Concise routes to pyrazolo[1,5-a]pyridin-3-yl pyridazin-3-ones

Article abstract of DOI:10.1039/b713638b

Cycloaddition of pyridine N-imine with 6-alkyl-4-oxohex-5-ynoates followed by condensation with hydrazine provides concise access to pharmacologically active 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazinones. For the first time alkynyl heterocycles are also shown to be effective dipolarophiles for pyridine N-imine, and analogous compounds can be accessed directly in modest yields through the reaction of 6-(alkyn-1-yl)pyridazin-3-one derivatives. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b713638b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Concise routes to pyrazolo[1,5-a]pyridin-3-yl pyridazin-3-ones†‡
a
Karen A. Johnston,a Robert W. Allcock,a Zhong Jiang,a Ian D. Collier,§ Haakon Blakli,a Georgina M. Rosair,a
a
Patrick D. Bailey,¶ Keith M. Morgan,a Yasushi Kohnob and David R. Adams*a
Received 5th September 2007, Accepted 6th November 2007
First published as an Advance Article on the web 22nd November 2007
DOI: 10.1039/b713638b
Cycloaddition of pyridine N-imine with 6-alkyl-4-oxohex-5-ynoates followed by condensation
with hydrazine provides concise access to pharmacologically active 6-(pyrazolo[1,5-
a]pyridin-3-yl)pyridazinones. For the first time alkynyl heterocycles are also shown to be
effective dipolarophiles for pyridine N-imine, and analogous compounds can be accessed directly
in modest yields through the reaction of 6-(alkyn-1-yl)pyridazin-3-one derivatives.
for FK838, Scheme 1, where cycloaddition of alkynoate 2 with
Introduction
pyridine N-imine (1), generated in situ by treatment of N-
The pyrazolo[1,5-a]pyridine subunit appears in compounds dis-
aminopyridinium iodide with base, afforded pyrazolopyridine 3
regioselectively.10 In this case, decarboxylation of the 3-position
followed by acetylation yielded acetylpyrazolopyridine 5. A more
concise route to 5 was developed on a pilot scale through
cycloaddition of 1 with alkynone 6, directly introducing the 3-
acetyl substituent. The N-substituted pyridazinone of FK838 was
subsequently built up from the methylketone over a number of
steps.
playing a considerable range of biological activities—in histamine
H3 receptor antagonists,1 dopamine receptor ligands,2 inhibitors
of cyclooxygenase-2,3 serotonin 5-HT3 receptor antagonists,4 P-
glycoprotein inhibitors,5 p38 kinase inhibitors,6 phosphodiesterase
(PDE) inhibitors,7 and in compounds8 with antiherpetic activity.
In many of these compounds, the pyrazolopyridine unit is
substituted at the 3-position. Pyrazolopyridines functionalized at
this position with a pyridazin-3-one or 4,5-dihydropyridazin-3-
one ring in particular have attracted recent interest because of
their adenosine receptor antagonist activity, e.g. FK838,9,10 and
PDE inhibitory activity, e.g. KCA-1312,11 Fig. 1.
Fig. 1 Pharmacologically active 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazin-
3-ones, FK838 and KCA-1312.
Synthesis of the pyrazolopyridine nucleus is routinely achieved
via a 1,3-dipolar cycloaddition strategy that is well suited for the
subsequent development of a 3-substituent. This is illustrated
aChemistry Department, School of Engineering and Physical Sciences,
Heriot-Watt University, Riccarton, Edinburgh, UK EH14 4AS. E-mail:
D.R.Adams@hw.ac.uk; Fax: +44 (0)131 451 3180; Tel: +44 (0)131 451
8021
Scheme 1 Representative synthesis of FK838.10 Reagents and condi-
tions: (i) N-aminopyridinium iodide, KOH, DMF, 32%; (ii) 47% aq.
HBr, D, 95%; (iii) conc. H2SO4, Ac2O, 41%; (iv) N-aminopyridinium
iodide, KOH–CH2Cl2, H2O, 93%; (v) OHCCO2H·2H2O, AcOH, DMF,
EtOAc, 65%; (vi) N2H4·H2O, Me2NAc, 105–110 ◦C, 95%; (vii) Br(CH2)3-
CO2Et–(PhCH2NEt3)Cl, K2CO3, DMF, MeOH 55 ◦C; (viii) NaOH–H2O,
89% over 2 steps.
bDiscovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd, 2399-1,
Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan
† Electronic supplementary information (ESI) available: Procedures for
preparation of N-aminopyridinium mesitylenesulfonate and compounds
23, 24, 26, 27 and 31; crystallographic data for compounds 17, 18 and 36.
See DOI: 10.1039/b713638b
‡ CCDC reference numbers 659630–659632. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/b713638b
As part of a programme to develop the PDE inhibitory activity
of KCA-1312 and analogues, we required a concise route to
6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazin-3-ones that would allow
§ Deceased.
