Tuned methods for conjugate addition to a vinyl oxadiazole; Synthesis of pharmaceutically important motifs

Article abstract of DOI:10.1039/c001772h

The addition of various nucleophiles to a vinyl 1,2,4-oxadiazole is described. Following optimisation, individual protocols tuned for the use of each specific class of reagent have been developed to allow the installation of nitrogen, sulfur, oxygen, and carbon nucleophiles, and leading to the preparation of a series of compounds containing the pharmaceutically important oxadiazole motif.

Full text of DOI:10.1039/c001772h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Tuned methods for conjugate addition to a vinyl oxadiazole; synthesis of
pharmaceutically important motifs†
Alan R. Burns,a Jennifer H. Kerr,b William J. Kerr,*a Joanna Passmore,b Laura C. Patersona and
Allan J. B. Watsona
Received 26th January 2010, Accepted 25th March 2010
First published as an Advance Article on the web 28th April 2010
DOI: 10.1039/c001772h
The addition of various nucleophiles to a vinyl 1,2,4-oxadiazole is described. Following optimisation,
individual protocols tuned for the use of each specific class of reagent have been developed to allow the
installation of nitrogen, sulfur, oxygen, and carbon nucleophiles, and leading to the preparation of a
series of compounds containing the pharmaceutically important oxadiazole motif.
Accessing oxadiazolylethylamines
Introduction
Recently, in efforts to access oxadiazolyl small molecules pos-
sessing an ethylamine motif, we envisaged a simple alkylation
strategy, as described in Scheme 1.11 To initiate this process, we
anticipated the construction of the oxadiazole by condensation
of benzamidoxime 5 with lactone 6, to give the alcohol 7.
Conversion to mesylate 8 would then allow alkylation of a series
of amines in a parallel synthesis fashion to produce a library of
oxadiazolylethylamines.
The 1,2,4-oxadiazole motif is an important pharmacophore within
medicinal chemistry and can be regarded as a bioisosteric, and
metabolically stable, replacement for an ester unit.1 Indeed, the
1,2,4-oxadiazole is present in several notable drug molecules,
including antitussive drugs, such as Perebron, 1,2 and Libexin, 2,3
as well as the serotonin agonist 3, for the treatment of migraine,4
and L-690548, 4, for the treatment of Alzheimer’s disease (Fig. 1).5
Scheme 1 Proposed route to oxadiazolylethylamines.
In contrast to that proposed, it was observed that upon
treatment of benzamidoxime 5 with b-lactone 6, alcohol 7 was
not isolated and instead vinyl oxadiazole 10 was obtained as
the major product (Scheme 2).11 Nevertheless, it was envisaged
that by employing vinyl oxadiazole 10 as an acceptor unit, the
desired products could still be obtained by exploiting a conjugate
addition protocol. Moreover, it was considered that this emerging
strategy would be more preparatively efficient overall, with access
to 10 being achieved more concisely than synthesis of mesylate 8.
Fig. 1 Therapeutic compounds containing the 1,2,4-oxadiazole unit.
Additionally, compounds containing the oxadiazole motif have
been the subject of interest as novel 5-HT3 antagonists.6 A number
of such compounds have been shown to be effective in the
control of cancer chemotherapy-induced emesis,7 and evidence
suggests therapeutic benefits towards migraine,8 schizophrenia,9
and anxiety.10 Therefore, considering the range of potential
biological applications, the formulation of more efficient synthetic
strategies to access functionalised compounds containing the
1,2,4-oxadiazole motif has emerged as an attractive preparative
goal.
aDepartment of Pure and Applied Chemistry, WestCHEM, University of
Strathclyde, 295 Cathedral Street, Glasgow, Scotland, UK G1 1XL. E-mail:
w.kerr@strath.ac.uk; Fax: +44 141 548 4822; Tel: +44 141 548 2959
bSchering-Plough Corporation, Newhouse, Motherwell, Scotland, UK ML1
5SH
† Electronic supplementary information (ESI) available: NMR spectra.
See DOI: 10.1039/c001772h
Scheme 2 Preparation of vinyl oxadiazole 10 and proposed access to
oxadiazolylethylamines.
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Table 1 Optimisation of the addition process with an alkylaminea
Moreover, the greater stability and easier handling of 10 rendered
the conjugate addition protocol more amenable to future parallel
synthesis programmes. To this end, the scope of the proposed
conjugate addition sequence, to gain access to compounds of type
9, was investigated.
