Novel syntheses of variably substituted pyrrolo[2,3-d]thiazoles

Article abstract of DOI:10.1055/s-0030-1258159

Pyrrolo[2,3-d]thiazoles are conveniently derived from the corresponding o-aminoalkynylthiazoles via microwave assisted 5-endo-dig cyclization. Methylene-bridged substituents in the 6-position are directly obtained from 5-exo-Heck cyclization based on the

Full text of DOI:10.1055/s-0030-1258159

3152
PAPER
Novel Syntheses of Variably Substituted Pyrrolo[2,3-d]thiazoles
S
ynthese
s
of Subst
a
ituted Pyrro
n
lo[2,3-
d
]thia
n
zole
s
es Koolman,*a,b Timo Heinrich,a Michael Reggelinb
a
Merck Serono, Frankfurter Str. 250, 64293 Darmstadt, Germany
E-mail: hannes.koolman@merck.de
Clemens-Schöpf-Institute of Organic Chemistry and Biochemistry, Technical University of Darmstadt, Petersenstr. 22, 64287 Darmstadt,
b
Germany
Fax +49(6151)165531; E-mail: re@punk.oc.chemie.tu-darmstadt.de
Received 12 March 2010; revised 10 May 2010
of the precursors. The functional groups in the latter case
need to be removed subsequently, if they are unwanted
within the target structure. Therefore, it would be desir-
able to develop a novel protocol without these drawbacks.
Abstract: Pyrrolo[2,3-d]thiazoles are conveniently derived from
the corresponding o-aminoalkynylthiazoles via microwave assisted
5-endo-dig cyclization. Methylene-bridged substituents in the 6-po-
sition are directly obtained from 5-exo-Heck cyclization based on
the same iodoaminothiazole precursor. Further structural variety is
accessible via Suzuki reaction of 2-chloroaminothiazoles prior to
cyclization or post-cyclization modifications.
We herein present a straightforward protocol for the con-
struction of variably substituted pyrrolo[2,3-d]thiazoles 1
based on palladium-mediated coupling prior to micro-
wave enhanced base-induced 5-endo-dig cyclization of
the intermediate o-aminoalkynylthiazoles. Based on our
experiences with the synthesis of pyrrole-fused hetero-
cycles7 and inspired by numerous publications in the field
of indoles8 we first aimed to build up the pyrrole moiety
in a one-step alkynylation/cyclization reaction based on
the corresponding o-iodoaminothiazoles 2 and alkynes 3,
respectively (Scheme 2).
Key words: thiazoles, pyrroles, heterocycles, microwave irradia-
tion
Pyrrolothiazoles represent an important class of hetero-
cyles,1 particularly useful for new materials,2 dyes,3 and
pharmacological applications.4 The rarely described pyr-
rolo[2,3-d]thiazoles 1 are interesting scaffolds suitable
even for novel drugs. Until now, their syntheses have al-
ways been based on two approaches differing in the con-
struction of the second cycle: formation of the pyrrole
moiety by thermally-induced cyclizations of azides5 or the
construction of the thiazole residue by bromine-induced
cyclization of pyrrolylthioureas6 (Scheme 1).
H
H
N
N
S
N
S
N
PG
R2
R1
R1
R2
+
I
1
2
3
Scheme 2 Retrosynthesis of pyrrolo[2,3-d]thiazoles via alkynyla-
H
N
tion/cyclization reaction
toluene
reflux
N3
N
S
N
S
Ac
Due to the common instability of comparable unprotected
aminoimidazoles9 we considered Boc-protected iodoami-
nothiazoles 2 to be viable precursors with sufficient
stability10 to fulfil the aforementioned task. Their synthe-
ses were based on commercially available thiazole-4-car-
boxylic acids 4 (Scheme 3).
O
O
H
N
xylene
reflux
N
S
N
S
CO2Et
HO
H
O
N
OEt
Me
N
S
N
S
N3
O
(PhO)2P(O)N3
R1
R1
O
Et3N, t-BuOH
reflux, 16 h
Me
N
S
4a R1 = H
5a R1 = H, 94%
NH
N
Br2, AcOH
4b R1 = pyridin-4-yl
4c R1 = Cl
5b R1 = pyridin-4-yl, 80%
5c R1 = Cl, 71%
N
H2N
CO2Me
H2N
S
CO2Me
NIS
DCE
Scheme 1 Currently known synthetic routes to pyrrolo[2,3-d]thia-
zoles
reflux or r.t., 2–18 h
H
O
N
Both approaches yield the bicyclic scaffolds bearing func-
tional groups, either required for further transformations
or merely present on account of the synthetic accessibility
N
R1
O
S
I
2a R1 = H, 85%
2b R1 = pyridin-4-yl, 85%
2c R1 = Cl, 61%
SYNTHESIS 2010, No. 18, pp 3152–3162
Advanced online publication: 12.07.2010
x
x.
x
x
.
2
0
1
0
DOI: 10.1055/s-0030-1258159; Art ID: T07810SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 3 Synthesis of precursors 2

PAPER
Syntheses of Substituted Pyrrolo[2,3-d]thiazoles
3153
Table 1 Tested Reaction Conditions for the Attempted Direct Synthesis of Pyrrolo[2,3-d]thiazoles
not detected:
R
Boc
NH
Boc
NH
R
NH
N
S
N
S
N
S
N
S
N
+
+
F
F
I
2a
3a
(2 equiv)
6a R = Boc
6b R = H
7
1a R = Boc
1b R = H
F
Entry Conditions
Yield (%)a or ratiob of 6a, 6b, and 7
1
2
3
4
5
6
7
Pd(OAc)2 (5 mol%), Ph3P (5 mol%), Na2CO3 (5 equiv), DMF, 100 °C, 3 h
19%:5%:n.d.
38%:0%:10%
5:1:7
Pd(OAc)2 (5 mol%), PB-PPh3c (10 mol%), Na2CO3 (3 equiv), DMF, 60 °C, 20 h
Pd(OAc)2 (5 mol%), Bu4NOAc (2.5 equiv), MeCN, reflux, 17 h
Pd(PPh3)2Cl2 (10 mol%), CuI (10 mol%), Et3N–MeCN (1:1), r.t., 18 hd
Pd(PPh3)2Cl2 (10 mol%), CuI (10 mol%), TBAF (3 equiv), THF, r.t., 18 hd
Pd(PPh3)2Cl2 (10 mol%), CuI (10 mol%), TBAF (3 equiv), THF, 70 °C mW, 90 min
Pd(dppf)Cl2×CH2Cl2 (5 mol%), CuI (10 mol%), THF, 50 °C, 6 he
1:0:1
1:20:1
1:16:3
85%:0%:trace
a Isolated yield.
b Product ratio determined by HPLC.
c Polymer-bound (PB) Ph3P was used (diphenylphosphino-polystyrene).
d Conversion of 2a was to an extent of 75%.
e Alkyne 3a used: 1.1 equiv.
Thiazol-4-carboxylic acids 4 were subjected to Curtius Disappointed by these results, we then turned to a directed
conditions with diphenylphosphoryl azide (DPPA) in tert- base-induced 5-endo-dig cyclization of the now readily
butyl alcohol directly yielding the corresponding carbam- available o-aminoalkynylthiazoles 6. Therefore, their syn-
ates 5 in high yields.11 The desired iodothiazoles 2 were thesis was finally optimized under previously employed7
thereupon obtained in good yields by treatment with N-io- Sonogashira coupling conditions using Pd(dppf)Cl2/CuI
dosuccinimide in dichloroethane (DCE).12
as catalyst system yielding 6a in 85% with only marginal
dehalogenation and without any Boc-group cleavage as
side reaction (Table 1, entry 7). O-Aminoalkynylthiazole
6a was then subjected to different cyclization conditions
(Table 2).