¶ Current address: School of Chemistry, University of Manchester, Oxford
Road, Manchester, UK, M13 9PL.
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step to form 8 (R2 = H). We also considered that use of an
alkynyl pyridazinone dipolarophile (9) might enable direct access
to target compounds of type 10 in a single step. These routes
might thus provide complementary access to both pyridazinone
and dihydropyridazinone analogues whilst facilitating convenient
multiple parallel synthesis of a wide range of pyridine ring-
substituted variants through combination of the dipolarophile
with a set of substituted pyridine N-imines (11). Reactions of
alkynyl heterocycles as dipolarophiles in cycloadditions with
pyridine N-imines have not, however, previously been reported
in the literature. In this paper we present the first examples of
such reactions and the utility of alkynes of types 7 and 9 for the
synthesis of pharmacologically active 6-(pyrazolo[1,5-a]pyridin-3-
yl)pyridazin-3-ones.
Results and discussion
Beginning with the alkynyl c-keto ester approach, ethyl 7-methyl-
4-oxooct-5-ynoate (13), Scheme 3, was prepared in a single step
by reaction of ethyl succinyl chloride (12) with (3-methylbut-1-
ynyl)magnesium bromide. Alkyne 13 underwent cycloaddition
with pyridine N-imine satisfactorily when treated with a mix-
ture of N-aminopyridinium mesitylenesulfonate13 and K2CO3 in
DMF at room temperature, affording pyrazolopyridine 14 in
56% yield. Subsequent condensation with hydrazine generated
dihydropyridazinone 15 (92% yield), completing a concise 3-step
sequence. Further derivatisation of the top ring was achieved
by oxidation to the corresponding pyridazinone (16) and by
alkylation to introduce a substituent at the N(2)-position (17 and
18). Attempts to access N(2)-substituted dihydropyridazinones
by direct condensation of keto ester 14 with monosubstituted
hydrazines (e.g. benzyl hydrazine) were unsuccessful however.
The vinylogous amide character of the ketone renders it less
susceptible to nucleophilic attack than the ester, and thus the
Scheme 2 Overall synthetic strategy.
series expansion for structure–activity relationship studies. While
the pyridine N-imine cycloaddition is one of the most widely
employed routes to pyrazolo[1,5-a]pyridines, it has been largely
confined to reactions with simple alkynoates or alkynones such
as 2 and 6 as the dipolarophiles.12 We sought to apply the
reaction with more advanced alkyne dipolarophiles that would
minimize the number of steps required for introduction of
the pyridazinone ring following pyrazolopyridine construction.
It was envisaged that the cycloaddition of dipolarophiles of
type 7 (Scheme 2), containing c-keto ester functionality, would
be straightforward. Subsequent condensation of the immediate
cycloaddition product with hydrazine would then complete the
formation of the dihydropyridazinone ring in just one additional
Scheme 3 Reagents and conditions: (i) (3-methylbut-1-ynyl)magnesium bromide, THF–Et2O, 0 ◦C, 48%; (ii) N-aminopyridinium mesitylenesulfonate,
K2CO3, DMF, 0 ◦C–rt, 56%; (iii) N2H4, AcOH (aq.), EtOH, D, 92%; (iv) Br2 in AcOH, D, 73%; (v) NaH, BnBr, DMF, rt, 70%; (vi) Cs2CO3, BnBr, DMF,
rt, 78%.
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unsubstituted terminus of the hydrazine reacts preferentially with
the ester to form a hydrazide.ꢀ The route shown in Scheme 3
was amenable to multiple parallel synthesis of an extensive range
of pyridine ring-substituted analogues through combination of
the dipolarophile with a set of substituted pyridine N-imines (11)
derived in situ from their parent N-aminopyridinium salts.†† The
requisite salts are readily prepared in a single step by reaction of O-
mesitylenesulfonylhydroxylamine with the appropriate pyridine.12
Attention was next focused upon alkynyl pyridazinone 21
as a dipolarophile, Scheme 4. This compound was prepared
by Sonogashira coupling of 3-methyl-1-butyne with excess 3,6-
dichloropyridazine (19) followed by treatment of the coupled
product (20) with hot acetic acid and aqueous acetate. Attempts
to achieve the cycloaddition of 21 with pyridine N-imine under
the conditions employed for alkynone 13 (at room temperature
in DMF) returned the dipolarophile unreacted. Under forcing
conditions (at 120 ◦C) an intractable mixture of polar components
was formed, and it was not possible to achieve the synthesis
of pyrazolopyridine 16 by this route. However, the N-benzyl
derivative (22) of alkynyl pyridazinone 21 proved more promising.
