New methodology for the N-alkylation of 2-amino-3-acylthiophenes

Article abstract of DOI:10.1039/c0ob01156h

2-Amino-3-acylthiophenes are known to allosterically modulate the A ₁ adenosine receptor and are also used as intermediates in the synthesis of therapeutic agents and pharmacophores such as thienoazepines and thienopyrimidines. The N-alkylation

Full text of DOI:10.1039/c0ob01156h

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PAPER
New methodology for the N-alkylation of 2-amino-3-acylthiophenes†
Luigi Aurelio, Bernard L. Flynn and Peter J. Scammells*
Received 13th December 2010, Accepted 29th March 2011
DOI: 10.1039/c0ob01156h
2-Amino-3-acylthiophenes are known to allosterically modulate the A1 adenosine receptor and are also
used as intermediates in the synthesis of therapeutic agents and pharmacophores such as
thienoazepines and thienopyrimidines. The N-alkylation of 2-aminothiophenes has been notoriously
difficult to accomplish under mild conditions and there are very few examples of N-alkylated
2-aminothiophenes in the literature, all of which use forcing conditions to effect the alkylation. Here we
describe the synthesis of such compounds under mild conditions utilising 2-carbamoylamino and
2-acylamino-3-acylthiophenes with caesium carbonate, and tetrabutylammonium iodide in DMF.
2-amino would therefore be highly desirable. There are only a
Introduction
few examples of the N-alkylation of 2-amino-3-acylthiophenes
The use of 2-amino-3-acylthiophenes is prevalent in the liter-
in the literature and these procedures employ high pressures
and temperatures,15 or strongly basic conditions with protecting
groups such as tosyl and ethyl carbamates which then require
harsh conditions for their removal.10,17–19 Herein, we report a mild
and simple method for the N-alkylation of various 2-amino-3-
acylthiophenes.
ature, and their syntheses via the method communicated by
Gewald1 provides a one-pot procedure to a large variety of
analogues.2 Not only are 2-amino-3-acylthiophenes known to act
as allosteric modulators of the A1 adenosine receptor,3–7 their
derivatization to thienopyrimidines8 and thienoazepines9,10 has
been used to produce pharmaceuticals and dyes.2 In particular,
the well known thienobenzodiazepine, Olanzapine (2),9 derived
from the 2-amino-5-methylthiophene-3-carbonitrile (1, Fig. 1), is
an FDA approved antipsychotic. 2-Amino-3-acylthiophenes have
also been employed as building blocks for potential therapeutic
agents such as anti-inflammatory,11 antitumor,12 antimicrobial,13
hypocholesterolemic,14 epileptic15 and antifungal16 agents. Yet one
particular chemical modification that has not been extensively
explored in terms of the potential SAR of such molecules is the
alkylation of the 2-amino group, which has proven to be difficult
to achieve. A simple and mild method for the alkylation of the
Results and discussion
Our group has been actively involved in the synthesis and biologi-
cal evaluation of 2-amino-3-acylthiophenes as allosteric modula-
tors of the A1 adenosine receptor.3–7 In attempts to functionalize
certain positions of the 2-amino-3-acylthiophenes, the 2-amino
group in most cases required protection. The phthaloyl, acetyl
and Boc groups are relatively easy to introduce and remove.3,6,7
Yet these protecting groups are susceptible to cleavage under basic
and acidic conditions and incorporating protecting groups that
are relatively stable to these conditions is desirable. The benzyl
carbamate fits this profile as it is relatively stable to basic and/or
acidic conditions and is removed by hydrogenolysis. To the best
of our knowledge there are only two examples in the literature
that utilise this protecting group for 2-amino-3-acylthiophenes,13,20
and in our hands these procedures failed. Carbamates are
typically introduced by reaction of the appropriate amine with
a chloroformate, dicarbonate, CDI, phosgene/triphosgene or
activated carbonate such as succinimidyl or benzotriazyl, but
these procedures have been unfruitful when applied to 2-amino-3-
acylthiophene substrates in our hands.21 Another facile method
for the introduction of carbamates was realised by Butcher22
in an attempt to N-benzylate secondary amines with benzyl
chloride and potassium carbonate in DMF, isolating the expected
product along with the corresponding benzyl carbamate. By
substituting potassium carbonate with caesium carbonate and
bubbling carbon dioxide into the mixture, Butcher was able to
isolate the corresponding carbamates in very good yield. This
Fig. 1 The antipsychotic Olanzapine (2) and the thiophene 1 from which
Olanzapine is derived.
Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical
Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052,
Australia. E-mail: peter.scammells@monash.edu; Fax: (+61) 3 9903 9582;
Tel: (+61) 3 9903 9542
† Electronic supplementary information (ESI) available: LC-MS traces
of compounds 8a–g, 11, 24a–c, 27a–d, 31a–c, 34a–c. See DOI:
10.1039/c0ob01156h
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method of N-carbamoylation of alkyl and aryl amines was further
modified by Salvatore et al.23 By introducing the phase transfer
catalyst, tetrabutylammonium iodide (TBAI), they were able
prevent direct N-alkylation and achieve chemoselective carbamate
formation.23
We initially envisaged a one-pot procedure in which one
equivalent of benzyl bromide was used to form the carbamate
and then in the same pot excess alkyl halide is added to effect N-
alkylation with various alkyl halides. Yet, under these conditions
only benzyl bromide and dialkylsulfates drove the N-alkylation
to completion. The incomplete alkylation was also evident in the
allylation of 3 (Scheme 1). When the thiophene 3 was subjected to
the one-pot synthesis of 5b approximately 20% of 5b was formed.
By adding a further three equivalents of allyl bromide the isolated
yield of 5b was 54% after chromatography. This suggested that the
one-pot procedure would only work well with the aforementioned
alkylating agents. Therefore, it was far more convenient to isolate
the carbamate with one equivalent of alkyl halide and then alkylate
in a second step.
By reducing the amount of benzyl bromide to 1.05 equivalents,
the carbamate 4b was isolated in 97% yield. This was a promising
result and at this stage it was decided to also employ a carbamate
that could survive the basic conditions of the alkylations and
could be removed under relatively mild conditions other than
hydrogenolysis. The p-methoxybenzyl (PMB) carbamate was well
suited since it can be removed via hydrogenolysis or under mildly
acidic conditions.21 This would then enable the incorporation of
unsaturated and benzylic alkyl groups that would otherwise be
compromised via hydrogenolysis if the benzyl carbamate was used.
The initial synthesis of 6 began by utilising the same conditions as
for the carbamate 4b, with 1.05 equivalents of PMB-Cl instead of
benzyl bromide and 3 equivalents each of caesium carbonate and
TBAI (Scheme 2). It was then found that the number of equivalents
of the other reagents could also be reduced without compromising
the yield and repeating the synthesis with 1.05, 1.5, and 1.0
equivalents of PMB-Cl, caesium carbonate and TBAI respectively,
6 was obtained in 92% yield (Scheme 2). The carbamate 6 was
then treated with 2 equivalents of caesium carbonate and half
In our first attempt at introducing the benzyl carbamate,
ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate
(3, Fig. 2), was used as an example and the conditions communi-
cated by Salvatore et al. were duplicated (three equivalents each of
benzyl bromide and TBAI). To our delight TLC revealed complete
consumption of starting material three hours after the addition
of benzyl bromide. At this stage it was assumed that the benzyl
carbamate was produced, yet 1H NMR of the crude product
showed that the N-benzyl-N-carbamoyl derivative 4a was the
sole product isolated. This result was advantageous in two ways;
firstly, the benzyl carbamate could be introduced with relative
ease and secondly, N-alkylation could be accomplished under
mild conditions. The serendipitous synthesis of the N-alkylated
derivative 4a was a novel outcome. There is no mention in the
work communicated by Salvatore et al.23 of any concomitant N-
alkylation of the carbamates synthesised whether they be alkyl or
aryl amines.
Fig. 2 N-Carbamoylation and N-alkylation of 3.
Scheme 1 Synthesis of N-carbamoyl and N-alkyl-N-carbamoyl derivatives of 3.
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Scheme 2 Synthesis of N-alkyl derivatives of 3.
an equivalent of TBAI in DMF followed by 2 equivalents of
alkylating agent at room temperature for 3–24 h providing the
compounds 7a–g. In all cases, with the exception of the isopropyl
derivative 10, alkylation was quantitative and did not require
chromatography. For example 10, 24 h reaction time effected
50% conversion to the N-isopropyl derivative (by 1H NMR) and
repeating the synthesis with eight equivalents each of isopropyl
iodide and caesium carbonate provided 77% of 10, 6% of 6 and 3%
of 9 after 27 h. Although the isopropyl carbamate 9 was isolated in
this reaction, albeit in very low yield, there was no sign of it in the
first attempt when using only 2 equivalents each of alkylating agent
and base. This was also the case with analogous N-alkylations and
so no carbamoylation was observed. The 1H NMR spectra of the
alkylated compounds indicated the presence of cis-trans isomers
of the carbamate at an approximate 1 : 3 ratio and this was also
evident in the 13C NMR.
Removing the PMB carbamate was performed under acidic
conditions since it is known to be at least as acid labile as a
Boc group.21,24,25 Under the acidic conditions the p-methoxybenzyl
cation 12 (Fig. 3) forms and is usually quenched with a cation
scavenger.25 By using the conditions of Chen et al.24 and adding 1.2
equivalents of triethylsilane as the cation scavenger, the carbamate
was removed within 20 min at room temperature. The deprotection
reaction was quenched with bicarbonate and the crude product
was chromatographed on silica gel. In all cases up to 20% of the
diphenylmethane 1326 had co-eluted with the product, but was
readily removed by recrystallization. Upon increasing the amount
Fig.
3
p-Methoxybenzyl cation 12 and 2,4¢-dimethoxy-5-methyl-
diphenylmethane 13.
of triethylsilane to 2.5 equivalents, 13 was still isolated, but in
dramatically reduced yield.
With the conditions for N-carbamoylation and N-alkylation
optimised for thiophene 3, the A1 adenosine receptor antagonist
1427 and allosteric modulator 1628 were subjected to the same
N-carbamoylation conditions (Scheme 3). In the case of 14,
intractable mixtures were observed after workup of the crude
product. Although small amounts of product were isolated by
chromatography, clean fractions could not be obtained and
therefore this route was abandoned. The allosteric modulator 16
was also subjected to CO2 mediated N-carbamoylation under the
same conditions used for 14. The desired carbamate 17a, was
isolated in 41% yield following column chromatography, along
with a 1.6 : 1 mixture of starting material 16 and the N-alkyl
derivative 17b. The carbamate was subjected to N-methylation
providing 17c in 92% yield and although subsequent alkylations
could be achieved with 17a, this intermediate was also abandoned
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Scheme 3 N-Carbamoylation of orthosteric antagonist 14 and allosteric modulator 16.
due to the low yields of the N-carbamoylation step. It was
presumed that the highly electrophilic nature of the benzyl halide
is too reactive and that once the carbamate is formed, it becomes
more reactive under the basic conditions than the intermediary
carbamic acid and therefore 17b forms.
with either dimethylsulfate or benzyl bromide to provide 21b or
21c respectively, only returning unreacted starting material. This
was also the case with 22b, only returning starting material upon
attempted methylation. On the contrary, the acetamides 20a and
22a reacted very well in these alkylations. The N-methylation of
20a proceeded with complete conversion to 21a and was isolated
in 69% after chromatography. Although the acetamide can be
removed with hydroxide this would also compromise the ethyl ester
in 21a, therefore removal with sodium ethoxide could be used as an
alternative.31 In the case of 22a, the acetyl group is quite convenient
in that it is readily installed in high yield and it is removed with
mild base hydrolysis.6 In fact the N-butyl derivative did not require
heating or excess 1-bromobutane to go to completion although it
required 40 h reaction time. The base hydrolysis in aqueous ethanol
was also advantageous in that the products precipitated during the
reaction and were simply filtered to provide pure product.
Although the PMB carbamate and the acetamide served well
in the alkylations, they also have their limitations. Installing the
PMB carbamate via the carbon dioxide mediated carbamoylation
proceeded well for 3, but not for 14 and 16. The acetamide
is easily installed and proved to be effective in the alkylation
step, yet it requires basic conditions for removal, which can
compromise other base sensitive groups and, in some cases, cause
rearrangement of the thiophene ring.4 Therefore, an orthogonal
protecting group to the acetamide would be a complementary
addition and the Boc group would serve well. It is readily installed
with Boc2O and removed with TFA. To ensure complete car-
bamoylation of 2-amino-3-acylthiophenes, we have found that two
equivalents of Boc2O are required for complete N-carbamoylation
to isolate the bis-carbamate since one equivalent gives rise to
mixtures of mono-Boc, di-Boc and starting material.7 The bis-
carbamate is highly susceptible to nucleophiles and by adding
excess hydrazine one of the carbamate groups is removed as tert-
butyl hydrazinecarboxylate and any excess Boc2O is also converted
The poor yields obtained for the N-carbamoylation of 14
and 16 prompted us to investigate N-activating groups that
could be suitable for the N-alkylation and subsequent mild
deprotection. The trifluoroacetamide is well known for its ready
introduction and mild removal with aqueous methanolic potas-
sium carbonate,29 and alkylation of trifluoroacetamides have
also been described in the literature.30 The trifluoroacetamide
18a (Scheme 4) was prepared and subjected to N-methylation
with dimethylsulfate under the standard conditions for 24 h.