Entry Equiv. Amine Conc. of 10/M Conc. of amine/M Yield (%)b
Conjugate additions to vinyl heterocycles
1
2
3
1.05
1.05
2.10
0.2
0.4
0.2
0.21
0.42
0.42
72
98
89
In a general sense, conjugate addition to vinyl heteroarenes
represents an effective method for the direct preparation of
pharmaceutically relevant architectures. These processes have
been documented for several heterocyclic systems and success has
been realised with a range of nucleophilic agents.12 With regards to
vinyl oxadiazoles, Swain et al.,6 and later Macor et al.,1a described
the addition of very specific nucleophiles to such substrates.
However, these processes lacked both the scope of nucleophile and
the preparative flexibility required for the generation of a diverse
series of oxadiazole-derived adducts. We, therefore, targeted the
development of simple and preparatively robust procedures for
the conjugate addition of a range of nucleophiles, which have the
potential to be used to develop libraries of substituted oxadiazoles
via parallel synthesis strategies.
a See Experimental Section. b Yield refers to isolated pure products.
Table 2 Conjugate addition of aliphatic amines to vinyl oxadiazole 10a
Entry
Amine
Product
Yield (%)b
1
2
3
4
5
nBuNH2
iBuNH2
tBuNH2
BnNH2
Et2NH
12a
12b
12c
12d
1
98
99
62
98
99
Results and discussion
To begin the study, the synthesis of the convenient and bench-
stable model substrate, 3-phenyl-5-vinyl-1,2,4-oxadiazole 10, was
altered to a more efficient and practically accessible reaction
sequence (Scheme 3).13 Treatment of benzonitrile with hydroxyl-
amine hydrochloride in the presence of base afforded benz-
amidoxime 5 in 89% yield, with this reaction also being readily
amenable to scale-up. Acylation at ambient temperature delivered
acrylic ester 11, which cyclised to the desired vinyloxadiazole 10
upon treatment with K2CO3 under microwave irradiation and in
near quantitative yield. Notably, the cyclisation step can also be
performed on larger scales either by using a 50 mL microwave
vessel (up to 25 mmol scale) or by conventional reflux for an
extended reaction time (6 h) with equivalent preparative efficiency.
a See Experimental Section. b Yield refers to isolated pure products.
secondary amines (Table 2). Yields of addition products in this
study were again very high, with the only transformation of
more moderate efficiency involving the sterically encumbered
tBuNH2 (Table 2, Entry 3), which provided the product 12c in
62% yield. Only minimal purification was required for all other
entries and, generally, concentration of the reaction mixture was
adequate to produce products of >95% purity, which would
allow ready adoption of such a preparative approach for the
generation of compound libraries. Moreover, using diethylamine
as the nucleophilic reaction component, we were able to prepare
Perebron 1 (Fig. 1) in 99% yield (Entry 5). This establishes an
expedient synthesis of this marketed pharmaceutical in a 93%
overall isolated yield following three steps from benzamidoxime
5; this compares favourably with the described literature method,
which proceeds in 80% yield over two steps from the same starting
compound 5.2
While simple alkyl amines participated efficiently in the desired
addition process, installation of aniline in a similar fashion proved
to be more preparatively challenging. Initial reactions using the
optimum conditions for the aliphatic amine substrates failed to
deliver any of the desired product (Table 3, Entry 1) and increasing
the temperature to reflux in DCM for a more extended reaction
period led to no improvement (Entry 2). When moving to heating
in a higher boiling solvent (PhMe) for 48 h, a low conversion
to product was obtained (Entry 3), and a slight enhancement was
noted when a protic solvent (nPrOH) was employed at reflux (Entry
4). Despite this, the reaction yields obtained here were less than
acceptable. Furthermore, addition of a series of base species (NaH,
K2CO3, Cs2CO3), as potential reaction promoters, unfortunately,
provided no improvements in the efficiency of the desired addition
process.
Scheme 3 Improved synthesis of vinyl oxadiazole 10.
Turning to the targeted conjugate addition reactions, initially we
treated 10 with nBuNH2 to ascertain whether the desired process
would proceed in the absence of any additional base reagent
(Table 1, Entry 1). Pleasingly, a good yield of addition product
12a was obtained, highlighting that 10 is a suitable acceptor unit.
Furthermore, a very brief optimisation of reaction concentration
delivered the desired product 12a in 98% isolated yield (Entry 2).
With these conditions operating efficiently, the reaction scope
was probed by extension to a small range of primary and
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Table 5 Screening of conditions for the addition of nBuSH to 10a
Table 3 Initial conjugate addition reactions using aniline
Entry
Conditions
Yield (%)a
Entry
Additive
Conditions
Yield (%)b
1
2
3
4
DCM, r.t., 20 h
0
0
5
14
1
2
3
4
5
6
7
—
—
DCM, r.t., 20 h
0
0
2
0
8
6
88
DCM, reflux, 48 h
PhMe, reflux, 48 h
nPrOH, reflux, 48 h
DCM, reflux, 20 h
THF, reflux, 20 h
THF, reflux, 20 h
DMF, 80 ◦C, 20 h
MeOH, reflux, 20 h
MeOH, reflux, 20 h
NaH (1.2 equiv.)
