Microwave-assisted synthesis of 3-aminobenzo[b]thiophene scaffolds for the preparation of kinase inhibitors

Article abstract of DOI:10.1039/c5ob00819k

Microwave irradiation of 2-halobenzonitriles and methyl thioglycolate in the presence of triethylamine in DMSO at 130°C provides rapid access to 3-aminobenzo[b]thiophenes in 58-96% yield. This transformation has been applied in the synthesis of the thieno

Full text of DOI:10.1039/c5ob00819k

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Microwave-assisted synthesis of 3-aminobenzo[b]-
thiophene scaffolds for the preparation of kinase
inhibitors†
Cite this: DOI: 10.1039/c5ob00819k
Mark C. Bagley,*a Jessica E. Dwyer,a Maria D. Beltran Molina,b Alexander W. Rand,a
Hayley L. Randa and Nicholas C. O. Tomkinsonb
Microwave irradiation of 2-halobenzonitriles and methyl thioglycolate in the presence of triethylamine in
DMSO at 130 °C provides rapid access to 3-aminobenzo[b]thiophenes in 58–96% yield. This transform-
ation has been applied in the synthesis of the thieno[2,3-b]pyridine core motif of LIMK1 inhibitors, the
benzo[4,5]thieno[3,2-e][1,4]diazepin-5(2H)-one scaffold of MK2 inhibitors and a benzo[4,5]thieno[3,2-d]-
pyrimidin-4-one inhibitor of the PIM kinases.
Received 23rd April 2015,
Accepted 11th May 2015
DOI: 10.1039/c5ob00819k
www.rsc.org/obc
Introduction
Benzothiophenes are naturally-occurring heterocycles, found
in petroleum deposits in their simplest form but also discov-
ered recently as a motif in more complex glycosides isolated
from the roots of E. grijissii.1 Benzothiophenes are important
components of organic semiconductors due to their potential
for elongated and highly delocalised electronic structures.2,3
Substituted benzothiophenes have also found application in
drug discovery as highly-privileged structures and valuable
building blocks in medicinal chemistry, being incorporated
into tubulin polymerisation inhibitors,4,5 acetyl-CoA carboxy-
lase inhibitors,6 antidepressants,7 and as estrogen receptor
modulators.8,9 Benzothiophenes are present in a number of
clinical agents, including Raloxifene,10 a selective estrogen
receptor modulator, Zileuton,11 an inhibitor of 5-lipoxygenase
and leukotriene biosynthesis used for the treatment of
asthma, and the antifungal agent Sertaconazole, which inhi-
bits the synthesis of ergosterol.12
Scaffolds based upon 2- or 3-aminobenzo[b]thiophenes
have enormous potential for further derivatization and have
shown great promise in fragment-based drug discovery and in
hit identification or lead development, including approaches
towards antimitotic agents5,13 and in the development of
inhibitors of kinase targets, such as the LIMK protein family,14
PIM-kinases15 and MAPK-2 kinase (MK2) (Fig. 1).16,17
A
number of 3-aminothieno[2,3-b]pyridine-2-carboxamide hits,
Fig. 1 Aminobenzothiophene scaffolds in drug discovery.
aDepartment of Chemistry, School of Life Sciences, University of Sussex, Falmer,
Brighton, East Sussex, BN1 9QJ, UK. E-mail: m.c.bagley@sussex.ac.uk
bWestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde,
such as 1, were identified from high throughput screening
(HTS) as inhibitors of LIMK1, leading to the development of
tricyclic derivatives such as 2a and the benzothieno[3,2-d]pyri-
Glasgow, G1 1XL, UK
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob00819k
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midine 2b as a LIMK1 inhibitor lead candidate, to disrupt transition metal-mediated processes from the corresponding
actin polymerisation and thus prevent the metastatic potential 3-halobenzo[b]thiophenes.39 However, methods for the syn-
of tumour cells where LIMK is over-expressed.14
thesis of 3-halobenzo[b]thiophenes are currently fairly limited.
Benzothienopyrimidinones have been investigated as PIM In particular, routes can be problematic when using ring halo-
kinase inhibitors.15 The PIM kinases (PIM1, PIM2 and PIM3) genation due to the low reactivity of the heteroaryl unit and its
have been implicated in tumourigenesis and simultaneous tar- functional group compatibility.40–43 The 5-endo-dig halocyclisa-
geting of all three isoforms has presented itself as a promising tion of ortho-alkynylaryl thiophenol derivatives offers an
approach in cancer therapy, with PIM triple knockout mice alternative approach,44–48 but this requires installation of an
found to be viable and fertile.18 The benzothiophene scaffold alkyne by metal-catalyzed cross-coupling followed by cyclisa-
was again identified from an initial HTS hit,15 leading to the tion, mediated by a halogen-containing electrophile, so can
development of a range of potent and selective benzo[b]thio- exhibit a number of inherent disadvantages.
phene-derived inhibitors such as 3 with nM activity (Ki values
of 2, 3 and 0.5 nM against PIM1, PIM2 and PIM3, respectively) rapid preparation of 3-halo and 3-amino-2-substituted benzo-
with oral bioavailability in mouse models. [b]thiophenes suitable for elaboration to a range of kinase
Herein, we present an annulation-based method for the
Examples of aminobenzothiophene derivatives are also inhibitors.49 It employs microwave irradiation as a convenient
found amongst inhibitors of the mitogen activated protein platform for fast reaction kinetics, and to improve reaction
kinase (MAPK) family of enzymes. These enzymes are essential efficiency, and avoids the need for metal-catalyzed processes to
for inflammatory cell signalling events and contain historically establish the parent heterocycle. This method is shown to be
popular drug targets for inflammatory diseases, including suitable to access the pharmacophore of a range of biologi-
rheumatoid arthritis and Crohn’s disease because of their cally-active scaffolds for application in medicinal chemistry
involvement in the production of pro-inflammatory cyto- and drug discovery.
kines,19 as well as being implicated in accelerated cellular
ageing in Werner syndrome (WS) via p38.20–23 MAPK-activated
protein kinase (MK2) is a rate-limiting kinase downstream of
Results and discussion
p38 in the MAPK pathway and has been the subject of many
studies in recent years,24 as MK2 knock-out mice possess
The benzothiophene-containing chemotypes appearing in
recent drug discovery programmes (Fig. 1) feature, or could in
principle be derived from, electron-poor aminobenzothio-
phene intermediates or their 7-aza analogues (Scheme 1). For
normal healthy phenotypes whereas p38 knock-out mice are
lethal.25 The aminobenzo[b]thiophene derivative PF-3644022
shows excellent kinase selectivity for MK2, in vivo potency on a
nanomolar scale and projected ADME characteristics that
suggested it was suitable for oral human dosing.17,26,27 However,
PF-3644022 was found to result in hepatotoxicity in dogs27 and
so the analogue PF029 was developed and exhibited an improved
toxicological profile with no loss of cellular potency. This was
rationalized through installation of a metabolic shunt onto the
reactive diazepinone ring and extension of the biaryl ring section
to increase the compound’s cationic character, thus reducing its
molecular affinity for transporter proteins.
As part of our interest in the synthesis of MAPK inhibitors
for the study of cellular ageing in Werner syndrome,20,28–33 the
benzothiophene scaffold, and its selectivity and cellular activity
profile for MK2 exemplified by PF-3644022, made it an attractive
target for synthesis. We have shown that treating young WS cell
cultures with p38 MAPK inhibitors can bring about a complete
reversal of the ageing phenotype, giving increased replicative
life-span, growth rates comparable to normal young cells and a
reduction in levels of F-actin stress fibres.20,23 These findings
suggested that WS could be amenable to therapeutic interven-
tion, but with high toxicity and poor kinase selectivity exhibited
in vivo by many p38 inhibitors,34–36 an inhibitor scaffold that
targeted the downstream kinase MK2 would offer a promising
alternative target.20,37
With such a range of biological properties, there is a conti-
nuing interest in the search for new methods to access substi-
tuted benzothiophenes.38 One approach, with the potential to
incorporate diversity into a target library, would be to employ Scheme 1 Benzothiophene precursors to kinase inhibitors.