In a model reaction the Boc-protected iodoaminothiazole
2a was reacted under various conditions with 4-fluo-
rophenylacetylene (3a) to study a putative alkynylation/
cyclization reaction (Table 1). However, under the tested
reaction conditions, the only products beside the dehalo- First attempts for the base-induced cyclization were per-
genated starting material 7 were those derived from formed with TBAF8b in tetrahydrofuran (Table 2, entries
alkyne-coupling 6a and subsequent cleavage of the Boc 1 and 2) leading to entire deprotection of the starting ma-
group 6b. In a preliminary experiment, standard Pd-cata- terial. Even under harsh microwave conditions (entry 2)
lyzed coupling conditions were used counting on an ami- the base strength was insufficient to induce cyclization of
nopalladation/reductive elimination mechanism8g without the amine 6b, which happened under these reaction con-
addition of a distinct base. The Boc-protected product 6a ditions. Further attempts with 1,5-diazabicyc-
was therein obtained in low yields (38% at 60 °C, Table 1, lo[4.3.0]non-5-ene (DBN) in different solvent systems13
entry 2), beside minor amounts of deprotected product 6b led to rapid decomposition of the reaction mixture (entries
at higher temperatures (entry 1). When a phosphine ligand 3 and 4), whereas application of sodium hydroxide in
was omitted and tetrabutylammonium acetate was em- N,N-dimethylformamide14 resulted in no reaction at 60 °C
ployed as base8b dehalogenation drastically increased (en- (entry 5). We then unsuccessfully examined the stronger
try 3). Applying typical Sonogashira conditions (entry base t-BuOK, first in t-BuOH, but outright under micro-
4)8e dehalogenation to the thiazole 7 remained a major wave irradiation conditions to take advantage of tempera-
side reaction. The use of tetrabutylammonium fluoride ture conditions above boiling point (entry 6). Finally, in
(TBAF)8f as base, thus expecting an in situ 5-endo-dig cy- combination with a polar aprotic solvent, the use of t-
clization, led to a nearly quantitatively deprotected alkyne BuOK15 led to the formation of 35% of the desired prod-
6b (entry 5). Even under harsher conditions (entry 6) this uct 1b after prolonged conventional heating of 46 hours
side product did not cyclize in situ into the desired pyrro- (entry 7). An extension of the reaction time to 62 hours led
lothiazole 1b.
to full conversion of the starting material 6a and an in-
creased yield of 53% of 1b (entry 8). As this long reaction
Synthesis 2010, No. 18, 3152–3162 © Thieme Stuttgart · New York

3154
H. Koolman et al.
PAPER
Table 2 Base-Induced Cyclization of o-Aminoalkynylthiazole 6a to the Corresponding Pyrrolo[2,3-d]thiazole 1
R
H
N
N
S
N
S
N
Boc
F
6a
1a R = Boc
1b R = H
F
Entry
Conditions
Yield (%)a
deprotect. (6b)
deprotect. (6b)
dec.
1
2
TBAF (3 equiv), THF, reflux, 1.5 h
TBAF (3 equiv), THF, 120 °C, mW, 20 min
DBN (5 equiv), DMF, 60 °C, 1 h
3
4
DBN (5 equiv), MeOH–H2O, 65 °C, 1 h
NaOH (5 equiv), DMF, 60 °C, 2 h
dec.
5
no reaction
no reaction
6
t-BuOK (1.7 equiv), t-BuOH, 110 °C, mW, 20 min
t-BuOK (1.7 equiv), NMP, 90 °C, 46 h
t-BuOK (1.7 equiv), NMP, 90 °C, 62 h
t-BuOK (1.7 equiv), NMP, 90 °C, mW, 15 minc
t-BuOK (1.7 equiv), NMP, 90 °C, mW, 20 minc
7
1a: 0%; 1b: 35%b
1a: 0%; 1b: 53%
1a: 0%; 1b: 55%b
1a: 0%; 1b: 66%
8
9
10
a Isolated yield.
b Starting material was partially recovered.
c Advanced microwave settings were used: 90 °C in combination with constant cooling led to an irradiation of 75 W (see experimental sections
for details and the Supporting Information for a full reaction parameter diagram).
time possibly accounted for decomposition processes of synthesis of the benzylated analogue of 1e and 1h, an ex-
either starting material or product, the reaction was con- cess of base and a prolonged reaction time were necessary
ducted with the same reagents in the presence of micro- to achieve full conversion (entry 7). The aminopyridinyl-
waves. To take full advantage of a high irradiation without substituted derivative 1i was derived from the correspond-
risking unwanted side reactions due to overheating, a con- ing Boc-protected alkyne 6i. Treatment of the reaction
stant temperature of 90 °C with concurrent nitrogen flow mixture for 60 minutes under microwave conditions led to
to cool the reaction vessel was tested. This resulted in an a quantitative cleavage of the Boc group within the target
irradiation power of approximately 75 W.16 After 20 min- molecule (entry 8).18 Attempts to synthesize the further-
utes, full conversion was achieved and the deprotected more unsubstituted 2-chloropyrrolothiazole 1j led to de-
pyrrolo[2,3-d]thiazole 1b was isolated in 66% yield as a composition of the starting material,19 whereas the 5-(4-
single product (entry 10).
fluorophenyl) derivative 1k proved to be stable and could
be isolated in 45% yield (entries 9 and 10). The method
further tolerates additional heterocyclic substituents in the
2-position (1l and 1m, entries 11 and 12). Their precursor
synthesis is based on Suzuki couplings using commercial-
ly available boronic acids (see Scheme 5, vide infra).
The methodology was then applied to the synthesis of
novel pyrrolo[2,3-d]thiazoles 1c–m (Table 3, entries 2–
12). Alkynylation of 2a with benzylalkyne 3b smoothly
led to the benzylated pyrrolo[2,3-d]thiazole 1c. Triethyl-
silylacetylene was chosen for the alkynylation of 2a to test
the lability of trialkylsilyl groups under the basic cycliza- Mechanistically, the pyrrole formation most likely in-
tion conditions. As anticipated, full cleavage of the trieth- volves the deprotonation of the carbamate nitrogen15 in 6a
ylsilyl group occurred and 1d was obtained in 44% and cyclization to the corresponding N-Boc-pyrrole deriv-
(Table 3, entry 3). This is the first reported facile synthesis ative 1a, which can be observed via mass spectrometry of
of an entirely unsubstituted pyrrolo[2,3-d]thiazole.17 3- the crude reaction mixtures, but was not isolated due to
Anilinyl- and 4-pyridinylpyrrolothiazoles 1e and 1f, re- concomitant deprotection to the desired pyrrolothiazole
spectively, were obtained from commercially available 1b (Scheme 4). To verify, whether the carbamate group
alkynes, under the stated conditions. The 3-hydroxyphe- was essential for an effective cyclization, 6a was
nylacetylene (6g) could not be cyclized under these con- deprotected20 to 6b and subjected to the same conditions.
ditions: a deprotonation of the more acidic hydroxy group As pyrrolothiazole 1b was isolated in comparable yields
led to a charged species, which appeared to be insuscepti- from this reaction it could be shown that cyclization is in
ble for an intramolecular nucleophilic cyclization. For the fact independent of any influence of a carbamate group.
Synthesis 2010, No. 18, 3152–3162 © Thieme Stuttgart · New York

PAPER
Syntheses of Substituted Pyrrolo[2,3-d]thiazoles
3155
Table 3 Synthesis of Novel Pyrrolo[2,3-d]thiazoles 1c–m by Sonogashira Alkynylation of Thiazoles 2 Followed by 5-endo-dig Cyclization
Boc
NH
Boc
NH
H
N
N
S
N
N
S
Pd(dppf)Cl2 (5 mol%), CuI (10 mol%)
t-BuOK (1.7 equiv)
R2
R1
R1
R1
R2
+
Cs2CO3 (3 equiv),
THF, 50 °C, 6 h
NMP, 90 °C, MW
20 min
S
I
R2
2a–c
3a–i
(1.1 equiv)
6a,c–j
1b–m
Entry Thiazole 2 Alkyne 3
Amino alkyne 6 Yield (%)a Pyrrolo[2,3-d]thiazole 1
Yield (%)b
66
H
N
S
N
F
1
2
2a
2a
6a
6c
85
92
1b
1c
F
3a
H
69
44c
69
N
N
S
N
S
3b
3d
H
N
SiEt3
3
4
2a
2a
6d
6e
92
1d
1e
H
N
N
S
66d
NH2
NH2
N
3e
3f
H
N
N
N
S
5
6
2a
2a
6f
97
80
1f
40
0
HCl
6g
–
1g
OH
NH
3g
H
N
N
S
7
8
2a
2a
6h
6i
92e
1h
1i
52f
NH
3h
H
N
N
S
N
30
53
20g
N
HN Boc
NH2
3i
SiEt3
9
2c
2a
6j
–
1j
0
3d
H
N
S
N
10
See Scheme 5
6k
1k
45h
Cl
F
H
N
N
N
S
11
2a
See Scheme 5
6l
1l
37i
H2N
F
N
Synthesis 2010, No. 18, 3152–3162 © Thieme Stuttgart · New York

3156
H. Koolman et al.
PAPER
Table 3 Synthesis of Novel Pyrrolo[2,3-d]thiazoles 1c–m by Sonogashira Alkynylation of Thiazoles 2 Followed by 5-endo-dig Cyclization
Boc
NH
Boc
NH
H
N
N
S
N
N
S
Pd(dppf)Cl2 (5 mol%), CuI (10 mol%)
t-BuOK (1.7 equiv)
R2
R1
R1
R1
R2
+
Cs2CO3 (3 equiv),
THF, 50 °C, 6 h
NMP, 90 °C, MW
20 min
S
I
R2
2a–c
3a–i
(1.1 equiv)
6a,c–j
1b–m
Entry Thiazole 2 Alkyne 3
Amino alkyne 6 Yield (%)a Pyrrolo[2,3-d]thiazole 1
Yield (%)b
H
N
S
N
1m 47j
F
12
2a
See Scheme 5
6m
N
NH2
a Reactions were performed with 1.5 mmol of thiazole 2 in 15 mL of THF; isolated yield.