K2CO3 (1.2 equiv.)
K2CO3 (1.2 equiv.)
AcOH (1.05 equiv.)
HCl (1.05 equiv.)
a Yield refers to isolated pure products.
a See Experimental Section. b Yield refers to isolated pure products.
Table 4 Use of Brønsted and Lewis acids in the addition of PhNH2 to
10a
Table 6 Screening of conditions for the addition of PhSH to 10a
Entry
Additiveb
Conditions
Yield (%)c
1
2
3
4
5
6
7
8
9
AcOH
AcOH
EtCO2H
—
AcOH
—
AcOH
LiClO4
BF3·OEt2
MeOH, reflux, 20 h
nPrOH, reflux, 20 h
nPrOH, reflux, 20 h
MeCN, mw, 188 ◦C, 1 h
MeCN, mw, 188 ◦C, 1 h
nPrOH, mw, 200 ◦C, 1 h
nPrOH, mw, 200 ◦C, 1 h
MeOH, reflux, 20 h
THF, reflux, 20 h
34
35
38
0
26
0
30
25
55
Entry
Additive
Conditions
Yield (%)b
1
2
3
4
5
6
7
—
—
DCM, r.t., 40 h
DCM, reflux, 20 h
THF, r.t., 24 h
THF, r.t., 24 h
THF, r.t., 24 h
MeOH, reflux, 20 h
MeOH, reflux, 20 h
50
94
79
85
58
23
40
NaH (1.2 equiv.)
K2CO3 (1.2 equiv.)
Cs2CO3 (1.2 equiv.)
AcOH (1.05 equiv.)
HCl (1.05 equiv.)
a See Experimental Section. b 1.05 equiv. c Yield refers to isolated pure
products.
a See Experimental Section. b Yield refers to isolated pure products.
At this point, an alternative strategy was considered, whereby
the electrophilicity of the vinyl oxadiazole would be augmented
by the addition of a Brønsted or Lewis acid. As shown in Table 4,
this approach clearly had the intended effect of enhancing the
acceptor capabilities of the oxadiazole unit. Use of Brønsted acids
delivered the desired addition product in modest yields, with the
use of (the higher boiling) propionic acid in n-propanol being
optimum (Table 4, Entry 3). Several reactions were also performed
under microwave irradiation. Whilst moderate yields were also
delivered in these cases, with a Brønsted acid additive (Entries
4–7), no improvement was observed over the results achievable
using conventional heating methods. In contrast, specific Lewis
acid promotion did, indeed, deliver further improvements to the
targeted addition process with aryl amines. When using BF3·OEt2
as an additive, the most efficient addition reaction with aniline in
this series was obtained with a 55% isolated yield of 12e (Entry 9).
Having formulated conditions for the use of both alkyl and
aryl amines with good to excellent levels of efficiency, attention
turned to the delivery of alternative nucleophilic species. Firstly,
sulfur-based nucleophiles are known to participate effectively in
conjugate addition processes and, as such, we attempted the
addition of a simple alkyl thiol to the vinyloxadiazole 10 (Table 5).
Under the standard conditions used with alkyl amines at either
room temperature or at reflux in DCM, no product was obtained
(Table 5, Entries 1 and 2). Moving to an additive study, a similar
reactivity profile was observed as with aniline, in which added base
reagents provided only very low conversions to product (Entries
3–5). On the other hand, the addition of HCl was found to deliver
a very good yield of the desired sulfide 13a (Entry 7).
A similar study was subsequently conducted with thiophenol.
In this case, it was found that an excellent yield of the intended
product could be obtained simply by heating in DCM (Table 6,
Entry 2). For completeness, an additive study was performed
which demonstrated that the presence of acid was detrimental
to the reaction (Entries 6 and 7). In contrast, the presence of
base provided a moderate preparative advantage by allowing good
yields of the aryl thiol addition product to be obtained at lower
(ambient) temperatures (Entries 3–5).
To build on the success of the emerging nucleophile-specific
addition methods which had been developed to this stage for
vinyloxadiazole, we next sought to install oxygen-based nucleo-
philes in a conjugate fashion. As shown in Table 7, successful
addition of alcohols was achievable in acceptable yields either
in the presence of basic (Entry 1) or acidic additives (Entry
2). Unfortunately, regardless of the conditions applied (with
acid/base additives and over various temperature/time studies),
phenol did not successfully participate in the desired addition
reaction.
