Use of 3-(trifluoromethyl)-1H-pyrazolo-[3,4-b]pyridine as a versatile building block

Article abstract of DOI:10.1016/j.tet.2015.06.050

A one-pot multigram synthesis of 3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine starting from 2-fluoropyridine using directed ortho metallation (DoM) technique is described. The compound contains an anionically activatable trifluoromethyl group and is a versatile building block for the microwave assisted synthesis of 3-substituted 1H-pyrazolo[3,4-b]pyridines.

Full text of DOI:10.1016/j.tet.2015.06.050

Tetrahedron 71 (2015) 5597e5601
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Use of 3-(trifluoromethyl)-1H-pyrazolo-[3,4-b]pyridine as a versatile
building block
*
€
Hartmut Schirok , Nils Griebenow, Chantal Furstner, Alicia M. Dilmac
Bayer HealthCare Pharmaceuticals AG, Global Drug Discovery, Medicinal Chemistry Wuppertal, Building 460, D-42096 Wuppertal, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 March 2015
Received in revised form 10 June 2015
Accepted 12 June 2015
Available online 23 June 2015
A one-pot multigram synthesis of 3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine starting from 2-
fluoropyridine using directed ortho metallation (DoM) technique is described. The compound contains
an anionically activatable trifluoromethyl group and is a versatile building block for the microwave as-
sisted synthesis of 3-substituted 1H-pyrazolo[3,4-b]pyridines.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Directed ortho metallation
Pyrazolopyridine
Trifluoromethyl
Anionic activation
Microwave assisted synthesis
O
Cl
1. Introduction
N
N
O
H2N
O
NH2
Cl
N
The discovery of new synthetic methods to further expand the
toolbox that allows for the rapid exploration and customization of
the pharmaceutical diversity space is one major focus for organic
chemists. Within this context, the synthesis of so-called ‘privileged
structures’1 is of considerable interest, because such structures
combine drug-like properties with the ability to address various
biological targets, depending on their substitution pattern. Exam-
ples include the synthesis of benzodiazepines,2 benzopyrans,3 bi-
phenyls,4 phenyl piperazines,5 and spiro-piperidines.6 In the course
of our ongoing efforts directed towards the synthesis of novel
scaffolds for medicinal chemistry purposes, we were interested in
the diversification of the 1H-pyrazolo[3,4-b]pyridine scaffold, an-
other example of a ‘privileged structure’. 1H-Pyrazolo[3,4-b]pyri-
dines, when appropriately substituted, exert potent and selective
actions at diverse sets of protein targets, including G protein-
coupled receptors, lyases and DNA polymerases. Besides their
well-known vasodilatatory activity found in therapeutics such as
Riociguat (A)7 1H-pyrazolo[3,4-b]pyridines have also demonstrated
activities as reverse transcriptase inhibitors represented by B,8
phosphodiesterase IV inhibitors such as C,9 and adenosine A2B re-
ceptor antagonists exemplified by D.10
O
N
N
N
N
N
N
H2N
N
H
F
Riociguat (A)
(B)
N
O
HN
O
N
N
O
NH2
N
O
H2N
N
O
N
N
N
N
H
(C)
(D)
In one of our drug discovery projects we required 1H-pyrazolo
[3,4-b]pyridine-3-carbonitrile (4) as a key building block.11 Initially,
the synthesis was established via 3-amino-pyrazolo-pyridine 2,
prepared from commercially available 2-chloro-3-cyanopyridine
(1) and hydrazine hydrate (Scheme 1).12 Diazotation followed by
treatment with sodium iodide in acetone provided 3-iodo-1H-
pyrazolo[3,4-b]pyridine (3),13 which was further transformed into
nitrile 4 with copper(I) cyanide in DMF. This synthetic route suf-
fered from moderate to low yields of 39% and 26% in the final two
* Corresponding author. Tel.: þ49 202 363926; fax: þ49 202 368149; e-mail
address: Hartmut.Schirok@bayer.com (H. Schirok).
http://dx.doi.org/10.1016/j.tet.2015.06.050
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

5598
H. Schirok et al. / Tetrahedron 71 (2015) 5597e5601
steps. Alternatively, we demonstrated the possibility to convert
aminoderivative 2 directly into the desired cyanide 4. However, the
overall yield remained low (15e35%). Thus, alternative synthetic
routes were considered.
charcoal, the trifluoromethyl compound 12 was essentially pure
and needed no further purification.