Upon workup the crude product was chromatographed and 10%
of starting material 18a was isolated followed by the desired
product 19a in 82% (90% conversion). Although this was a good
result, the fact that the reaction did not go to completion was
surprising compared to the N-methylation of carbamate 6. Thus,
the acetamide 18b was available and also subjected to identical N-
1
methylation conditions as 18a and H NMR revealed complete
conversion to product 19b in 92%. When both 18a and 18b
were separately subject to N-alkylation with isopropyl iodide
under identical conditions, the trifluoroacetamide 19c did not
form only returning the starting material 18a. Yet, the acetamide
18b reacted with isopropyl iodide to form 19d in 83% yield
(by LCMS). The lower reactivity of the trifluoroacetamide 18a
compared to the acetamide 18b may result from the electron
withdrawing trifluoromethyl group stabilising the anion formed
upon deprotonation of the trifluoroacetamide. To see whether or
not there was a trend with the trifluoroacetyl group, compounds 14
and 16 were both acetylated and trifluoroacetylated and subjected
to N-alkylation reactions to compare with the results obtained
with 18a,b (Scheme 4). Trifluoroacetamide 20b did not react at all
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Scheme 4 N-Alkylation of N-acyl 2-amino-3-acylthiophenes.
to tert-butyl hydrazinecarboxylate, which is easily removed using
a short silica column. The Boc derivatives 25, 26 and 28 (Scheme
5) were synthesised and subjected to the standard alkylation con-
ditions. N-Methylation and N-benzylation proceeded smoothly
at room temperature and the conversion of starting material was
quantitative as expected for all three carbamates 25, 26 and 28.
The other test was to see whether or not a poorly electrophilic
reagent would N-alkylate these derivatives. 1-Bromobutane was
chosen for this purpose and, in the case of 25, complete alkylation
was observed under the standard conditions, whereas 26 and 28
did not react to completion. After 24 h at room temperature only
trace amounts of N-alkylated material were observed by TLC in
the case of 26. By adding a further two equivalents each of◦1-
bromobutane and caesium carbonate and then heating to 60 C
for a further 24 h the starting material had disappeared and two
new compounds were observed by TLC. The NMR of the crude
product revealed that the N-alkylation was complete and that
a substantial amount of trans-esterification had occurred. This
outcome is not surprising since small amounts of moisture can
affect the hydrolysis of 26 at the elevated temperature and excess
reagents present would esterify the carboxylate that formed. In
the case of 28 up to 10% of starting material was observed by
LCMS after 24 h at room temperature. By adding a further two
equivalents each of 1-bromobutane and caesium carbonate and
prolonging the reaction time, the amount of starting material was
reduced to 1–2% and after deprotection, the crude product was
readily purified by recrystallization.
Until now the focus has been the N-alkylation of 2-amino-
3-acylthiophenes. We also wanted to investigate the utility of
the method to see if it can be extended to anilines. There
are many procedures for N-alkylating anilines and some of the
more common methods utilize the reduction of Schiff bases,19,32
amination of aryl halides,33 or taking Boc protected anilines either
in anhydrous DMF34 or THF35 solution and treating with NaH
and an alkylating agent. Also, the alkylation of tosylamides36 or
simply alkylating the free aminoarene directly, which provides
mixtures of mono and di-alkyl products that require chromatog-
raphy for separation.37 Again, some of these procedures require
heating, expensive reagents and protecting groups that are difficult
to remove. The commercially available vinylogous amides 2-
aminobenzophenone (29) and 1-aminofluoren-9-one (32) (Scheme
6) were available and converted to the Boc derivatives 30 and 33
and subjected to the alkylation conditions as with the previous
Boc compounds 25, 26 and 28. To our delight, the alkylations
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Scheme 5 N-Alkylation of N-Boc-2-amino-3-acylthiophenes.
proceeded smoothly and excess reagents were only required in
the case of the N-butyl derivative 34b (4 equivalents each of
1-bromobutane and caesium carbonate) to drive the reaction to
completion without any heating.
N–H (vinylogous imide), enabling sufficient deprotonation to
be achieved under weakly basic conditions so as to achieve
substitution through the anionic intermediate 39, to give 40
(Scheme 7, eqn 2).
The improvements achieved here in the N-substitution of 2-
aminothiophenes and anilines bearing o-carboxyl groups 35 is
likely to reside in a change in the nature of the nucleophilic
nitrogen that results from attachment of a carbonyl protect-
ing/activating group (carbamoyl or amide). The reaction of
unactivated amines 35, performed in the presence of a weak
base, would require nucleophilic attack of an electrophile (R-
I/Br) by the lone-pair of electrons on the nitrogen to give the
cation 36, followed by rapid loss of a proton to give 37 (Scheme
7, eqn 1). However, the electron deficiency of the carbonyl in
35 and its strong hydrogen bonding interaction with the amine
N–H, enforces a coplanar arrangement of the aryl, carbonyl and
amine p-systems, diminishing the nucleophilicity of the amine
electron-lone-pair, disfavouring formation of 36. These features
are clearly apparent in an X-ray crystal structure of a related (2-
aminoindeno[2,1-b]thiophen-3-yl)(phenyl)methanone, in which a
“resonance-enhanced” intramolecular hydrogen between the 2-
amino and adjacent carbonyl oxygen was clearly apparent from
inspection of the relevant bond distances.6 The presence of a
N-carbonyl group in 38 increases the acidity of the remaining
Conclusion
The one pot N-carbamoylation and N-alkylation of 2-amino-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (3) has pro-
vided a method for mild N-alkylation of what otherwise was
particularly difficult to achieve. The ease in which N-alkylation
takes place is exemplified by the n-butyl and isopropyl deriva-
tives that would otherwise be extremely difficult to install with
classical methods. Even though preliminary experiments have
shown that the acetyl group is slightly enhanced in the N-
alkylation, both carbamates and acetyl groups are complementary
options in terms of the conditions required for their cleavage.
The unreactivity of trifluoroacetamides was initially particularly
interesting in that they are known to react well in such reactions,
yet this was not the case for 2-amino-3-acylthiophenes. This
method now provides a means to further explore the SAR
of N-alkylated versions of thienoazepines and thienopyrim-
idines that are used as building blocks for potential therapeutic
agents.
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Scheme 6 N-Alkylation of N-Boc 2-aminobenzophenone 30 and 1-aminofluoren-9-one 33.
Ethyl 2-(benzyl(benzyloxycarbonyl)amino)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (4a)
To a 50 mL two neck flask fitted with a nitrogen inlet was added
3 (0.428 g, 1.9 mmol) and then purged with nitrogen. Caesium
carbonate (1.86 g, 5.7 mmol) and TBAI (2.1 g, 5.7 mmol) were
added followed by anhydrous DMF (10 mL). The nitrogen inlet
was replaced with a carbon dioxide inlet and CO2 (g) was bubbled
through the stirred mixture at a steady rate for 1 h. Benzyl bromide
(0.677 mL, 5.7 mmol) was added in one portion with continual
bubbling of CO2 (g) for 3.5 h. The CO2 (g) inlet was removed and
the mixture was diluted with ether (100 mL) and then washed
with water (6 ¥ 150 mL), then brine (20 mL). The ethereal layer
was dried (MgSO4), filtered and then concentrated to a resin.
The resin was chromatographed on silica gel eluting with CH2Cl2
affording 4a as a clear colourless resin that slowly solidified upon
refrigeration (0.601 g, 70%). A small portion was recrystallized
from petroleum ether. Mp 56–58 C. H NMR d 7.52–7.03 (m,
10H, ArH), 5.28–5.14 (m, 2H, ArCH2), 4.80 (m, 2H, ArCH2),
4.33–3.81 (m, 2H, OCH2CH3), 2.93–2.70 (m, 2H, CH2), 2.72–2.50
(m, 2H, CH2), 1.98–1.61 (m, 4H, 2 ¥ CH2), 1.28–1.11 (m, 2H,
OCH2CH3). 13C NMR d 162.5, 155.7, 146.0, 137.0, 136.6, 134.6,
133.6, 128.8, 128.4, 128.3, 127.8, 127.7, 127.6, 126.2, 67.6, 60.2,
55.7, 26.0, 25.0, 22.8, 22.5, 14.1. LCMS Rf (min) = 7.19. MS m/z
450.1 (M + H).
Scheme 7 Mechanistic considerations.
Experimental
General methods
◦
1
Melting points were determined with an electrothermal melting
point apparatus and are uncorrected. All reagents and anhydrous
DMF were purchased from Sigma-Aldrich and used without fur-
ther purification. LR grade methanol, petroleum ether (40–60 ◦C),
ethyl acetate, diethyl ether and dichloromethane were purchased
1
from Merck and were used without further purification. All H
NMR and 13C NMR spectra were recorded on a Bruker Avance
III 400 Ultrashield Plus spectrometer at 400.13 and 100.62 MHz,
respectively. Unless stated otherwise, samples were dissolved in
CDCl3. Thin-layer chromatography was conducted on 0.2 mm
plates using Merck silica gel 60 F254. Column chromatography was
achieved using Merck silica gel 60 (particle size 0.063–0.200 mm,
70–230 mesh) and eluent percentages are described in volume
(%v/v). High resolution mass spectra (HR-ESI) were obtained on
a Waters LCT Premier XE (TOF) using electrospray ionization.
Compound purity was analyzed via LCMS (Agilent 1200 series
LC coupled directly to a photodiode array detector and an Agilent
6100 Quadrupole MS) using a Phenomenex column (Luna 5 mm
C8, 50 mm ¥ 4.60 mm ID).
Ethyl 2-(benzyloxycarbonylamino)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (4b)
To a 50 mL two neck flask fitted with a nitrogen inlet was added
3 (0.428 g, 1.9 mmol) and then purged with nitrogen. Caesium
carbonate (1.86 g, 5.7 mmol) and TBAI (2.1 g, 5.7 mmol) were
added followed by anhydrous DMF (10 mL). The nitrogen inlet
was replaced with a carbon dioxide inlet and CO2 (g) was bubbled
through the stirred mixture at a steady rate for 1 h. Benzyl bromide
(0.238 mL, 2.0 mmol) was added in one portion with continual
bubbling of CO2 (g) for 3.5 h. The CO2 (g) inlet was removed and
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the mixture was diluted with ether (100 mL) and then washed with
water (6 ¥ 150 mL), then brine (20 mL). The ethereal layer was
dried (MgSO4), filtered and then concentrated affording 4b as an
off white solid (0.663 g, ◦97%) a small portion was recrystallized
from MeOH. Mp 77–79 C. 1H NMR d 10.58 (s, 1H, NH), 7.47–
7.29 (m, 5H, ArH), 5.25 (s, 2H, ArCH2), 4.30 (q, J = 7.1 Hz, 2H,
OCH2CH3), 2.80–2.69 (m, 2H, CH2), 2.69–2.55 (m, 2H, CH2),
1.86–1.70 (m, 4H, 2 ¥ CH2), 1.36 (t, J = 7.1 Hz, 3H, OCH2CH3).
13C NMR d 166.3, 153.0, 149.3, 135.7, 131.3, 128.6, 128.5, 128.4,
125.7, 110.9, 67.8, 60.4, 26.5, 24.4, 23.1, 22.9, 14.4. LCMS Rf
(min) = 7.15. MS m/z 360.2 (M + H).
inlet was replaced with a carbon dioxide inlet and CO2 (g) was
bubbled through the stirred mixture at a steady rate for 1 h. p-
Methoxybenzyl chloride (1.35 mL, 9.97 mmol) was added in one
portion with continual bubbling of CO2 (g) for 3.5 h. The CO2 (g)
inlet was removed and the mixture was diluted with ether (200 mL)
and then washed with water (6 ¥ 250 mL), then brine (20 mL). The
ethereal layer was dried (MgSO4), filtered and then concentrated
affording 6 as an off white solid (3.41 g, 92%). A small portion
was recrystallized from MeOH. Mp 91–93 ◦C. 1H NMR d 10.52
(s, 1H, NH), 7.44–7.27 (m, 2H, ArH), 7.01–6.73 (m, 2H, ArH),
5.17 (s, 2H, ArCH2), 4.28 (q, J = 7.1 Hz, 2H, OCH2CH3), 3.80
(s, 3H, OCH3), 2.81–2.66 (m, 2H, CH2), 2.67–2.53 (m, 2H, CH2),
1.89–1.57 (m, 4H, 2 ¥ CH2), 1.34 (t, J = 7.1 Hz, 3H, OCH2CH3).
13C NMR d 166.2, 159.8, 153.0, 149.3, 131.3, 130.3, 127.7, 125.5,
114.0, 110.7, 67.7, 60.3, 55.3, 26.5, 24.4, 23.0, 22.8, 14.3. LCMS
Rf (min) = 7.07. MS m/z 390.2 (M + H).
