solid, mp.
107–111 C. Major rotamer: H-NMR (400 MHz, CDCl3): d =
1.29 (s, 9H), 4.02 (d, J = 24.2 Hz, 1H), 4.50 (d, J = 24.2 Hz, 1H),
4.80 (d, J = 16.4 Hz, 1H), 5.06 (d, J = 16.4 Hz, 1H), 5.77 (bs, 1H),
6.88–7.53 (m, 10 H); 13C-NMR (100 MHz, CDCl3): d = 28.1, 38.6,
51.9, 63.2, 72.9, 126.3, 126.6, 126.8, 128.3, 128.6, 129.5, 136.7,
138.4, 167.7, 174.0, 206.4. Selected signals of the minor rotamer:
1H-NMR (400 MHz, CDCl3): d = 1.08 (s, 9H), 4.40 (m, 1H), 4.62
(m, 1H), 4.73 (bs, 1H), 4.88 (m, 1H), 5.23 (m, 1H); 13C-NMR
(100 MHz, CDCl3): d = 49.3. HRMS (CI) calcd for C22H25N2O2S2
[M + H]+: 381.1637. Found; 381.1630.
1
(dec.). H-NMR (400 MHz, CDCl3): d = 1.09 (s, 9H), 5.26 (d,
J = 9.2 Hz, 1H), 7.01 (d, J = 9.2 Hz, 1H), 7.46 (m, 2H), 7.53 (m,
1H), 7.58 (s, 1H), 7.81 (m, 2H); 13C-NMR (100 MHz, CDCl3):
d = 26.6, 36.0, 59.2, 118.6 (J = 320 Hz), 127.0, 128.7, 131.9, 133.1,
133.9, 145.6, 165.1, 166.9. HRMS (CI) calcd for C16H18N2O4F3S2
[M + H]+: 423.0660. Found; 423.0632.
◦
1
2-[1-(N-Benzoyl-N-benzylamino)-2-methylpropyl]-5-thiazolyl
triflate (9c). Carboxylic acid 3c (100 mg, 0.26 mmol) was
dissolved in CH2Cl2 (3 mL) under N2 before N-methylmorpholine
(53 mg, 0.52 mmol) and triflic anhydride (135 mg, 0.47 mmol)
were added. After stirring for 30 min at room temperature the
solvent was removed in vacuo and the crude product was purified
by flash chromatography (silica, hexanes–EtOAc, 7 : 3) to give 9c
in 50% yield (64 mg, 0.13 mmol) as a pale orange solid, mp. 80–
◦
1
84 C. Major rotamer: H-NMR (400 MHz, CDCl3): d = 0.88
(d, J = 4.0 Hz, 3H), 1.15 (d, J = 4.8 Hz, 3H), 3.02 (m, 1H), 4.52
(d, J = 15.8 Hz, 1H), 4.68 (d, J = 15.8 Hz, 1H), 4.78 (d, J =
9.6 Hz, 1H), 6.81–7.53 (m, 11H); 13C-NMR (100 MHz, CDCl3):
d = 19.8, 20.3, 29.8, 53.4, 66.9, 118.7 (q, JC,F = 320 Hz), 126.8,
127.2, 127.4, 128.3, 128.5, 129.9, 131.7, 136.2, 136.4, 147.5, 164.7,
172.8. Selected signals of the minor rotamer: 1H-NMR (400 MHz,
CDCl3): d = 0.78 (bs, 3H), 0.98 (bs, 3H), 2.73 (bs, 1H), 5.10 (bs,
1H); 13C-NMR (100 MHz, CDCl3): d = 45.2. HRMS (CI) calcd
for C22H22N2O4F3S2 [M + H]+: 499.0973. Found: 499.0909.
General procedure for the synthesis of 5-thiazolyl esters. The
carboxylic acid 3 (n mmol) was dissolved in abs. THF (10 n mL)
under N2. Subsequently NEt3 (3.0 n mmol) and the corresponding
acid chloride (2.0 n mmol) was added slowly. The reaction
mixture was allowed to stir overnight at room temperature
before it was hydrolyzed. After washing with brine, drying and
evaporation of the solvent, the crude product was purified by flash
chromatography.