The trifluoromethyl substituted pyrazolopyridine 12 proved to
be much less reactive than the corresponding azaindole 6. Stirring
in aqueous ammonia at 60 ꢂC led to a clean conversion of 3-
trifluoromethyl substituted 7-azaindole 6 to the 3-cyano de-
rivative within hours, whereas the reaction of pyrazolopyridine 12
was still not complete after heating overnight. With sodium amide
in toluene at room temperature and even at 100 ꢂC, 12 remained
unchanged.
A direct comparison of the stability of 3-trifluoromethyl-7-
azaindole (6, R¼H) and 3-(trifluoromethyl)-1H-pyrazolo[3,4-b]
pyridine (12) in aqueous solution at pH 10 and 37 ꢂC demonstrated
impressively the difference in reactivity of both compounds (Fig. 1).
Whilst the azaindole 6 was completely hydrolyzed to the acid
within less than 4 h, the pyrazolopyridine 12 remained unchanged
under these conditions. These results are in concordance with the
recent report by Ermolenko et al., according to which the hydrolysis
Scheme 1. Reagents and conditions: (a) N2H4ꢀH2O, EtOH, reflux. (b) 1. BF3ꢀOEt2, iso-
amylnitrite, THF, ꢁ10 ꢂC; 2. NaI, acetone, 0e5 ꢂC / rt. (c) CuCN, DMF, 135 ꢂC. (d) 1.
BF3ꢀOEt2, isoamylnitrite, THF, ꢁ10 ꢂC; 2. CuCN, acetonitrile, 0 ꢂC / rt.
Recently, we developed a high-yielding synthesis of a 3-cyano-
7-azaindole 8 based on anionic activation14 of trifluoromethyl an-
alog 6, which undergoes rapid aminolysis via highly reactive
methide intermediate 7 (Scheme 2).15 An analogous pathway to
nitrile 4 would start from the trifluoromethyl substituted pyr-
azolopyridine 12 (Scheme 3). On the basis of our work on CF3-
azaindoles,16 we prepared 3-(trifluoromethyl)-1H-pyrazolo[3,4-b]
pyridine in a one-pot procedure from 2-fluoropyridine (5).11
Scheme 2. Synthesis of 3-cyano-7-azaindole 8.15,16
Fig. 1. Stability of 6 and 12 at pH 10 and 37 ꢂC.
Scheme 3. Reagents and conditions: (a) LDA, THF, ꢁ78 ꢂC; then CF3COOEt; then
N2H4ꢀH2O, reflux.
of 5-substituted-3-trifluoromethylpyrazoles requires microwave
heating.23 Yang et al. prepared 3-cyanopyrazoles from 3-
trifluoromethyl analogs in aqueous ammonia in sealed tubes.24
Similarly, when 12 was heated in aqueous ammonia to 140 ꢂC in
sealed tubes in a microwave oven the desired nitrile 4 was formed
in 90% yield (Scheme 4). Concomitant ammonium fluoride was
separated by trituration with hot ethyl acetate/tert-butyl methyl
ether and filtration. The product contained up to 10% of the cor-
responding primary amide, which could be separated by
chromatography.