b Reactions were performed with 0.75 mmol of aminoalkyne 6 in 4.5 mL of NMP; isolated yield.
c Reaction carried out at 90 °C for 10 min.
d Reaction carried out at r.t. for 18 h.
e Reaction carried out at 50 °C for 24 h.
f Reaction carried out with t-BuOK (3 equiv) at 90 °C for 60 min.
g Reaction run on a 0.25 mmol scale; 90 °C, 30 min.
h Reaction run on a 2 mmol scale; 90 °C, 15 min.
i Reaction run on a 0.25 mmol scale; 90 °C, 15 min.
j Reaction run on a 0.5 mmol scale; 90 °C, 15 min.
zole 1k via nucleophilic substitution to give 1n,o
(Scheme 5).
Boc
NH
Boc
N
S
N
S
N
t-BuOK (1.7 equiv)
To further access substitutions in the 6-position of the pyr-
rolo[2,3-d]thiazole core a methodology, which was re-
cently published for the synthesis of thieno[2,3-
b]pyrroles,23 was adapted to yield benzyl-substituted de-
rivatives 8a,b (Table 4). For this purpose the iodothia-
zoles 2a and 2b were allylated with cinnamyl bromide
employing Cs2CO3 as base. The reaction mixture was sub-
sequently treated with Pd(OAc)2/PPh3 to induce 5-exo-
Heck cyclization24 followed by rearrangement23 to the
corresponding Boc-protected pyrrolothiazoles. After
aqueous workup, the crude mixture was evaporated to-
gether with silica gel and heated in vacuo for the indicated
time to cleave the Boc group, conveniently yielding 8a,b
after subsequent flash chromatography in this overall one-
pot procedure in 49 and 53% yield, respectively.
F
NMP, 90 °C MW
20 min
1a
6a
F
SiO2, 80°C, 30 h
51%
66%
NH2
N
H
N
N
S
t-BuOK (1.7 equiv)
S
F
NMP, 90 °C MW
20 min
6b
1b
50%
F
Scheme 4 Influence of the carbamate group on the cyclization
In summary, we have developed a novel synthesis of pyr-
rolo[2,3-d]thiazoles. Employing a base-induced 5-endo-
dig cyclization or intramolecular Heck reaction as key
steps, variable substituents in all positions can be intro-
duced. Particularly, the introduction of residues in the 2-
position are easily accessible after expedient halogena-
tion, thus enabling a synthesis of highly functionalized
novel heterocycles without the need for potentially
dispensable groups due to the synthesis routine. Further
studies towards Larock-type reactions of o-iodoaminothi-
azoles with alkynes are currently in progress in our group.
Due to the activated 2-position within the 2-chloro-5-io-
dothiazole moiety, the alkynylation of 2c as putative cy-
clization precursor for 1k resulted in mono- 6k and
disubstituted 6p derivatives under various conditions. We
therefore introduced the 2-chloro substituent after the
alkynylation reaction (Scheme 5). This was achieved in
78% yield by reaction with N-chlorosuccinimide (NCS)
after lithiation at –78 °C.21
A further derivatization prior or after the cyclization reac-
tion then allowed a variable introduction of substituents.
For example aryl moieties were introduced in 6k22 by
Suzuki coupling and the resulting alkynes 6l,n cyclized to
the corresponding pyrrolo[2,3-d]thiazoles 1l and 1m in 37
and 47%, respectively. Furthermore, secondary amines
were introduced into the 2-position of pyrrolo[2,3-d]thia-
All reagents obtained commercially were used without further puri-
fication. DMF and THF were obtained from Aldrich in septum-
sealed bottles over molecular sieves under N2 and handled using sy-
ringe/Schlenk techniques. Petroleum ether (PE) used refers to the
fraction boiling in the range 50–70 °C. NMP was obtained from
Synthesis 2010, No. 18, 3152–3162 © Thieme Stuttgart · New York

PAPER
Syntheses of Substituted Pyrrolo[2,3-d]thiazoles
3157
Boc
NH
Table 4 Synthesis of 6-Substituted Pyrrolo[2,3-d]thiazoles 8
Boc
NH
1. Cs2CO3 (4 equiv),
N
S
N
R1
DMF (1.5 equiv), r.t., 2 h
Cl
Boc
S
2c
I
H
N
NH
N
S
Br
N
S
R2
6k R1 = Cl, R2 = 4-F-C6H4
6p R1 = 4-F-C6H4 C, R2 = 4-F-C6H4
R1
R1
2. Pd(OAc)2 (5 mol%)
Ph3P (10 mol%)
I
DMF, 100 °C, 19 h
3. aq extraction then SiO2, heat
2a,b
8a,b
Boc
NH
N
S
Entry Thiazole 2 Boc cleavage Pyrrolo[2,3-d]
thiazole 8
Yield
R1
(%)a
H
N
S
N
Table 3
entry 10
Cl
F
1
2
2a
5 h, 100 °C 8a R1 = H
19 h, 50 °C
8b R1 = 4-pyridinyl
49
2b
53
F
6a R1 = H
6k R1 = Cl
1k
a Isolated yield.
1) n-BuLi (2.1 equiv)
THF, –78 °C
2) NCS, 78%
with a VG Autospec sector field mass spectrometer. EI-HRMS
spectra were acquired with a GCT Premier 95 whereas ESI-HRMS
spectra were obtained from a Thermo LTQ XL Orbitrap with ESI
interface. ESI-MS spectra were recorded using an Agilent 6110
Quadrupole LC/MS with ESI interface G1946 (positive or negative
ionization). The APCI-MS data was acquired with a Finnigan LCQ
Deca. Melting points were taken on samples in open capillary tubes
employing a HWS SGV500 melting point apparatus and are uncor-
rected.
Pd(dppf)Cl2 (5 mol%), ArB(OR)2 (1.5 equiv) HNR2, MW
K2CO3 (3 equiv), DMF–DME–H2O
85 °C, 24–44 h
for 1n–o
Boc
H
NH
N
S
N
S
N
Table 3
R1
entries 11
and 12
R1
F
tert-Butyl N-(1,3-Thiazol-4-yl)carbamates 5; General Proce-
dure
To a solution of the corresponding 4-thiazolecarboxylic acid 4
(37.55 mmol) in t-BuOH (180 mL) was added Et3N (5.80 mL, 41.84
mmol) followed by diphenylphosphoroyl azide (9.10 mL, 42.19
mmol) at 0 °C (ice-bath). The mixture was then stirred for 16 h at
reflux. After cooling to r.t., the solvent was evaporated in vacuo, the
crude residue redissolved in CH2Cl2 (100 mL), and washed with
brine (2 × 100 mL). The organic layer was dried (Na2SO4) and the
solvent removed in vacuo. The product was purified by column
chromatography on silica gel (cyclohexane–EtOAc).
N
F
1l R1
=
NH2
N
N
37%
6l R1
=
NH2
N
1m R1
=
24%
N
H2N
6m R1
=
47%
N
tert-Butyl N-(1,3-Thiazol-4-yl)carbamate (5a)
Yield: 94%; beige crystals; mp 153–155 °C.
1H NMR (300 MHz, DMSO-d6): d = 1.47 (s, 9 H), 7.23 (d, J = 2.0
Hz, 1 H), 8.89 (d, J = 2.2 Hz, 1 H), 10.15 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 28.0, 79.3, 98.3, 149.4, 151.7,
152.7.
H2N
1n R1
1o R1
=
N
N
O
50%
N
91%
N
=
41%
MS (ESI): m/z (%) = 145 (100, [M – t-Bu + 2 H]+), 201 (5, [M +
H]+).
Scheme 5 Derivatization in 2-position of thiazoles and pyrrolo[2,3-
d]thiazoles
Anal. Calcd for C8H12N2O2S: C, 47.98; H, 6.04; N, 13.99; S, 16.01.