2-[1-(N-Benzoyl-N-benzylamino)-2,2-dimethylpropyl]-5-thia-
zolyl ethyl carbonate (6d). According to the general procedure for
the synthesis of 5-thiazolyl esters carbonate 6d was obtained from
carboxylic acid 3d31 (500 mg, 1.25 mmol) and ethyl chloroformate
(277 mg, 2.50 mmol) in◦94% yield (530 mg, 1.17 mmol) as pale
orange solid, mp. 87–89 C. Major rotamer: 1H-NMR (400 MHz,
CDCl3): d = 1.26 (s, 9H), 1.40 (t, J = 6.4 Hz, 3H), 4.37 (m, 2H),
4.62 (d, J = 16.4 Hz, 1H), 5.37 (d, J = 16.4 Hz, 1H), 6.08 (bs,
1H), 6.37–7.56 (m, 11H); 13C-NMR (100 MHz, CDCl3): d = 14.1,
28.1, 38.8, 51.7, 61.1, 66.1, 125.9, 126.1, 126.3, 126.9, 127.9, 128.9,
129.4, 137.4, 138.8, 148.9, 151.8, 158.9, 173.6. Selected signals of
the minor rotamer: 1H-NMR (400 MHz, CDCl3): d = 1.05 (s, 9H),
5.01–5.05 (m, 2H), 5.14 (d, J = 13.6 Hz, 1H); 13C-NMR (100 MHz,
CDCl3): d = 48.5, 67.6; HRMS (CI) calcd for C25H29N2O4S [M +
H]+: 453.1848. Found; 453.1845; Anal. calcd for C25H28N2O4S
(452.58): C, 66.35; H, 6.24; N, 6.19. Found: C, 66.13; H, 6.37;
N, 6.23%.
2-[1-(N-Benzoyl-N-benzylamino)-2,2-dimethylpropyl]-5-thia-
zolyl triflate (9d). According to triflate 9c, 9d was obtained from
carboxylic acid 3d (1.00 g, 2.51 mmol) as a pale red solid (620 mg,
1.21 mmol, 48%), mp. 105–107 ◦C. Major rotamer: 1H-NMR
(400 MHz, CDCl3): d = 1.25 (s, 9H), 4.63 (d, J = 16.0 Hz, 1H),
5.24 (d, J = 16.0 Hz, 1H), 5.91 (bs, 1H), 6.43–7.62 (m, 11H); 13C-
NMR (100 MHz, CDCl3): d = 28.2, 38.8, 52.1, 67.9, 118.6 (J = 320
Hz), 125.9, 126.5, 128.1, 128.2, 129.4, 130.0, 133.3, 136.8, 138.2,
1
146.5, 162.5, 173.7. Selected signals of the minor rotamer: H-
NMR (400 MHz, CDCl3): d = 1.07 (s, 9 H, H-17), 5.01–5.09 (m,
2H); 13C-NMR (100 MHz, CDCl3): d = 48.3. HRMS (CI) calcd
for C23H24N2O4F3S2 [M + H]+: 513.1130. Found: 513.1067.
General procedure for microwave assisted Suzuki couplings of
triflates 9. A solution of triflate 9 (n mmol), the corresponding
boronic acid (1.1 n mmol), Pd(OAc)2 (5 mol%), PPh3 (0.2 n mmol)
and K2CO3 (1.5 n mmol) in DMF (12 n mL) was placed in a
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microwave oven and heated to 70 ◦C for 20 min (200 Watt). After
cooling to room temperature the solution was diluted with ethyl
acetate and the organic layer was washed twice with H2O, brine
and was dried (Na2SO4). After evaporation of the solvent, the
crude product was purified by flash chromatography.
2-[1-(N-Benzoyl-N-benzylamino)-2-methylpropyl]-5-allyl-thia-
zole (14c). Triflate 9c (100 mg, 0.20 mmol), LiCl (42.4 mg,
1.00 mmol), Pd(OAc)2 (4.7 mg, 0.01 mmol) and PPh3 (10.6 mg,
0.04 mmol) were dissolved in abs. THF (2 mL) under N2.