The ortho lithiation of 2-fluoropyridine (5) is based on the
acidifying effect of the halogen atom and is a powerful method of
introducing functional groups to an aromatic nucleus. As shown in
17
ꢀ
extensive investigations mainly done by Queguiner
and
Schlosser,18 lithium-bases, commonly lithium diisopropylamide,
promote a hydrogen/metal exchange at the 3-position. The reaction
conditions of the deprotonation reported in the literature vary from
ꢁ78 ꢂC to 0 ꢂC and from 1 to 4 h. When we warmed the lithiation
reaction mixture to temperatures above ꢁ40 ꢂC, the mixture turned
brownish and increasing amounts of o-diisopropylaminopyridine
could be identified as byproduct.19 This aromatic substitution re-
action20 could best be avoided by performing the deprotonation at
ꢁ78 ꢂC for 4 h. Subsequently, trifluoroacetic acid ethyl ester was
added as an electrophile and reacted instantaneously. After aque-
ous work-up, we isolated the hydrate of the trifluoroacetyl com-
pound (Scheme 3) rather than the carbonyl compound 9 itself.21
This hydrate could be purified by sublimation and dehydrated by
azeotropic distillation with toluene.22 Later-on we discovered that
the isolation of intermediate 9 was dispensable. When we added
hydrazine hydrate to the reaction mixture and stirred it at slightly
elevated temperatures for several hours, the desired bicyclic com-
pound 12 was formed (Scheme 3). The work-up was very simple,
since all components of the crude mixture except the target com-
pound are water soluble. After treatment of the crude product with
Scheme 4. Reagents and conditions: (a) aq NH3-solution, m
W, 140 ꢂC. (b) BnBr, Cs2CO3,
DMF, rt.

H. Schirok et al. / Tetrahedron 71 (2015) 5597e5601
5599
Table 1
To gain further insight into the mechanism of this trans-
Reaction of 12 with different nucleophiles
formation, we protected the acidic nitrogen in 12 by benzylation
(Scheme 4). According to the assumption that the reactivity of 12
relies on the push-pull system present in the molecule, and that N-
deprotonation is required previous to the reaction with a nucleo-
phile, the N-benzylated compound 14 did not react under the de-
scribed reaction conditions in the microwave oven. In addition, we
examined the stability of compounds 12 and 14 in 1 N sodium
hydroxide solution at 50 ꢂC. We found the N-benzylated compound
14 stable under these conditions, whilst 80% of the unprotected
pyrazolopyridine 12 was consumed after the same period of time
(see Fig. 2).
CF3
R
150 °C
μW
N
N
N
N
nucleophile
(Table 1)
aq. NaOH
N
N
H
H
12
4, 16-21
Entry
1
Nucleophile
Product
Yield %
CN
aq NH3
4
90
N
N
H
N
O
O
O
N
2
3
16
17
95
N
H
N
N
H
N
HN
N
N
N
42
82
H2N
NH2
N
N
N
N
N
H
O
4
18
HO
NH2
N
N
H
N
O
N
5
6
7
19
20
21
63
40
64
HO
NH2
Fig. 2. Stability of 12 and 14 in 1 N NaOH at 50 ꢂC.
N
N
H
Me2N
S
We previously reported on the syntheses of heterocycle
substituted 1H-pyrazolo[3,4-b]pyridines in 3e4 steps starting from
4.11c Herein, we show that such compounds are also easily acces-
sible in a single synthetic step from 12. Indeed, applying microwave
heating, the trifluoromethyl compound 12 reacts with other nu-
cleophiles, and several heterocycle substituted 1H-pyrazolo[3,4-b]
pyridines were synthesized (Table 1). In aqueous sodium hydroxide
solution as solvent and with an amine present, amides were iso-
lated, as for example the morpholide 16 (entry 2), which was iso-
lated in 95% yield. Binucleophilic reagents gave heteroaromatics:25
1,2-diaminobenzene yielded benzimidazole 17 (entry 3), and 2-
aminophenol reacted to benzoxazole 18 (entry 4). Hydrazino-
carbothiamides afforded thiadiazoles 20 and 21 (entry 6 and 7).