Ethyl 2-(((allyloxy)carbonyl)amino)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (5a) and ethyl
2-(allyl((allyloxy)carbonyl)amino)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (5b)
To a 50 mL two neck flask fitted with a nitrogen inlet was added
3 (0.428 g, 1.9 mmol) and then purged with nitrogen. Caesium
carbonate (1.86 g, 5.7 mmol) and TBAI (2.1 g, 5.7 mmol) were
added followed by anhydrous DMF (10 mL). The nitrogen inlet
was replaced with a carbon dioxide inlet and CO2 (g) was bubbled
through the stirred mixture at a steady rate for 1 h. Allyl bromide
(0.482 mL, 5.7 mmol) was added in one portion with continual
bubbling of CO2 (g) for 3.5 h and then left to stir overnight. The
next day a further aliquot of allyl bromide (0.482 mL, 5.7 mmol)
was added and the mixture was stirred for a further 24 h. The
mixture was diluted with ether (100 mL) and then washed with
water (6 ¥ 150 mL), then brine (20 mL). The ethereal layer
was dried (MgSO4), filtered and then concentrated to a resin.
The resin was chromatographed on silica gel eluting with 5%
ethyl acetate–petroleum ether affording 5a as a clear colourless
resin that slowly solidified upon refrigeration (0.247 g, 42%).
Mp 51–53 C. H NMR d 10.53 (s, 1H, NH), 5.94 (ddt, J =
17.1, 10.5, 5.7 Hz, 1H, OCH2CHCH2), 5.35 (ddd, J = 17.2, 2.9,
1.5 Hz, 1H, OCHHCHCH2), 5.25 (ddd, J = 10.4, 2.5, 1.2 Hz, 1H,
OCHHCHCH2), 4.68 (dt, J = 5.7, 1.2 Hz, 2H, OCH2CHCH2),
4.28 (q, J = 7.1 Hz, 2H, OCH2CH3), 2.72 (t, J = 5.1 Hz, 2H, CH2),
2.59 (t, J = 5.1 Hz, 2H, CH2), 1.87–1.59 (m, 4H, 2 ¥ CH2), 1.34
(t, J = 7.1 Hz, 3H, OCH2CH3). 13C NMR d 166.2, 152.8, 149.3,
132.0, 131.3, 125.6, 118.6, 110.8, 66.6, 60.4, 26.5, 24.4, 23.0, 22.8,
14.3. LCMS Rf (min) = 7.03. MS m/z 310.2 (M + H).
General procedure for the synthesis of N-alkylated thiophenes
(8a–g)
To a 50 mL two neck flask fitted with a nitrogen inlet was added
6 (0.195 g, 0.5 mmol) and then purged with nitrogen. Caesium
carbonate (0.326 g, 1.0 mmol) and TBAI (0.092 g, 0.25 mmol)
were added followed by anhydrous DMF (3 mL). The alkylating
reagent (1.0 mmol) was added and the reaction was stirred at
room temperature and for 3–24 h. Upon completion of the
reaction (TLC), the mixture was diluted with ether (50 mL) and
then washed with water (6 ¥ 150 mL), then brine (20 mL). The
ethereal layer was dried (MgSO4), filtered and then concentrated
to an oil affording the carbamates 7a–g, which were used without
further purification in the next step. The resin was taken up
in CH2Cl2 (1 mL) and triethylsilane (0.192 mL, 1.2 mmol) was
added followed by TFA (0.116 mL, 1.5 mmol) and stirred at room
temperature for 15–30 min. The mixture was diluted with ether
(20 mL) and quenched with saturated bicarbonate solution. The
aqueous layer was removed and the organic layer was washed with
water (10 mL) and then brine (5 mL), dried (MgSO4), filtered and
then concentrated to an oil affording the crude thiophenes 8a–g,
that was chromatographed on silica gel with 5% ethyl acetate–
petroleum ether. Solids were recrystallized from petroleum ether
or methanol.
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1
Ethyl 2-((((4-methoxybenzyl)oxy)carbonyl)(methyl)amino)-4,5,
6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (7a). Carbamate
6 was reacted with dimethylsulfate to obtain 7a as an oil (0.213
g). 1H NMR (cis : trans isomers, 1 : 3) d 7.41–7.07 (m, 2H, ArH),
6.96–6.72 (m, 2H, ArH), 5.16–4.91 (m, 2H, ArCH2), 4.23–3.94 (m,
2H, OCH2CH3), 3.83–3.68 (m, 3H, OCH3), 3.19 (s, 3H, NCH3),
2.83–2.71 (m, 2H, CH2), 2.72–2.58 (m, 2H, CH2), 1.88–1.67 (m,
4H, 2 ¥ CH2), 1.23–1.11 (m, 3H, OCH2CH3). 13C NMR (cis : trans
isomers) d 162.4, 159.4, 155.4, 148.0, 134.8, 133.1, 130.2, 129.7,
128.8, 125.9, 113.8, 113.7, 67.7, 67.3, 60.2, 55.2, 39.2, 39.1, 26.0,
25.0, 22.9, 22.5, 14.1. LCMS Rf (min) = 6.77. MS m/z 426.1 (M +
Na).
Further elution afforded 5b as a clear colourless resin (0.360 g,
54%). 1H NMR (cis : trans isomers, 1 : 3) d 6.00–5.59 (m, 2H,
OCH2CHCH2, NCH2CHCH2), 5.38–4.94 (m, 4H, OCH2CHCH2,
NCH2CHCH2), 4.67–4.43 (m, 2H, OCH2CHCH2), 4.23–4.06 (m,
4H, NCH2CHCH2, OCH2CH3), 2.80–2.66 (m, 2H, CH2), 2.66–
2.53 (m, 2H, CH2), 1.83–1.61 (m, 4H, 2 ¥ CH2), 1.24 (t, J = 7.1 Hz,
3H, OCH2CH3). 13C NMR d 162.4, 154.7, 145.9, 134.4, 133.1,
132.8, 132.5, 126.1, 118.0, 117.1, 66.3, 60.1, 54.5, 25.9, 24.9, 22.7,
22.4, 14.1. LCMS Rf (min) = 6.83. MS m/z 350.2 (M + H).
Ethyl 2-((((4-methoxybenzyl)oxy)carbonyl)amino)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (6)
Ethyl 2-(methylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxylate (8a). Yield 42% (0.05 g), obtained as a white solid
after recrystallization from petroleum ether. Mp 62–64 C. H
NMR d 7.79–7.35 (m, 1H. NH), 4.23 (q, J = 7.1 Hz, 2H,
OCH2CH3), 2.96 (d, J = 5.2 Hz, 3H, NCH3), 2.77–2.64 (m, 2H,
To a 100 mL two neck flask fitted with a nitrogen inlet was added
3 (2.14 g, 9.5 mmol) and then purged with nitrogen. Caesium
carbonate (4.64 g, 14.25 mmol) and TBAI (3.51 g, 9.5 mmol)
were added followed by anhydrous DMF (50 mL). The nitrogen
◦
1
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CH2), 2.59–2.48 (m, 2H, CH2), 1.84–1.65 (m, 4H, 2 ¥ CH2), 1.32
(t, J = 7.1 Hz, 3H, OCH2CH3). 13C NMR d 166.8, 166.4, 133.3,
116.6, 102.3, 59.3, 33.4, 27.0, 24.8, 23.5, 23.0, 14.7. LCMS Rf
(min) = 6.77. HR-ESI calcd for C12H18NO2S+ (M + H) 240.1053,
found 240.1046.
2H, NCH2CH2CH2CH3), 2.83–2.72 (m, 2H, CH2), 2.72–2.61
(m, 2H, CH2), 1.89–1.70 (m, 4H, 2 ¥ CH2), 1.61–1.54 (m,
2H, NCH2CH2CH2CH3), 1.42–1.25 (m, 2H, NCH2CH2CH2CH3),
1.15 (t, J = 7.0 Hz, 3H, OCH2CH3), 0.90 (t, J = 7.2 Hz, 3H,
NCH2CH2CH2CH3). 13C NMR (100 MHz, cis : trans isomers) d
162.7, 159.4, 155.3, 146.6, 134.8, 133. 130.2, 129.7, 128.9, 126.1,
113.8, 113.7, 67.7, 67.2, 60.3, 60.2, 55.3, 52.0, 30.0, 26.1, 25.1, 22.9,
22.6, 20.0, 14.1, 13.9. LCMS Rf (min) = 7.29. MS m/z 468.2 (M +
Na).
Ethyl 2-(ethyl(((4-methoxybenzyl)oxy)carbonyl)amino)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (7b). Carbamate
6
was reacted with diethylsulfate to obtain 7b as an oil (0.24 g).
1H NMR (cis : trans isomers, 1 : 3) d 7.41–7.11 (m, 2H, ArH),
6.95–6.73 (m, 2H, ArH), 5.19–4.87 (m, 2H, ArCH2), 4.22–3.92
(m, 2H, OCH2CH3), 3.83–3.70 (m, 3H, OCH3), 3.71–3.53 (m, 2H,
NCH2CH3), 2.84–2.72 (m, 2H, CH2), 2.72–2.58 (m, 2H, CH2),
1.92–1.68 (m, 4H, 2 ¥ CH2), 1.17 (m, 6H, OCH2CH3, NCH2CH3).
13C NMR (cis : trans isomers) d 162.7, 159.4, 155.1, 146.1, 134.8,
133.1, 130.2, 129.7, 128.9, 126.4, 113.9, 113.7, 69.4, 67.1, 60.2, 55.3,
47.0, 26.1, 25.1, 22.9, 22.6, 14.6, 14.1, 13.2. LCMS Rf (min) = 6.93.
MS m/z 440.1 (M + Na).
Ethyl
2-(butylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxylate (8d). Obtained as a clear colourless oil (0.109 g,
77%). 1H NMR d 7.79–7.63 (m, 1H, NH), 4.23 (q, J = 7.1 Hz, 2H,
OCH2CH3), 3.24–3.15 (m, 2H, NCH2CH2CH2CH3), 2.7–2.67 (m,
2H, CH2), 2.56–2.47 (m, 2H, CH2), 1.82–1.60 (m, 6H, 2 ¥ CH2,
NCH2CH2CH2CH3), 1.48–1.38 (m, 2H, NCH2CH2CH2CH3),
1.32 (t, J = 7.1 Hz, 3H, OCH2CH3), 0.94 (t, J = 7.4 Hz, 3H,
NCH2CH2CH2CH3). 13C NMR d 166.8, 165.3, 133.0, 116.2,
102.0, 59.1, 47.0, 31.4, 27.0, 24.7, 23.4, 23.0, 20.2, 14.6, 13.8.
LCMS Rf (min) = 7.46. HR-ESI calcd for C15H24NO2S+ (M + H)
282.1522, found 282.1515.
Ethyl
2-(ethylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxylate (8b). Obtained as a clear colourless oil (0.113 g,
89%). 1H NMR d 7.72–7.55 (m, 1H, NH), 4.23 (q, J = 7.1 Hz, 2H,
OCH2CH3), 3.22 (qd, J = 7.2, 5.5 Hz, 2H, NCH2CH3), 2.80–2.63
(m, 2H, CH2), 2.59–2.45 (m, 2H, CH2), 1.85–1.60 (m, 4H, 2 ¥
CH2), 1.32 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.30 (t, J = 7.2 Hz,
3H, NCH2CH3). 13C NMR d 166.7, 165.0, 133.0, 116.3, 102.1,
59.1, 41.9, 27.0, 24.7, 23.4, 23.0, 14.7, 14.6. LCMS Rf (min) =
7.03. HR-ESI calcd for C13H20NO2S+ (M + H) 254.1209, found
254.1205.
Ethyl 2-(allyl(((4-methoxybenzyl)oxy)carbonyl)amino)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (7e). Carbamate
6
was reacted with allyl bromide to obtain 7e as an oil (0.226 g). 1H
NMR (cis : trans isomers, 1 : 3) d 7.40–7.12 (m, 2H, ArH), 6.95–
6.73 (m, 2H, ArH), 6.00–5.77 (m, 1H, NCH2CHCH2), 5.21–4.96
(m, 4H, ArCH2, NCH2CHCH2), 4.24–3.94 (m, 4H, OCH2CH3,
NCH2CHCH2), 3.84–3.70 (m, 3H, OCH3), 2.83–2.71 (m, 2H,
CH2), 2.70–2.60 (m, 2H, CH2), 1.87–1.70 (m, 4H, 2 ¥ CH2), 1.16
(t, J = 7.0 Hz, 3H, OCH2CH3). 13C NMR (cis : trans isomers) d
162.6, 159.4, 155.2, 146.1, 134.7, 133.4, 133.0, 130.2, 129.8, 128.8,
126.3, 118.1, 117.8, 113.7, 67.8, 67.4, 60.3, 55.3, 54.7, 30.4, 26.1,
25.1, 22.9, 22.6, 14.1. LCMS Rf (min) = 6.92. MS m/z 452.2 (M +
Na).