Found: C, 47.90; H, 6.10; N, 14.00; S, 16.60.
Merck and used without further purification or distillation. TLC
analyses were run on precoated silica gel plates (Merck 60F254) and
the spots were visualized using a UV lamp. Flash and gravity chro-
matography were carried out on columns using silica gel 60 Merck
(63–200 mm) as the stationary phase. Microwave-assisted syntheses
were carried out in septum-capped glass vials, which were flushed
with N2 prior to closing. Irradiation was carried out in a monomode
Biotage EmrysOptimizer microwave with temperature and pressure
monitoring. The N2 cooling stream featured a pressure of 3 bar.
NMR spectra were recorded in DMSO-d6 at 300 K on a Bruker
Avance 300 (300 MHz and 75 MHz spectra), Bruker Avance II 400
(400 MHz and 100 MHz spectra) and Bruker Avance DRX 500
(500 MHz spectra), respectively. Chemical shifts are given in ppm
relative to TMS as internal standard. EI-MS spectra were obtained
tert-Butyl N-(2-Pyridin-1,3-thiazol-4-yl)carbamate (5b)
Yield: 80%; white-grey crystals; mp 192–193 °C (PE).
1H NMR (300 MHz, DMSO-d6): d = 1.49 (s, 9 H), 7.45 (s, 1 H),
7.81 (dd, J = 4.5, 1.6 Hz, 2 H), 8.70 (dd, J = 4.5, 1.6 Hz, 2 H), 10.38
(s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 28.0, 79.7, 101.6, 119.5, 139.3,
150.0, 150.7, 152.8, 161.2.
MS (EI, 70eV): m/z (%) = 57 (100, [CCH3]+), 177 (80, [M – Boc]+),
277 (10, [M]+).
MS (ESI): m/z (%) = 278 (100, [M + H]+).
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Anal. Calcd for C13H15N3O2S: C, 56.30; H, 5.45; N, 5.15; S, 11.56.
Found: C, 56.30; H, 5.50; N, 5.10; S, 12.10.
6 h. After cooling to r.t. and filtering over Celite, the solvent was
removed in vacuo. The crude residue was redissolved in EtOAc (50
mL) and washed with brine (2 × 50 mL). The organic layer was
dried (Na2SO4) and the solvent removed in vacuo. The product was
purified by column chromatography or flash chromatography on
silica gel (cyclohexane–EtOAc).
tert-Butyl N-(2-Chloro-1,3-thiazol-4-yl)carbamate (5c)
Yield: 71%; white crystals; mp 118–119 °C (Et2O).
1H NMR (300 MHz, DMSO-d6): d = 1.46 (s, 9 H), 7.17 (s, 1 H),
10.26 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 28.0, 79.7, 101.3, 146.5, 148.5,
152.5.
MS (ESI): m/z (%) = 179 (100, [M – t-Bu + 2 H]+).
HRMS (ESI): m/z [M + H]+ calcd for C8H11CIN2O2S: 235.0308;
tert-Butyl N-{5-[2-(4-Fluorophenyl)ethynyl]-1,3-thiazol-4-
yl}carbamate (6a)
Yield: 85%; pale-yellow solid; mp 139–144 °C (Et2O).
1H NMR (400 MHz, DMSO-d6): d = 1.45 (s, 9 H), 7.22–7.39 (m, 2
H), 7.50–7.68 (m, 2 H), 8.98 (s, 1 H), 9.62 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 27.4, 78.9, 96.3, 105.6, 115.3
found: 234.9027.
2
3
(d, JC,F = 22 Hz), 117.9, 117.9, 132.9 (d, JC,F = 8 Hz), 150.6,
151.8, 152.1, 161.6 (d, 1JC,F = 246 Hz).
MS (ESI): m/z (%) = 319 (100, [M + H]+).
tert-Butyl N-(5-Iodo-1,3-thiazol-4-yl)carbamates 2; General
Procedure
To a solution of the corresponding carbamate 5 (3.99 mmol) in DCE
(40 mL) was added N-iodosuccinimide (1033 mg, 4.59 mmol) and
the reaction mixture was heated to reflux for 2 h. After cooling to
r.t., the organic layer was washed with H2O (2 × 50 mL) and sat. aq
Na2S2O3 (50 mL), dried (Na2SO4), and the solvent removed in vac-
uo. The product was purified by flash chromatography on silica gel
(cyclohexane–EtOAc, 8:2 to 1:1).
Anal. Calcd for C16H15FN2S: C, 60.36; H, 4.75; N, 8.80; S, 10.07.
Found: C, 60.20; H, 4.70; N, 8.78; S, 10.19.
tert-Butyl N-[5-(3-Phenylprop-1-ynyl)-1,3-thiazol-4-yl]carbam-
ate (6c)
Yield: 92%; pale-yellow solid; mp 121–122 °C.
1H NMR (300 MHz, DMSO-d6): d = 1.41 (s, 9 H), 3.93 (s, 2 H),
tert-Butyl N-(5-Iodo-1,3-thiazol-4-yl)carbamate (2a)
Yield: 85%; white crystals; mp 119–120 °C (Et2O).
1H NMR (300 MHz, DMSO-d6): d = 1.44 (s, 9 H), 8.99 (s, 1 H),
9.12 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 28.0, 79.0, 152.2 (2 ×), 152.9,
157.2.
7.15–7.45 (m, 5 H), 8.88 (s, 1 H), 9.33 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 25.1, 27.9, 71.6, 79.1, 97.5,
126.6, 127.8, 128.4, 136.0, 150.5, 2 × 151.3, 152.6.
MS (ESI): m/z (%) = 259 (100, [M – t-Bu + 2 H]+), 314 (68, [M]+),
315 (10, [M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C17H18N2O2S: 315.1167;
found: 315.1161.
MS (EI, 70 eV): m/z (%) = 57 (95, [CCH3]+), 226 (100, [M – Boc]+),
326 (17, [M]+).
HRMS (ESI): m/z [M + H]+ calcd for C8H11IN2O2S: 326.9664;
found: 326.9658.
tert-Butyl N-{5-[(Triethylsilyl)ethynyl]-1,3-thiazol-4-yl}car-
bamate (6d)
Yield: 92%; pale-beige solid; mp 88–90 °C (Et2O).
tert-Butyl N-(2-Pyridin-5-iodo-1,3-thiazol-4-yl)carbamate (2b)
Yield: 85%; pink solid; mp 197–198 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.46 (s, 9 H), 7.80 (dd,
J = 4.5, 1.6 Hz, 2 H), 8.72 (dd, J = 5.9, 1.5 Hz, 2 H), 9.27 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 27.5, 73.1, 78.9, 118.9, 138.2,
150.3, 152.3, 152.3, 165.4.
1H NMR (300 MHz, DMSO-d6): d = 0.62 (dt, J = 8.3, 4.2 Hz, 6 H),
0.98 (t, J = 7.8 Hz, 9 H), 1.43 (s, 9 H), 8.91 (s, 1 H), 9.39 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 3.7, 7.3, 27.9, 79.1, 94.9,
101.4, 107.6, 151.4, 152.3, 152.4.
MS (APCI): m/z (%) = 239 (40, [M – Boc + H]+), 282 (100, [M – t-
Bu + 2 H]+), 338 (17, [M]+).
MS (EI, 70 eV): m/z (%) = 57 (100, [CCH3]+), 303 (80, [M – Boc]+),
HRMS (ESI): m/z [M + H]+ calcd for C16H26N2O2SSi: 339.1562;
found: 339.1032.
403 (10, [M]+).
Anal. Calcd for C13H14N3O2S: C, 38.72; H, 3.50; N, 10.42; S, 7.95.
Found: C, 39.10; H, 3.50; N, 10.40; S, 7.80.
tert-Butyl N-{5-[(3-Aminophenyl]ethynyl]-1,3-thiazol-4-yl}car-
bamate (6e)
tert-Butyl N-(2-Chloro-5-iodo-1,3-thiazol-4-yl)carbamate (2c)
Yield: 66%; dark-white solid; mp 166–177 °C (MeOH).
Yield: 61%; pale-yellow crystals; mp 77–78 °C (Et2O).
1H NMR (300 MHz, DMSO-d6): d = 1.44 (s, 9 H), 9.15 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 28.0, 71.7, 79.5, 149.7, 151.8,
152.7.
MS (ESI): m/z (%) = 304 (100, [M – t-Bu + 2 H]+).