Compound 22 was prepared either by alkylation of 21 with benzyl
bromide or by rearranging the synthetic sequence: beginning with
hydrolysis of 3,6-dichloropyridazine (19) to 6-chloropyridazin-
3(2H)-one (23),14 followed by N-benzylation to 2415 and finally
Sonogashira coupling with 3-methyl-1-butyne. Alkyne 22 was
also unreactive with pyridine N-imine at room temperature.
However, at elevated temperature (120 ◦C), treatment of 22
with N-aminopyridinium mesitylenesulfonate (2 equivalents) and
K2CO3 in DMF over 48 h afforded pyrazolopyridine 18 in 26%
yield. Alkynyl pyridazine 20 was also found to react under
these conditions and afforded pyrazolopyridine 25 in 20% yield.
Treatment of 25 with hot acetic acid and aqueous acetate afforded
the pyridazinone (16), which had not been directly accessible from
21. The use of a dipolarophile such as 22 necessarily gives rise
to the pyridazinone product. Access to the dihydropyridazinone
therefore requires reduction, which can be achieved by treatment
with zinc in acetic acid, as illustrated for the conversion of 18
into 17.
Similar chemistry with the N-phenyl analogue (28) of alkynyl
pyridazine 22 afforded a concise route to pyrazolopyridines 29
and 30, Scheme 5. In this case the acetylenic dipolarophile was
prepared from pyridazinedione 26.16 Thus, chlorination of 26
with POCl3 afforded chloropyridazinone 2717 and subsequent
Sonogashira coupling with 3-methyl-1-butyne afforded alkyne 28
in 76% yield for the two steps. The cycloaddition reaction was
ꢀ D. R. Adams, R. W. Allcock, P. D. Bailey, I. D. Collier, Z. Jiang and
K. M. Morgan, unpublished results.
†† Detailed PDE inhibitory activities for our 6-(pyrazolo[1,5-a]pyridin-3-
yl)pyridazin-3-one series will be presented elsewhere.
Scheme 4 Reagents and conditions: (i) 3-methyl-1-butyne (0.5 equiv.), (i-Pr)2NH, Bu4NI, CuI, Pd(PPh3)4, THF, 90 ◦C (sealed vessel), 53%; (ii) AcOH,
NaOAc (aq.), reflux, 87%; (iii) K2CO3, BnBr, DMF, rt, 82%; (iv) AcOH, D, 95%; (v) Cs2CO3, BnBr, DMF, rt, 78%; (vi) 3-methyl-1-butyne, (i-Pr)2NH,
Bu4NI, CuI, Pd(PPh3)4, THF, 80 ◦C (sealed vessel), 83%; (vii) N-aminopyridinium mesitylenesulfonate (2–3 equiv.), K2CO3, DMF, 120 ◦C; 25, 20%; 16,
intractable mixture formed; 18, 26%; (viii) AcOH, NaOAc (aq), D, 80%; (ix) Zn, AcOH, D, 56%.
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first of these steps was compromised by some competing N-
debenzylation under the reaction conditions with POCl3. As with
the preparation of alkynyl pyridazinones 22 and 28, however,
the Sonogashira coupling to 33 was efficient (91%), provided
that a sealed reaction vessel was used to prevent loss of the
volatile 3-methyl-1-butyne reactant. The cycloaddition step af-
forded pyrazolopyridine 34 in 40% yield when conducted under
similar conditions to the preceding examples in hot DMF.
To test further the scope of the cycloaddition reaction of
pyridine N-imine with alkynyl heterocycles, attention was turned
to alkynyl pyridine 35, prepared in 41% yield by Sonogashira
coupling of 2-chloropyridine with 3-methyl-1-butyne (Scheme 7).
Reaction of alkyne 35 with N-aminopyridinium mesitylenesul-
fonate (2 equiv.) and K2CO3 in DMF at 95 ◦C over 18 h afforded
the target pyrazolopyridine (36) in just 3% yield together with
38% recovery of unreacted alkyne. At reduced temperature (80 ◦C)
over 40 h the yield of pyrazolopyridine 36 rose to 10% with 53%
recovery of unreacted alkyne, suggesting that the reaction outcome
is compromised by competing degradation pathways at higher
temperature.‡‡
Scheme 5 Reagents and conditions: (i) POCl3, D, 77%; (ii) 3-methyl-
1-butyne, (i-Pr)2NH, Bu4NI, CuI, Pd(PPh3)4, THF, 80 ◦C (sealed vessel),
99%; (iii) N-aminopyridinium mesitylenesulfonate (2 equiv.), K2CO3,
DMF, 120 ◦C, 50%; (iv) Zn, AcOH, D, 84%.
conducted, as before, with N-aminopyridinium mesitylenesul-
fonate and K2CO3 in hot DMF, affording pyrazolopyridine 29 in
50% yield. Reduction of the latter with zinc in acetic acid efficiently
gave the corresponding dihydropyridazinone (30; 84% yield).