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example, the PIM kinase inhibitor scaffold 4 has been heating, under basic conditions was complete in 3 min at
accessed from 5-bromobenzothiophene 5a, using the halogen 100 °C and gave the carboxylic acid 11 in excellent yield. Sub-
as a handle for library diversification in a late-stage Suzuki sequent heating with excess bromine and sodium acetate in
coupling.15 Similarly, it could be hypothesized that inhibitors glacial acetic acid did give 3-bromobenzothiophene 13 in good
of MK2 for study in WS cells, such as PF-3644022 (Fig. 1), yield after esterification using methyl iodide on a number of
could be prepared from the same core motif 5, using 5-nitro- occasions. However, the bromination was found to be highly
benzothiophene 5b, rather than by the functionalization of variable and efforts to develop an alternative process using
6-nitroquinoline as reported by Anderson et al.17 This microwave heating were constantly frustrated56 and so a more
approach would enable the synthesis of a range of diverse reliable and efficient route was sought. The poor yield of this
chemical tools from a single common template. The original bromination reaction is catalogued in a recent report.57
route to MK2 hit compound 6a, prior to the development of
In an alternative approach, our success in the microwave-
PF-3644022,16 employed cinnamic acid 8a in reaction with assisted synthesis of 10 was adapted to incorporate an amino
thionyl chloride in chlorobenzene at 120 °C to establish the group at C-3, amenable by diazotization chemistry to provide
3-chlorobenzothiophene scaffold 7a (Scheme 1).50 Unfortu- efficient access to 3-bromobenzothiophene 13. The cyclocon-
nately this route would be wholly inappropriate for the syn- densation of methyl thioglycolate with 2-nitrobenzonitriles
thesis of benzothiophene 7b for elaboration to the desired under basic conditions has been established by Beck,58–60 and
intermediate 6b on route to PF-3644022, as altering the substi- adapted methods with halide displacement have also been
tuent-directing effects to a nitro group results in poor yields reported.61–64 By switching the base from NaOMe61 to Et3N63
and inseparable mixtures of 7b and 7c in the benzothiophene and heating either 5-bromo-2-fluorobenzonitrile (14a) or
synthesis, as well as giving other side products, as reported by 2-fluoro-5-nitrobenzonitrile (14b) and methyl thioglycolate
Higa.51 Hence an alternative route had to be sought.
gave the corresponding 3-aminobenzothiophene 5a,b in very
Our first approach towards scaffold 6b used an alternative high yield (Scheme 3), e.g. for 5b either at 100 °C in DMSO for
and established method to access 3-halobenzothiophenes by 2 h using conductive heating (95% yield) or under microwave
halogenation of the corresponding benzothiophene.40 The irradiation at 130 °C for 11 min (94% yield), after simply
condensation of methyl thioglycolate with 2-chloro-5-nitrobenz- pouring the reaction mixture into ice-water and collecting the
aldehyde (9) under basic conditions gave methyl 5-nitrobenzo[b]- product by filtration. Subsequent deaminative bromination60
thiophene-2-carboxylate (10) in high yield (Scheme 2). We have of aminobenzo[b]thiophene 5b using tert-butyl nitrite in aceto-
shown in previous work how microwave dielectric heating can nitrile in the presence of copper(II) bromide gave the target
be used to dramatically reduce reaction times in the synthesis bromobenzothiophene 13 in excellent yield by this much more
of inhibitor scaffolds.30,32,33,37,52 Given that elevated tempera- direct route.
ture has promoted this,53,54 and a closely-related process for
The scope of this method was further explored by investi-
the synthesis of 2-acetylbenzothiophenes,55 we carried out this gating a number of substrates (Scheme 4, Table 1), suitable for
transformation under microwave irradiation at 90 °C to give
the benzothiophene 10 in good yield, whilst shortening the
reaction time from 17 h to 15 min. Selective halogenation at
C-3 of 10 was facilitated in a convoluted sequence of reactions
via the carboxylic acid 11 to overcome poor heterocycle reactiv-
ity.40 Saponification, again conducted by microwave dielectric
Scheme 3 Reagents and conditions: (i) Et3N, DMSO, 100 °C, 2 h; H2O;
(ii) Et3N, DMSO, microwaves, 130 °C, 11 min; H2O; (iii) tert-BuONO,
CuBr2, MeCN, 0 °C; RT, 2 h; HCl (aq.).
Scheme 2 Reagents and conditions: (i) K2CO3, DMF, RT, 17 h; (ii)
K2CO3, DMF, microwaves, 90 °C, 15 min; (iii) NaOH, MeOH–H2O, reflux,
3 h; (iv) NaOH, MeOH–H2O, microwaves, 100 °C, 3 min; (v) Br2, AcOH,
NaOAc, 55 °C, 48 h; (vi) MeI, K2CO3, DMF, RT, 3 h.
Scheme 4 Synthesis of benzothiophenes 5a–h and 7-aza–16.
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Table 1 Scope of the microwave-assisted synthesis of 3-amino ben-
zothiophenes 5a–h (Y = NH2) and the 7-aza analogue 16
Time/
mina
Yieldb
(%)
Entry Substrate
R
X
Z
Product
1
2
3
4
14a
14b
14c
14d
14e
14f
14g
14g
14g
14h
15a
15b
15c
5-Br
5-NO2
5-Cl
4-CF3
4-NO2
5-Ph
H
H
H
5-CF3
H
H
F
F
F
F
F
F
F
CH 11
CH 11
CH 11
CH 18
CH 35
CH 15
CH 15
5a
5b
5c
96
94
92
5d (R = 6-CF3) 80
5e (R = 6-NO2) 67
5f
5g
5g
5g
5h
16
16
16
5
6c
7
85
65
23
47
88
66
69
51
8
9
10
11
12
13
Br CH 15
I
F
F
Cl
Br
CH 15
CH 20
N
N
N
15
15
15
Scheme 5 Reagents and conditions: (i) Pd(OAc)2 (5 mol%), Cs2CO3,
(
)-BINAP (13 mol%), PhMe, microwaves, 150 °C, 75 min; (ii) TFA, CH2Cl2,
H
RT, 4.5 h; (iii) NaOMe, MeOH, 50 °C, 2 h; reflux, 2 h; HCl (aq.).
a Hold time at the given temperature, as measured by the in-built IR
sensor, by modulation of the initial microwave power. b Isolated yield
of product 5 or 16 after reaction according to Scheme 4, cooling in a
stream of compressed air and pouring the reaction mixture into iced
water. c Product was isolated by aqueous work up, followed by
purification by column chromatography on silica gel.
Finally, an application of our microwave-assisted method to
access a pre-functionalized benzothiophene 5i for direct trans-
formation to a benzo[4,5]thieno[3,2-d]pyrimidin-4-one scaffold
21 as a chemical tool for PIM kinase inhibition15,66 was investi-
gated. This inhibitor exhibits subnanomolar to single-digit
nanomolar Ki values against all three PIM kinases and has
been co-crystallised with PIM1, guiding subsequent SAR
studies. It was postulated that rather than introducing the
cyclopropylvinyl group by a late-stage Suzuki coupling, in
accordance with the original diversification study, this group
could be incorporated from the start in order to access 20
directly. To that end, 2-fluorobenzonitrile 14i was prepared by
the Pd-catalyzed Suzuki–Miyaura coupling of 5-bromo-2-fluoro-
benzonitrile (14a) and the corresponding boronate ester at
80 °C,15 and heated with methyl thioglycolate in the presence
elaboration to a range of benzothiophene-containing scaffolds
found in drug discovery (Fig. 1).