HRMS (ESI): m/z [M + H]+ calcd for C8H10ClIN2O2S: 360.9274;
1H NMR (400 MHz, DMSO-d6): d = 1.45 (s, 9 H), 5.27 (s, 2 H),
6.57–6.71 (m, 3 H), 7.05 (t, J = 7.8 Hz, 1 H), 8.95 (s, 1 H), 9.50 (s,
1 H).
13C NMR (100 MHz, DMSO-d6): d = 27.4, 77.1, 78.8, 98.4, 106.7,
114.3, 115.3, 118.0, 121.6, 128.7, 148.3, 150.1, 151.6, 151.9.
MS (EI, 70 eV): m/z (%) = 215 (100, [M – Boc]+), 315 (20, [M]+).
MS (ESI): m/z (%) = 316 (100, [M + H]+).
found: 360.9269.
Anal. Calcd for C16H17N3O2S: C, 60.93; H, 5.43; N, 13.32; S, 10.17.
Found: C, 60.90; H, 5.30; N, 13.10; S, 10.10.
tert-Butyl N-[5-(2-Alkynyl)-1,3-thiazol-4-yl]carbamates 6; Gen-
eral Procedure
Cs2CO3 (2.93 g, 9 mmol) was dried in a Schlenk tube and suspended
in anhyd THF (50 mL) under N2. The corresponding carbamate 2 (3
mmol) followed by the corresponding alkyne 3 (3.30 mmol), Pd(dp-
pf)Cl2·CH2Cl2 (122 mg, 0.15 mmol), and CuI (57 mg, 0.30 mmol)
were added under N2. The reaction mixture was heated to 50 °C for
tert-Butyl N-{5-[(Pyridin-4-yl]ethynyl]-1,3-thiazol-4-yl}car-
bamate (6f)
Yield: 97%; yellow solid; mp 160–165 °C (Et2O).
Synthesis 2010, No. 18, 3152–3162 © Thieme Stuttgart · New York

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Syntheses of Substituted Pyrrolo[2,3-d]thiazoles
3159
1H NMR (400 MHz, DMSO-d6): d = 1.46 (s, 9 H), 7.45 (dd,
J = 4.4, 1.6 Hz, 2 H), 8.63 (dd, J = 4.4, 1.6 Hz, 2 H), 9.05 (s, 1 H),
9.83 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 27.4, 79.0, 83.3, 94.8, 103.8,
124.2, 129.4, 149.4, 151.6, 151.7, 153.5.
tert-Butyl N-{2-Chloro-5-[2-(4-fluorophenyl)ethynyl]-1,3-thiaz-
ol-4-yl}carbamate (6k)
A dried Schlenk tube was charged with 6a (2.63 g, 8.26 mmol) un-
der N2. After addition of anhyd THF (100 mL), the reaction mixture
was cooled to –78 °C and n-BuLi (15% in n-hexane, 11 mL, 17.34
mmol, 2.1 equiv) was added slowly. After stirring for 20 min at
–78 °C, N-chlorosuccinimide (1.12 g mg, 8.38 mmol) dissolved in
anhyd THF (3 mL) under N2 was added via a syringe. After stirring
for 15 min at –78 °C, the mixture was quenched with n-BuOH (10
mL) and warmed to r.t. The solvent was then removed in vacuo and
the crude product directly purified via column chromatography on
silica gel (cyclohexane–EtOAc, 99:1). After removing the solvent
in vacuo, the product was crystallized from PE to yield 6k (2.3 g,
78%) as a pale beige solid; mp 133–134 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.44 (s, 9 H), 7.25–7.42 (m, 2
H), 7.52–7.62 (m, 2 H), 9.80 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 27.4, 77.2, 79.3, 97.2, 107.4,
115.6 (d, 2JC,F = 22 Hz), 117.4, 133.1 (d, 3JC,F = 9 Hz), 147.2, 148.1,
151.5, 161.8 (d, 1JC,F = 246 Hz).
MS (EI, 70 eV): m/z (%) = 57 (90, [CCH3]+), 201 (80, [M – Boc]+),
301 (10, [M]+).
HRMS (ESI): m/z [M + H]+ calcd for C15H15N3O2S: 302.0963;
found: 302.0959.
tert-Butyl N-{5-[(3-Hydroxyphenyl)ethynyl]-1,3-thiazol-4-
yl}carbamate (6g)
Yield: 80%; beige solid; mp 170–171 °C (Et2O).
1H NMR (300 MHz, DMSO-d6): d = 1.44 (s, 9 H), 6.77–6.97 (m, 3
H), 7.21 (t, J = 7.9 Hz, 1 H), 8.96 (s, 1 H), 9.53 (s, 1 H), 9.71 (br s,
1 H).
13C NMR (75 MHz, DMSO-d6): d = 27.9, 78.5, 79.3, 98.0, 106.7,
116.5, 117.4, 121.9, 122.8, 129.8, 151.0, 152.4 (2 ×), 157.3.
MS (ESI): m/z (%) = 296 (100, [M – t-Bu + 2 H]+).
HRMS (ESI): m/z [M + H]+ calcd for C16H14ClFN2O2S: 353.0526;
MS (EI, 70 eV): m/z (%) = 57 (55, [CCH3]+), 216 (100, [M – Boc]+),
316 (17, [M]+).
found: 353.0522.
Anal. Calcd for C16H16N2O3S: C, 60.74; H, 5.10; N, 8.85; S, 10.14.
Found: C, 60.03; H, 5.10; N, 8.66; S, 10.07.
tert-Butyl N-{2-Heteroaryl-5-[2-(4-fluorophenyl)ethynyl]-1,3-
thiazol-4-yl}carbamates 6l and 6m; General Procedure
To a solution of 6k (705 mg, 2.00 mmol) and the corresponding bo-
ronic acid (3 mmol) or the corresponding boronic acid ester, respec-
tively, in DMF (4 mL), H2O (2 mL) and ethylene glycol dimethyl
ether (DME, 8 mL) were added K2CO3 (829 mg, 6 mmol) and
Pd(dppf)Cl2·CH2Cl2 (81 mg, 0.10 mmol). After passing argon
through the reaction mixture for 10 min, the reaction vessel was
sealed and heated to 85 °C (44 h for 6l; 24 h for 6m). After cooling
to r.t., the mixture was extracted with brine (2 × 25 mL) and the
combined aqueous layers were extracted with EtOAc (25 mL). The
organic layer was dried (Na2SO4) and the solvent removed in vacuo.
The product was purified by flash chromatography on silica gel (cy-
clohexane–EtOAc, 1:2; 1% Et3N).
tert-Butyl N-(5-{3-[(Benzylamino)phenyl]ethynyl}-1,3-thiazol-
4-yl)carbamate (6h)
Yield: 92%; yellow solid; mp 126–129 °C (Et2O).
1H NMR (400 MHz, DMSO-d6): d = 1.43 (s, 9 H), 4.28 (d, J = 6.0
Hz, 2 H), 6.47 (t, J = 6.1 Hz, 1 H), 6.61–6.70 (m, 3 H), 7.04–7.13
(m, 1 H), 7.18–7.31 (m, 1 H), 7.31–7.45 (m, 4 H), 8.94 (s, 1 H), 9.49
(s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 27.4, 45.6, 77.3, 78.8, 98.4,
106.6, 113.1, 113.2, 118.2, 121.7, 126.1, 126.5, 127.8, 128.7, 139.2,
148.2, 150.2, 151.7, 151.9.
MS (ESI): m/z (%) = 250 (100, [M – t-Bu + 2 H]+), 406 (20, [M +
H]+).
Anal. Calcd for C23H23N3O2S: C, 68.12; H, 5.72; N, 10.36; S, 7.91.
Found: C, 67.63; H, 5.80; N, 10.14; S, 8.00.
tert-Butyl N-{2-(2-Aminopyrimidin-5-yl)-5-[2-(4-fluorophe-
nyl)ethynyl]-1,3-thiazol-4-yl}carbamate (6l)
Yield: 24%; yellow solid; mp 201–203 °C.
1H NMR (300 MHz, DMSO-d6): d = 1.46 (s, 9 H), 7.23–7.49 (m, 4
H), 7.51–7.70 (m, 2 H), 8.72 (s, 2 H), 9.63 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 27.4, 78.7, 79.0, 96.8, 103.4,
115.6 (d, 2JC,F = 22 Hz), 118.0, 132.8 (d, 3JC,F = 9 Hz), 150.4, 151.7,
155.2, 155.5, 159.5, 161.6 (d, 1JC,F = 247 Hz), 163.4.
tert-Butyl N-(5-{3-[2-(Boc)-aminopyridin-4-ylphenyl]ethynyl}-
1,3-thiazol-4-yl)carbamate (6i)
Yield: 30%; beige solid; mp 250 °C (dec.).