Alkynyl phthalazinone 33 was also found to be effective as a
dipolarophile for pyridine N-imine, Scheme 6. This compound was
prepared in two steps from phthalazinedione 3118 by chlorination
with POCl3 followed by Sonogashira coupling of the intermediate
chloride (32) with 3-methyl-1-butyne. The yield (17%) for the
Scheme 7 Reagents and conditions: (i) 3-methyl-1-butyne, (i-Pr)2NH, CuI,
Pd(PPh3)4, THF, 70 ◦C (sealed vessel), 41%; (ii) MeI, THF, 60 ◦C, 72%;
(iii) N-aminopyridinium mesitylenesulfonate (2 equiv.), K2CO3 (4 equiv.),
DMF, 80 ◦C, 10%; (iv) N-aminopyridinium mesitylenesulfonate (2 equiv.),
K2CO3 (4 equiv.), DMF, 95 ◦C, 18 h, 39%.
As with the reactions of the alkynyl pyridazine and pyridazinone
derivatives, the cycloaddition of alkynyl pyridine 35 proceeded
with regiocontrol favouring exclusive formation of a product (36)
in which the heterocycle from the dipolarophile is connected to the
3-position of the pyrazolopyridine. The alternative regioisomer
‡‡ Some unreacted dipolarophile was also recovered from the reactions of
the two N-benzyl diazinones (22 and 33), though not from the reactions
of the N-phenyl pyridazinone (28) or the chloropyridazine (20). Alkyne
recovery was respectively 43% and 39% from the reactions of 22 and 33,
which were conducted with two equivalents of the N-aminopyridinium
mesitylenesulfonate. Attempts to improve the yield of isolated product in
these reactions with prolonged reaction times were ineffective. Use of larger
excesses of N-aminopyridinium salt in the reaction complicated product
isolation by generating quantities of tarry residue.
Scheme 6 Reagents and conditions: (i) POCl3, D, 17%; (ii) 3-methyl-
1-butyne, (i-Pr)2NH, Bu4NI, CuI, Pd(PPh3)4, THF, 80 ◦C (sealed vessel),
91%; (iii) N-aminopyridinium mesitylenesulfonate (2 equiv.), K2CO3,
DMF, 100 ◦C, 40%.
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was not detected. The regiochemical outcome of this reaction was
determined from the NOESY spectrum of 36 and confirmed by the
acquisition of an X-ray crystal structure, Fig. 2. The regiochemical
outcome for the cycloaddition of alkynyl pyridazinone 22 was
similarly confirmed by acquisition of NOESY spectra and X-
ray crystal structures for the product (18) and its reduced
analogue (17). These structures also served to substantiate the
regiochemistry assigned to the reaction of alkynone 13 with
pyridine N-imine, Scheme 3.
pyridine N-imine. When conducted under identical conditions
to the reaction of alkynyl pyridine 35, with N-aminopyridinium
mesitylenesulfonate (2 equiv.) and K2CO3 in DMF at 95 ◦C over
18 h, a greatly improved 39% yield of the pyrazolopyridine product
(38) was obtained from the cycloaddition step. However, the yields
of the cycloaddition reactions of 35 and 37 were not improved with
extended reaction times. Indeed, in the case of alkynyl pyridinium
salt 37 the reaction time could be reduced substantially without
significant reduction in the yield of pyrazolopyridine product.
Thus, the yield of 38 was 37% when the reaction was conducted at
95 ◦C over the reduced duration of 2 h.
Examination of the 13C chemical shifts for the alkyne carbons
of compounds 35 and 37 suggests that quaternisation of the
pyridine nitrogen exerts a substantial polarizing effect upon the
alkyne, which may contribute to the improved reactivity of 37.
The alkyne a and b carbons of compound 35 give resonances at
dC 80 and 96 respectively, whereas the corresponding carbons in
alkynyl pyridinium salt 37 give signals at dC 71 and 117. The
enhanced polarisation of alkyne 37 is also reflected in partial
charge calculations, which give values of −0.130 and −0.109 for
the a and b carbons respectively in alkyne 35 and values of −0.289
and −0.079 for the corresponding carbons in alkyne 37.§§
Conclusions
In summary, concise routes to pharmacologically active 6-
(pyrazolo[1,5-a]pyridin-3-yl)pyridazin-3-ones have been devel-
oped using alkynyl c-keto ester and alkynyl pyridazinone dipo-
larophiles for cycloaddition with pyridine N-imines. Use of the
alkynyl c-keto ester in the cycloaddition furnishes the dihy-
dropyridazinone following an additional hydrazine condensation
step; the alkynyl pyridazinone affords the pyrazolopyridine-
pyridazinone directly. Application of standard reduction and
oxidation procedures permits pyridazinone–dihydropyridazinone
ring interconversion. Previously reported reactions of pyridine
N-imines have been confined to simple alkynone or alkynoate
dipolarophiles. We show here for the first time that reactions
with alkynyl heterocycles are feasible, albeit requiring elevated
temperature. Although yields for the cycloaddition step are
modest, the alkynyl heterocycles are readily prepared through
robust Sonogashiracoupling procedures andallow for veryconcise
routes to pyrazolopyridines substituted at C-3 with a heterocycle.