It was found that the process was most efficient for highly
electron-poor precursors, such as 14a–d (entries 1–4), and was
generally most effective with 2-fluorides, but could also accom-
modate bromides and iodides albeit with reduced efficiency
(Table 1, entries 8 and 9). In most cases a very simple work up
procedure was effective, providing benzothiophenes 5a–h in
65–96% yield in reaction times varying between 11 and
35 min, depending upon substrate. The efficiency compared
well to other available methods (cf. Table 1, entry 7, with Beck
synthesis of 5g,58 52% yield after 20 h), and so this method
was adopted as the route of choice to access the benzothio-
phene scaffold. Furthermore, it was possible to apply the pro-
cedure to the synthesis of 7-azabenzothiophene 16 using
2-halonicotinonitriles 15a–c. Interestingly, the choice of
halogen as substrate did not cause much variation in the yield
of azabenzothiophene product 16 (entries 11–13), which rep-
resents the core heterocyclic motif of the 3-aminothieno[2,3-b]-
pyridine-2-carboxamide inhibitors14 of LIMK1.
Having developed this rapid microwave-assisted method to
prepare benzothiophenes, the 5-nitro analogue 13 was further
elaborated to the benzo[4,5]thieno[3,2-e][1,4]diazepin-5(2H)-
one MK2 inhibitor scaffold 6b. Buchwald–Hartwig coupling of
(R)-tert-butyl (1-aminopropan-2-yl)carbamate (17) and bromo-
benzothiophene 13 gave a good yield of the N-arylated product
18 under microwave irradiation at 150 °C after 75 min
(Scheme 5). Subsequent Boc-deprotection using TFA and lacta-
mization by treatment with NaOMe using a modified pro-
cedure of Boschelli65 under conductive heating gave the MK2
inhibitor scaffold 6b, bearing suitable functionality for further
elaboration, in essentially quantitative yield.
Scheme 6 Reagents
and
conditions:
(i)
trans-2-cyclopropyl-
vinylboronic acid pinacol ester, Pd(Ph3)2Cl2 (10 mol%), 1 M Na2CO3,
DME/EtOH/H2O, 80 °C, 16 h; (ii) Et3N, DMSO, microwaves, 130 °C,
35 min; (iii) 2-chloroacetonitrile, HCl, dioxane, RT, 16 h; (iv) Me2NH,
EtOH, RT, 16 h; SCX column, MeOH/CH2Cl2; NH3, MeOH.
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of Et3N in DMSO at 130 °C for 35 min under microwave form mass spectrometry, NSI refers to nano-electrospray ioniza-
irradiation to give the corresponding benzothiophene 5i in tion and EI refers to electron ionization. A number of high
reasonable yield after purification by column chromatography resolution mass spectra were obtained courtesy of the EPSRC
(Scheme 6). The cyclopropylvinyl group was found to be com- Mass Spectrometry Service at University College of Wales,
patible with the subsequent chemistry: reaction of 5i with Swansea, UK using the ionization methods specified.
chloroacetonitrile in 4 N HCl in dioxane gave chloromethyl
Synthetic procedures
derivative 19 which, on reaction with dimethylamine, under-
went further cyclization to give the thienopyrimidinone scaffold
General procedure for synthesis of 3-aminobenzo[b]thio-
20 after purification by immobilization on an acidic resin. Thus phenes 5 from benzonitriles 14. A mixture of the benzonitrile
the method delivered this known PIM kinase inhibitor by an 14 (1.0 equiv.), methyl thioglycolate (1.05 equiv.) and triethyl-
extremely rapid route, suitable for biological study.
amine (3.1 equiv.) in dry DMSO (2 M) was irradiated in a
Biotage Initiator 2.5 EXP EU or CEM Discover microwave
synthesizer at 130 °C for the time specified (hold time) by
modulating the initial microwave power. After cooling to room
temperature in a stream of compressed air, the reaction
mixture was poured into ice-water and the resulting solid col-
Experimental
Materials and methods
Commercially available reagents were used without further lected, washed with water and dried in vacuo to give the
purification; solvents were dried by standard procedures. Light desired product.
petroleum refers to the fraction with bp 40–60 °C and ether
Methyl
3-amino-5-bromobenzo[b]thiophene-2-carboxylate
refers to diethyl ether. Unless otherwise stated, reactions were (5a). 5-Bromo-2-fluorobenzonitrile (14a) (0.50 g, 2.50 mmol),
performed under an atmosphere of air. Flash chromato- methyl thioglycolate (0.22 mL, 2.60 mmol) and triethylamine
graphy was carried out using Merck Kieselgel 60 H silica or (1.10 mL, 7.75 mmol) were reacted according to the above
Matrex silica 60. Analytical thin layer chromatography was general procedure for 11 min to give the title compound
carried out using aluminium-backed plates coated with Merck (700 mg, 96%) as a brown solid, mp 170–171 °C (Found [ES+]:
Kieselgel 60 GF254 that were visualised under UV light (at 254 285.9535. C10H979BrNO2S [MH] requires 285.9532); IR (neat)
and/or 360 nm). Microwave irradiation experiments were per- νmax/cm−1 3477 (N–H), 3363 (N–H), 2954 (C–H), 1681 (CvO);
formed in a sealed Pyrex tube using a self-tunable CEM Discover, 1H NMR (400 MHz, d6-DMSO) δH/ppm 8.44 (1H, d, J = 1.9 Hz,
CEM Explorer or Biotage Initiator 2.5 EXP EU focused monomo- 4-CH), 7.82 (1H, d, J = 8.6 Hz, 7-CH), 7.64 (1H, dd, J = 8.6, 1.9
dal microwave synthesizer at the given temperature using the Hz, 6-CH), 7.17 (2H, bs, NH2), 3.79 (3H, s, Me); 13C NMR
instrument’s in-built IR temperature measuring device, by (101 MHz, d6-DMSO) δC/ppm 164.6 (C), 148.6 (C), 137.7 (C),
varying the irradiation power (initial power given in parentheses). 133.2 (C), 131.0 (C), 125.7 (CH), 125.2 (CH), 117.1 (CH), 96.1
Fully characterized compounds were chromatographically (C), 51.4 (Me); m/z (ES) 286 (M[79Br]H+, 100%).