In summary we have developed an efficient one-pot synthesis of
3-(trifluoromethyl)-1H-pyrazolo-[3,4-b]pyridine from 2-fluoro
pyridine. It was shown to be much less reactive than its carbon
analog, 3-trifluoromethyl-7-azaindole. However, we demonstrated
its use as a versatile building block under microwave assisted
heating giving rapid access to various 3-substituted 1H-pyrazolo-
[3,4-b]pyridines in moderate to high yields.
N
H
N
Me2N
N
NH2
S
N
N
H
N
MeNPh
N
Ph
MeN
S
H
N
N
NH2
S
N
N
N
H
detection. All 1H NMR and 13C NMR spectra were recorded in
DMSO-d6. Spin multiplicities are given as s (singlet), d (doublet), t
(triplet), q (quartet), and m (multiplet) as well as br (broad). All
microwave irradiation experiments were carried out using the
EmrysÔ optimizer microwave from Biotage. The reactions were
performed in Biotage microwave vials (for 0.5e2 mL or 2e5 mL)
sealed with a septum. The power range was up to 300 W at
2.45 GHz.
2. Experimental
Unless otherwise noted, all materials were obtained from
commercial suppliers and used without further purification. Flash
chromatography was done on silica gel 60 (0.063e0.200 mm) from
Merck KgaA, Darmstadt, Germany. Preparative HPLC chromatog-
raphy was done on a 250 mmꢀ30 mm column packed with YMC gel
2.1. 3-(Trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (12)
To a solution of freshly prepared LDA (108 mmol) in THF
(180 mL) at ꢁ75 ꢂC was added 2-fluoropyridine (7.00 g,
72.1 mmol), and the mixture was stirred for 4 h at this tempera-
ture. Ethyl trifluoroacetate (18.4 g, 130 mmol) was added quickly.
ODS-AQ S5/15
mM, with acetonitrile/water as eluent and UV-

5600
H. Schirok et al. / Tetrahedron 71 (2015) 5597e5601
The internal temperature raised to ꢁ40 ꢂC. The mixture was
cooled again to ꢁ75 ꢂC, and hydrazine hydrate (28.9 g, 577 mmol)
was added. The reaction was heated to 70 ꢂC for 6 h. Subsequently,
volatile components were removed in vacuo. Water (300 mL) was
added, and the mixture was heated to reflux and filtered. The
residue was dissolved in ethyl acetate (300 mL) and this solution
was dried over sodium sulfate, stirred with charcoal and filtrated.
After evaporation of the solvent, 7.86 g (55%) of the title com-
pound was obtained as a pale yellow solid. 1H NMR (400 MHz,
2.5. 3-(1H-Benzimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridine
(17)
To compound 12 (150 mg, 0.80 mmol) and benzene-1,2-diamine
(104 mg, 0.96 mmol) was added a 1 N aqueous sodium hydroxide
solution (3.0 mL), and the mixture was heated in a microwave oven
to 150 ꢂC for 10 min. The mixture was diluted with water and
extracted twice with ethyl acetate. The solvent was evaporated, and
the residue was purified by preparative HPLC to yield 80 mg (42%)
of the title compound as a white solid. 1H NMR (400 MHz, DMSO-
DMSO-d6):
d
7.43 (dd, J¼8.1, 4.4 Hz, 1H), 8.34 (d, J¼8.1 Hz, 1H), 8.72
(dd, J¼4.4, 1.5 Hz, 1H), 14.67 (br s, 1H). 13C NMR (125 MHz, DMSO-
d6):
d
7.19e7.29 (m, 2H), 7.39 (dd, J¼8.1, 4.4 Hz,1H), 7.53 (d, J¼7.1 Hz,
1
d6):
d
110.7, 119.1, 121.5 (q, JC,F¼269 Hz), 128.7, 132.5 (q,
1H), 7.74 (d, J¼7.1 Hz, 1H), 8.65 (dd, J¼4.4, 1.0 Hz, 1H), 8.85 (dd,
2JC,F¼38.2 Hz), 150.6, 151.7. HRMS m/z calcd for C7H4F3N3:
J¼7.8, 1.0 Hz, 1H), 13.12 (br s, 1H), 14.19 (br s, 1H). 13C NMR
187.0357; found: 187.0357.