Allytributylstannane (102 mg, 0.30 mmol) was added dropwise
and the mixture was allowed to stir at 60 ◦C overnight. After
evaporation of the solvent, the crude product was purified by flash
chromatography (silica, hexanes–EtOAc, 7 : 3) to give 14c in 51%
yield (40.0 mg, 0.102 mmol) as pale yellow, highly viscous oil.
Major rotamer: 1H-NMR (400 MHz, CDCl3): d = 0.72 (bs, 3H),
0.90–0.97 (m, 5 H), 1.24–1.40 (m, 3H), 2.75 (bs, 1H), 4.72 (m, 1H),
4.85 (d, J = 9.6 Hz, 1H), 4.98 (d, J = 14.4 Hz, 1H), 6.60–7.71
(m, 11H); 13C-NMR (100 MHz, CDCl3): d = 13.5, 17.5, 19.7, 20.2,
26.8, 30.9, 45.3, 66.1, 119.3, 119.9, 126.4, 127.4, 127.9, 128.2, 128.6,
129.7, 136.6, 138.3, 141.9, 142.6, 167.2, 167.7, 172.8. Selected
2-[1-(N-Benzoyl-N-benzylamino)-2,2-dimethylpropyl]-5-phenyl-
thiazole (10d). According to the general procedure for microwave
assisted Suzuki couplings thiazole 10d was obtained from triflate
9d (80 mg, 0.156 mmol), phenylboronic acid (22 mg, 0.172 mmol),
Pd(OAc)2 (3.6 mg, 0.008 mmol), PPh3 (8.3 mg, 0.031 mmol) and
K2CO3 (32.3 mg, 0.234 mmol) in 76% yield (52.0 mg, 0.118 mmol)
as a pale red solid, mp. 144–148. Major rotamer: 1H-NMR
(400 MHz, CDCl3): d = 1.34 (s, 9H), 4.70 (d, J = 16.4 Hz, 1H),
5.50 (d, J = 16.4 Hz, 1H), 6.33 (s, 1H), 6.42–7.97 (m, 16H); 13C-
NMR (100 MHz, CDCl3): d = 28.1, 38.8, 51.6, 60.6, 126.0, 126.3,
126.8, 127.7, 127.9, 128.1, 128.3, 128.5, 129.0, 131.1, 132.3, 138.4,
138.9, 139.3, 164.8, 173.7. Selected signals of the minor rotamer:
1H-NMR (400 MHz, CDCl3): d = 1.13 (s, 9H), 5.11 (d, J = 13.6 Hz,
1H), 5.22–5.26 (m, 2H); 13C-NMR (100 MHz, CDCl3): d = 48.5,
67.5; HRMS (CI) calcd for C28H29N2OS [M + H]+: 441.2001.
Found: 441.2020.
1
signals of the minor rotamer: H-NMR (400 MHz, CDCl3): d =
0.97 (bs, 3H), 1.17 (bs, 3H), 1.64 (m, 1H), 2.98 (bs, 1H), 4.54 (d,
J = 15.6 Hz, 1H), 4.72 (m, 1H), 5.46 (d, J = 9.6 Hz, 1H); 13C-NMR
(100 MHz, CDCl3): d = 27.8, 30.3, 50.9, 62.8, 119.3, 119.9, 141.9,
142.6, 167.2, 167.7; HRMS (CI) calcd for C21H21N2OS [M - allyl +
H]+: 351.1523. Found; 351.1530.