homogeneous. Melting points were determined on a Kofler
Methyl
3-amino-5-nitrobenzo[b]thiophene-2-carboxylate
hot stage apparatus or Stanford Research Systems Optimelt (5b). 2-Fluoro-5-nitrobenzonitrile (14b) (0.50 g, 3.0 mmol),
and are uncorrected. Specific rotations were measured at the methyl thioglycolate (0.30 mL, 3.3 mmol) and triethylamine
indicated temperature (in °C) using a ADP440 polarimeter (Bel- (1.3 mL, 9.3 mmol) were reacted according to the above general
lingham + Stanley) at the sodium D line and are given in deg procedure for 11 min to give the title compound (0.71 g, 94%) as an
cm−3 g−1 dm−1 with concentration c in 10−2 g cm−3. Infra-red orange solid, mp 243.4–244.1 °C (acetone) (lit.,67 mp 244–246 °C)
spectra were recorded in the range 4000–600 cm−1 on a Perkin- (Found [FTMS]: 253.0280. C10H9N2O4S [MH] requires 253.0278); IR
Elmer 1600 series FTIR spectrometer using an ATR probe or a (neat) νmax/cm−1 3445 (N–H), 3342 (N–H), 1681 (CvO), 1572
1
Shimadzu IRAffinity-1 equipped with an ATR accessory and are (NO2), 1432 (C–C), 1328 (NO2), 1276 (C–O), 1093 (C–O); H NMR
reported in cm−1. NMR spectra were recorded using a Varian (500 MHz, d6-DMSO) δH/ppm 9.24 (1H, d, J = 2 Hz, 4-CH), 8.29
VNMRS instrument operating at 400 or 500 MHz or a Bruker (1H, dd, J = 9, 2 Hz, 6-CH), 8.12 (1H, d, J = 9 Hz, 7-CH), 7.47 (2H,
Avance III 400 MHz or Bruker Avance DRX 500 MHz for 1H bs, NH2), 3.82 (3H, s, Me); 13C NMR (100 MHz, d6-DMSO) δC/ppm
spectra and 100 or 126 MHz for 13C spectra; J values were 164.2 (C), 149.6 (C), 144.9 (C), 144.5 (C), 131.4 (C), 124.3 (CH),
recorded in Hz and multiplicities were expressed by the usual 122.0 (CH), 119.4 (CH), 96.8 (C), 51.4 (Me); m/z (EI) 252 (M•+,
1
conventions. Low resolution mass spectra were determined 100%), 219 (72). H and 13C NMR spectroscopic analyses were in
using a Waters Q-TOF Ultima using electrospray positive good agreement with literature data.67
ionization, A Waters LCT premier XE using atmospheric
Methyl
3-amino-5-chlorobenzo[b]thiophene-2-carboxylate
pressure chemical ionization (APcI), an Agilent 6130 single (5c). 5-Chloro-2-fluorobenzonitrile (14c) (0.50 g, 3.2 mmol),
quadrupole with an APcI/electrospray dual source, a Fisons methyl thioglycolate (0.30 mL, 3.36 mmol) and triethylamine
Instrument VG Autospec using electron ionization at 70 eV (1.38 mL, 9.92 mmol) were reacted according to the above
(low resolution) or a ThermoQuest Finnigan LCQ DUO electro- general procedure for 11 min to give the title compound
spray, unless otherwise stated. TOFMS refers to time-of-flight (710 mg, 92%) as a colourless solid, mp 170–172 °C (Found
mass spectrometry, ES refers to electrospray ionization, CI refers [ES+]: 242.0039. C10H935ClNO2S [MH] requires 242.0037); IR
to chemical ionization (ammonia), FTMS refers to Fourier trans- (neat) νmax/cm−1 3477 (N–H), 3365 (N–H), 1681 (CvO), 1278
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1
(C–O); H NMR (500 MHz, d6-DMSO) δH/ppm 8.30 (1H, d, J = 149.9 (C), 139.6 (C), 138.0 (C), 136.2 (C), 132.2 (C), 129.0 (CH),
2.1 Hz, 4-CH), 7.88 (1H, d, J = 8.6 Hz, 7-CH), 7.53 (1H, dd, J = 127.5 (CH), 127.2 (CH), 126.7 (CH), 123.6 (CH), 121.0 (CH),
8.6, 2.1 Hz, 6-CH), 7.17 (2H, bs, NH2), 3.79 (3H, s, Me); 13C NMR 95.0 (C), 51.2 (Me); m/z (ES) 284 (MH+, 100%).
(126 MHz, d6-DMSO) δC/ppm 164.6 (C), 148.7 (C), 137.3 (C),
Methyl
3-aminobenzo[b]thiophene-2-carboxylate
(5g).
132.7 (C), 129.1 (C), 128.4 (CH), 125.0 (CH), 122.7 (CH), 96.2 (C), 2-Fluorobenzonitrile (14g) (0.16 mL, 1.5 mmol), methyl thio-
51.4 (Me); m/z (ES) 242 (M[35Cl]H+, 100%). 1H NMR spectro- glycolate (0.135 mL, 1.5 mmol) and triethylamine (0.63 mL,
scopic analyses were in good agreement with literature data.15
4.5 mmol) were reacted according to the above general pro-
Methyl 3-amino-6-(trifluoromethyl)benzo[b]thiophene-2-car- cedure for 15 min to give the title compound (203 mg, 65%) as
boxylate (5d). 2-Fluoro-4-(trifluoromethyl)benzonitrile (14d) a purple solid, mp 107.6–107.8 °C (MeOH–H2O) (lit.,58 mp
(0.50 g, 2.64 mmol), methyl thioglycolate (0.24 mL, 110–111 °C) (Found [ES+]: 208.0434. C10H10NO2S [MH] requires
2.73 mmol) and triethylamine (1.14 mL, 8.20 mmol) were 208.0432); IR (neat) νmax/cm−1 3434 (N–H), 3337 (N–H), 1659
reacted according to the above general procedure for 20 min (CvO), 1520, 1289 (C–O); 1H NMR (500 MHz, d6-DMSO)
to give the title compound (580 mg, 80%) as a colourless δH/ppm 8.13 (1H, d, J = 8.1 Hz, 4-CH), 7.82 (1H, d, J = 8.1 Hz,
solid, mp 159–161 °C (Found [ES+]: 298.0120. C11H8F3NNaO2S 7-CH), 7.50 (1H, m, 6-CH), 7.39 (1H, m, 5-CH), 7.15 (2H, bs,
[MNa] requires 298.0124); IR (neat) νmax/cm−1 3471 (N–H), NH2), 3.78 (3H, s, Me); 13C NMR (101 MHz, d6-DMSO) δC/ppm
3344 (N–H), 2964 (C–H), 1664 (CvO); 1H NMR (400 MHz, 164.8 (CvO), 149.8 (3-C), 138.8 (7α-C), 131.4 (3α-C), 128.5
d6-DMSO) δH/ppm 8.38–8.32 (2H, 5-CH and 7-CH), 7.72 (1H, d, (6-CH), 123.8 (5-CH), 123.1 (4-CH), 123.1 (7-CH), 94.4 (2-C),
J = 8.7 Hz, 4-CH), 7.26 (2H, bs, NH2), 3.82 (3H, s, Me); 13C NMR 51.2 (Me); m/z (ES) 207 (M•+, 93%), 176 (30), 175 (100),
(126 MHz, d6-DMSO) δC/ppm 164.5 (C), 148.8 (C), 138.9 (C), 147 (34), 146 (37). NMR spectroscopic analyses were in good
134.1 (C), 128.4 (q, 2JC–F = 31.8 Hz, C), 124.2 (q, 1JC–F = 272.7 Hz, agreement with literature data.59,68
C), 124.1 (CH), 121.0–120.7 (m, CH), 120.3–120.0 (m, CH), 97.4
(C), 51.5 (Me); m/z (ES) 276 (MH+, 100%).
Methyl 3-amino-5-(trifluoromethyl)benzo[b]thiophene-2-car-
boxylate (5h). 2-Fluoro-5-(trifluoromethyl)benzonitrile (14h)
Methyl 3-amino-6-nitrobenzo[b]thiophene-2-carboxylate (5e). (0.50 g, 2.6 mmol), methyl thioglycolate (0.24 mL, 2.73 mmol)
2-Fluoro-4-nitrobenzonitrile (14e) (0.50 g, 3.00 mmol), methyl and triethylamine (1.14 mL, 8.20 mmol) were reacted accord-
thioglycolate (0.28 mL, 3.15 mmol) and triethylamine ing to the above general procedure for 20 min to give the
(1.29 mL, 9.30 mmol) were reacted according to the above title compound (640 mg, 88%) as a colourless solid, mp
general procedure for 35 min to give the title compound 140–141 °C (Found [ES+]: 298.0121. C11H8F3NNaO2S [MNa]
(510 mg, 67%) as a colourless solid, mp 228–231 °C (lit.,58 mp requires 298.0120); IR (neat) νmax/cm−1 3468 (N–H), 3335
229–231 °C) (Found [ES+]: 275.0101. C10H8N2NaO4S [MNa] (N–H), 1664 (CvO); 1H NMR (400 MHz, d6-DMSO) δH/ppm
requires 275.0097); IR (neat) νmax/cm−1 3489 (N–H), 3367 (N– 8.67 (1H, bs, 4-CH), 8.09 (1H, d, J = 8.5 Hz, 7-CH), 7.79 (1H,
H), 1697 (CvO), 1624 (C–O); 1H NMR (400 MHz, d6-DMSO) δH/ dd, J = 8.5, 1.5 Hz, 6-CH), 7.34 (2H, s, NH2), 3.82 (3H, s, Me);
ppm 8.90 (1H, d, J = 2.1 Hz, 7-CH), 8.37 (1H, d, J = 8.7 Hz, 13C NMR (101 MHz, d6-DMSO) δC/ppm 164.5 (C), 149.3 (C),
2
1
4-CH), 8.19 (1H, dd, J = 8.7, 2.1 Hz, 5-CH), 7.30 (2H, bs, NH2), 142.5 (C), 131.3 (C), 124.9 (q, JC–F = 32.7 Hz, C), 124.5 (q, JC–F
3.83 (3H, s, Me); 13C NMR (101 MHz, d6-DMSO) δC/ppm 164.3 = 272.1 Hz, C), 124.4 (C–H), 124.1 (m, C–H), 120.7 (m, C–H),
(C), 148.4 (C), 147.0 (C), 138.8 (C), 135.6 (C), 124.2 (CH), 119.8 96.2 (C), 51.4 (Me); m/z (ES) 276 (MH+, 100%).