Ethyl 2-((((4-methoxybenzyl)oxy)carbonyl)(propyl)amino)-4,5,
6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (7c). Carbamate
6 was reacted with 1-iodopropane to obtain 7c as an oil (0.224
g). 1H NMR (cis : trans isomers, 1 : 3) d 7.42–7.11 (m, 2H, ArH),
6.95–6.72 (m, 2H, ArH), 5.21–4.91 (m, 2H, ArCH2), 4.23–3.90
(m, 2H, OCH2CH3), 3.78–3.76 (m, 3H, OCH3), 3.57–3.48 (m, 2H,
NCH2CH2CH3), 2.82–2.71 (m, 2H, CH2), 2.71–2.62 (m, 2H, CH2),
1.87–1.72 (m, 4H, 2 ¥ CH2), 1.67–1.54 (m, 2H, NCH2CH2CH3),
1.15 (t, J = 7.1 Hz, 3H, OCH2CH3), 0.88 (t, J = 7.3 Hz, 3H,
NCH2CH2CH3). 13C NMR (100 MHz, cis : trans isomers) d 162.6,
159.4, 155.3, 146.7, 134.8, 133.0, 130.2, 129.7, 128.9, 126.1, 113.8,
113.7, 67.6, 67.2, 60.2, 55.3, 53.8, 26.1, 25.0, 22.9, 22.6, 21.7, 21.2,
14.1, 11.2. LCMS Rf (min) = 7.17. MS m/z 454.1 (M + Na).
Ethyl
2-(allylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxylate (8e). Yield 70% (0.093 g), obtained as a white
solid after recrystallization from methanol. Mp 40–43 ◦C.
1H NMR d 7.86–7.77 (m, 1H, NH), 5.95–5.85 (m, 1H,
NCH2CHCH2), 5.35–5.27 (m, 1H, NCH2CHCHH), 5.22–5.16
(m, 1H, NCH2CHCHH), 4.24 (q, J = 7.1 Hz, 2H, OCH2CH3),
3.90–3.80 (m, 2H, NCH2CHCH2), 2.76–2.68 (m, 2H, CH2),
2.56–2.48 (m, 2H, CH2), 1.81–1.69 (m, 4H, 2 ¥ CH2), 1.32 (t,
J = 7.1 Hz, 3H, OCH2CH3). 13C NMR d 166.7, 164.7, 133.6,
133.0, 117.0, 116.7, 102.9, 59.2, 49.5, 27.0, 24.7, 23.4, 23.0, 14.6.
LCMS Rf (min) = 7.02. HR-ESI calcd for C14H20NO2S+ (M + H)
266.1209, found 266.1199.
Ethyl
2-(propylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-
3-carboxylate (8c). Clear colourless oil (0.109 g, 81%). 1H
NMR d 7.82–7.67 (m, 1H, NH), 4.24 (q, J = 7.1 Hz, 2H,
OCH2CH3), 3.20–3.12 (m, 2H, NCH2CH2CH3), 2.76–2.68 (m,
2H, CH2), 2.57–2.48 (m, 2H, CH2), 1.90–1.57 (m, 6H, 2 ¥ CH2,
NCH2CH2CH3), 1.33 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.00 (t, J =
7.4 Hz, 3H, NCH2CH2CH3). 13C NMR d 166.8, 165.4, 133.0,
116.2, 102.1, 59.2, 49.2, 27.0, 24.8, 23.4, 23.0, 22.7, 14.6, 11.6.
LCMS Rf (min) = 7.25. HR-ESI calcd for C14H22NO2S+ (M + H)
268.1366, found 268.1367.
Ethyl
2-((((4-methoxybenzyl)oxy)carbonyl)(prop-2-yn-1-
yl)amino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (7f).
Carbamate 6 was reacted with propargyl bromide to obtain 7f as
an oil (0.266 g). 1H NMR (cis : trans isomers, 1 : 3) d 7.41–7.16 (m,
2H, ArH), 6.98–6.69 (m, 2H, ArH), 5.22–4.94 (m, 2H, ArCH2),
4.47–4.29 (m, 2H, NCH2CCH), 4.20–3.94 (m, 2H, OCH2CH3),
3.83–3.67 (m, 3H, OCH3), 2.83–2.73 (m, 2H, CH2), 2.72–2.62 (m,
2H, CH2), 2.28 (t, J = 2.5 Hz, 1H, NCH2CCH), 1.89–1.70 (m,
4H, 2 ¥ CH2), 1.15 (t, J = 7.1 Hz, 3H, OCH2CH3). 13C NMR
(100 MHz, cis : trans isomers) d 162.4, 159.5, 155.0, 144.6, 134.7,
134.2, 130.2, 129.7, 128.4, 126.7, 113.7, 78.7, 73.3, 68.1, 67.7, 60.3,
Ethyl 2-(butyl(((4-methoxybenzyl)oxy)carbonyl)amino)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (7d). Carbamate
6
was reacted with 1-bromobutane to obtain 7d as an oil (0.220
g). 1H NMR (cis : trans isomers, 1 : 3) d 7.41–7.10 (m, 2H, ArH),
6.95–6.72 (m, 2H, ArH), 5.17–4.92 (m, 2H, ArCH2), 4.21–3.91
(m, 2H, OCH2CH3), 3.83–3.69 (m, 3H, OCH3), 3.64–3.49 (m,
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55.7, 55.2, 53.5, 41.3, 41.0, 26.0, 25.1, 22.8, 22.5, 14.0. LCMS Rf
(min) = 6.66. MS m/z 450.2 (M + Na).
Further elution provided the starting material 6 (0.029 g,
6%) and finally 10 as a clear colourless oil (0.166 g, 77%). H
1
NMR (cis : trans isomers, 1 : 3) d 7.38–7.06 (m, 2H, ArH), 6.91–
6.71 (m, 2H, ArH), 5.24–4.86 (m, 2H, ArCH2), 4.65–4.31 (m,
1H, NCH(CH3)2), 4.23–3.86 (m, 2H, OCH2CH3), 3.84–3.69 (m,
3H, OCH3), 2.83–2.72 (m, 2H, CH2), 2.71–2.60 (m, 2H, CH2),
1.87–1.70 (m, 4H, 2 ¥ CH2), 1.27–0.97 (m, 9H, NCH(CH3)2,
OCH2CH3). 13C NMR (cis : trans isomers) d 162.9, 159.3, 155.0,
142.3, 134.6, 133.4, 130.5, 129.6, 129.0, 128.2, 113.7, 66.9, 60.1,
55.2, 50.0, 26.1, 25.0, 22.9, 22.6, 14.0. LCMS Rf (min) = 7.07. MS
m/z 454.2 (M + Na).
Ethyl
2-(prop-2-yn-1-ylamino)-4,5,6,7-tetrahydrobenzo[b]-
thiophene-3-carboxylate (8f). Yield 87% (0.114 g) obtained as
a white solid after recrystallization from petroleum ether. Mp
◦
1
77–79 C. H NMR d 7.77 (t, J = 5.2 Hz, 1H, NH), 4.25 (q,
J = 7.1 Hz, 2H, OCH2CH3), 4.00 (dd, J = 6.0, 2.5 Hz, 2H,
NCH2CCH), 2.75–2.70 (m, 2H, CH2), 2.58–2.53 (m, 2H, CH2),
2.27 (t, J = 2.5 Hz, 1H, NCH2CCH), 1.81–1.70 (m, 4H, 2 ¥ CH2),
1.33 (t, J = 7.1 Hz, 3H, OCH2CH3). 13C NMR d 166.6, 163.2,
133.3, 118.0, 104.6, 79.3, 72.1, 59.5, 36.3, 27.0, 24.8, 23.4, 23.0,
14.6. LCMS Rf (min) = 6.65. HR-ESI calcd for C14H18NO2S+ (M
+ H) 264.1053, found 264.1056.
Ethyl 2-(isopropylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxylate (11)
Ethyl 2-(benzyl(((4-methoxybenzyl)oxy)carbonyl)amino)-4,5,6,
7-tetrahydrobenzo[b]thiophene-3-carboxylate (7g). Carbamate 6
was reacted with benzyl bromide to obtain 7g as an oil (0.309
g). 1H NMR (cis : trans isomers, 1 : 3) d 7.41–7.20 (m, 7H, ArH),
6.93–6.78 (m, 2H, ArH), 5.23–5.05 (m, 2H, ArCH2), 4.89–4.65
(m, 2H, ArCH2), 4.21–3.93 (m, 2H, OCH2CH3), 3.86–3.71 (m,
3H, OCH3), 2.87–2.72 (m, 2H, CH2), 2.68–2.53 (m, 2H, CH2),
1.85–1.70 (m, 4H, 2 ¥ CH2), 1.16 (t, J = 7.0 Hz, 3H, OCH2CH3).
13C NMR (cis : trans isomers) d 162.5, 160.7, 159.4, 155.7, 155.1,
146.1, 137.1, 135.2, 134.6, 133.5, 129.7, 129.0, 128.8, 128.7, 128.6,
128.6, 128.5, 128.5, 26.0, 24.9, 22.8, 22.5, 14.0. LCMS Rf (min) =
7.05. MS m/z 502.1 (M + Na).
The oil 10 was taken up in CH2Cl2 (1 mL) and triethylsilane
(0.192 mL, 1.2 mmol) was added followed by TFA (0.116 mL,
1.5 mmol) and stirred at room temperature for 15–30 min. The
mixture was diluted with ether (20 mL) and quenched with
saturated bicarbonate solution. The aqueous layer was removed
and the organic layer was washed with water (10 mL) and then
brine (5 mL), dried (MgSO4), filtered and then concentrated to an
oil that was chromatographed on silica gel with 5% ethyl acetate–
petroleum ether providing 11 as a clear colourless oil (0.09 g, 88%).
1H NMR d 7.68 (d, J = 7.9 Hz, 1H, NH), 4.23 (q, J = 7.1 Hz, 2H,
OCH2CH3), 3.48 (dhept, J = 8.1, 6.4 Hz, 1H, NCH(CH3)2), 2.75–
2.67 (m, 2H, CH2), 2.56–2.48 (m, 2H, CH2), 1.82–1.69 (m, 4H, 2 ¥
CH2), 1.32 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.28 (d, J = 6.4 Hz,
6H, NCH(CH3)2). 13C NMR d 166.9, 164.1, 132.9, 116.3, 102.1,
59.2, 49.3, 27.1, 24.8, 23.5, 23.1, 23.0 14.7. LCMS Rf (min) =
7.30. HR-ESI calcd for C14H22NO2S+ (M + H) 268.1366, found
268.1363.
Ethyl 2-(benzylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxylate (8g). The title compound (0.156 g, 99%) was
obtained as a wh◦ite solid after recrystallization from petroleum
1
ether. Mp 90–92 C. H NMR d 8.16 (t, J = 5.4 Hz, 1H, NH),
7.41–7.27 (m, 5H, ArH), 4.44 (d, J = 5.9 Hz, 2H, ArCH2), 4.28 (q,
J = 7.1 Hz, 2H, OCH2CH3), 2.82–2.73 (m, 2H, CH2), 2.58–2.51
(m, 2H, CH2), 1.87–1.72 (m, 4H, 2 ¥ CH2), 1.36 (t, J = 7.1 Hz,
3H, OCH2CH3). 13C NMR d 166.8, 164.7, 137.8, 133.0, 128.8,
127.6, 127.5, 116.9, 103.1, 59.3, 51.1, 27.0, 24.7, 23.4, 23.0, 14.6.
LCMS Rf (min) = 7.15. HR-ESI calcd for C18H22NO2S+ (M + H)
316.1366, found 316.1363.
4-Methoxybenzyl (3-(4-chlorobenzoyl)-4,5,6,7-
tetrahydrobenzo[b]thiophen-2-yl)carbamate (17a)
To a 50 mL two neck flask fitted with a nitrogen inlet was
added 16 (0.554 g, 1.9 mmol) and then purged with nitrogen.
Caesium carbonate (1.86 g, 5.7 mmol) and TBAI (2.1 g, 5.7 mmol)
were added followed by anhydrous DMF (10 mL). The nitrogen
inlet was replaced with a carbon dioxide inlet and CO2 (g) was
bubbled through the stirred mixture at a steady rate for 2 h. p-
Methoxybenzyl chloride (0.271 mL, 2.0 mmol) was added to the
mixture in one portion with continual bubbling of CO2 (g) for a
further 3.5 h. The mixture was stirred overnight then diluted with
ether (100 mL) and then washed with water (6 ¥ 150 mL), then
brine (20 mL). The ethereal layer was dried (MgSO4), filtered and
then concentrated to a resin. The resin was chromatographed on
silica gel eluting with 10% ethyl acetate–petroleum ether affording
17a as a clear orange resin (0.351 g, 41%). 1H NMR d 10.54 (s, 1H,
NH), 7.50–7.45 (m, 2H, ArH), 7.43–7.38 (m, 2H, ArH), 7.37–7.32
(m, 2H, ArH), 6.92–6.87 (m, 2H, ArH), 5.19 (s, 2H, ArCH2), 3.81
(s, 3H. OCH3), 2.70–2.62 (m, 2H, CH2), 1.94–1.86 (m, 2H, CH2),
1.81–1.73 (m, 2H, CH2), 1.58–1.49 (m, 2H, CH2). 13C NMR d
192.9, 159.9, 153.3, 150.4, 139.2, 137.8, 130.4, 130.2, 129.6, 128.6,
127.6, 127.1, 120.4, 114.0, 68.0, 55.3, 27.6, 24.4, 23.0, 22.8. LCMS
Rf (min) = 7.11. MS m/z 454.2 (M - H).