Finally, we turned briefly to the use of carbon-based nucleo-
philes with vinyloxadiazole 10 (Table 8). Pleasingly, addition of
diethyl malonate proceeded to deliver 15a in 51% yield, using
NaH as the base reagent (Entry 1). Additionally, use of the more
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Table 7 Addition of alcohols to 10a
liquid reagents were added via syringe. Microwave reactions were
performed in a CEM Discover dedicated microwave reactor in
sealed tubes. Light petroleum refers to the fraction of b.p. 30–
40 ◦C. Thin layer chromatography was carried out using Camlab
silica plates coated with indicator UV254. These were analysed
using a Mineralight UVGL-25 lamp or developed using vanillin
or potassium permanganate solutions. Flash column chromatog-
raphy was carried out using Prolabo silica gel (230–400 mesh). IR
spectra were obtained on a Perkin Elmer Spectrum One machine.
1H and 13C NMR spectra were recorded on a Bruker DPX 400
spectrometer at 400 MHz and 100 MHz, respectively, or a Bruker
DRX 500 spectrometer at 500 MHz and 125 MHz, respectively.
Chemical shifts are reported in ppm. Coupling constants are
reported in Hz.
Entry
R
Additive
Conditions
Yield (%)b
1
2
Et
NaH (1.2 equiv.)
HCl (1.05 equiv.)
EtOH, r.t., 20 h
78
63
nPr
nPrOH, reflux, 20 h
a See Experimental Section. b Yield refers to isolated pure products.
Table 8 Addition of carbon-based nucleophiles to 10a
Synthesis of Vinyloxadiazole, 10
(a) Preparation of 5. A solution of benzonitrile (1 equiv.,
25 mmol, 2.55 mL), hydroxylamine hydrochloride (2 equiv.,
i
50 mmol, 3.475 g) and Pr2NEt (2 equiv., 50 mmol, 8.76 mL)
Entry
Nucleophile
Product
15a
Conditions
Yield (%)b
in EtOH (250 mL) was heated at 80 ◦C for 18 h. The solution was
cooled to room temperature and the solvent removed in vacuo.
The residue was partitioned between DCM (100 mL) and H2O
(100 mL) and the organic phase separated. The aqueous phase
was further extracted with DCM (3 ¥ 100 mL) and the organic
extracts were combined. After drying (MgSO4) and filtering, the
organic solution was concentrated to afford 5 as a viscous oil
(3.04 g, 89%).
1
2
H2C(CO2Et)2
(1.05 equiv.)
nBu2CuLi
NaH (1.2 equiv.),
THF, r.t., 5 h
51
40
15b
Et2O, -78 ◦C, 2 h
(1.2 equiv.)
a See Experimental Section. b Yield refers to isolated pure products.
challenging butyl cuprate delivered the desired product 15b in a
moderate 40% yield (Entry 2). Further endeavours, employing a
range of additives and conditions, did not improve upon the result
shown for this latter process.
(b) Preparation of 11. To a solution of 5 (1 equiv., 20.9 mmol,
2.84 g) in DCM (230 mL) was added acryloyl chloride (1.2 equiv.,
25 mmol, 2.03 mL). The mixture was stirred for 3 h at room
temperature before quenching with an aq. solution of NaHCO3
(100 mL). The organic layer was separated and the aqueous
layer was further extracted with DCM (2 ¥ 50 mL). The organic
extracts were combined, dried (MgSO4), filtered, and concentrated
to afford 11 as an off-white solid (3.856 g, 97%).
Conclusions
In conclusion, after a broad screening process, we have developed
a series of practically-convenient conditions which allow for
the effective conjugate addition of a range of nucleophiles to
a vinyl 1,2,4-oxadiazole. In particular, the individual protocols
are tuned for the use of each specific class of nucleophile and
enable the efficient introduction of alkylamines and alkyl and aryl
thiols without the requirement for any appreciable purification
protocols and which will be readily applicable within parallel
synthesis programmes. Additionally, further specific conditions
for the introduction of aryl amines, aliphatic alcohols, and carbon-
based nucleophiles have also been established which, despite being
somewhat less efficient, have the potential for ready adoption
within medicinal chemistry or agrochemical environments. Over-
all, by employment of a common heterocyclic core and a spectrum
of suitable nucleophiles, these procedures will allow the flexible
and effective production of arrays of compounds containing the
biologically significant oxadiazole motif.
(c) Preparation of 10.
(i) Microwave conditions. A microwave tube charged with 11
(1 equiv., 2.63 mmol, 0.5 g), 1,4-dioxane (5 mL) and K2CO3 (2
equiv., 5.26 mmol, 0.726 g) was heated at 120 ◦C for 20 min
in a microwave reactor. The mixture was allowed to cool before
being filtered and concentrated to a residue which was purified by
column chromatography eluting with 10% Et2O/light petroleum
to afford 10 as a colourless oil (0.439 g, 97%).