(CH), 118.5 (CH), 99.8 (C), 51.7 (Me); m/z (ES) 253 (MH+, 20%),
Methyl (E)-3-amino-5-(2-cyclopropylvinyl)benzo[b]thiophene-
252 (M•+, 100). 1H NMR spectroscopic analyses were in good 2-carboxylate (5i). (E)-5-(2-Cyclopropylvinyl)-2-fluorobenzoni-
agreement with literature data.63
trile (14i) (0.25 g, 1.33 mmol), methyl thioglycolate (0.12 mL,
Methyl 3-amino-5-phenylbenzo[b]thiophene-2-carboxylate 1.39 mmol) and triethylamine (0.57 mL, 4.12 mmol) were
(5f). 4-Fluoro-[1,1′-biphenyl]-3-carbonitrile (14f) (0.30 g, reacted according to modified general procedure for
a
1.52 mmol), methyl thioglycolate (0.14 mL, 1.59 mmol) and 35 min. After cooling in a stream of compressed air, EtOAc
triethylamine (0.65 mL, 4.74 mmol) were reacted according to (25 mL) was added and the solution was washed sequentially
a modified general procedure for 15 min. After cooling in with water (3 × 25 mL) and brine (3 × 25 mL), dried over
a stream of compressed air, EtOAc (25 mL) was added and the MgSO4 and evaporated in vacuo. Purification by flash chrom-
solution was washed sequentially with water (3 × 25 mL) and atography on silica gel, eluting with light petroleum–EtOAc
brine (3 × 25 mL), dried over MgSO4 and evaporated in vacuo. (4 : 1), gave the title compound (210 mg, 58%) as a colourless
Purification by flash chromatography on silica gel, eluting solid, mp 131–132 °C (Found [ES+]: 274.0899. C15H16NO2S [M]
with light petroleum–EtOAc (4 : 1), gave the title compound requires 274.0896); IR (neat) νmax/cm−1 3481 (N–H), 3365 (N–
(380 mg, 85%) as a colourless solid, mp 96–97 °C (Found [ES+]: H), 1672 (CvO); 1H NMR (400 MHz, d6-DMSO) δH/ppm 8.12
284.0741. C16H14NO2S [MH] requires 284.0740); IR (neat) νmax
/
(1H, d, J = 1.6 Hz, 4-CH), 7.71 (1H, d, J = 8.5 Hz, 7-CH), 7.50
cm−1 3439 (N–H), 3338 (N–H), 2949 (C–H), 1658 (CvO); 1H (1H, dd, J = 8.5, 1.6 Hz, 6-CH), 7.12 (2H, bs, NH2), 6.53 (1H, d,
NMR (400 MHz, d6-DMSO) δH/ppm 8.54 (1H, s, 4-CH), 7.91 J = 15.8 Hz, CH), 5.93 (1H, dd, J = 15.8, 9.1 Hz, CH), 3.78
(1H, d, J = 8.5 Hz, 7-CH), 7.84 (1H, d, J = 8.5 Hz, 6-CH), 7.78 (3H, s, Me), 1.69–1.55 (1H, m, CH), 0.86–0.80 (2H, m,
(2H, d, J = 7.5 Hz, 2′,6′-PhH), 7.51 (2H, app t, J = 7.5 Hz, 3′,5′- CHH), 0.56–0.49 (2H, m, CHH); 13C NMR (101 MHz, d6-
PhH), 7.39 (1H, t, J = 7.5 Hz, 4′-PhH), 7.26 (2H, bs, NH2), 3.80 DMSO) δC/ppm 164.8 (C), 149.7 (C), 136.9 (C), 135.2 (C), 133.7
(3H, s, Me); 13C NMR (101 MHz, d6-DMSO) δC/ppm 164.8 (C), (CH), 131.9 (C), 126.4 (CH), 126.4 (CH), 123.1 (CH), 119.4 (CH),
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94.9 (C), 51.2 (Me), 14.4 (CH), 7.1 (CH2); m/z (ES) 274 (MH+, of compressed air, the reaction mixture was poured into water
100%). and the resulting solid filtered under reduced pressure, washed
(3R)-3-Methyl-9-nitro-1,2,3,4-tetrahydro-5H-[1]benzothieno- with water and dried in air to give the title compound (0.84 g,
[3,2-e][1,4]diazepin-5-one (6b). A solution of (R)-methyl 3- 88%) as an off-white solid, mp 216.8–218.5 °C (lit.,69 mp
((2-((tert-butoxycarbonyl)amino)propyl)amino)-5-nitrobenzo[b]- 213–215 °C), with identical spectroscopic properties.
thiophene-2-carboxylate (18) (0.30 g, 0.73 mmol) in TFA (10%
5-Nitrobenzo[b]thiophene-2-carboxylic acid (11), using con-
v/v in CH2Cl2) (5.7 mL, 7.3 mmol) was stirred at room tempera- ductive heating. A solution of aqueous NaOH (1 M; 5 mL,
ture for 4.5 h. When salt formation was confirmed by TLC ana- 5 mmol) was added to a solution of methyl 5-nitrobenzo[b]-
lysis [Rf 0.3 in MeOH–CH2Cl2 (1 : 9)] the mixture was thiophene-2-carboxylate (10) (0.40 g, 1.7 mmol) in MeOH
evaporated in vacuo. The residue was dissolved in a mixture of (5.5 mL) and the mixture was heated at reflux for 3 h. After
MeOH (5 mL) and NaOMe (25 wt% in MeOH; 1 mL, 4.4 mmol) cooling to room temperature, the solution was acidified with
and warmed to 50 °C for 2 h before heating at reflux for 2 h. 1 M HCl (aq.) and the resulting solid filtered under reduced
The reaction mixture was then allowed to cool to room tem- pressure and dried in air to give the title compound (0.36 g,
perature, cooled in an ice bath, neutralized by the addition of 95%) as an off-white powder, mp 241.4–242.7 °C (lit.,71 mp
hydrochloric acid (1 M) and stirred at 0 °C for 30 min. The 239–241 °C) (Found [TOFMS]: 224.0020. C9H6NO4S [MH]
resulting solid was isolated by filtration under reduced requires 224.0018); IR (neat) νmax/cm−1 2844 (br, O–H), 1670
pressure, washed with water and dried in air to give the title (CvO), 1600 (C–C), 1511 (NO2), 1344 (NO2), 1313 (C–O); 1H
compound (0.18 g, 100%) as a red powder, mp 337.4–342.4 °C NMR (500 MHz, CD3OD) δH/ppm 8.87 (1H, d, J = 2 Hz, 4-CH),
(dec.) (Found [ES+]: 278.0590. C12H1sN3O3S [MH] requires 8.30 (1H, dd, J = 9, 2 Hz, 6-CH), 8.24 (1H, s, 3-CH), 8.15 (1H, d,
278.0594); [α]2D4 +110.6 (c 0.04, MeOH); IR (neat) νmax/cm−1 J = 9 Hz, 7-CH); 13C NMR (125 MHz, CD3OD) δC/ppm 164.8 (C),
3307 (N–H), 1598 (CvO), 1501 (NO2), 1438 (C–C), 1318 (NO2), 148.9 (5-C), 147.5 (C), 140.3 (C), 140.0 (C), 132.0 (3-CH), 125.1
1
1102 (C–N), 736 (N–H); H NMR (500 MHz, d6-DMSO) δH/ppm (7-CH), 122.3 (4-CH), 121.9 (6-CH); m/z (EI) 223 (M•+, 100%),
9.03 (1H, d, J = 2 Hz, 10-CH), 8.22 (1H, dd, J = 9, 2 Hz, 8-CH), 195 (38), 149 (37). 1H NMR spectroscopic analyses were in
8.05 (1H, d, J = 9 Hz, 7-CH), 8.02 (1H, m, 1-NH), 7.95 (1H, d, J = good agreement with literature data.53
3 Hz, 4-NH), 3.60 (1H, m, 3-CH), 3.39 (2H, m, 2-CH2), 1.16 (3H,
5-Nitrobenzo[b]thiophene-2-carboxylic acid (11), using
d, J = 7 Hz, Me); 13C NMR (125 MHz, d6-DMSO) δC/ppm 164.2 microwave-assisted heating. A mixture of methyl 5-nitrobenzo-
(5-C), 145.3 (C), 144.2 (C), 141.8 (C), 132.9 (C), 123.8 (7-CH), [b]thiophene-2-carboxylate (10) (0.20 g, 0.84 mmol), aqueous
120.8 (8-CH), 118.6 (10-CH), 108.6 (C), 50.6 (2-CH2), 47.6 (3-CH), NaOH solution (1 M; 2.5 mL) and MeOH (3.5 mL) was irra-
18.6 (Me); m/z (ES) 277 (M•+, 87%), 262 (24), 234 (29), 206 (30).