(125 MHz, DMSO-d6): d 111.5, 112.8, 118.2, 119.0, 121.6, 122.9, 131.3,
134.2, 135.6, 143.8, 146.5, 149.7, 152.7. HRMS m/z calcd for C13H9N5
þ [Hþ]: 236.0931; found: 236.0936.
2.2. 1H-Pyrazolo[3,4-b]pyridine-3-carbonitrile (4)
Compound 12 (500 mg, 2.67 mmol) was suspended in aqueous
ammonia solution (33%, 10 mL). The mixture was heated in a sealed
tube in the microwave oven to 140 ꢂC for 10 min. Volatiles were
evaporated. To the residue was added ethyl acetate (100 mL) and
tert-butyl methyl ether (25 mL), and the mixture was heated to
70 ꢂC. The hot mixture was filtered, and the residue was washed
with tert-butyl methyl ether. The combined filtrates were evapo-
rated to yield the title compound as slightly yellow residue
(389 mg, 90%), which contained traces of corresponding primary
2.6. 3-(1,3-Benzoxazol-2-yl)-1H-pyrazolo[3,4-b]pyridine (18)
To compound 12 (50 mg, 0.27 mmol) and 2-aminophenol
(35 mg, 0.32 mmol) was added a 1 N aqueous sodium hydrox-
ide solution (0.75 mL), and the mixture was heated in a micro-
wave oven to 150 ꢂC for 10 min. It was then diluted with water
and extracted twice with ethyl acetate.
4 N HCl solution
was added (pH 4), and the mixture was extracted again with
ethyl acetate. The combined organic layers were dried over so-
dium sulfate, and the solvent was evaporated. The residue was
purified by preparative HPLC to yield 52 mg (82%) of the title
amide. 1H NMR (400 MHz, DMSO-d6):
8.46 (dd, J¼8.2, 1.5 Hz, 1H), 8.73 (dd, J¼4.5, 1.5 Hz, 1H), 15.02 (br s,
1H). 13C NMR (125 MHz, DMSO-d6):
113.5,115.5,116.9,119.6,128.7,
d
7.47 (dd, J¼8.2, 4.5 Hz, 1H),
d
compound as a
tan solid. 1H NMR (400 MHz, DMSO-d6):
150.9, 151.0. HRMS m/z calcd for C7H4N4: 144.0436; found:
144.0430.
d
7.44e7.52 (m, 3H), 7.89 (t, J¼8.4 Hz, 2H), 8.71 (d, J¼4.4 Hz, 1H),
8.76 (d, J¼8.1 Hz, 1H), 14.42 (br s, 1H). 13C NMR (125 MHz, DMSO-
d6):
d 111.0, 113.3, 118.9, 119.8, 125.0, 125.8, 130.4, 131.9, 141.1,
149.5, 150.1, 152.3, 157.4. HRMS m/z calcd for
236.0698; found: 236.0698.
C13H8N4O:
2.3. 1-Benzyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine
(14)
A mixture of compound 12 (50 mg, 0.27 mmol), benzylbromide
(50 mg, 0.29 mmol) and caesiumcarbonate (104 mg, 0.32 mmol)
was stirred overnight at room temperature in DMF (1.0 mL). It was
then diluted with tert-butyl methyl ether and washed with water.