Ethyl 2-(isopropyl(((4-methoxybenzyl)oxy)carbonyl)amino)-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (10)
To a 50 mL two neck flask fitted with a nitrogen inlet was added
6 (0.195 g, 0.5 mmol) and then purged with nitrogen. Caesium
carbonate (0.652 g, 2.0 mmol) and TBAI (0.092 g, 0.25 mmol)
were added followed by anhydrous DMF (3 mL). 2-Iodopropane
(0.20 mL, 2 mmol) was added and the reaction mixture was stirred
at rt for 24 h. A further aliquot of 2-iodopropane (0.20 mL,
2 mmol) and caesium carbonate (0.652 g, 2 mmol) were added and
stirred a further 3 h. The mixture was diluted with ether (50 mL)
and then washed with water (6 ¥ 150 mL), then brine (20 mL). The
ethereal layer was dried (MgSO4), filtered and then concentrated
to an oil which was chromatographed on silica gel with 5% ethyl
acetate–petroleum ether providing initially compound 9 as a white
solid (0.004 g, 3%). 1H NMR d 10.42 (s, 1H, NH), 5.03 (hept, J =
6.2 Hz, 1H, OCH(CH3)2), 4.30 (q, J = 7.1 Hz, 2H, OCH2CH3),
2.83–2.68 (m, 2H, CH2), 2.68–2.53 (m, 2H, CH2), 1.85–1.69 (m,
4H, 2 ¥ CH2), 1.36 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.30 (d, J =
6.3 Hz, 6H, OCH(CH3)2).
Further elution afforded a mixture of starting material 16 and
17b in a 1.6 : 1 ratio respectively as an orange resin (0.342 g).
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4-Methoxybenzyl (3-(4-chlorobenzoyl)-4,5,6,7-
tetrahydrobenzo[b]thiophen-2-yl)(methyl)carbamate (17c)
carbonate (0.326 g, 1.0 mmol) and TBAI (0.092 g, 0.25 mmol)
were added followed by anhydrous DMF (3 mL). To the stirred
mixture was added dimethylsulfate (0.095 mL, 1.0 mmol) and
left to stir overnight. The mixture was diluted with diethyl ether
(50 mL) and then washed with water (6 ¥ 150 mL), then brine
(20 mL). The ethereal layer was dried (MgSO4), filtered and then
concentrated to an oil affording the crude carbamates 19a,b,
that were chromatographed on silica gel with 5% ethyl acetate–
petroleum ether.
To a 25 mL two neck flask fitted with a nitrogen inlet was added
17a (0.062 g, 0.14 mmol) and then purged with nitrogen. Caesium
carbonate (0.089 g, 0.27 mmol) and TBAI (0.025 g, 0.068 mmol)
were added followed by anhydrous DMF (0.816 mL). To the stirred
mixture was added dimethylsulfate (0.026 mL, 0.27 mmol) and
left to stir overnight. Upon completion of the reaction (TLC), the
mixture was diluted with ether (10 mL) and then washed with
water (6 ¥ 15 mL), then brine (5 mL). The ethereal layer was dried
(MgSO4), filtered and then concentrated affording the N-alkylated
carbamate 17c as a resin (0.059 g, 92%). 1H NMR d 7.81–7.45 (m,
2H, ArH), 7.23–7.10 (m, 4H, ArH), 6.85 (d, J = 8.6 Hz, 2H,
ArH), 4.94 (s, 2H, ArCH2), 3.82 (s, 3H, OCH3), 3.13–2.90 (m,
3H, NCH3), 2.75–2.68 (m, 2H, CH2), 2.53–2.30 (m, 2H, CH2),
1.88–1.81 (m, 2H, CH2), 1.77–1.68 (m, 2H, CH2).
Ethyl
2-(2,2,2-trifluoro-N-methylacetamido)-4,5,6,7-tetrahy-
drobenzo[b]thiophene-3-carboxylate (19a). Initial fractions
provided starting material 18a (0.016 g, 10%) and further elution
provided 19a as a colorless resin (0.137 g, 82%). 1H NMR d
4.26–4.18 (m, 2H, OCH2CH3), 3.28 (s, 3H, NCH3), 2.89–2.59 (m,
4H, 2 ¥ CH2), 1.85–1.68 (m, 4H, 2 ¥ CH2), 1.26 (t, J = 7.1 Hz,
3H, OCH2CH3). 13C NMR d 161.7, 157.3 (q, J = 35.8 Hz), 143.5,
135.8, 135.2, 128.1, 116.2 (q, J = 288.3 Hz), 60.8, 40.5, 26.1, 25.1,
22.7, 22.3, 14.1. LCMS Rf (min) = 6.70. MS m/z 290.1 (100%).
Ethyl 2-(2,2,2-trifluoroacetamido)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (18a)
Ethyl 2-(N-methylacetamido)-4,5,6,7-tetrahydrobenzo[b]thio-
phene-3-carboxylate (19b). The target compound was isolated as
a colourless resin (0.129 g, 92%). 1H NMR d 4.26 (q, J = 7.1 Hz,
2H, OCH2CH3), 3.18 (s, 3H, NCH3), 2.82–2.76 (m, 2H, CH2),
2.73–2.67 (m, 2H, CH2), 1.94 (s, 3H, COCH3), 1.89–1.76 (m, 4H,
2 ¥ CH2), 1.31 (t, J = 7.1 Hz, 3H, OCH2CH3). 13C NMR d 171.3,
162.3, 148.9, 135.1, 134.5, 127.0, 60.7, 37.8, 26.0, 25.1, 22.8, 22.4,
21.9, 14.2. LCMS Rf (min) = 6.16. MS m/z 236.1 (100%), 194.1
(25).
To a 50 mL two neck flask fitted with a nitrogen inlet was added
3 (1.0 g, 4.44 mmol) and then purged with nitrogen. To this
was added CH2Cl2 (10 mL) followed by triethylamine (1.24 mL,
8.88 mmol) and then cooled in an ice bath. Then trifluoroacetic
anhydride (0.94 mL, 6.66 mmol) was added dropwise and the
mixture left to stir for 2 h. The mixture was then diluted with
ethyl acetate (50 mL) and washed with water (4 ¥ 20 mL) then
brine (10 mL). The organic layer was dried (MgSO4), filtered and
then concentrated to a solid that was recrystallised from me◦thanol
affording 18a as a lemon solid (1.27 g, 89%). Mp 130–132 C. 1H
NMR d 12.29 (s, 1H, NH), 4.37 (q, J = 7.1 Hz, 2H, OCH2CH3),
2.83–2.76 (m, 2H, CH2), 2.72–2.65 (m, 2H, CH2), 1.87–1.75 (m,
4H, 2 ¥ CH2), 1.40 (t, J = 7.1 Hz, 3H, OCH2CH3). 13C NMR d
166.4, 153.5 (q, J = 39.1 Hz), 143.9, 132.0, 129.5, 115.8 (q, J = 287.0
Hz), 114.8, 61.3, 26.3, 24.6, 22.9, 22.7, 14.3. LCMS Rf (min) = 7.00.
MS m/z 320.2 (M-H). HR-ESI calcd for C13H15F3NO3S+ (M + H)
322.0719, found 322.0710.
General procedure for the synthesis of N-isopropyl thiophenes 19c,d
To a 50 mL two neck flask fitted with a nitrogen inlet was added
18a or 18b (0.5 mmol) and then purged with nitrogen. Caesium
carbonate (1.3 g, 4.0 mmol) and TBAI (0.092 g, 0.25 mmol)
were added followed by anhydrous DMF (3 mL). 2-Iodopropane
(0.40 mL, 4.0 mmol) was added and the reaction was stirred at
room temperature overnight. The mixture was diluted with ether
(50 mL) and then washed with water (6 ¥ 150 mL), then brine
(20 mL). The ethereal layer was dried (MgSO4), filtered and then
Ethyl 2-acetamido-4,5,6,7-tetrahydrobenzo[b]thiophene-
3-carboxylate (18b)
1
concentrated. Analysis of the crude product with H NMR and
LCMS showed that 19c did not form and only starting material
was returned. In the case of 19d 83% conversion by LCMS and 1H
NMR.
To a 50 mL round bottom flask was added 3 (1.0 g, 4.44 mmol)
and acetic anhydride (4 mL) and then refluxed for several minutes.
Upon cooling a precipitate formed and while stirring saturated
bicarbonate solution was slowly added until gaseous evolution
ceased. The solid was filtered and washed with copious amounts
of water and suction dried to afford 18b as an off white solid
(1.15 g, 97%). Mp 122–124 ◦C. 1H NMR d 11.26 (s, 1H, NH), 4.32
(q, J = 7.1 Hz, 2H, OCH2CH3), 2.80–2.73 (m, 2H, CH2), 2.67–2.60
(m, 2H, CH2), 2.25 (s, 3H, COCH3), 1.84–1.72 (m, 4H, 2 ¥ CH2),
1.38 (t, J = 7.1 Hz, 3H, OCH2CH3). 13C NMR d 166.7, 166.5,
147.6, 130.5, 126.5, 111.1, 60.3, 26.3, 24.3, 23.6, 22.9, 22.8, 14.2.
LCMS Rf (min) = 6.43. MS m/z 268.2 (M + H). HR-ESI calcd for
C13H18NO3S+ (M + H) 268.1002, found 268.0990.
Ethyl 5-acetamido-3-(3-chlorophenyl)-4-oxo-3,4-
dihydrothieno[3,4-d]pyridazine-1-carboxylate (20a)
To a 25 mL round bottom flask was added 14 (0.5 g, 1.43 mmol)
and acetic anhydride (5 mL) and then refluxed for several minutes.
Upon cooling a precipitate formed and while stirring methanol
(5 mL) was added and the mixture chilled on ice for 30 min
and then filtered and the filter cake was washed with ice cold
methanol and suction dried affording 20a as yellow needles
◦
1
(0.502 g, 90%).%). Mp 188–190 C. H NMR d 10.98 (s, 1H,
NH), 7.88 (d, J = 0.8 Hz, 1H, ArH), 7.66 (t, J = 1.8 Hz, 1H, ArH),
7.54 (ddd, J = 7.8, 2.0, 1.4 Hz, 1H, ArH), 7.43 (t, J = 7.8 Hz,
1H, ArH), 7.38 (ddd, J = 8.0, 1.9, 1.4 Hz, 1H, ArH), 4.48 (q, J =
7.1 Hz, 2H, OCH2CH3), 2.33 (s, 3H, COCH3), 1.44 (t, J = 7.1 Hz,
3H, OCH2CH3). 13C NMR d 167.5, 162.7, 159.0, 146.8, 141.3,
General procedure for the synthesis of N-methylated thiophenes
19a,b
To a 50 mL two neck flask fitted with a nitrogen inlet was added
18a or 18b (0.5 mmol) and then purged with nitrogen. Caesium
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134.6, 134.5, 129.9, 128.4, 126.4, 126.0, 124.2, 115.4, 111.57, 62.5,
N-(3-(4-Chlorobenzoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-
23.4, 14.4. LCMS Rf (min) = 6.23. MS m/z 392.1 (M + H).
2,2,2-trifluoroacetamide (22b)
To a 50 mL two neck flask fitted with a nitrogen inlet was added
16 (0.70 g, 2.40 mmol) and then purged with nitrogen. To this
was added CH2Cl2 (15 mL) followed by triethylamine (0.669 mL,
4.80 mmol) and then cooled in an ice bath. Trifluoroacetic
anhydride (0.508 mL, 3.60 mmol) was added dropwise and the
mixture left to stir for 1.5 h. The mixture was then diluted
with CH2Cl2 (50 mL) and washed with water (4 ¥ 20 mL). The
organic layer was dried (MgSO4) and then concentrated to a solid
that was chromatographed on silica gel eluting with 5% ethyl
acetate–petroleum ether affording 22b as a lemon solid whi◦ch was
recrystallised from methanol (0.377 g, 41%). Mp 128–130 C. 1H
NMR d 12.11 (s, 1H, NH), 7.55–7.51 (m, 2H, ArH), 7.47–7.43
(m, 2H, ArH), 2.77–2.70 (m, 2H, CH2), 2.04–1.97 (m, 2H, CH2),
1.86–1.78 (m, 2H, CH2), 1.62–1.53 (m, 2H, CH2). 13C NMR d
194.0, 154.2 (q, J = 39.3 Hz), 144.7, 138.7, 138.3, 130.9, 130.8,
129.7, 128.9, 123.6, 115.6 (q, J = 287.1 Hz), 27.6, 24.5, 22.8, 22.7.
LCMS Rf (min) = 6.96. MS m/z 388.1 (M + H).