diated at 100 °C for 3 min (hold time) in a pressure-rated glass
Methyl 5-nitrobenzo[b]thiophene-2-carboxylate (10), pre- tube (10 mL) using a CEM Discover microwave synthesizer by
pared under ambient conditions. Methyl thioglycolate moderating the initial power (100 W). After cooling in a flow of
(0.48 mL, 5.4 mmol) and K2CO3 (0.89 g, 6.5 mmol) were added compressed air, the reaction mixture was diluted with water,
sequentially to a solution of 2-chloro-5-nitrobenzaldehyde acidified with 1 M HCl and the resulting solid was filtered
(1.01 g, 5.4 mmol) in DMF (6.5 mL) and the mixture was under reduced pressure, washed with water and dried in air to
stirred at room temperature for 17 h. The reaction was then give the title compound (0.16 g, 94%) as an off-white powder,
quenched in ice-water and the resulting solid collected, mp 241.3–242.1 °C (lit.,71 mp 239–241 °C), with identical spec-
washed with water and dried in vacuo to give the title compound troscopic properties.
(1.22 g, 95%) as an off-white solid, mp 213.3–217.6 °C (lit.,69
mp 213–215 °C) (Found [FTMS
NSI]: 255.0435. According to a modified literature procedure,57 bromine
3-Bromo-5-nitrobenzo[b]thiophene-2-carboxylic acid (12).
+
p
C10H11N2O4S [MNH4] requires 255.0434); IR (neat) νmax/cm−1 (1.4 mL, 27 mmol) was added portion-wise to a solution of
3093 (C–H), 1701 (CvO), 1528 (NO2), 1439 (C–C), 1342 (NO2), 5-nitrobenzo[b]thiophene-2-carboxylic acid (11) (1.0 g,
1302 (C–O); 1H NMR (500 MHz, CDCl3) δH/ppm 8.80 (1H, d, J = 4.5 mmol) and anhydrous sodium acetate (1.13 g, 13 mmol) in
2 Hz, 4-CH), 8.32 (1H, dd, J = 9, 2 Hz, 6-CH), 8.20 (1H, s, glacial acetic acid (28 mL) under N2. A reflux condenser was
3-CH), 8.01 (1H, d, J = 9 Hz, 7-CH), 4.00 (3H, s, Me); 13C NMR fitted and the solution heated at 55 °C for 27 h. After cooling
(125 MHz, CDCl3) δC/ppm 162.2 (C), 147.4 (C), 145.9 (C), 138.3 to room temperature, the solution was poured into ice-water
(C), 137.2 (C), 130.7 (3-CH), 123.6 (7-CH), 121.2 (9-CH), 120.9 and the resulting solid isolated by vacuum filtration and dried
(7-CH), 52.9 (Me); m/z (EI) 237 (M•+, 100%), 206 (63), 160 (25). in air to give the title compound (1.02 g, 75%) as a yellow
1H NMR spectroscopic analyses were in good agreement with powder, mp 309.5–316.8 °C (lit.,40 mp 307–309 °C) (Found
literature data.53,70
[TOF MS]: 301.9126. C9H579BrNO4S [MH] requires 301.9123);
Methyl 5-nitrobenzo[b]thiophene-2-carboxylate (10), using IR (neat) νmax/cm−1 2961 (br, O–H), 1701 (CvO), 1600 (C–C),
microwave-assisted conditions. A mixture of 2-chloro-5-nitro- 1511 (NO2), 1347 (NO2), 1270 (C–O), 620 (C–Br); 1H NMR
benzaldehyde (0.75 g, 4.0 mmol), methyl thioglycolate (0.45 mL, (500 MHz, CD3OD) δH/ppm 8.83 (1H, d, J = 2 Hz, 4-CH), 8.39
5 mmol) and K2CO3 (0.67 g, 4.8 mmol) in DMF (4.5 mL) was (1H, dd, J = 9, 2 Hz, 6-CH), 8.21 (1H, d, J = 9 Hz, 7-CH); m/z (EI)
irradiated at 90 °C for 15 min (hold time) in a pressure-rated 303 (M[81Br]•+, 98%), 301 (M[79Br]•+, 96), 293 (17), 291 (13).
glass tube (35 mL) using a CEM Discover microwave synthesizer
Methyl
3-bromo-5-nitrobenzo[b]thiophene-2-carboxylate
by moderating the initial power (100 W). After cooling in a flow (13), from acid 12. According to a modified literature pro-
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cedure,57 iodomethane (0.46 mL, 7.4 mmol) was added to a general procedure for 15 min to give the title compound
solution of 3-bromo-5-nitrobenzo[b]thiophene-2-carboxylic (36 mg, 69%) as a yellow solid, mp 191 °C (dec.) (lit.,13 mp
acid (12) (1.12 g, 3.7 mmol) and K2CO3 (1.28 g, 9.2 mmol) in 194–196 °C) (Found [ES+]: 209.0380. C9H9N2O2S [MH] requires
DMF (15 mL). After stirring at room temperature for 3 h, the 209.0385); IR (neat) νmax/cm−1 3417 (N–H), 3314, 3202, 2943,
1
reaction mixture was quenched with saturated aqueous NH4Cl 1679 (CvO), 1291 (C–O), 1127 (C–O); H NMR (500 MHz, d6-
solution, poured into excess water and filtered under reduced DMSO) δH/ppm 8.68 (1H, dd, J = 4.6, 1.6 Hz, 6-CH), 8.54 (1H,
pressure. The collected solid was washed with water and dried dd, J = 8.1, 1.6 Hz, 4-CH), 7.46 (1H, dd, J = 8.1, 4.6 Hz, 5-CH),
in air to give the title compound (1.09 g, 93%) as an off-white 7.30 (2H, bs, NH2), 3.80 (3H, s, Me); 13C NMR (101 MHz,
powder, mp 211.5–212.5 °C (lit.,40 mp 211–212 °C) (Found d6-DMSO) δC/ppm 164.7 (CvO), 159.7 (7α-C), 150.7 (6-CH),
[TOF MS]: 315.9279. C10H779BrNO4S [MH] requires 315.9279); 147.7 (3-C), 131.4 (4-CH), 125.5 (3α-C), 119.4 (5-CH), 93.2 (2-C),
IR (neat) νmax/cm−1 3101 (C–H), 1691 (CvO), 1600 (C–C), 1514 51.4 (Me); m/z (EI) 208 (M•+, 100%), 177 (28), 176 (93), 148 (60).