(ii) Reflux conditions. A solution of 11 (1 equiv., 2.63 mmol,
0.5 g), 1,4-dioxane (5 mL) and K2CO3 (2 equiv., 5.26 mmol, 0.726
g) was heated at 120 ◦C for 6 h. The mixture was allowed to
cool before being filtered and concentrated to a residue which was
purified by column chromatography eluting with 10% Et2O/light
petroleum to afford 10 as a colourless oil (0.453 g, 100%).
Experimental
Conjugate addition of alkylamines to 10
All reactions were carried out using conventional glassware and
procedures. Starting materials and solvents were used as obtained
from commercial suppliers without further purification. For air
sensitive reactions, standard protocols were employed using dry
solvents and under a N2 atmosphere. Solutions, solvents and
To a solution of 10 (1 equiv., 1 mmol, 172 mg) in DCM
(2.5 mL) was added the amine (1.05 equiv., 1.05 mmol). The
reaction mixture was then stirred at room temperature for 20 h
before concentrating in vacuo to a residue which was purified by
column chromatography eluting with 10% Et2O/light petroleum
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to afford the desired addition product. For example, using nBuNH2
Conjugate addition of carbon-based nucleophiles to 10
(1.05 mmol, 0.101 mL) gave 12a as a pale yellow oil (240 mg, 98%).
(i) Using diethyl malonate and NaH. To a solution of 10
(1 equiv., 1 mmol, 172 mg) in THF (2.5 mL) was added NaH
(60% dispersion in mineral oil, 1.2 equiv., 1.2 mmol, 48 mg). The
mixture was then stirred for 5 h under N2 before quenching with
NaHCO3 aq. solution (5 mL). The mixture was then extracted
with DCM (4 ¥ 15 mL). The organic extracts were combined,
dried (MgSO4), filtered, and concentrated in vacuo to a residue
which was purified by column chromatography eluting with 10%
Et2O/light petroleum to afford 15a as a colourless oil (170 mg,
51%).
(ii) Using nBu2CuLi. To a solution of CuI (1.2 equiv.,
1.2 mmol, 229 mg) in dry Et2O (10 mL) at -78 ◦C was added nBuLi
(2.38 M in hexane, 2.4 equiv., 2.4 mmol, 1.01 mL) drop-wise over
5 min. The mixture was stirred at -78 ◦C for 1 h before the addition
of a solution of 10 (1 equiv., 1 mmol, 172 mg) in Et2O (2 mL) over
5 min. The mixture was then stirred at -78 ◦C for 2 h before
quenching with H2O (10 mL). The mixture was allowed to warm
to room temperature before extraction with Et2O (3 ¥ 15 mL).
The organic extracts were combined, dried (MgSO4), filtered, and
concentrated in vacuo to a residue which was purified by column
chromatography eluting with 10% Et2O/light petroleum to afford
15b as a colourless oil (93 mg, 40%).
Conjugate addition of PhNH2 to 10
To a solution of 10 (1 equiv., 1 mmol, 172 mg) in THF (2.5 mL) was
added aniline (1.05 equiv., 1.05 mmol, 0.096 mL) and BF3·OEt2
(1.05 equiv., 1.05 mmol, 0.133 mL). The reaction mixture was
then refluxed for 20 h before cooling to room temperature and
quenching with NaHCO3 aq. solution (5 mL). The mixture was
then extracted with DCM (4 ¥ 15 mL). The organic extracts
were combined, dried (MgSO4), filtered, and concentrated in
vacuo to a residue which was purified by column chromatography
eluting with 10–50% Et2O/light petroleum to afford 12e as a
yellow/brown solid (145 mg, 55%).
Conjugate addition of nBuSH to 10
To a solution of 10 (1 equiv., 1 mmol, 172 mg) in MeOH (2.5 mL)
n
was added BuSH (1.05 equiv., 1.05 mmol, 0.113 mL) and HCl
(1 M solution in Et2O, 1.05 equiv., 1.05 mmol, 1.05 mL). The
reaction mixture was then refluxed for 20 h before cooling to
room temperature and quenching with NaHCO3 aq. solution
(5 mL). The mixture was then extracted with DCM (4 ¥ 15 mL).
The organic extracts were combined, dried (MgSO4), filtered, and
concentrated in vacuo to a residue which was purified by column
chromatography eluting with 10% Et2O/light petroleum to afford
13a as a yellow oil (232 mg, 88%).
Compound data
Compound 5. Viscous colourless oil; nmax(CH2Cl2)/cm-1 3598,
3519, 3410, 2924, 1647, 1581; dH (400 MHz, CDCl3) 8.52 (1H,
s), 7.65 (2H, dd, J 9.8, 2.8), 7.45-7.38 (3H, m), 4.90 (2H, s); dC
(100 MHz, CDCl3) 152.6, 132.5, 130.0, 128.7, 125.9; Anal. Calcd.
for C7H8N2O requires C, 61.75%; H, 5.92%; N, 20.58%. Found:
C, 62.65%; H, 5.85%; N, 20.58%; HRMS (ES) Found [M + H]+
137.0708, C7H9N2O requires 137.0709.