Ethyl 3-(3-chlorophenyl)-4-oxo-5-(2,2,2-trifluoroacetamido)-3,4-
dihydrothieno[3,4-d]pyridazine-1-carboxylate (20b)
To a 50 mL two neck flask fitted with a nitrogen inlet was added
14 (0.50 g, 1.43 mmol) and then purged with nitrogen. To this
was added CH2Cl2 (10 mL) followed by triethylamine (0.398 mL,
2.86 mmol) and then cooled in an ice bath. Trifluoroacetic
anhydride (0.303 mL, 2.14 mmol) was added dropwise and the
mixture left to stir for 1.5 h. The mixture was then diluted
with CH2Cl2 (50 mL) and washed with water (4 ¥ 20 mL). The
organic layer was dried (MgSO4), filtered through a silica gel
pad eluting with CH2Cl2 and then concentrated to a solid that
was recrystallised from me◦thanol affording 20b as a lemon solid
(0.52 g, 82%). Mp 168–170 C. 1H NMR d 11.88 (s, 1H, NH), 8.14
(s, 1H, ArH), 7.66 (t, J = 1.8 Hz, 1H, ArH), 7.60–7.51 (m, 1H,
ArH), 7.44 (t, J = 7.9 Hz, 1H, ArH), 7.40 (dt, J = 8.0, 1.6 Hz, 1H,
ArH), 4.50 (q, J = 7.1 Hz, 2H, OCH2CH3), 1.46 (t, J = 7.1 Hz,
3H, OCH2CH3). 13C NMR d 162.4, 158.8, 154.3 (q, J = 40.3 Hz),
143.1, 140.9, 134.8, 134.3, 130.0, 128.8, 126.3, 125.7, 124.2, 118.1,
115.4 (q, J = 286.6 Hz), 114.6, 62.7, 14.4. LCMS Rf (min) = 6.70.
MS m/z 446.0 (M + H).
General procedure for the synthesis of N-alkyl thiophenes 24a–c
To a 25 mL two neck flask fitted with a nitrogen inlet was added
22a (0.167 g, 0.5 mmol) and then purged with nitrogen. Caesium
carbonate (0.326 g, 1.0 mmol) and TBAI (0.092 g, 0.25 mmol)
were added followed by anhydrous DMF (3.0 mL). The alkylating
agent (1.0 mmol) was added and the reaction was stirred at
room temperature for 24–40 h. The mixture was diluted with
ether (25 mL) and then washed with water (6 ¥ 50 mL), then
brine (20 mL). The ethereal layer was dried (MgSO4), filtered and
then concentrated to a yellow resin. The resin was taken up in
ethanol (4 mL), water (1 mL) was added, followed by NaOH
(0.1 g, 2.5 mmol) and heated on an oil bath (35–40 ◦C) for 4 h
in which time a precipitate formed. The mixture was cooled to
room temperature and filtered on a Buchner funnel/flask and the
filter cake washed with 2 : 1 EtOH : H2O (5 mL) and suction dried
affording the N-alkylated thiophenes 24a–c as bright yellow solids.
Ethyl 3-(3-chlorophenyl)-5-(N-methylacetamido)-4-oxo-3,4-
dihydrothieno[3,4-d]pyridazine-1-carboxylate (21a)
To a 25 mL two neck flask fitted with a nitrogen inlet was added
20a (0.044 g, 0.11 mmol) and then purged with nitrogen. Caesium
carbonate (0.072 g, 0.22 mmol) and TBAI (0.021 g, 0.056 mmol)
were added followed by anhydrous DMF (0.667 mL). To the stirred
mixture was added dimethylsulfate (0.021 mL, 0.22 mmol) and left
to stir at room temperature overnight. The mixture was diluted
with ether (25 mL) and then washed with water (6 ¥ 50 mL), then
brine (20 mL). The ethereal layer was dried (MgSO4), filtered and
then concentrated to a resin which was chromatographed on silica
gel with 0–30% ethyl acetate–petroleum ether affording 21a as a
1
pale yellow resin (0.031 g, 69%). H NMR d 8.57–8.40 (m, 1H,
(4-Chlorophenyl)(2-(methylamino)-4,5,6,7-tetrahydrobenzo[b]-
thiophen-3-yl)methanone (24a). Dimethylsulfate was used as the
alkylating agent and the targ◦et compound was isolated in 61%
ArH), 7.70–7.59 (m, 1H, ArH), 7.59–7.47 (m, 1H, ArH), 7.44–7.33
(m, 2H, ArH), 4.49 (q, J = 7.1 Hz, 2H, OCH2CH3), 3.57–3.29 (m,
3H, NCH3), 2.02–1.91 (m, 3H, COCH3), 1.45 (t, J = 7.1 Hz, 3H,
OCH2CH3). LCMS Rf (min) = 5.95. MS m/z 406.1 (M + H).
1
yield (0.093 g). Mp 149–151 C. H NMR d 9.52–9.37 (m, 1H,
NH), 7.37–7.33 (m, 4H, ArH), 3.05 (d, J = 5.2 Hz, 3H, NCH3),
2.59–2.49 (m, 2H, CH2), 1.80–1.68 (m, 4H, 2 ¥ CH2), 1.53–1.43
(m, 2H, CH2). 13C NMR d 189.7, 170.1, 141.2, 135.6, 131.7, 128.8,
128.3, 118.2, 113.3, 33.4, 28.2, 25.0, 23.2, 23.0. LCMS Rf (min) =
6.90. HR-ESI calcd for C16H17ClNOS+ (M + H) 306.0714, found
306.0709.
N-(3-(4-Chlorobenzoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-
yl)acetamide (22a)
To a 50 mL round bottom flask was added 16 (1.0 g, 3.43 mmol)
and acetic anhydride (5 mL) and then refluxed for several minutes.
While stirring, the cooled mixture was quenched with saturated
bicarbonate solution (added slowly) until gaseous evolution ceased
and extracted with CH2Cl2 (3 ¥ 30 mL). The combined organics
were dried (MgSO4), filtered and then concentrated affording 22a
(2 - (Butylamino) - 4,5,6,7 - tetrahydrobenzo[b]thiophen - 3 - yl)(4 -
chlorophenyl)methanone (24b). 1-Bromobutane was used as the
alkylating agent and the target compound was isolated in 36%
◦
1
1
as a pale yellow foam (0.90 g, 79%). H NMR d 11.29 (s, 1H,
yield (0.062 g). Mp 109–111 C. H NMR d 9.62 (t, J = 4.6 Hz,
1H, NH), 7.38–7.33 (m, 4H, ArH), 3.29 (td, J = 6.9, 5.8 Hz,
2H, NCH2CH2CH2CH3), 2.57–2.48 (m, 2H, CH2), 1.79–1.67
(m, 6H, 2 ¥ CH2, NCH2CH2CH2CH3), 1.53–1.41 (m, 4H, CH2,
NCH2CH2CH2CH3), 0.96 (t, J = 7.4 Hz, 3H, NCH2CH2CH2CH3).
13C NMR d 189.5, 169.1, 141.3, 135.6, 131.5, 128.8, 128.3, 118.0,
113.2, 47.3, 31.1, 28.2, 25.0, 23.2, 23.0, 20.3, 13.8. LCMS Rf (min) =
NH), 7.52–7.48 (m, 2H, ArH), 7.45–7.40 (m, 2H, ArH), 2.70–2.64
(m, 2H, CH2), 2.26 (s, 3H, COCH3), 1.96–1.88 (m, 2H, CH2),
1.82–1.73 (m, 2H, CH2), 1.58–1.50 (m, 2H, CH2). 13C NMR d
193.6, 167.7, 148.9, 139.2, 138.0, 129.7, 129.6, 128.7, 128.1, 120.8,
27.7, 24.4, 23.9, 23.0, 22.9. LCMS Rf (min) = 6.56. MS m/z
334.1 (M + H).
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7.53. HR-ESI calcd for C19H23ClNOS+ (M + H) 348.1183, found
348.1184.
Ethyl
2-(butylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxylate (8d). The title compound was isolated in 71% yield
(0.10 g) and was material was identical in all respects to the
material 8d via the general procedure described above.
(2-(Benzylamino)-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-
chlorophenyl)methanone (24c). Benzyl bromide was used as the
alkylating agent and the targ◦et compound was isolated in 32%
Ethyl 2-(benzylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxylate (8g). The title compound was isolated in 60% yield
(0.095 g) and was identical in all respects to the material 8g via
the general procedure described above.
1
yield (0.061 g). Mp 135–137 C. H NMR d 9.92–9.81 (m, 1H,
NH), 7.50–7.23 (m, 9H, ArH), 4.50 (d, J = 5.7 Hz, 2H, ArCH2),
2.59–2.45 (m, 2H, CH2), 1.86–1.66 (m, 4H, 2 ¥ CH2), 1.54–1.42
(m, 2H, CH2). 13C NMR d 189.9, 168.3, 141.0, 136.8, 135.7, 131.4,
2 ¥128.8, 128.2, 127.8, 127.5, 118.4, 113.8, 51.2, 28.1, 24.8, 23.1,
22.9. LCMS Rf (min) = 7.27. HR-ESI calcd for C22H21ClNOS+ (M
+ H) 382.1027, found 382.1017.
Ethyl 5-((tert-butoxycarbonyl)amino)-3-(3-chlorophenyl)-4-oxo-
3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylate (26)
To a 50 mL round bottom flask was added 14 (0.5 g, 1.43 mmol),
dioxane (15 mL), Boc2O (0.655 g, 3.0 mmol) and DMAP (0.018 g,
0.14 mmol) and the mixture was heated on an oil bath (40 ◦C)
for 2 h with stirring. Then N2H4·H2O (0.152 mL, 3.14 mmol)
was added to the mixture and continued to stir at 40 ◦C for
3 h then stirred at room temperature overnight. The mixture
was concentrated and then dissolved in ethyl acetate (50 mL)
and washed with water (2 ¥ 150 mL) and then brine (20 mL)
dried (MgSO4), filtered and then concentrated to a solid that was
chromatographed on silica gel with 10% ethyl acetate–petroleum
ether providing 26 as a yellow solid that was recrystallised from
methanol (0.411 g, 64%). Mp 170 ◦C dec. 1H NMR d 10.10 (s, 1H,
NH), 7.80 (d, J = 1.4 Hz, 1H, ArH), 7.66 (dd, J = 1.9, 1.4 Hz, 1H,
ArH), 7.54 (ddd, J = 7.8, 2.0, 1.4 Hz, 1H, ArH), 7.41 (t, J = 7.8 Hz,
1H, ArH), 7.36 (ddd, J = 8.0, 1.9, 1.4 Hz, 1H, ArH), 4.48 (q, J =
7.1 Hz, 2H, OCH2CH3), 1.55 (s, 9H, C(CH3)3), 1.45 (t, J = 7.1 Hz,
3H, OCH2CH3). 13C NMR d 162.7, 158.9, 152.1, 149.5, 141.4,
134.4, 134.4, 129.7, 128.1, 126.2, 125.4, 124.1, 113.8, 110.3, 83.2,
62.3, 28.2, 14.4. LCMS Rf (min) = 7.00. MS m/z 448.2 (M - H).
Ethyl 2-(tert-butoxycarbonylamino)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (25)
To a 50 mL round bottom flask was added 3 (0.5 g, 2.22 mmol),
dioxane (15 mL), Boc2O (1.02 g, 4.67 mmol) and DMAP (0.027 g,
0.22 mmol) and the mixture was heated on an oil bath (40 ◦C) for 16
h with stirring. N2H4·H2O (0.322 mL, 6.66 mmol) was added to the
mixture and continued to stir at 40 ◦C for 6 h then stirred at room
temperature overnight. The mixture was evaporated and then
chromatographed on silica gel with 0–5% ethyl acetate–petroleum
ether providing 25 as an off white solid that was recrystallised from
methanol (0.628 g, 87%). Mp 110–112 ◦C dec. 1H NMR d 10.30
(s, 1H, NH), 4.27 (q, J = 7.1 Hz, 2H, OCH2CH3), 2.77–2.63 (m,
2H, CH2), 2.63–2.48 (m, 2H, CH2), 1.83–1.61 (m, 2H, 2 ¥ CH2),
1.49 (s, 9H, C(CH3)3), 1.33 (t, J = 7.1 Hz, 2H, OCH2CH3). 13C
NMR d 166.4, 152.16, 149.9, 131.0, 125.1, 110.1, 81.7, 60.2, 28.2,
26.5, 24.3, 23.0, 22.9, 14.3. LCMS Rf (min) = 7.31. MS m/z 326.1
(M + H).
General procedure for the synthesis of N-alkylated thiophenes
27a,d
General procedure for the synthesis of N-alkylated thiophenes
8a,d,g from 25
To a 25 mL two neck flask fitted with a nitrogen inlet was added
26 (0.150 g, 0.33 mmol) and then purged with nitrogen. Caesium
carbonate (0.217 g, 0.67 mmol) and TBAI (0.062 g, 0.17 mmol)
were added followed by anhydrous DMF (2 mL). The alkylating
agent (0.67 mmol) was added and the reaction was stirred at room
temperature for 3–24 h. Upon completion of the reaction (TLC),
the mixture was diluted with ether (25 mL) and then washed with
water (6 ¥ 50 mL), then brine (20 mL). The ethereal layer was
dried (MgSO4), filtered and then concentrated to an oil affording
the N-alkylated carbamates which were chromatographed on silica
gel with 10% ethyl acetate–petroleum ether. The carbamates were
taken up in CH2Cl2 (0.5 mL) and cooled in an ice bath and TFA
(0.25 mL) was added and the mixture stirred for 3 h at 0 ◦C.
The mixture was diluted with CH2Cl2 (10 mL) and quenched with
saturated bicarbonate solution. The aqueous layer was removed
and the organic layer was washed with water (10 mL) and then
brine (5 mL), dried (MgSO4), filtered and then concentrated to
a yellow resin that slowly solidifies. The solids were recrystallised
from methanol affording the thiophenes 27a,d as bright yellow
solids.