(NO2), 1347 (NO2), 1089 (C–O), 1052 (C–O), 617 (C–Br); 1H 1H NMR spectroscopic analyses were in good agreement with
NMR (500 MHz, CDCl3) δH/ppm 8.90 (1H, d, J = 2 Hz, 4-CH), literature data.13
8.38 (1H, dd, J = 9, 2 Hz, 6-CH), 8.00 (1H, d, J = 9 Hz, 7-CH),
tert-Butyl [(2R)-1-aminopropan-2-yl]carbamate (17). Accord-
4.02 (3H, s, Me); 13C NMR (125 MHz, CDCl3) δc/ppm 161.0 (C), ing to a modified literature procedure,72 a solution of Boc-D-
146.5 (5-C), 144.6 (C), 138.9 (C), 131.0 (3α-C), 123.8 (7-CH), Ala-OH (0.50 g, 2.64 mmol) and HOBt·H2O (0.41 g, 3.0 mmol)
122.2 (6-CH), 121.3 (4-CH), 115.6 (3-CH), 53.0 (Me); m/z (EI) in CH2Cl2 (20 mL) was cooled to 0 °C and EDCI·HCl (0.58 g,
317 (M[81Br]•+, 100%), 315 (M[79Br]•+, 94), 286 (58), 284 (55).
Methyl
3.0 mmol) was added. The solution was allowed to warm to
3-bromo-5-nitrobenzo[b]thiophene-2-carboxylate room temperature and stirred for 30 min. The solution was
(13), from 3-aminobenzothiophene 5b. Following the pro- then cooled to 0 °C, aqueous NH3 (18.1 M; 0.6 mL) was added
cedure of Iaroshenko et al.,60 CuBr2 (0.94 g, 4.2 mmol) was drop-wise and the mixture was stirred at room temperature for
added to a solution of tert-butyl nitrite (0.45 mL, 3.8 mmol) in 30 min. Any solid residue was removed by filtration and the fil-
dry MeCN (11 mL) at 0 °C under argon. Methyl 3-amino-4- trate was washed sequentially with water (20 mL) and brine
nitrobenzo[b]thiophene-2-carboxylate (5b) (0.69 g, 2.7 mmol) (2 × 20 mL), dried (MgSO4) and evaporated in vacuo. Purifi-
was then added portion-wise and the solution kept at 0 °C cation by flash column chromatography on SiO2, gradient
until nitrogen evolution ceased. The reaction mixture was eluting with MeOH–CH2Cl2 (from 3–7% MeOH), gave Boc-D-
allowed to warm to room temperature, stirred for 2 h and then Ala-NH2 (0.37 g, 75%) as colourless crystals, mp
poured into dilute hydrochloric acid (10%; 25 mL). The 127.5–128.2 °C (lit.,73 mp 120–121 °C). According to a modi-
aqueous mixture was extracted with EtOAc (3 × 30 mL) and the fied literature procedure,74 BH3·SMe2 (2 M in THF; 13.5 mL,
organic extracts were combined, dried (Na2SO4) and evapor- 27 mmol) was added portion-wise to a solution Boc-D-Ala-NH2
ated in vacuo to give the title compound (0.86 g, 99%) as an (0.5 g, 2.7 mmol) in dry THF (9 mL) under N2 at 0 °C. The reac-
orange solid, mp 212.3–213.0 °C (acetone) (lit.,40 mp 211–212 °C), tion mixture was allowed to warm to room temperature, stirred
with identical spectroscopic and spectrometric properties.
(E)-5-(2-Cyclopropylvinyl)-2-fluorobenzonitrile (14i). To
for 18 h, evaporated in vacuo and treated with MeOH (3 ×
15 mL), stirring and evaporating in vacuo each time. Purifi-
a
solution containing 5-bromo-2-fluorobenzonitrile (14a) (3.0 g, cation by ion exchange chromatography using an Isolute SPE
15.0 mmol), Pd(PPh3)2Cl2 (1.0 g, 1.5 mmol) and trans-2-cyclo- SCX-2 flash column, eluting first with MeOH and then with a
propylvinylboronic acid pinacol ester (3.7 mL, 18 mmol) in solution of NH3 in MeOH (2 M), gave the title compound
DME/EtOH/H2O (7 : 2 : 3) (50 mL) was added aqueous Na2CO3 (0.39 g, 84%) as a colourless oil [Rf 0.3 in MeOH–CH2Cl2 (1 : 9)]
solution (1 M; 27 mL). The resulting mixture was placed under (Found [ES+]: 175.1443. C8H19N2O2 [MH] requires 175.1441);
an atmosphere of nitrogen and heated at 80 °C for 16 h after [α]2D4 −5.7 (c 1.1, MeOH); IR (neat) νmax/cm−1 2973 (C–H), 1685
which time the reaction was cooled to room temperature and (CvO), 1521 (N–H), 1364 (CH3 deformation), 1247 (C–O), 1165
1
filtered through Celite. Purification by flash column chromato- (C–N), 1045 (C–O), 872 (N–H); H NMR (500 MHz, CDCl3) δH/
graphy on silica gel, eluting with light petroleum–EtOAc (9 : 1), ppm 4.78 (1H, m, NHBoc), 3.60 (1H, m, 2-CH), 2.70 (1H, m, 1-
gave the title compound (2.4 g, 86%) as a yellow oil (Found [ES+]: CHH), 2.59 (1H, m, 1-CHH), 1.40 (9H, s, CMe3), 1.08 (3H, d, J =
188.0868. C12H11NF [MH] requires 188.0870); IR (neat) νmax/cm−1 7 Hz, 3-Me); 13C NMR (125 MHz, CDCl3) δC/ppm 155.7 (C),
1
3007 (C–H), 2496 (CN), 1672 (CvC); H NMR (400 MHz, CDCl3) 79.1 (C), 48.6 (2-CH), 47.4 (4-CH2), 28.4 (CMe3), 18.5 (Me).
δH/ppm 7.53–7.46 (2H, m), 7.16–7.08 (1H, m), 6.39 (1H, d, J = 1H NMR spectroscopic analyses were in good agreement with
15.7 Hz), 5.71 (1H, dd, J = 15.7, 9.0 Hz), 1.65–1.53 (1H, m), literature data.75
0.92–0.84 (2H, m), 0.59–0.52 (2H, m); 13C NMR (101 MHz,
(R)-Methyl 3-((2-((tert-butoxycarbonyl)amino)propyl)amino)-
CDCl3) δC/ppm 161.7 (d, J = 258.2 Hz), 137.9, 135.3 (d, J = 3.5 Hz), 5-nitrobenzo[b]thiophene-2-carboxylate (18). According to a
131.8 (d, J = 7.9 Hz), 130.0, 124.2, 116.5 (d, J = 20.3 Hz), 101.5 (d, modified literature procedure,76 (R)-tert-butyl (1-aminopropan-
J = 15.7 Hz), 77.2, 14.7, 7.6; m/z (ES) 188 (MH+, 100%).