1H NMR (400 MHz, DMSO-d6): d = 1.44 (s, 9 H), 1.48 (s, 9 H),
7.79–7.87 (m, 2 H), 8.37 (d, J = 1.1 Hz, 1 H), 8.97 (s, 1 H), 9.62 (s,
1 H), 10.09 (s, 1 H).
MS (ESI): m/z (%) = 417 (100, [M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C20H24N4O4S: 417.1596;
MS (ESI): m/z (%) = 356 (60, [M – t-Bu + 2 H]+), 412 (100, [M +
H]+).
HRMS (ESI): m/z [M + H]+ calcd for C20H18FN5O2S: 412.1243;
found: 412.1242.
found: 417.1589.
tert-Butyl N-{2-Chloro-5-[3-(triethylsilyl)ethynyl]-1,3-thiazol-
4-yl}carbamate (6j)
Yield: 53%; pale-yellow oil.
1H NMR (300 MHz, DMSO-d6): d = 0.58–0.67 (m, 6 H), 0.98 (t,
J = 7.8 Hz, 9 H), 1.43 (s, 9 H), 9.59 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 3.6, 7.2, 27.8, 79.6, 93.4,
102.9, 109.5, 147.3, 149.0, 152.0.
MS (ESI): m/z (%) = 317 (100, [M – t-Bu + 2 H]+).
HRMS (ESI): m/z [M + H]+ calcd for C16H25ClN2O2SSi: 373.1172;
tert-Butyl N-{2-(2-Aminopyridin-3-yl)-5-[2-(4-fluorophe-
nyl)ethynyl]-1,3-thiazol-4-yl}carbamate (6m)
Yield: 50%; bright-yellow solid; mp 170–172 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.48 (s, 9 H), 6.67 (dd, J = 7.7,
4.7 Hz, 1 H), 7.35–7.25 (m, 2 H), 7.58–7.67 (m, 4 H), 7.90 (dd,
J = 7.7, 1.7 Hz, 1 H), 8.13 (dd, J = 4.7, 1.7 Hz, 1 H), 9.89 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 27.4, 78.4, 79.3, 97.2, 100.8,
108.2, 111.7, 115.5 (d, 2JC,F = 23 Hz), 118.0, 132.9 (d, 3JC,F = 8 Hz),
135.6, 149.3, 150.6, 151.4, 155.1, 161.6 (d, 1JC,F = 247 Hz), 163.0.
MS (ESI): m/z (%) = 411 (100, [M + H]+).
found: 373.1165.
HRMS (ESI): m/z [M + H]+ calcd for C21H19FN4O2S: 411.1291;
found: 411.1282.
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4H-Pyrrolo[2,3-d]thiazoles 1; General Procedure
13C NMR (75 MHz, DMSO-d6): d = 99.6, 115.0, 117.9, 113.0,
The corresponding alkyne 6 (0.75 mmol) was dissolved in NMP
(4.5 mL) in a microwave flask and treated with t-BuOK (143 mg,
1.27 mmol) under a blanket of N2. The vessel was sealed under N2
and irradiated with microwaves for 20 min at 90 °C (employing a
constant stream of N2). After cooling to r.t., the slurry mixture was
diluted with Et2O (50 mL) and washed with brine (2 × 50 mL). The
aqueous layer was extracted with Et2O (50 mL) and the combined
organic layers were dried (Na2SO4), and the solvent removed in
vacuo. The crude product, which may partially contain remaining
traces of NMP, was purified by column chromatography on silica
gel (cyclohexane–EtOAc, 1:1).
139.3, 150.0, 153.3, 154.0.
Benzyl[3-(4H-pyrrolo[2,3-d]thiazol-5-yl)phenyl]amine (1h)
Yield: 52%; yellow solid; mp 169–170 °C.
1H NMR (400 MHz, DMSO-d6): d = 4.34 (d, J = 6.1 Hz, 2 H), 6.27
(t, J = 6.1 Hz, 1 H), 6.51 (dd, J = 8.0, 1.5 Hz, 1 H), 6.71 (d, J = 1.9
Hz, 1 H), 6.88–7.01 (m, 2 H), 7.07 (t, J = 7.8 Hz, 1 H), 7.22 (t,
J = 7.3 Hz, 1 H), 7.33 (t, J = 7.6 Hz, 2 H), 7.41 (d, J = 7.6 Hz, 2 H),
8.74 (s, 1 H), 12.20 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 45.8, 95.4, 107.0, 111.1,
111.7, 113.8, 126.0, 126.7, 127.7, 128.7, 132.6, 136.6, 139.8, 148.4,
149.7, 152.1.
5-(4-Fluorophenyl)-4H-pyrrolo[2,3-d]thiazole (1b)
Yield: 66%; grey-white solid; mp 244–245 °C.
MS (ESI): m/z (%) = 306 (100, [M + H]+).
1H NMR (300 MHz, DMSO-d6): d = 6.87 (d, J = 2.0 Hz, 1 H), 7.20–
7.29 (m, 2 H), 7.75–7.83 (m, 2 H), 8.77 (s, 1 H), 12.33 (br s, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C18H15N3S: 305.0986; found:
306.1051.
13C NMR (100 MHz, DMSO-d6): d = 96.6, 114.6, 115.8 (d,
3
2JC,F = 19 Hz), 126.0 (d, JC,F = 7 Hz), 129.2, 135.2, 150.8, 153.0,
4-(4H-Pyrrolo[2,3-d]thiazol-5-yl)pyridin-2-ylamine (1i)
Yield: 20%; yellow solid; mp 175 °C (Et2O–MeOH, 99:1; dec.).
161.0 (d, 1JC,F = 250 Hz).
1H NMR (500 MHz, DMSO-d6): d = 6.05 (s, 2 H), 6.51 (d, J = 8.6
Hz, 1 H), 6.66 (d, J = 1.9 Hz, 1 H), 7.75 (dd, J = 8.6, 2.4 Hz, 1 H),
8.35 (d, J = 2.2 Hz, 1 H), 8.68 (d, J = 3.5 Hz, 1 H), 12.09 (s, 1 H).
MS (ESI): m/z (%) = 219 (100, [M + H]+).
HRMS (EI): m/z [M]+ calcd for C11H7FN2S: 218.0314; found:
218.0312.
MS (ESI): m/z (%) = 217 (100, [M + H]+).
5-Benzyl-4H-pyrrolo[2,3-d]thiazole (1c)
Yield: 69%; brown crystals; mp 117–122 °C (Et2O).
1H NMR (400 MHz, DMSO-d6): d = 3.99 (s, 2 H), 6.13 (br s, 1 H),
7.17–7.32 (m, 5 H), 8.62 (s, 1 H), 11.78 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 33.9, 96.5, 112.3, 125.6,
127.8, 127.9, 136.0, 139.3, 148.1, 150.9.
MS (APCI): m/z (%) = 215 (100, [M + H]+).
HRMS (EI): m/z [M]+ calcd for C12H10N2S: 214.0564; found:
2-Chloro-5-(4-fluorophenyl)-4H-pyrrolo[2,3-d]thiazole (1k)
Yield: 45%; beige solid; mp 150 °C (Et2O; dec.).
1H NMR (300 MHz, DMSO-d6): d = 6.83 (s, 1 H), 7.13–7.35 (m, 2
H), 7.66–7.90 (m, 2 H), 12.48 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 97.2, 115.8 (d, 2JC,F = 21 Hz),
126.1 (d, 3JC,F = 7 Hz), 128.8, 134.4, 145.9, 147.2, 150.1, 161.2 (d,
1JC,F = 243 Hz).
MS (ESI, –): m/z (%) = 250 (100, [M – 2 H]–), 251 (20, [M – 1 H]–),
214.0637.
252 (45, [M]–).
HRMS (ESI): m/z [M + H]+ calcd for C11H6ClFN2S: 253.0002;
found: 252.9998.
4H-Pyrrolo[2,3-d]thiazole (1d)
Yield: 44%; dark-white solid; mp 150–151 °C.
1H NMR (300 MHz, DMSO-d6): d = 6.39 (dd, J = 3.1, 1.8 Hz, 1 H),
7.11–7.13 (m, 1 H), 8.73 (d, J = 1.3 Hz, 1 H), 11.79 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 98.8, 112.9, 122.9, 150.4,
151.9.
5-[5-(4-Fluorophenyl)-4H-pyrrolo[2,3-d]thiazol-2-yl]pyrimi-
din-2-ylamine (1l)
Yield: 37%; orange solid; mp 220 °C (PE; dec.).