To a 50 mL two neck flask fitted with a nitrogen inlet was added
25 (0.163 g, 0.5 mmol) and then purged with nitrogen. Caesium
carbonate (0.326 g, 1.0 mmol) and TBAI (0.092 g, 0.25 mmol)
were added followed by anhydrous DMF (3 mL). The alkylating
agent (1.0 mmol) was added and the reaction was stirred at room
temperature for 3–24 h. Upon completion of the reaction (TLC),
the mixture was diluted with ether (50 mL) and then washed with
water (6 ¥ 150 mL), then brine (20 mL). The ethereal layer was
dried (MgSO4), filtered and then concentrated to an oil affording
the carbamates, which were used without further purification
in the next step. The resin was taken up in CH2Cl2 (1 mL)
and TFA (0.5 mL) was added and stirred at room temperature
for 3 h. The mixture was diluted with CH2Cl2 (20 mL) and
quenched with saturated bicarbonate solution. The organic layer
was removed and the aqueous layer was extracted with CH2Cl2 (2 ¥
10 mL) and the combined organics were dried (MgSO4), filtered
and then concentrated to afford the thiophenes 8a,d,g that were
chromatographed on silica gel with 5% ethyl acetate–petroleum
ether. Solids were recrystallized from petroleum ether or methanol.
Ethyl 2-(methylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxylate (8a). The title compound was isolated in 96% (0.115
g) and was identical in all respects to the material 8a via the general
procedure described above.
Ethyl 3-(3-chlorophenyl)-5-(methylamino)-4-oxo-3,4-dihydro-
thieno[3,4-d]pyridazine-1-carboxylate
(27a). Dimethylsulfate
was used as the alkylating agent and the title◦compound was
1
obtained in 67% yield (0.081 g). Mp 179–181 C. H NMR d
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7.65 (t, J = 1.9 Hz, 1H, ArH), 7.59–7.50 (m, 2H, ArH, NH), 7.37
(t, J = 8.0 Hz, 1H, ArH), 7.31 (ddd, J = 8.0, 2.0, 1.2 Hz, 1H,
ArH), 7.19 (d, J = 1.0 Hz, 1H, ArH), 4.44 (q, J = 7.1 Hz, 2H,
OCH2CH3), 3.06 (d, J = 5.2 Hz, 3H, NCH3), 1.43 (t, J = 7.1 Hz,
3H, OCH2CH3). 13C NMR d 165.6, 163.12, 159.3, 141.8, 134.3,
134.2, 129.6, 127.6, 127.5, 126.1, 124.0, 104.2, 103.0, 62.1, 34.0,
14.4. LCMS Rf (min) = 6.44. HR-ESI calcd for C16H15ClN3O3S+
(M + H) 364.0517, found 364.0517.
ArH), 4.37 (t, J = 6.8 Hz, 2H, OCH2CH2CH2CH3), 3.32–3.21 (m,
2H, NCH2CH2CH2CH3), 1.82–1.66 (m, 4H, OCH2CH2CH2CH3),
1.52–1.40 (m, 4H, NCH2CH2CH2CH3), 0.98 (t, J = 7.4 Hz, 3H,
OCH2CH2CH2CH3), 0.96 (t, J = 7.4 Hz, 3H, NCH2CH2CH2CH3).
13C NMR d 164.6, 163.1, 159.4, 141.8, 134.3, 134.2, 129.6, 127.5,
127.3, 126.0, 123.9, 104.1, 102.6, 65.9, 47.8, 30.9, 30.7, 20.1,
19.3, 13.9, 13.8. LCMS Rf (min) = 7.36. HR-ESI calcd for
C21H25ClN3O3S+ (M + H) 434.1300, found 434.1285.
Further elution provided Boc protected 27c (0.030 g). 1H NMR
d 8.37 (s, 1H, ArH), 7.63 (t, J = 1.9 Hz, 1H, ArH), 7.55–7.51
(m, 1H, ArH), 7.39 (t, J = 7.8 Hz, 1H, ArH), 7.34 (ddd, J =
8.1, 1.9, 1.3 Hz, 1H, ArH), 4.48 (q, J = 7.1 Hz, 2H, OCH2CH3),
3.75 (t, J = 7.1 Hz, 2H, NCH2CH2CH2CH3), 1.60–1.28 (m, 16H,
NCH2CH2CH2CH3, C(CH3)3, OCH2CH3), 0.89 (t, J = 7.3 Hz,
3H, NCH2CH2CH2CH3).
Ethyl
5-(benzylamino)-3-(3-chlorophenyl)-4-oxo-3,4-dihydro-
thieno[3,4-d]pyridazine-1-carboxylate (27d). Benzyl bromide
was used as the alkylating agent and the title◦compound was
1
obtained in 84% yield (0.123 g). Mp 116–118 C. H NMR d
8.01 (t, J = 5.6 Hz, 1H, NH), 7.66 (t, J = 1.9 Hz, 1H, ArH),
7.54 (ddd, J = 7.9, 2.0, 1.2 Hz, 1H, ArH), 7.41–7.28 (m, 6H,
ArH), 7.18 (d, J = 1.0 Hz, 1H, ArH), 4.48–4.40 (m, 4H, ArCH2,
OCH2CH3), 1.42 (t, J = 7.1 Hz, 3H, OCH2CH3). 13C NMR d
163.8, 163.0, 159.3, 141.7, 136.0, 134.3, 134.2, 129.6, 129.0, 128.3,
127.8, 127.6, 127.2, 126.1, 124.0, 104.9, 103.6, 62.1, 51.7, 14.4.
LCMS Rf (min) = 6.81. HR-ESI calcd for C22H19ClN3O3S+ (M +
H) 440.0830, found 440.0830.
The carbamate was taken up in CH2Cl2 (0.2 mL) and cooled
in an ice bath and TFA (0.10 mL) was added and the mixture
stirred for 3 h at 0 ◦C. The mixture was diluted with CH2Cl2
(10 mL) and quenched with saturated bicarbonate solution. The
aqueous layer was removed and the organic layer was washed with
water (10 mL) and then brine (5 mL), dried (MgSO4), filtered
and then concentrated to a yellow resin that slowly solidified
and was recrystallised from methanol affording 27c as a gold
Butyl 5-(butylamino)-3-(3-chlorophenyl)-4-oxo-3,4-
dihydrothieno[3,4-d]pyridazine-1-carboxylate (27b) and ethyl
5-(butylamino)-3-(3-chlorophenyl)-4-oxo-3,4-dihydrothieno[3,4-
d]pyridazine-1-carboxylate (27c)
◦
1
coloured solid (0.055 g, 82%). Mp 99–102 C. H NMR d 7.64
(t, J = 1.9 Hz, 1H, ArH), 7.60 (t, J = 5.5 Hz, 1H, NH), 7.53
(ddd, J = 7.9, 1.9, 1.2 Hz, 1H, ArH), 7.37 (t, J = 8.0 Hz,
1H, ArH), 7.31 (ddd, J = 8.0, 1.9, 1.2 Hz, 1H, ArH), 7.15 (s,
1H, ArH), 4.44 (q, J = 7.1 Hz, 2H, OCH2CH3), 3.31–3.23 (m,
2H, NCH2CH2CH2CH3), 1.76–1.66 (m, 2H, NCH2CH2CH2CH3),
1.51–1.40 (m, 5H, NCH2CH2CH2CH3, OCH2CH3), 0.96 (t, J =
7.4 Hz, 3H, NCH2CH2CH2CH3). 13C NMR d 164.7, 163.1, 159.4,
141.8, 134.3, 134.2, 129.6, 127.7, 127.3, 126.2, 124.1, 104.1, 102.7,
62.1, 47.9, 31.0, 20.2, 14.4, 13.8. LCMS Rf (min) = 7.05. HR-ESI
calcd for C19H21ClN3O3S+ (M + H) 406.0987, found 406.0993.
To a 25 mL two neck flask fitted with a nitrogen inlet was
added 26 (0.120 g, 0.27 mmol) and then purged with nitrogen.
Caesium carbonate (0.174 g, 0.53 mmol) and TBAI (0.049 g,
0.13 mmol) were added followed by anhydrous DMF (1.6 mL). 1-
Bromobutane (0.057 mL, 0.53 mmol) was added and the reaction
was stirred at room temperature 24 h. Then a further portion
of caesium carbonate (0.174 g, 0.53 mmol) and 1-bromobutane
(0.057 mL, 0.53 mmol) were added and the mixture was heated
to 60 ◦C for 24 h. The cooled mixture was diluted with ether
(25 mL) and then washed with water (6 ¥ 50 mL), then brine
(20 mL). The ethereal layer was dried (MgSO4), filtered and then
concentrated to a resin which was chromatographed on silica gel
with 5% ethyl acetate–petroleum ether providing Boc protected
27b (0.083 g). 1H NMR d 8.35 (s, 1H, ArH), 7.64 (t, J = 1.9 Hz,
1H, ArH), 7.57–7.52 (m, 1H, ArH), 7.39 (t, J = 7.9 Hz, 1H, ArH),
7.33 (ddd, J = 8.0, 1.9, 1.3 Hz, 1H, ArH), 4.42 (t, J = 6.8 Hz, 2H,
OCH2CH2CH2CH3), 3.75 (t, J = 7.1 Hz, 2H, NCH2CH2CH2CH3),
1.84–1.76 (m, 2H, OCH2CH2CH2CH3), 1.60–1.27 (m, 15H
C(CH3)3, OCH2CH2CH2CH3, NCH2CH2CH2CH3), 0.99 (t, J =
7.4 Hz, 3H, OCH2CH2CH2CH3), 0.89 (t, J = 7.3 Hz, 3H,
NCH2CH2CH2CH3).
The carbamate was taken up in CH2Cl2 (0.5 mL) and cooled
in an ice bath and TFA (0.25 mL) was added and the mixture
stirred for 3 h at 0 ◦C. The mixture was diluted with CH2Cl2
(10 mL) and quenched with saturated bicarbonate solution. The
aqueous layer was removed and the organic layer was washed with
water (10 mL) and then brine (5 mL), dried (MgSO4), filtered and
then concentrated to a yellow resin that slowly solidifies and was
recrystallised from methanol affording 27b as a gold coloured
solid (0.055 g, 82%). Mp 92–94 ◦C. 1H NMR d 7.66 (t, J =
1.9 Hz, 1H, ArH), 7.60 (t, J = 5.5 Hz, 1H, NH), 7.55 (ddd, J =
8.0, 2.0, 1.2 Hz, 1H, ArH), 7.36 (t, J = 8.0 Hz, 1H, ArH), 7.30
(ddd, J = 8.0, 2.0, 1.2 Hz, 1H, ArH), 7.12 (d, J = 1.0 Hz, 1H,
tert-Butyl 3-(4-chlorobenzoyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-
2-ylcarbamate (28)
To a 50 mL round bottom flask was added 16 (0.5 g, 1.71 mmol),
dioxane (10 mL), Boc2O (0.785 g, 3.6 mmol) and DMAP (0.021 g,
0.17 mmol) and the mixture was heated on an oil bath (40 ◦C) for
16 h with stirring. Then N2H4·H2O (0.249 mL, 5.14 mmol) was
added to the mixture which was stirred at 40 ◦C for 6 h then stirred
at room temperature overnight. The mixture was concentrated
and then chromatographed on silica gel with 0–5% ethyl acetate–
petroleum ether providing 28 as a yellow foam (0.538 g, 80%). 1H
NMR d 10.42 (s, 1H. NH), 7.55–7.45 (m, 2H, ArH), 7.44–7.32 (m,
2H, ArH), 2.69–2.59 (m, 2H, CH2), 1.95–1.86 (m, 2H, CH2), 1.82–
1.71 (m, 2H, CH2), 1.58–1.47 (m, 11H, C(CH3)3, CH2). 13C NMR d
193.0, 152.5, 151.3, 139.4, 137.7, 130.0, 129.7, 128.7, 126.7, 120.0,
82.3, 28.3, 27.7, 24.4, 23.1, 23.0. LCMS Rf (min) = 7.34. MS m/z
390.1 (M - H).
General procedure for the synthesis of N-alkylated thiophenes
24a–c from 28
To a 50 mL two neck flask fitted with a nitrogen inlet was added
25 (0.098 g, 0.25 mmol) and then purged with nitrogen. Caesium
carbonate (0.163 g, 0.5 mmol) and TBAI (0.046 g, 0.125 mmol)
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were added followed by anhydrous DMF (1.5 mL). The alkylating
reagent (0.5 mmol) was added and the reaction was stirred at
room temperature for 3–24 h. In the case of 24b a further aliquot
of 1-bromobutane (0.054 mL, 0.5 mmol) and caesium carbonate
(0.163 g, 0.5 mmol) were added and stirred a further 16 h. Upon
completion of the reaction (TLC), the mixture was diluted with
ether (25 mL) and then washed with water (6 ¥ 75 mL), then brine
(10 mL). The ethereal layer was dried (MgSO4), filtered and then
concentrated to an oil affording the carbamates, which were used
without further purification in the next step. The resin was taken
up in CH2Cl2 (0.5 mL) and TFA (0.25 mL) was added and stirred
at room temperature for 3 h. The mixture was diluted with CH2Cl2
(10 mL) and quenched with saturated bicarbonate solution. The
organic layer was removed and the aqueous layer was extracted
with CH2Cl2 (2 ¥ 10 mL) and the combined organics were dried
(MgSO4), filtered and then concentrated to afford the thiophenes
24a–c, that were recrystallized from methanol.
ethereal layer was dried (MgSO4), filtered and then concentrated
to an oil affording the carbamates, which were used without
further purification in the next step. The resin was taken up in
CH2Cl2 (0.5 mL) and TFA (0.25 mL) was added and stirred at
room temperature for 3 h. The mixture was diluted with CH2Cl2
(10 mL) and quenched with saturated bicarbonate solution. The
organic layer was removed and the aqueous layer was extracted
with CH2Cl2 (2 ¥ 10 mL) and the combined organics were dried
(MgSO4), filtered and then concentrated to afford the crude
benzophenones that were chromatographed on silica gel with 0–
5% ethyl acetate–petroleum ether providing 31a–c.