2-[1-(N-Benzoylamino)-2-methylpropyl]-thiazole (15a). A so-
lution of triflate 9a (50 mg, 0.122 mmol), Pd(OAc)2 (2.8 mg,
0.006 mmol) and PPh3 (6.5 mg, 0.025 mmol) in abs. THF (0.5 mL)
was heated to 60 ◦C under N2, before a solution of NEt3 (24.7 mg,
0.244 mmol) and formic acid (11.5 mg, 0.244 mmol) in THF
(0.5 mL) was added dropwise. The solution was stirred for 6 h
at this temperature and after evaporation of the solvent, the crude
product was purified by flash chromatography (silica, hexanes–
EtOAc, 7 : 3) to give 15a in 94◦% yield (30.0 mg, 0.115 mmol) as
2-[1-(N-Benzoylamino)-2-methylpropyl]-5-(p-methoxyphenyl)-
thiazole (11a). According to the general procedure for microwave
assisted Suzuki couplings thiazole 11a was obtained from triflate
9a (50 mg, 0.122 mmol), p-methoxyphenylboronic acid (22.9 mg,
0.146 mmol), Pd(OAc)2 (2.9 mg, 0.006 mmol), PPh3 (6.5 mg,
0.025 mmol) and K2CO3 (25.4 mg, 0.184 mmol) in 85% yield
(38.0 mg, 0.104 mmol) as a pale yellow solid, mp. 135–137 ◦C.
1H-NMR (400 MHz, CDCl3): d = 1.03 (d, J = 6.8 Hz, 3H), 1.06
(d, J = 6.8 Hz, 3H), 2.45 (dqq, J = 6.8, 6.8, 6.4 Hz, 1H), 5.41 (dd,
J = 8.4, 6.4 Hz, 1H), 6.91 (m, 2H), 7.08 (d, J = 8.4 Hz, 1H), 7.43–
7.46 (m, 3H), 7.51 (m, 1H), 7.77 (s, 1H), 7.85 (m, 2H); 13C-NMR
(100 MHz, CDCl3): d = 18.2, 19.2, 33.8, 55.3, 56.5, 114.5, 123.7,
127.1, 128.0, 128.6, 131.6, 134.3, 136.7, 139.1, 159.7, 166.9, 167.9;
HRMS (CI) calcd for C21H23N2O2S [M + H]+: 367.1480. Found:
367.1450.
1
pale yellow solid, mp. 97–100 C. H-NMR (400 MHz, CDCl3):
d = 0.98 (d, J = 6.8 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 2.43 (m, 1H),
5.45 (dd, J = 7.6, 6.8 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.26 (d, J =
3.2 Hz, 1H), 7.44 (m, 2H), 7.50 (m, 1H), 7.74 (d, J = 3.2 Hz, 1H),
7.83 (d, J = 7.2 Hz); 13C-NMR (100 MHz, CDCl3): d = 18.1, 19.1,
34.0, 56.3, 118.6, 127.1, 128.6, 131.6, 134.3, 142.3, 166.9, 169.8;
HRMS (CI) calcd for C14H17N2OS [M + H]+: 261.1062. Found;
261.1024.
2-[1-(N -Benzoyl-N -benzylamino)-2-methylpropyl]-5-phenyl-
ethynyl-thiazole (12c). Triflate 9c (100 mg, 0.20 mmol), CuI
(3.8 mg, 0.02 mmol), Pd(OAc)2 (4.7 mg, 0.01 mmol) and PPh3
(10.6 mg, 0.04 mmol) were dissolved in DMF (2 mL) under argon.
2,6-lutidine (109 mg, 1.00 mmol) and phenylacetylene (27.4 mg,
0.26 mmol) were added dropwise and the mixture was allowed
to stir overnight at room temperature. After evaporation of the
solvent, the crude product was purified by flash chromatography
(silica, hexanes–EtOAc, 7 : 3) to give 12c in 95% yield (85.0 mg,
0.19 mmol) as pale yellow, highly viscous oil. Major rotamer: 1H-
NMR (400 MHz, CDCl3): d = 0.91 (bs, 3H), 1.16 (bs, 3H), 3.03
(bs, 1H), 4.70–4.75 (m, 1H), 4.99 (d, J = 14.0 Hz, 1H), 5.14 (d, J =
8.8 Hz, 1H), 6.79–7.82 (m, 16H); 13C-NMR (100 MHz, CDCl3):
d = 19.8, 20.3, 30.2, 45.3, 66.1, 79.1, 96.2, 120.1, 122.2, 126.5,
127.1, 127.4, 128.1, 128.4, 128.8, 129.5, 129.7, 130.1, 131.4, 136.6,
136.9, 145.1, 146.1, 168.6, 172.7. Selected signals of the minor
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft as
well as the Fonds der Chemischen Industrie is gratefully acknowl-
edged.
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