Experimental
Fig. 2 X-Ray crystal structures of compounds 17 (top), 18 (middle) and
36 (bottom).
General details
Commercially available reagents from Aldrich, Avocado and Lan-
caster chemical companies were generally used as supplied without
further purification. Tetrahydrofuran, diethyl ether and toluene
were dried by distillation from sodium-benzophenone ketyl under
argon. ‘Light petroleum’ refers to the fraction boiling between
40 ◦C and 60 ◦C. Anhydrous N,N-dimethylformamide was
purchased from Aldrich and used as supplied from Sure/SealTM
bottles. With the exception of the pyridine N-imine cycloadditions,
which were carried out in air to facilitate oxidation of the
Cycloaddition reactions of alkynoate and alkynone dipo-
larophiles with pyridine N-imines are typically conducted within
a temperature range of 0–25 ◦C. In contrast, cycloaddition
of the alkynyl heterocycles presented here requires significantly
elevated temperatures in order to proceed. This requirement was
thought likely to reflect reduced dipolarophilic reactivity due to
the comparatively modest electron demand exerted on the alkyne
by the heterocycle. Increased electron demand in the heterocycle
might therefore be expected to enhance the reactivity of the
dipolarophile. In order to verify this expectation at a qualitative
level, alkynyl pyridine 35 was quaternised with methyl iodide and
the resulting alkynyl pyridinium salt (37) tested in the reaction with
§§ Partial charges calculated using standard semi-empirical AM1 methods
within CAChe software.
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immediate dihydropyrazolopyridine cycloadduct, reactions were
routinely carried out under an inert atmosphere of argon or
nitrogen. Analytical thin layer chromatography was carried out
using aluminium backed plates coated with Merck Kieselgel 60
GF254 (Art. 05554). Developed plates were visualized under ultra-
violet light (254 nm) and/or alkaline potassium permanganate
NaHCO3 solution (300 mL) for 1 h. The mixture was extracted
with CH2Cl2 (100 mL); the separated organic phase was washed
with brine, (50 mL), dried (MgSO4) and evaporated to give to
give the title compound (15.6 g; 48%) as a pale red oil in >90%
purity: dH (200 MHz; CDCl3) 1.20 (6 H, d, J 6.9, CH(CH3)2), 1.22
(3 H, t, J 7.1, OCH2CH3), 2.55–2.63 (2 H, m, CH2-2), 2.69 (1 H,
sept, J 6.9, CH(CH3)2), 2.79–2.88 (2 H, m, CH2-3), 4.11 (2 H, q,
J 7.1, OCH2CH3); dC (50 MHz; CDCl3) 14.2 (OCH2CH3), 20.8
(CH(CH3)2), 21.9 (CH(CH3)2), 28.2 (CH2-2), 40.1 (CH2-3), 60.9
(OCH2CH3), 79.6 (C-5), 99.7 (C-6), 172.2 (C-1), 185.9 (C-4); m/z
(EI) 196 (3%, M+), 167 (6%, M+ − Et), 151 (26%, M+ − OEt),
R
dip. Flash chromatography was performed using DAVISILꢀ silica
˚
(60 A; 35–70 lm) from Fisher (cat. S/0693/60). Fully character-
ized compounds were chromatographically homogeneous.