The organic layer was dried over sodium sulfate and the solvent
was evaporated. The crude product was purified by column chro-
matography (eluent: cyclohexane/ethyl acetate 3:1) to yield 50 mg
2.7. 2-(1H-Pyrazolo[3,4-b]pyridin-3-yl)[1,3]oxazolo[4,5-b]pyr-
idine (19)
To compound 12 (150 mg, 0.80 mmol) and 2-amino-pyridin-3-
ol (106 mg, 0.32 mmol) was added a 1 N aqueous sodium hy-
droxide solution (3.0 mL), and the mixture was heated in a micro-
wave oven to 150 ꢂC for 10 min. The precipitate was collected by
suction filtration and washed with methanol to yield 120 mg (63%)
(67%) of the title compound. 1H NMR (400 MHz, DMSO-d6):
d 5.82
(s, 2H), 7.26e7.37 (m, 5H), 7.50 (dd, J¼8.2, 4.5 Hz, 1H), 8.39 (d,
of the title compound. 1H NMR (400 MHz, DMSO-d6):
d 7.51 (dd,
J¼8.2 Hz, 1H), 8.79 (dd, J¼4.5, 1.2 Hz, 1H). 13C NMR (125 MHz,
J¼8.1, 4.6 Hz, 1H), 7.52 (dd, J¼8.3, 4.9 Hz, 1H), 8.33 (dd, J¼8.3, 1.2 Hz,
1H), 8.61 (dd, J¼4.9,1.2 Hz,1H), 8.73 (dd, J¼4.6,1.5 Hz,1H), 8.78 (dd,
J¼8.1, 1.5 Hz, 1H), 14.72 (br s, 1H). 13C NMR (125 MHz, DMSO-d6):
1
DMSO-d6):
d
50.8, 111.4 (q, JC,F¼1.4 Hz), 119.7, 121.4 (q,
1JC,F¼269 Hz), 127.7, 127.9, 128.7, 129.3, 131.5 (q, JC,F¼38.6 Hz),
136.2, 149.8, 151.0. HRMS m/z calcd for C14H10F3N3: 277.0827;
found: 277.0825.
2
d
113.6, 119.2, 120.9, 130.4, 131.4, 142.0, 146.6, 150.2, 152.4, 155.2,
159.8. HRMS m/z calcd for C12H7N5O þ [Hþ]: 238.0724; found:
238.0724.
2.4. 3-(Morpholin-4-ylcarbonyl)-1H-pyrazolo[3,4-b]pyridine
(16)
2.8. N,N-Dimethyl-5-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1,3,4-
thiadiazol-2-amine (20)
To compound 12 (100 mg, 0.53 mmol) and morpholine (93 mg,
1.07 mmol) was added a 1 N aqueous sodium hydroxide solution
(2.0 mL), and the mixture was heated in a microwave oven to 150 ꢂC
for 10 min. The mixture was extracted with ethyl acetate, neutral-
ized with 4 N HCl solution and again extracted. The combined or-
ganic layers were dried over sodium sulfate, and the solvent was
evaporated to yield 117 mg (95%) of the title compound. 1H NMR
To compound 12 (200 mg, 1.07 mmol) and N,N-dimethylhy-
drazinecarbothioamide (153 mg, 1.28 mmol) was added a 1 N
aqueous sodium hydroxide solution (4.0 mL), and the mixture was
heated in a microwave oven to 150 ꢂC for 10 min. The precipitate
was collected by suction filtration and washed with water to yield
106 mg (40%) of the title compound as a tan solid. 1H NMR
(400 MHz, DMSO-d6):
(dd, J¼8.1, 4.5 Hz, 1H), 8.42 (dd, J¼8.1, 1.5 Hz, 1H), 8.60 (dd, J¼4.5,
1.5 Hz, 1H), 14.15 (br s, 1H). 13C NMR (125 MHz, DMSO-d6):
42.3,
d
3.63e3.75 (m, 6H), 4.07e4.15 (m, 2H), 7.32
(400 MHz, DMSO-d6):
(dd, J¼8.0, 1.5 Hz, 1H), 8.63 (dd, J¼4.4, 1.5 Hz, 1H), 14.08 (br s, 1H).