1H NMR (400 MHz, DMSO-d6): d = 6.89 (d, J = 1.9 Hz, 1 H), 7.20
(s, 2 H), 7.21–7.30 (m, 4 H), 8.74 (s, 2 H), 12.37 (s, 1 H).
MS (APCI): m/z (%) = 125 (100, [M + H]+).
HRMS (EI): m/z [M]+ calcd for C5H4N2S: 124.0095; found:
124.0080.
13C NMR (100 MHz, DMSO-d6): d = 96.6, 113.7, 115.2 (d,
3
2JC,F = 18 Hz), 117.5, 125.3 (d, JC,F = 8 Hz), 128.6, 132.1, 133.9,
154.7, 155.2, 160.3 (d, 1JC,F = 266 Hz), 162.9.
MS (ESI): m/z (%) = 312 (100, [M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C15H10FN5S: 312.0719; found:
3-(4H-Pyrrolo[2,3-d]thiazol-5-yl)phenylamine (1e)
Yield: 69%; pale-yellow solid; mp 160–161 °C (Et2O).
1H NMR (300 MHz, DMSO-d6): d = 5.10 (s, 2 H), 6.49 (d, J = 7.5
Hz, 1 H), 6.69 (d, J = 1.6 Hz, 1 H), 6.98–6.83 (m, 3 H), 7.05 (t,
J = 8.0 Hz, 1 H), 8.73 (s, 1 H), 12.15 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 95.8, 109.7, 112.3, 112.9,
114.3, 129.2, 133.2, 137.1, 148.8, 150.0, 152.7.
312.0713.
3-[5-(4-Fluorophenyl)-4H-pyrrolo[2,3-d]thiazol-2-yl]pyridin-2-
ylamine (1m)
Yield: 47%; orange solid; mp 300–301 °C (PE–Et2O, 1:3).
MS (ESI): m/z (%) = 216 (100, [M + H]+).
HRMS (EI): m/z [M]+ calcd for C11H9N3S: 215.0517; found:
1H NMR (300 MHz, DMSO-d6): d = 6.63–6.74 (m, 1 H), 6.92 (s, 1
H), 7.19–7.35 (m, 2 H), 7.53 (s, 2 H), 7.80 (dd, J = 8.8, 5.4 Hz, 2 H),
7.93 (dd, J = 7.7, 1.6 Hz, 1 H), 8.06 (dd, J = 4.7, 1.6 Hz, 1 H), 12.39
(s, 1 H).
215.0520.
5-(Pyridin-4-yl)-4H-pyrrolo[2,3-d]thiazole (1f)
Yield: 40%; dark crystals; mp 185–187 °C.
1H NMR (300 MHz, DMSO-d6): d = 7.21 (d, J = 1.9 Hz, 1 H), 7.73
(dd, J = 4.6, 1.6 Hz, 2 H), 8.54 (d, J = 6.2 Hz, 2 H), 8.91 (s, 1 H),
12.66 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 97.2, 111.1, 112.3, 114.0,
2
115.7 (d, JC,F = 28 Hz), 125.9, 126.0, 129.0 (2 ×), 134.9, 135.0,
149.1, 151.4, 155.0, 161.0 (d, 1JC,F = 242 Hz), 163.4 (3JC,F not ob-
served).
MS (ESI): m/z (%) = 311 (100, [M + H]+).
Synthesis 2010, No. 18, 3152–3162 © Thieme Stuttgart · New York

PAPER
Syntheses of Substituted Pyrrolo[2,3-d]thiazoles
3161
HRMS (ESI): m/z [M + H]+ calcd for C16H11FN4S: 311.0766; found:
311.0757.
13C NMR (100 MHz, DMSO-d6): d = 32.1, 111.8, 113.0, 119.8,
125.4, 127.8, 128.0, 140.0, 149.7, 151.3.
MS (APCI): m/z (%) = 215 (100, [M + H]+).
HRMS (EI): m/z [M]+ calcd for C12H10N2S: 214.0565; found:
5-(4-Fluorophenyl)-2-morpholin-4-yl-4H-pyrrolo[2,3-d]thia-
zole (1n)
214.0584.
A microwave flask was charged with 1k (126 mg, 0.50 mmol), fol-
lowed by morpholine (2 mL), sealed with a septum, and irradiated
with microwaves at 130 °C for 2 h. After cooling to r.t., the reaction
mixture was directly purified via column chromatography (cyclo-
hexane–EtOAc, 1:1) to yield 1n (139 mg, 91%) as beige crystals;
mp 240–248 °C.
1H NMR (300 MHz, DMSO-d6): d = 3.35–3.51 (m, 4 H), 3.66–3.81
(m, 4 H), 6.65 (d, J = 1.3 Hz, 1 H), 7.16 (t, J = 8.9 Hz, 2 H), 7.55–
7.69 (m, 2 H), 11.78 (s, 1 H).
6-Benzyl-2-pyridin-4-yl-4H-pyrrolo[2,3-d]thiazole (8b)
Yield: 53%; beige solid; mp 185–187 °C (MeOH).
1H NMR (400 MHz, DMSO-d6): d = 3.94 (s, 2 H), 7.08–7.39 (m, 6
H), 7.75 (dd, J = 4.5, 1.6 Hz, 2 H), 8.61 (dd, J = 4.5, 1.6 Hz, 2 H),
11.86 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 31.9, 113.7, 114.4, 118.5,
122.0, 125.6, 127.9, 128.0, 139.7, 140.4, 150.0, 151.1, 159.1.
13C NMR (75 MHz, DMSO-d6): d = 48.0, 65.3, 97.2, 105.4, 115.5
(d, 2JC,F = 21 Hz), 124.5 (d, 3JC,F = 7 Hz), 128.8, 129.9, 148.6, 160.1
(d, 1JC,F = 240 Hz), 170.6.
MS (ESI): m/z (%) = 292 (100, [M + H]+).
HRMS (EI): m/z [M]+ calcd for C17H13N3S: 291.0830; found:
291.0819.
MS (ESI): m/z (%) = 304 (100, [M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C15H14FN3OS: 304.0920;
found: 304.0911.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
5-(4-Fluorophenyl)-2-(4-pyridin-4-ylmethylpiperazin-1-yl)-4H-
pyrrolo[2,3-d]thiazole (1o)
References
A microwave flask was charged with 1k (63 mg, 0.25 mmol), fol-
lowed by 1-(4-pyridylmethyl)piperazine (443 mg, 2.50 mmol),
EtN(i-Pr)2 (85 mL, 0.5 mmol), and i-PrOH (2 mL). The vessel was
sealed and irradiated with microwaves for 1 h at 130 °C, followed
by heating to 130 °C for 18 h in an oil bath. After cooling to r.t., the
mixture was directly purified by flash chromatography (EtOAc to
EtOAc–MeOH, 98:2; 1% Et3N) to yield 1o (41 mg, 41%), which
was recrystallized as a beige solid (Et2O–PE); mp 170 °C (dec.).
1H NMR (400 MHz, DMSO-d6): d = 2.52–2.56 (m, 4 H), 3.42–3.49
(m, 5 H), 3.59 (s, 2 H), 6.65 (d, J = 1.9 Hz, 1 H), 7.16 (t, J = 8.9, 2
H), 7.37 (d, J = 5.6 Hz, 2 H), 7.62 (dd, J = 8.8, 5.4 Hz, 2 H), 8.53
(d, J = 5.3 Hz, 2 H), 11.77 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 47.4, 51.2, 59.9, 96.7, 105.0,
115.0 (d, 2JC,F = 22 Hz), 120.5, 123.2, 123.9 (d, 3JC,F = 8 Hz), 128.1,
129.4, 147.6 (d, 1JC,F = 220 Hz), 148.2, 149.1, 169.8.
MS (ESI): m/z (%) = 394 (100, [M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C21H20FN5S: 394.1501; found:
(1) For a review of pyrrolo[2,1-b]thiazoles, see: Tverdokhlebov,
A. V. Heterocycles 2007, 71, 761.
(2) Nakamura, T.; Hioki, T.; Ohzeki, K.; Hanaki, N. US Patent
Appl. US 20020058216, 2002; Chem. Abstr. 2002, 136,
393179.
(3) Dekhtyar, M. L. Dyes Pigm. 2007, 74, 744.
(4) For examples of 2-acylpyrrole derivatives including
pyrrolo[2,3-d]thiazoles, see: (a) Heffernan, M. L. R.;
Dorsey, J. M.; Fang, Q. K.; Foglesong, R. J.; Hopkins, S. C.;
Jones, M. L.; Jones, S. W.; Ogbu, C. O.; Perales, J. B.;
Soukri, M.; Spear, K. L.; Varney, M. A. PCT Int. Appl. US
20080058395, 2008; Chem. Abstr. 2008, 148, 278900.