Melting points were determined using a Stuart Scientific SMP10
apparatus and are uncorrected. IR spectra were recorded on a
Perkin Elmer 1600 FT IR spectrometer. Spectra were recorded
as potassium bromide discs, as solutions in CHCl3, or as films
between sodium chloride plates. Mass spectra were obtained on
Kratos Concept IS EI (electron impact) and Fisons VG Quattro
+
129 (39%, M+ − C≡CCH(CH3)2), 43 (100%, C3H7 ); (found: M+,
196.1099. C11H16O3 requires 196.1099).
Ethyl 4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-4-oxobutanoate
(14)
1
(electrospray) spectrometers. H NMR spectra were recorded at
200 and 400 MHz on Bruker AC200 and DPX400 spectrometers;
13C NMR spectra were recorded at 50 and 101 MHz on the
same instruments. Chemical shifts are recorded in parts per
million (d in ppm) and are referenced against solvent signals (dC
77.16 for chloroform and dC 39.52 for methyl sulfoxide) for 13C
spectra and solvent residual resonances (dH 7.26 for chloroform
Powdered K2CO3 (5.64 g, 40.8 mmol) was added to an ice-
cooled solution of 1-aminopyridinium mesitylenesulfonate (6.00 g,
20.4 mmol) in DMF (150 mL) to afford a deep purple heterogenous
mixture. After 15 min 13 (4.60 g, 23.4 mmol) was added and the
mixture stirred for 1 h. The mixture was allowed to attain rt over
18 h and was then partitioned between brine (150 mL) and EtOAc
(70 mL). The aqueous phase was further extracted with EtOAc
(2 × 70 mL), and the combined organic extracts dried (MgSO4)
and evaporated. The residual oil was subjected to flash column
chromatography (5 : 2 light petroleum–EtOAc) to afford the title
compound (3.29 g; 56%) as a colourless powder: mp 72–73 ◦C
(from EtOAc–light petroleum); mmax(KBr)/cm−1 2975, 2935, 1738,
1640, 1618, 1503, 1462, 1441, 1418, 1382, 1368, 1286, 1217, 1178,
1155, 1089, 1018, 998, 804, 763; dH (400 MHz; CDCl3) 1.25 (3 H,
t, J 7.1, OCH2CH3), 1.38 (6 H, d, J 6.9, CH(CH3)2), 2.77 (2 H, t,
J 6.6, CH2-2), 3.23 (2 H, t, J 6.6, CH2-3), 3.78 (1 H, sept, J 6.9,
1
and dH 2.50 methyl sulfoxide) for H spectra.19 Chemical shift
values are accurate to 0.01 ppm and 0.1 ppm respectively. J
values are given in Hz. Multiplicity designations used are: s, d,
t, q, sept and m for singlet, doublet, triplet, quartet, septet and
multiplet respectively. In 13C NMR spectra, signals corresponding
to CH, CH2, or CH3 groups are assigned from DEPT. Elemental
analyses were carried out by the analytical service of the Chemistry
Department at Heriot-Watt University using an Exeter CE-440
Elemental Analyser.
Ethyl 7-Methyl-4-oxooct-5-ynoate (13)
ꢁ
ꢁ
CH(CH3)2), 4.15 (2 H, q, J 7.1, OCH2CH3), 6.88 (1 H, dt, J6 ,4 1.3,
J6 ,5 6.9, J6 ,7 6.9, H-6ꢁ), 7.37 (1 H, ddd, J5 ,7 1.2, J5 ,6 6.9, J5 ,4 9.0,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ ꢁ
(Part 1) 3-Methyl-1-butyne (11.2 g, 164 mmol) was dissolved in
H-5ꢁ), 8.09 (1 H, dt, J4 ,5 9.0, J4 ,6 1.1, J4 ,7 1.1, H-4ꢁ), 8.45 (1 H,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ ꢁ
◦
anhydrous THF (300 mL) and cooled to −15 C (salt–ice bath)
dt, J7 ,6 6.9, J7 ,5 1.1, J7 ,4 1.1, H-7ꢁ); dC (101 MHz; CDCl3) 14.3
(OCH2CH3), 22.3 (CH(CH3)2), 27.9 (CH(CH3)2), 28.3 (CH2-2),
37.0 (CH2-3), 60.7 (OCH2CH3), 109.6 (C-3ꢁ), 113.4 (CH-6ꢁ), 119.2
(CH-4ꢁ), 127.9 (CH-5ꢁ), 129.3 (CH-7ꢁ), 141.8 (C-3aꢁ), 164.1 (C-2ꢁ),
173.3 (C-1), 192.0 (C-4); m/z (EI) 288 (61%, M+), 243 (52%, M+ −
OEt), 215 (55%, M+ − CO2Et), 187 (93%, M+ − CH2CH2CO2Et);
(found: M+, 288.1474. C16H20N2O3 requires 288.1474); (found C,
66.71; H, 7.03; N, 9.74. C16H20N2O3 requires: C, 66.65; H, 6.99; N,
9.72%).¶¶
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under argon. EtMgBr (3 M solution in Et2O; 55 mL, 165 mmol)
was added slowly over 40 min to give a golden brown homogenous
solution. The mixture was allowed to attain 15 ◦C and was
stirred at that temperature for 18 h. (Note: the alkynyl magnesium
bromide may precipitate!). Further alkyne (ca. 2 mL, 20 mmol)
was added; the mixture was heated at 45 ◦C for 1 h and then cooled
to rt.