(2-(Methylamino)phenyl)(phenyl)methanone (31a). The title
compound was obtained as a yellow solid in 86% yield (0.031
g). Mp 48–50 ◦C. 1H NMR d 8.67–8.45 (m, 1H, NH), 7.64–7.58
(m, 2H, ArH), 7.54–7.39 (m, 5H, ArH), 6.77 (d, J = 8.1 Hz, 1H,
ArH), 6.55 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H, ArH), 2.98 (d, J =
5.1 Hz, 3H, NCH3). 13C NMR d 199.4, 152.8, 140.7, 135.6, 135.1,
130.7, 129.0, 128.1, 117.38, 113.7, 111.2, 29.5. LCMS Rf (min) =
6.28. HR-ESI calcd for C14H14NO+ (M + H) 212.1070, found
212.1064.
(4-Chlorophenyl)(2-(methylamino)-4,5,6,7-tetrahydrobenzo[b]-
thiophen-3-yl)methanone (24a). The title compound was ob-
tained in 71% yield (0.054 g) and was identical in all respects
to the material 24a via the general procedure described above.
(2-(Butylamino)phenyl)(phenyl)methanone (31b). The title
compound was obtained as a viscous yellow oil in 84% yield
(0.036 g). 1H NMR d 8.72–8.54 (m, 1H, NH), 7.70–7.56 (m, 2H,
ArH), 7.55–7.28 (m, 5H, ArH), 6.78 (d, J = 8.4 Hz, 1H, ArH), 6.51
(ddd, J = 8.1, 7.1, 1.1 Hz, 1H, ArH), 3.27 (td, J = 7.0, 5.2 Hz, 2H,
NCH2CH2CH2CH3), 1.79–1.66 (m, 2H, NCH2CH2CH2CH3),
1.58–1.45 (m, 2H, NCH2CH2CH2CH3), 0.99 (t, J = 7.3 Hz, 3H,
NCH2CH2CH2CH3). 13C NMR d 199.4, 152.2, 140.8, 135.7,
135.1, 130.8, 129.1, 128.1, 117.0, 113.5, 111.6, 42.6, 31.3, 20.5,
14.0. LCMS Rf (min) = 6.92. HR-ESI calcd for C17H20NO+ (M +
H) 254.1539, found 254.1545.
(2 - (Butylamino) - 4,5,6,7 - tetrahydrobenzo[b]thiophen - 3 - yl)(4 -
chlorophenyl)methanone (24b). The title compound was obtained
in 64% yield (0.056 g) and was identical in all respects to the
material 24b via the general procedure described above.
(2-(Benzylamino)-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-
chlorophenyl)methanone (24c). The title compound was obtained
in 78% yield (0.075 g) and was identical in all respects to the
material 24c via the general procedure described above.
tert-Butyl 2-benzoylphenylcarbamate (30). To a 50 mL round
bottom flask was added 29 (0.438 g, 2.22 mmol), and Boc2O
(1.02 g, 4.67 mmol) and DMAP (0.027 g, 0.22 mmol) and the
mixture was heated on an oil bath (65–70 ◦C) for 2 h with stirring.
Then EtOH (0.5 mL) was added followed by N2H4·H2O (0.322 mL,
6.66 mmol) was added to the mixture and continued to stir at 65–
70 ◦C for 2 h then stirred at room temperature overnight. The
mixture was concentrated and then chromatographed on silica
gel with 0–5% ethyl acetate–petroleum ether providing 30 as an
(2-(Benzylamino)phenyl)(phenyl)methanone (31c). The title
compound was obtained as a viscous yellow oil in 95% yield (0.046
g). 1H NMR d 9.09–8.68 (m, 1H, NH), 7.59–7.49 (m, 2H, ArH),
7.46–7.40 (m, 2H, ArH), 7.40–7.33 (m, 2H, ArH), 7.33–7.14 (m,
6H, ArH), 6.65 (d, J = 8.5 Hz, 1H, ArH), 6.47 (ddd, J = 8.1, 7.1,
1.1 Hz, 1H, ArH), 4.42 (d, J = 5.6 Hz, 2H, ArCH2). 13C NMR
d 199.6, 151.7, 140.6, 138.7, 135.6, 135.1, 130.9, 129.2, 128.8,
128.2, 127.4, 127.3, 117.7, 114.3, 112.2, 47.1. LCMS Rf (min) =
6.71. HR-ESI calcd for C20H18NO+ (M + H) 288.1383, found
288.1373.
◦
1
off white solid (0.297 g, 45%). Mp 100–102 C dec. H NMR
d 10.06 (s, 1H, NH), 8.41 (d, J = 8.0 Hz, 1H, ArH), 7.71–7.65
(m, 2H, ArH), 7.59–7.42 (m, 5H, ArH), 6.98 (ddd, J = 8.0, 7.3,
1.1 Hz, 1H, ArH), 1.51 (s, 9H, C(CH3)3). 13C NMR d 199.4,
153.09, 141.5, 138.9, 134.2, 133.6, 132.4, 130.0, 128.3, 122.8, 120.8,
120.0, 80.6, 28.4. LCMS Rf (min) = 6.67. MS m/z 198.2 (100%),
102.2 (75).
tert-Butyl 9-oxo-9H-fluoren-1-ylcarbamate (33)
To a 50 mL round bottom flask was added 32 (0.433 g, 2.22 mmol),
Boc2O (1.02 g, 4.67 mmol) and DMAP (0.027 g, 0.22 mmol) and
the mixture was heated on an oil bath (65–70 ◦C) for 3 h with
stirring. Then EtOH (0.5 mL) was added followed by N2H4·H2O
(0.322 mL, 6.66 mmol) was added to the mixture and continued to
stir at 65–70 ◦C for 2 h then stirred at room temperature overnight.
The mixture was concentrated and then chromatographed on silica
gel with 0–5% ethyl acetate–petroleum ether providing 33 as a
yellow◦resin that solidified upon refrigeration (0.60 g, 92%). Mp
66–68 C dec. 1H NMR d 9.34 (s, 1H, NH), 8.12 (d, J = 8.5 Hz,
1H, ArH), 7.64–7.59 (m, 1H, ArH), 7.52–7.39 (m, 3H, ArH), 7.29
(td, J = 7.2, 1.5 Hz, 1H, ArH), 7.11 (dd, J = 7.2, 0.7 Hz, 1H,
ArH), 1.55 (s, 9H, C(CH3)3). 13C NMR d 195.1, 152.6, 143.9,
143.7, 140.0, 136.6, 134.5, 134.1, 129.0, 123.9, 120.5, 118.8, 117.5,
General procedure for the synthesis of N-alkylated
2-aminobenzophenones 31a–c
To a 50 mL two neck flask fitted with a nitrogen inlet was
added 30 (0.050 g, 0.17 mmol) and then purged with nitrogen.
Caesium carbonate (0.110 g, 0.34 mmol) and TBAI (0.031 g,
0.084 mmol) were added followed by anhydrous DMF (1.0 mL).
The alkylating reagent (0.34 mmol) was added and the reaction
was stirred at room temperature for 3–24 h. Upon completion of
the reaction (TLC), the mixture was diluted with ether (20 mL)
and then washed with water (6 ¥ 50 mL), then brine (10 mL). The
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114.0, 81.1, 28.3. LCMS Rf (min) = 6.86. MS m/z 196.1 (100%),
102.3 (20).
109.0, 46.6. LCMS Rf (min) = 6.76. HR-ESI calcd for C20H16NO+
(M + H) 286.1226, found 286.1231.
General procedure for the synthesis of N-alkylated
1-aminofluoren-9-one 34a–c
Acknowledgements
To a 50 mL two neck flask fitted with a nitrogen inlet was added
33 (0.050 g, 0.17 mmol) and then purged with nitrogen. Caesium
carbonate (0.110 g, 0.34 mmol) and TBAI (0.031 g, 0.084 mmol)
were added followed by anhydrous DMF (1.0 mL). The alkylating
reagent (0.34 mmol) was added and the reaction was stirred at
room temperature for 3–24 h. In the case of 34b a further aliquot
of 1-bromobutane (0.037 mL, 0.34 mmol) and caesium carbonate
(0.110 g, 0.34 mmol) were added and stirred a further 16 h. Upon
completion of the reaction (TLC), the mixture was diluted with
ether (20 mL) and then washed with water (6 ¥ 50 mL), then
brine (10 mL). The ethereal layer was dried (MgSO4), filtered
and then concentrated to an oil affording the carbamates, which
were used without further purification in the next step. The resin
was taken up in CH2Cl2 (0.5 mL) and TFA (0.25 mL) was added
and stirred at room temperature for 3 h. The mixture was diluted
with CH2Cl2 (10 mL) and quenched with saturated bicarbonate
solution. The organic layer was removed and the aqueous layer
was extracted with CH2Cl2 (2 ¥ 10 mL) and the combined organics
were dried (MgSO4), filtered and then concentrated to afford the
crude fluorenones that were chromatographed on silica gel with
0–5% ethyl acetate–petroleum ether providing 34a–c.
The authors thank the Australian Research Council for financial
support.
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1-(Methylamino)-9H-fluoren-9-one (34a). The title compound
was obtained as a yellow solid after recrystallization from
◦
1
methanol in 42% yield (0.015 g). Mp 125–127 C. H NMR d
7.60–7.54 (m, 1H, ArH), 7.47–7.42 (m, 1H, ArH), 7.39 (td, J =
7.4, 1.1 Hz, 1H, ArH), 7.32–7.26 (m, 1H, ArH), 7.26–7.21 (m, 1H,
ArH), 7.04–6.90 (m, 1H, NH), 6.76 (dd, J = 7.0, 0.5 Hz, 1H, ArH),
6.53 (d, J = 8.5 Hz, 1H, ArH), 2.97 (d, J = 5.2 Hz, 3H, NCH3).
13C NMR d 195.0, 149.5, 144.8, 143.3, 136.9, 135.4, 133.3, 128.7,
123.1, 120.4, 114.2, 112.3, 108.5, 29.2. LCMS Rf (min) = 6.18.
HR-ESI calcd for C14H12NO+ (M + H) 210.0913, found 210.0919.
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1-(Butylamino)-9H-fluoren-9-one (34b). The title compound
was obtained as a viscous orange oil in 88% yield (0.037 g).
1H NMR d 7.63–7.50 (m, 1H, ArH), 7.48–7.40 (m, 1H, ArH),
7.37 (td, J = 7.4, 1.1 Hz, 1H, ArH), 7.30–7.17 (m, 2H, ArH),
7.14–7.00 (m, 1H, NH), 6.73 (dd, J = 7.0, 0.5 Hz, 1H, ArH),
6.52 (d, J = 8.5 Hz, 1H, ArH), 3.25 (td, J = 7.0, 5.8 Hz,
2H, NCH2CH2CH2CH3), 1.71–1.58 (m, 2H, NCH2CH2CH2CH3),
1.53–1.38 (m, 2H, NCH2CH2CH2CH3), 0.97 (t, J = 7.3 Hz, 3H,
NCH2CH2CH2CH3). 13C NMR d 194.8, 148.8, 144.8, 143.2, 136.7,
135.4, 133.2, 128.6, 122.9, 120.3, 113.9, 112.7, 108.3, 42.2, 31.6,
20.2, 13.9. LCMS Rf (min) = 6.80. HR-ESI calcd for C17H18NO+
(M + H) 252.1383, found 252.1377.
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1-(Benzylamino)-9H-fluoren-9-one (34c). The title compound
was obtained as a yellow solid after recrystallization from
petroleum ether in 63% yield (0.030 g). Mp 114–115 ◦C. 1H NMR
d 7.63–7.58 (m, 1H, ArH), 7.52 (t, J = 4.6 Hz, 1H, NH), 7.49–7.45
(m, 1H, ArH), 7.42 (td, J = 7.4, 1.1 Hz, 1H, ArH), 7.38–7.26 (m,
6H, ArH), 7.25–7.19 (m, 1H, ArH), 6.80 (dd, J = 7.1, 0.5 Hz,
1H, ArH), 6.51 (d, J = 8.5 Hz, 1H, ArH), 4.54 (d, J = 6.1 Hz,
2H, ArCH2). 13C NMR d 195.1, 148.6, 144.9, 143.4, 138.7, 136.9,
135.4, 133.5, 128.9, 128.8, 127.5, 127.1, 123.2, 120.5, 114.6, 113.2,
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