Conjugate addition of PhSH to 10
To a solution of 10 (1 equiv., 1 mmol, 172 mg) in DCM (2.5 mL)
was added PhSH (1.05 equiv., 1.05 mmol, 0.108 mL). The reaction
mixture was then refluxed for 24 h before concentrating in vacuo to
a residue which was purified by column chromatography eluting
with 10% Et2O/light petroleum to afford 13b as a yellow oil
(265 mg, 94%).
Compound 10. Colourless oil; nmax(CH2Cl2)/cm-1 3074, 2960,
1648, 1593, 1563, 1542; dH (400 MHz, CDCl3) 8.11 (2H, dd, J
9.8, 2.7), 7.55-7.47 (3H, m), 6.78 (1H, dd, J 17.7, 11.0), 6.61 (1H,
dd, J 17.7, 0.9), 6.01 (1H, dd, J 11.0, 0.9); dC (100 MHz, CDCl3)
174.5, 168.7, 131.2, 128.9, 128.7, 127.5, 126.8, 120.6; Anal. Calcd.
for C10H8N2O requires C, 69.76%; H, 4.68%; N, 16.27%. Found:
C, 69.78%; H, 4.41%; N, 16.42%; HRMS (ES) Found [M + H]+
173.0709, C10H9N2O requires 173.0709.
Conjugate addition of alcohols to 10
(i) Using NaH. To a solution of 10 (1 equiv., 1 mmol, 172 mg)
in EtOH (2.5 mL) was added NaH (60% dispersion in mineral oil,
1.2 equiv., 1.2 mmol, 48 mg). The reaction mixture was then stirred
under N2 for 20 h before quenching with NaHCO3 aq. solution
(5 mL). The mixture was then extracted with DCM (4 ¥ 15 mL).
The organic extracts were combined, dried (MgSO4), filtered, and
concentrated in vacuo to a residue which was purified by column
chromatography eluting with 10% Et2O/light petroleum to afford
14a as a colourless oil (170 mg, 78%).
◦
Compound 11. Off-white solid; Mp 69–70 C; nmax(CH2Cl2)/
cm-1 3528, 3421, 1701, 1634; dH (400 MHz, CDCl3) 7.73 (2H, dd,
J 7.9, 1.5), 7.52-7.41 (3H, m), 6.56 (1H, dd, J 17.3, 1.0), 6.32
(1H, dd, J 17.3, 10.5), 5.92 (1H, dd, J 10.5, 1.0), 5.11 (2H, s); dC
(100 MHz, CDCl3) 163.9, 156.8, 131.4, 131.1, 131.0, 128.7, 126.8,
126.7; Anal. Calcd. for C10H10N2O2 requires C, 63.15%; H, 5.30%;
N, 14.73%. Found: C, 63.11%; H, 5.22%; N, 14.75%; HRMS (ES)
Found [M + H]+ 191.0814, C10H11N2O2 requires 191.0815.
(ii) Using HCl. To a solution of 10 (1 equiv., 1 mmol, 172 mg)
in nPrOH (2.5 mL) was added HCl (1 M solution in Et2O,
1.05 equiv., 1.05 mmol, 1.05 mL). The reaction mixture was
then refluxed for 20 h before cooling to room temperature and
quenching with NaHCO3 aq. solution (5 mL). The mixture was
then extracted with DCM (4 ¥ 15 mL). The organic extracts were
combined, dried (MgSO4), filtered, and concentrated in vacuo to a
residue which was purified by column chromatography eluting
with 10% Et2O/light petroleum to afford 14b as a yellow oil
(146 mg, 63%).
Compound 12a. Pale yellow oil; nmax(CH2Cl2)/cm-1 3692,
2960, 2931, 2861, 1595, 1571, 1476, 1447; dH (400 MHz, CDCl3)
8.08 (2H, dd, J 7.5, 2.3), 7.51-7.46 (3H, m), 3.51 (4H, s), 2.68
(2H, t, J 7.2), 1.50 (2H, quintet, J 7.3), 1.46 (3H, sextet, J 7.3),
0.93 (3H, t, J 7.3); dC (100 MHz, CDCl3) 178.8, 168.5, 131.1,
129.0, 127.6, 127.1, 49.4, 46.4, 32.4, 27.6, 20.6, 14.2; Anal. Calcd.
for C14H19N3O requires C, 68.54%; H, 7.81%; N, 17.30%. Found:
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C, 68.25%; H, 7.75%; N, 17.34%; HRMS (ES) Found [M + H]+
246.1599, C14H20N3O requires 246.1601.