(Part 2) The alkynyl magnesium bromide solution from part 1
was cannulated over a period of 3 h into an ice-cooled solution
of ethyl succinyl chloride (71.0 mL, 498 mmol) in anhydrous
Et2O (600 mL). The resulting pale yellow heterogenous mixture
was quenched by addition of saturated NH4Cl solution (20 mL),
concentrated to 200 mL in vacuo and diluted with saturated
NaHCO3 solution (200 mL). The mixture was stirred for 1 h. The
organic layer was then separated from the basic aqueous phase,
washed with brine (40 mL), dried (MgSO4) and concentrated
in vacuo to give the product as a red-brown oil. The crude
product was subjected to flash column chromatography, eluting
with light petroleum–EtOAc (10 : 1). Fractions containing the
target material were combined, concentrated in vacuo and then
distilled under reduced pressure through a 15 cm fractionating
column (84–120 ◦C, 3 mmHg) to afford a yellow oil (26.3 g). This
oil was then dissolved in THF (10 mL) and stirred with saturated
6-(2-Isopropylpyrazolo[1,5-a]pyridin-3-yl)-4,5-dihydropyridazin-
3(2H)-one (15)
Keto ester 14 (2.80 g, 9.71 mmol) was boiled for 18 h in a mixture
of aqueous hydrazine buffered to pH 5 with AcOH (1.84 M in
H2NNH2; 53 mL, 97.5 mmol) and EtOH (30 mL). The mixture
¶¶ NMR assignments for compounds 14, 16, 18, 25, 29 and 36 were
supported by the acquisition of NOESY, HSQC and HMBC spectra;
assignments for compounds 20 and 21 were supported by the acquisition
of HSQC and HMBC spectra; assignments for salt 38 were supported by
the acquisition of COSY, NOESY, HSQC and HMBC spectra; 13C NMR
assignments for compound 22 were supported by the acquisition of an
1
HSQC spectrum. H NMR spectra of salts 37 and 38 are shown in the
accompanying ESI file.†
180 | Org. Biomol. Chem., 2008, 6, 175–186
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was then concentrated in vacuo to afford an aqueous slurry that
was extracted with CH2Cl2 (2 × 50 mL). The combined organic
extracts were washed with brine (2 × 20 mL), dried (MgSO4) and
evaporated to give the crude product (2.45 g) as a buff powder.
Trituration of the latter with hot Et2O (50 mL) afforded the title
2-Benzyl-6-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-4,5-
dihydropyridazin-3(2H)-one (17)
Method 1. NaH (60% w/w dispersion in oil; 30.0 mg,
0.750 mmol) was added to a solution of 15 (100 mg, 0.390 mmol)
in anhydrous DMF (5 mL) under argon. The mixture was stirred
for 1 h at rt after which time BnBr (1 M solution in DMF; 0.50 mL,
0.50 mmol) was added. The mixture was stirred for a further 90 min
and then diluted with water (10 mL) and extracted with EtOAc
(2 × 15 mL). The combined organic extracts were washed with
brine (2 × 10 mL), dried (MgSO4) and evaporated. The residual
oil was subjected to flash column chromatography (10 : 1 CH2Cl2–
Et2O) to afford the title compound (95.0 mg; 70%) as a colourless
powder.
◦
compound (2.30 g; 92%) as a colourless powder: mp 211–212 C
(from EtOAc–light petroleum); mmax(KBr)/cm−1 3212, 3076, 2958,
1661, 1632, 1537, 1519, 1373, 1325, 1258, 1223, 951, 757, 736;
dH (200 MHz; CDCl3) 1.40 (6 H, d, J 6.9, CH(CH3)2), 2.58–2.67
(2 H, m, CH2-4), 3.00–3.09 (2 H, m, CH2-5), 3.45 (1 H, sept, J 6.9,
CH(CH3)2), 6.79 (1 H, dt, J6 ,4 1.4, J6 ,5 6.9, J6 ,7 6.9, H-6ꢁ), 7.21
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(1 H, ddd, J5 ,7 1.2, J5 ,6 6.9, J5 ,4 8.9, H-5ꢁ), 7.78 (1 H, dt, J4 ,5 8.9,
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J4 ,6 1.1, J4 ,7 1.1, H-4ꢁ), 8.43 (1 H, dt, J7 ,6 6.9, J7 ,5 1.1, J7 ,4 1.1,
H-7ꢁ), 8.58 (1 H, br s, NH); dC (50 MHz; 20% CD3OD/CDCl3)
22.2 (CH(CH3)2), 25.2 (CH2), 26.0 (CH2), 26.9 (CH(CH3)2), 105.0
(C-3ꢁ), 112.3 (CH-6ꢁ), 117.8 (CH-4ꢁ), 125.3 (CH-5ꢁ), 128.1 (CH-
7ꢁ), 138.8 (C-3aꢁ), 148.2 (C-6), 159.6 (C-2ꢁ), 167.9 (C-3); m/z (EI)
256 (34%, M+), 198 (20%), 170 (13%), 184 (70%); (found: M+,
256.1322. C14H16N4O requires 256.1324); (found C, 65.51; H, 6.25;
N, 21.72. C14H16N4O requires: C, 65.61; H, 6.29; N, 21.86%).