13C NMR (125 MHz, DMSO-d6):
41.1, 111.4, 118.3, 130.8, 136.3,
d
3.18 (s, 6H), 7.36 (dd, J¼8.0, 4.4 Hz,1H), 8.59
d
d
46.9, 66.1, 66.4, 114.8, 118.2, 131.1, 138.1, 149.5, 151.6, 161.0. HRMS m/
z calcd for C11H12N4O2: 232.0960; found: 232.0962.
150.0, 151.2, 152.4, 170.4. HRMS m/z calcd for C10H10N6S: 246.0688;
found: 246.0680.

H. Schirok et al. / Tetrahedron 71 (2015) 5597e5601
5601
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1,3,4-thiadiazol-2-amine (21)
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nylhydrazinecarbothioamide (174 mg, 0.96 mmol) was added a 1 N
aqueous sodium hydroxide solution (3.0 mL), and the mixture was
heated in a microwave oven to 150 ꢂC for 10 min. The mixture was
diluted with water and extracted twice with ethyl acetate. The
solvent was evaporated, and the residue was purified by pre-
parative HPLC to yield 159 mg (64%) of the title compound as a tan
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20, 1634e1637.
solid. 1H NMR (400 MHz, DMSO-d6):
d 3.60 (s, 3H), 7.35e7.40 (m,
2H), 7.52 (t, J¼7.7 Hz, 2H), 7.56e7.59 (m, 2H), 8.60 (dd, J¼7.3, 1.5 Hz,
1H), 8.64 (dd, J¼4.4, 1.5 Hz, 1H), 14.13 (s, 1H). 13C NMR (125 MHz,
DMSO-d6):
d 40.61, 111.6, 118.5, 124.5, 127.0, 130.0, 130.8, 136.0,
146.5, 150.1, 151.7, 152.5, 169.3. HRMS m/z calcd for C15H12N6S þ
[Hþ]: 309.0917; found: 309.0908.
€
11. (a) Schirok, H.; Griebenow, N.; Furstner, C.; Mittendorf, J.; Stasch, J.-P.; Wunder,
Acknowledgements
F.; Schlemmer, K.-H.; Heitmeier, S.; Stoll, F. PCT Int. Appl. WO 2007124854,
2007. (b) Furstner, C.; Schirok, H.; Griebenow, N.; Mittendorf, J.; Stasch, J.-P.;
€
Wunder, F. PCT Int. Appl. WO 2007128454, 2007. (c) Griebenow, N.; Schirok,
H.; Mittendorf, J.; Straub, A.; Follmann, M.; Stasch, J.-P.; Knorr, A.; Schlemmer,
K.-H.; Redlich, G. Bioorg. Med. Chem. Lett. 2013, 23, 1197e1200.
We thank Dr. P. Schmitt, C. Streich, and D. Bauer for recording
NMR spectra and helpful discussions. In addition we are grateful to
€
G. Wiefel-Hubschmann and H. Musche for HRMS measurements.
12. Lynch, B. M.; Khan, M. A.; Teo, H. C.; Pedrotti, F. Can. J. Chem. 1988, 66, 420e428.
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Supplementary data
14. (a) Kiselyov, A. S.; Strekowski, L. Org. Prep. Proced. Int. 1996, 291e318; (b) Ki-
selyov, A. S. Mini-Rev Org. Chem. 2007, 4, 183e189.
15. (a) Schirok, H.; Kast, R.; Figueroa-Perez, S.; Bennabi, S.; Gnoth, M. J.; Feurer, A.;
Supplementary data (Spectral 1H and 13C NMR data for com-
pounds 4, 12, 14, and 16e21.) related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2015.06.050.
ꢀ
€
Heckroth, H.; Thutewohl, M.; Paulsen, H.; Knorr, A.; Hutter, J.; Lobell, M.;
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Munter, K.; Geiß, V.; Ehmke, H.; Lang, D.; Radtke, M.; Mittendorf, J.; Stasch, J.-P.
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