C, 67.81%; H, 5.00%; N, 9.81%; HRMS (ES) Found [M + H]+
283.0901, C16H15N2OS requires 283.0900.
Compound 12b. Pale yellow oil; nmax(CH2Cl2)/cm-1 3692,
2958, 2842, 1595, 1571, 1476, 1447; dH (400 MHz, CDCl3) 8.08
(2H, dd, J 5.6, 2.3), 7.53-7.45 (3H, m), 3.14 (4H, s), 2.49 (2H, d,
J 6.8), 1.76 (1H, septet, J 6.7), 1.44 (1H, s), 0.92 (6H, d, J 6.7);
dC (100 MHz, CDCl3) 178.8, 168.4, 131.3, 129.0, 127.6, 127.1,
57.7, 46.5, 28.5, 27.6, 20.8; Anal. Calcd. for C14H19N3O requires
C, 68.54%; H, 7.81%; N, 17.30%. Found: C, 68.18%; H, 7.61%;
N, 17.50%; HRMS (ES) Found [M + H]+ 246.1600, C14H20N3O
requires 246.1601.
Compound 14a. Colourless oil; nmax(CH2Cl2)/cm-1 3055, 2980,
2875, 2831, 1595, 1572, 1551, 1477, 1443; dH (400 MHz, CDCl3)
8.06 (2H, dd, J 7.5, 2.2), 7.51-7.43 (3H, m), 3.91 (2H, t, J 6.7), 3.54
(2H, q, J 7.0), 3.22 (2H, t, J 6.7), 1.19 (3H, t, J 7.0); dC (100 MHz,
CDCl3) 177.8, 168.5, 131.2, 129.0, 127.6, 127.1, 66.7, 66.6, 28.0,
15.2; Anal. Calcd. for C12H14N2O2 requires C, 66.04%; H, 6.47%;
N, 12.84%. Found: C, 65.86%; H, 6.31%; N, 12.86%; HRMS (ES)
Found [M + H]+ 219.1129, C12H15N2O2 requires 219.1128.
Compound 14b. Yellow oil; nmax(CH2Cl2)/cm-1 3076, 2981,
2877, 2831, 1596, 1572, 1551, 1528, 1443; dH (500 MHz, CDCl3)
8.09 (2H, dd, J 6.8, 1.7), 7.52-7.46 (3H, m), 3.92 (2H, t, J 6.6),
3.46 (2H, t, J 6.6), 3.23 (2H, t, J 6.6), 1.59 (2H, sextet, J 7.1), 0.90
(3H, t, J 7.4); dC (125 MHz, CDCl3) 177.7, 168.3, 131.1, 128.8,
127.4, 126.9, 72.9, 66.7, 27.8, 22.7, 10.5; HRMS (ES) Found [M +
H]+ 233.1285, C13H17N2O2 requires 233.1285.
Compound 12c.14 Pale yellow oil; nmax(CH2Cl2)/cm-1 3692,
2969, 2867, 1595, 1571, 1477, 1447; dH (400 MHz, CDCl3) 8.08
(2H, dd, J 7.3, 2.0), 7.51-7.46 (3H, m), 3.10 (4H, s), 1.14 (9H, s); dC
(125 MHz, CDCl3) 178.8, 168.2, 131.1, 128.8, 127.4, 126.9, 50.6,
39.5, 29.0, 28.6.
Compound 12d. Pale yellow oil; nmax(CH2Cl2)/cm-1 3693,
3029, 2926, 2850, 1595, 1571, 1477, 1447; dH (400 MHz, CDCl3)
8.08 (2H, dd, J 7.6, 1.9), 7.53-7.47 (3H, m), 7.34 (4H, d, J 4.3),
7.27 (1H, m), 3.87 (2H, s), 3.17 (4H, s); dC (100 MHz, CDCl3)
178.7, 168.5, 140.1, 131.3, 129.0, 128.6, 128.2, 127.6, 127.2, 127.0,
53.6, 45.7, 27.6; Anal. Calcd. for C17H17N3O requires C, 73.10%;
H, 6.13%; N, 15.04%. Found: C, 72.86%; H, 6.06%; N, 15.16%;
HRMS (ES) Found [M + H]+ 280.1443, C17H18N3O requires
280.1444.