(b) See also: Barker, A. J.; Kettle, J. G.; Faull, A. W. PCT
Int. Appl. WO 199940914, 1999; Chem. Abstr. 1999, 131,
170342.
(5) For the original synthesis of pyrrolo[3,2-d]thiazoles, see:
(a) Shafiee, A.; Mazloumi, A.; Cohen, V. I. J. Heterocycl.
Chem. 1979, 16, 1563. (b) Athmani, S.; Farhat, M. F.;
Iddon, B. J. Chem. Soc., Perkin Trans. 1 1992, 973.
(c) Sparey, T.; Abeywickrema, P.; Almond, S.; Brandon, N.;
Byrne, N.; Campbell, A.; Hutson, P. H.; Jacobson, M.;
Jones, B.; Munshi, S.; Pascarella, D.; Pike, A.; Prasad, G. S.;
Sachs, N.; Sakatis, M.; Sardana, V.; Venkatramane, S.;
Young, M. B. Bioorg. Med. Chem. Lett. 2008, 18, 3386.
(6) (a) Grehn, L. Chem. Scr. 1978, 13, 78. (b) Rao, K. E.;
Padmanabhan, S.; Lown, J. W. Actual. Chim. Ther. 1993, 20,
159.
394.1447.
6-(Arylmethyl)-4H-pyrrolo[2,3-d]thiazoles 8; General Proce-
dure
The corresponding o-iodocarbamate 2a,b (2 mmol) and 2.6 g (8
mmol) Cs2CO3 was dissolved in anhyd DMF (10 mL) in a dried
Schlenk tube under N2 and treated with cinnamyl bromide (622 mg,
3 mmol). After stirring for 2 h at r.t. (TLC monitoring), Pd(OAc)2
(22 mg, 0.10 mmol) and Ph3P (52 mg, 0.20 mmol) were added and
the mixture was stirred for 19 h at 100 °C. After cooling to r.t., the
mixture was diluted with brine (50 mL) and extracted with EtOAc
(3 × 50 mL). The combined organic layers were dried (Na2SO4) and
the solvent removed in vacuo together with SiO2 (2 g). The solid
was heated in vacuo (10 mbar) at the indicated temperature and
time. Subsequently, the product was purified by flash chromatogra-
phy on silica gel (cyclohexane–EtOAc, 1:1).
(7) Koolman, H.; Heinrich, T.; Böttcher, H.; Rautenberg, W.;
Reggelin, M. Bioorg. Med. Chem. Lett. 2009, 19, 1879.
(8) For examples of indole syntheses, see: (a) Mackmann, R.
L.; Katz, B. A.; Breitenbucher, J. G.; Hui, H. C.; Verner, E.;
Luong, C.; Liu, L.; Sprengeler, A. J. Med. Chem. 2001, 44,
3856. (b) Palimkar, S. S.; Kumar, P. H.; Lahoti, R. J.;
Srinivasan, K. V. Tetrahedron 2006, 62, 5109.
(c) Saejueng, P.; Bates, C. G.; Venkataraman, D. Synthesis
2005, 1706. (d) Lu, B. Z.; Zhao, W.; Wei, H.-X.; Dufour,
M.; Farina, V.; Senanayake, C. H. Org. Lett. 2006, 8, 3271.
(e) Gomtsyan, A.; Didomenico, S.; Lee, C.-H.; Stewart, A.
O.; Bhagwat, S. S.; Kowaluk, E. A.; Jarvis, M. F. Bioorg.
Med. Chem. Lett. 2004, 14, 4165. (f) For an explicit
example of a Boc-protected iodoaniline being cyclized to the
corresponding indole after Sonogashira coupling employing
6-Benzyl-4H-pyrrolo[2,3-d]thiazole (8a)
Yield: 49%; white solid; mp 133–135 °C (H2O–MeCN).
1H NMR (400 MHz, DMSO-d6): d = 3.90 (s, 2 H), 7.01 (dd, J = 2.3,
1.3 Hz, 1 H), 7.14–7.34 (m, 5 H), 8.65 (d, J = 1.3 Hz, 1 H), 11.58
(s, 1 H).
Synthesis 2010, No. 18, 3152–3162 © Thieme Stuttgart · New York

3162
H. Koolman et al.
PAPER
W.; Knochel, P. Angew. Chem. Int. Ed. 2000, 39, 2488;
TBAF as base in a one-pot procedure, see: Suzuki, N.;
Yasaki, S.; Yasuhara, A.; Sakamoto, T. Chem. Pharm. Bull.
2003, 51, 1170. (g) For a discussion of aminopalladation/
reductive elimination reactions for the syntheses of indoles,
see: Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett.
1992, 33, 3915. (h) See also: Tyrell, E.; Whiteman, L.;
Williams, N. Synthesis 2009, 829.
Angew. Chem. 2000, 112, 2607.
(16) See supporting information for a detailed reaction parameter
diagram.
(17) Pyrrolo[3,2-d]thiazole as a keratin dyeing compound is
claimed, but its synthesis is not explicitly stated, see:
Murphy, B. P.; Glenn, R. W. Jr.; Lim, M. I.; Gardlik, J. M.;
Jones, S. D.; Laidig, W. D.; Shaffer, J. D. PCT Int. Appl.
WO 2005077324, 2005; Chem. Abstr. 2005, 143, 234964.
(18) The low yield can be attributed to decomposition processes
due to the considerably intense and long-lasting irradiation
of the reaction mixture.
(9) Al-Shaar, A. H. M.; Gilmour, D. W.; Lythgoe, D. J.;
McClenaghan, I.; Ramsden, C. A. J. Chem. Soc., Perkin
Trans. 1 1992, 2779.
(10) The yields of 4- and 5-aminothiazoles are low and rapid
decomposition to a black solid is particularly mentioned for
the 4-aminothiazole, see: Diener, H.; Zollinger, H. Can. J.
Chem. 1986, 64, 1102.
(19) The formation of a black slurry residue is observed, probably
due to polymerization..
(11) Yang, Y.; Hörnfeldt, A.-B.; Gronowitz, S. Chem. Scr. 1988,
28, 275.
(20) Several conditions were tested for the Boc cleavage of 6a:
TFA in CH2Cl2, ethanolic HCl in CH2Cl2 and heating with
SiO2, with the latter being the superior method. In all cases
partial decompostion occurred and oxidation of the alkyne
appeared as the major side reaction.
(21) All tried standard halogenation conditions for thiazoles
affected the alkyne, or led to decomposition: iodination with
NIS in CH2Cl2, DME, or MeCN with or without addition of
K2CO3 at ambient or elevated temperatures. Best yields were
obtained with N-chlorosuccinimide as electrophile
compared to CCl4 and quenching the reaction mixture with
n-BuOH compared to H2O, respectively.
(12) The 2,5-diiodothiazole as a side-product in the synthesis of
thiazole 2a could only be observed in traces via mass
spectrometry. When scaling this reaction up to a 35 mmol,
CH2Cl2 as solvent and a reaction time of 18 h at r.t. were
used to achieve comparable yields.
(13) The syntheses of azaindoles via DBN-mediated cyclization
of Boc-protected o-aminoalkynylpyridines are reported in:
(a) Choi-Sledeski, Y.-M.; Kearney, R.; Poli, G.; Pauls, H.;
Gardner, C.; Gong, Y.; Becker, M.; Davis, R.; Spada, A.;
Liang, G.; Chu, V.; Brown, K.; Collussi, D.; Leadley, R.;
Rebello, S.; Moxey, P.; Morgan, S.; Bentley, R.; Kasiewski,
C.; Maignan, S.; Guilloteau, J.-P.; Mikol, V. J. Med. Chem.
2003, 46, 681. (b) Harcken, C.; Ward, Y.; Thomson, D.;
Riether, D. Synlett 2005, 3121.
(22) Attempted Suzuki-couplings after cyclization to the
unprotected pyrrolothiazoles only led to traces of product
after prolonged reaction times, probably due to the influence
of the free pyrrole NH group.
(14) Sanz, R.; Guilarte, V.; Castraviejo, M. P. Synlett 2009, 3006.
(15) Knochel and co-workers mention the importance of NMP as
solvent in combination with t-BuOK to induce cyclization to
the pyrrole moiety: Rodriguez, A. L.; Koradin, C.; Dohle,
(23) Wensbo, D.; Gronowitz, S. Tetrahedron 1995, 51, 10323.
(24) Products resulting from 6-endo-cyclization could not be
detected in any case.
Synthesis 2010, No. 18, 3152–3162 © Thieme Stuttgart · New York