2-yl)carbamate (17) (35 mg, 0.20 mmol) was added to a stirred
Methyl 3-aminothieno[2,3-b]pyridine-2-carboxylate (16). mixture of methyl 3-bromo-5-nitrobenzo[b]thiophene-2-carboxy-
2-Chloro-3-pyridinecarbonitrile (15b) (35 mg, 0.25 mmol), late (13) (50 mg, 0.16 mmol), Cs2CO3 (73 mg, 0.22 mmol),
methyl thioglycolate (0.22 mL, 0.25 mmol) and triethylamine ( )-BINAP (13 mg, 0.02 mmol) and Pd(OAc)2 (2.0 mg, 8.0 μmol)
(0.10 mL, 0.72 mmol) were reacted according to the above in dry toluene (1.0 mL) under N2 and the mixture was irra-
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Paper
diated at 150 °C for 75 min (hold time) in a pressure-rated give the title compound as a colourless solid (55 mg, 94%), mp
glass tube (10 mL) using a CEM Discover microwave synthesi- 202–203 °C (dec.) (Found [ES+]: 326.1324 C18H20N3OS [MH]
zer by moderating the initial power (200 W). After cooling in a requires 326.1322); IR (neat) νmax/cm−1 2873 (br, C–H), 1672
flow of compressed air, the reaction mixture was partitioned (CvO), 1587 (CvC); 1H NMR (400 MHz, d6-DMSO) δH/ppm
between water (20 mL) and EtOAc (30 mL). The aqueous layer 12.41 (1H, bs, NH), 8.09 (1H, d, J = 1.5 Hz, 4-CH), 8.03 (1H, d,
was further extracted with EtOAc (2 × 30 mL) and the organic J = 8.5 Hz, 7-CH), 7.69 (1H, dd, J = 8.5, 1.5 Hz, 6-CH), 6.68 (1H,
extracts were combined, washed with brine (30 mL), dried d, J = 15.8 Hz, CH), 6.01 (1H, dd, J = 15.8, 9.2 Hz, CH), 3.52
(Na2SO4) and evaporated. Purification by flash column chrom- (2H, s, CH2), 2.29 (6H, s, Me), 1.66–1.56 (1H, m, CH), 0.85–0.78
atography on SiO2 (dry load), gradient eluting with light pet- (2H, m, CHH), 0.61–0.54 (2H, m, CHH); 13C NMR (101 MHz,
roleum to Et2O–light petroleum (1 : 1), gave the title compound d6-DMSO) δC/ppm 158.5 (C), 157.2 (C), 152.7 (C), 138.3 (C),
(50 mg, 76%) as a red solid, mp 182.9–184.0 °C (Found [ES+]: 136.2 (CH), 135.2 (CH), 134.6 (C), 126.5 (C), 126.2 (CH), 123.9
410.1378. C18H24N3O6S [MH] requires 410.1380); [α]2D4 +55.3 (c (CH), 122.0 (C), 119.7 (CH), 61.3 (CH2), 45.1 (Me, Me), 14.7
0.1, MeOH); IR (neat) νmax/cm−1 3355 (N–H), 2954 (C–H), 1672 (CH), 7.2 (CH2, CH2); m/z (ES) 326 (MH+, 100%). 1H NMR spec-
(CvO), 1588 (NO2) 1508 (C–C), 1325 (NO2), 1230 (C–O), 1060 troscopic analyses were in good agreement with literature data
1
(C–N); H NMR (500 MHz, d6-DMSO) δH/ppm 8.94 (1H, m, 4- for the corresponding HCl salt.15
CH), 8.27 (1H, d, J = 9 Hz, 6-CH), 8.15 (1H, d, J = 9 Hz, 7-CH),
7.54 (1H, m, 3-NH), 6.87 (1H, d, J = 6 Hz, 2′-NH), 3.81 (4H, m,
1′-CHH and OMe), 3.76 (1H, m, 2′-CH), 3.57 (1H, m, 1′-CHH), Conclusions
1.32 (9H, s, CMe3), 1.12 (1H, d, J = 6 Hz, 3′-Me); 13C NMR
This method for the microwave-assisted synthesis of 3-amino-
benzo[b]thiophenes is rapid, simple to carry out and generally
high yielding. It has been applied in the synthesis of a range
of functional benzothiophenes and their 7-aza analogues and
constitutes a very efficient route to the corresponding 3-halo-
benzothiophenes using diazonium chemistry. Applications of
this process have been shown in the synthesis of the thieno-
[2,3-b]pyridine core motif of LIMK1 inhibitors using 2-halopyr-
(125 MHz, d6-DMSO) δC/ppm 164.0 (C), 155.1 (C), 150.3 (3-C),
145.2 (C), 144.3 (C), 131.1 (3α-C), 124.7 (7-CH), 121.6 (6-CH),
120.5 (4-CH), 99.5 (2-C), 77.6 (CMe3), 51.7 (OMe), 50.5 (1′-CH2),
46.2 (2′-CH), 28.1 (CMe3), 18.3 (3′-Me); m/z (EI) 410 (MH+,
100%), 409 (M•+, 70).
Methyl 3-((1-amino-2-chloroethylidene)amino)-5-((E)-2-cyclo-
propylvinyl)benzo[b]thiophene-2-carboxylate hydrochloride (19).
Methyl (E)-3-amino-5-(2-cyclopropylvinyl)benzo[b]thiophene-
idine-3-carbonitriles, the benzo[4,5]thieno[3,2-e][1,4]diazepin-
2-carboxylate (5i) (200 mg, 0.73 mmol) was suspended in a
5(2H)-one scaffold of MK2 inhibitors with functionality suit-
solution of HCl in 1,4-dioxane (4 M; 3 mL) and chloro-
acetonitrile (91 μL, 1.43 mmol) was added drop-wise. The
reaction mixture was stirred at room temperature for 16 h
able for subsequent modification using Buchwald–Hartwig
chemistry, and a benzo[4,5]thieno[3,2-d]pyrimidin-4-one target
as a chemical tool for inhibition of PIM kinases. In the case of
and the suspension was filtered under reduced pressure,
inhibitors of MK2, the use of this approach has been shown to
washed with light petroleum (60 mL) and dried in vacuo for
6 h to give the title compound (110 mg, 39%) as a colourless
be superior to traditional bromination chemistry using the
parent benzothiophene heterocycle. Given the speed, efficiency
solid, mp 195–197 °C (dec.) (Found [ES+]: 317.0512.
and reliability of these methods, and their ability to incorpor-
C16H1435ClN2OS [MH − MeOH] requires 317.0515); IR (neat)
ate a wide range of functionality, these approaches are likely to
νmax/cm−1 3332 (br, N–H), 3001 (C–H), 2675 (C–H), 1676
1
find application in providing chemical tools, rapidly, reliably
and efficiently, for advancing studies in chemical biology, as
well as to access targets in medicinal chemistry.
(CvO), 1620 (CvC); H NMR (400 MHz, CD3OD) δH/ppm 7.91
(1H, d, J = 8.6 Hz, 7-CH), 7.72 (1H, d, J = 1.5 Hz, 4-CH), 7.67
(1H, dd, J = 8.6, 1.5 Hz, 6-CH), 6.60 (1H, d, J = 15.8 Hz, CH),
5.96 (1H, dd, J = 15.8, 9.1 Hz, CH), 4.73 (2H, s, CH2), 3.94 (3H,
s, Me), 1.65–1.55 (1H, m, CH), 0.87–0.79 (2H, m, CHH),
0.59–0.48 (2H, m, CHH); 13C NMR (101 MHz, CD3OD) δC/ppm
166.3 (C), 162.4 (C), 138.9 (C), 138.3 (CH), 138.0 (C), 135.8 (C),
130.5 (C), 130.4 (C), 127.7 (CH), 127.3 (CH), 124.6 (CH), 119.6
(CH), 53.4 (Me), 40.1 (CH), 15.5 (CH), 7.8 (CH2, CH2); m/z (ES)
349 (M[35Cl]H+, 100%).
(E)-8-(2-Cyclopropylvinyl)-2-((dimethylamino)methyl)benzo-
[4,5]thieno[3,2-d]pyrimidin-4(3H)-one (20). Compound 19
(70 mg, 0.18 mmol) was added to a solution of dimethylamine
in ethanol (33%; 3 mL) and the reaction mixture was stirred at
room temperature for 16 h. The solvent was evaporated
in vacuo and the resulting colourless solid was dissolved in
MeOH–CH2Cl2 (1 : 1; 5 mL) and loaded onto an SCX cartridge
(1 g). The cartridge was flushed with MeOH (3 × 5 mL) and
then eluted with a solution of NH3 in MeOH (2 M; 8 mL) to
Acknowledgements
We thank the EPSRC-BBSRC-MRC sponsored network
SMS-Drug (EP/I037229/1; award to MCB and NCOT), EPSRC
(studentship awards to JED and HLR) and the R M Phillips
Trust (award to MCB) for support of this work and Dr Alaa
Abdul-Sada at the University of Sussex and the EPSRC Mass
Spectrometry Service at the University of Wales, Swansea UK
for mass spectra.
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