Compound 15a. Colourless oil; nmax(CH2Cl2)/cm-1 3055, 2980,
2874, 2831, 1752, 1595, 1572, 1477, 1443; dH (400 MHz, CDCl3)
8.08 (2H, dd, J 7.7, 1.9), 7.53-7.45 (3H, m), 4.26-4.20 (4H, q, J
7.2), 3.57 (1H, t, J 7.3), 3.07 (2H, t, J 7.6), 2.49 (2H, q, J 7.5),
1.29 (6H, t, J 7.1); dC (100 MHz, CDCl3) 178.8, 170.3, 168.8,
131.4, 129.0, 127.6, 127.0, 61.9, 50.9, 25.4, 24.4, 14.3; Anal. Calcd.
for C17H20N2O5 requires C, 61.44%; H, 6.07%; N, 8.43%. Found:
C, 61.56%; H, 5.88%; N, 8.58%; HRMS (ES) Found [M + H]+
333.1443, C17H21N2O5 requires 333.1445.
Compound 1.2 Pale yellow oil; nmax(CH2Cl2)/cm-1 2937, 2974,
2876, 2821, 1595, 1571, 1476, 1447; dH (500 MHz, CDCl3) 8.08
(2H, dd, J 7.3, 2.1), 7.50-7.46 (3H, m), 3.11-3.07 (2H, m), 3.04-
3.01 (2H, m), 2.59 (4H, q, J 7.2), 1.06 (6H, t, J 7.1); dC (125 MHz,
CDCl3) 178.9, 168.3, 131.0, 128.8, 127.4, 127.0, 49.6, 46.9, 25.0,
12.0.
Compound 15b. Colourless oil; nmax(CH2Cl2)/cm-1 3065, 2982,
2860, 2831, 1594, 1570, 1528, 1425; dH (400 MHz, CDCl3) 8.08
(2H, dd, J 7.4, 2.1), 7.53-7.46 (3H, m), 2.95 (2H, t, J 7.6), 1.88
(2H, quintet, J 7.6), 1.46-1.40 (2H, m), 1.36-1.32 (4H, m), 0.89
(3H, t, J 7.3); dC (100 MHz, CDCl3) 180.3, 168.5, 131.2, 129.0,
127.6, 127.2, 31.5, 28.9, 26.9(2), 22.6, 14.2; HRMS (ES) Found
[M + H]+ 231.1491, C14H19N2O requires 231.1492.
Compound 12e. Yellow-brown solid; Mp 83-84 ◦C;
n
max(CH2Cl2)/cm-1 3437, 3044, 2982, 2830, 1603, 1571, 1551,
1508, 1439; dH (400 MHz, CDCl3) 8.10 (2H, dd, J 7.6, 1.9),
7.53-7.48 (3H, m), 7.22 (2H, t, J 7.9), 6.77 (1H, t, J 7.3), 6.69
(2H, d, J 7.7), 4.17 (1H, s), 3.74 (2H, t, J 6.5), 3.26 (2H, t, J 6.5);
dC (100 MHz, CDCl3) 178.5, 168.9, 147.6, 131.8, 130.0, 129.4,
128.0, 127.3, 118.8, 113.8, 41.2, 27.2; HRMS (ES) Found [M +
H]+ 266.1286, C16H16N3O requires 266.1288.
Acknowledgements
We would like to thank the EPSRC Mass Spectrometry Service,
University of Wales, Swansea for analyses.
Notes and references
Compound 13a. Yellow oil; nmax(CH2Cl2)/cm-1 3056, 2981,
2874, 2831, 1594, 1571, 1551, 1443; dH (500 MHz, CDCl3) 8.08
(2H, dd, J 7.7, 1.9), 7.53-7.46 (3H, m), 3.24 (2H, t, J 7.7), 3.03
(2H, t, J 7.6), 2.59 (2H, t, J 7.4), 1.60 (2H, quintet, J 7.4), 1.42
(2H, sextet, J 7.4), 0.93 (3H, t, J 7.3); dC (125 MHz, CDCl3)
178.1, 168.4, 131.2, 128.8, 127.4, 126.8, 31.9, 31.6, 28.5, 27.7, 21.9,
13.6; HRMS (ES) Found [M + H]+ 263.1214, C14H19N2OS requires
263.1213.
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Compound 13b. Yellow oil; nmax(CH2Cl2)/cm-1 3045, 2989,
2831, 1594, 1571, 1551, 1443; dH (400 MHz, CDCl3) 8.06 (2H,
dd, J 6.9, 1.4), 7.53-7.47 (3H, m), 7.44 (2H, dd, J 6.9, 1.4),
7.33 (2H, t, J 7.4), 7.26 (1H, t, J 7.3), 3.42 (2H, t, J 7.5), 3.25
(2H, t, J 7.4); dC (100 MHz, CDCl3) 178.3, 168.9, 134.8, 131.7,
131.4, 129.8, 129.4, 128.0, 127.7, 127.3, 31.4, 27.8; Anal. Calcd.
for C16H14N2OS requires C, 68.06%; H, 5.00%; N, 9.92%. Found:
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This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2777–2783 | 2783
©