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Method 2. A mixture of Zn dust (5.4 mg, 83 lmol) and 18
(32.6 mg, 94.7 lmol) in AcOH (2 mL) was boiled for 10 h,
adding further zinc dust (30.2 mg, 459 lmol) in increments until
TLC indicated consumption of 18. The mixture was then cooled,
filtered through celite and evaporated to afford a residue that
was partitioned between EtOAc (30 mL) and saturated NaHCO3
solution (10 mL). The organic phase was separated, washed with
additional volumes of NaHCO3 solution (2 × 10 mL) followed by
brine (3 × 10 mL), dried (Na2SO4) and evaporated. The resulting
residue was subjected to flash column chromatography (gradient
elution from 1 : 9 to 1 : 1 EtOAc–light petroleum) to afford
the title compound (18.4 mg; 56%) as a colourless powder: mp
126–127 ◦C (from EtOAc–light petroleum); mmax(KBr)/cm−1 3088,
2970, 1668, 1532, 1397, 1377, 1220, 1138, 1028, 930, 755, 700;
dH (200 MHz; CDCl3) 1.34 (6 H, d, J 6.9, CH(CH3)2), 2.61–2.69
(2 H, m, CH2), 2.95–3.04 (2 H, m, CH2), 3.36 (1 H, sept, J 6.9,
6-(2-Isopropylpyrazolo[1,5-a]pyridin-3-yl)pyridazin-3(2H)-one
(16)
Method 1. Bromine in AcOH (1 M; 22.0 mL, 22.0 mmol) was
added dropwise over a period of 25 min to a solution of 15 (512 mg,
2.00 mmol) in AcOH (15 mL) at rt. The mixture was boiled for
30 min, then cooled, diluted with water (20 mL) and extracted with
CH2Cl2 (2 × 20 mL). The combined organic extracts were washed
with saturated NaHCO3 solution (2 × 20 mL) followed by brine
(15 mL) and then dried (MgSO4) and evaporated. Trituration of
the resulting yellow foam with Et2O (3 × 2 mL) afforded the title
compound (370 mg; 73%) as a colourless powder.
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CH(CH3)2), 5.04 (2 H, s, CH2Ph), 6.72 (1 H, dt, J6 ,4 1.4, J6 ,5
6.9, J6 ,7 6.9, H-6ꢁ), 7.08 (1 H, ddd, J5 ,7 1.1, J5 ,6 6.9, J5 ,4 8.9,
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H-5ꢁ), 7.26–7.48 (6 H, complex overlapping m, H-4ꢁ and Ph), 8.37
(1 H, dt, J7 ,6 6.9, J7 ,5 1.1, J7 ,4 1.1, H-7ꢁ); dC (50 MHz; CDCl3)
22.7 (CH(CH3)2), 26.0 (CH2), 27.4 (CH(CH3)2), 27.5 (CH2), 51.8
(CH2Ph), 105.3 (C-3ꢁ), 112.2 (CH-6ꢁ), 118.2 (CH-4ꢁ), 125.2 (CH-
5ꢁ), 127.4 (Ph para-CH), 128.5 (2× Ph CH), 128.6 (2× Ph CH),
128.8 (CH-7ꢁ), 138.0 (Ph C), 139.1 (C-3aꢁ), 148.5 (C-6), 160.1 (C-
2ꢁ), 165.2 (C-3); m/z (EI) 346 (30%, M+), 255 (10%, M+ − Bn);
(found: M+, 346.1818. C21H22N4O requires 346.1794), 303.1230
(0.42%, M+ − C3H7 requires 303.1246); (found C, 72.52; H, 6.32;
N, 16.06. C21H22N4O requires: C, 72.81; H, 6.40; N, 16.17%).¶¶
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Method 2. A mixture of AcOH (20 mL), NaOAc·3H2O (1.00 g,
2.00 mmol), water (1.00 mL) and 25 (380 mg, 1.39 mmol) was
heated in an oil bath thermostatted at 120 ◦C for 5 h. Most of
the AcOH was then removed by distillation at reduced pressure
to afford a residue that was partitioned between EtOAc (50 mL)
and saturated NaHCO3 solution (50 mL). The organic phase was
separated, further washed with saturated NaHCO3 solution (2 ×
50 mL), dried (MgSO4) and evaporated. The resulting residue
was recrystallised from CHCl3–light petroleum to afford the title
compound (282 mg; 80%) as a colourless crystalline solid: mp
221–222 ◦C (from CHCl3–EtOAc–MeOH); mmax(KBr)/cm−1 3436,
3036, 2968, 2867, 1675, 1657, 1638, 1590, 1545, 1534, 1494, 1274,
1267, 1218, 1008; dH (400 MHz; CDCl3) 1.38 (6 H, d, J 6.9,
2-Benzyl-6-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)pyridazin-
3(2H)-one (18)
Method 1. To a stirred solution of 16 (100 mg, 0.393 mmol) in
anhydrous DMF (5 mL) under argon was added Cs2CO3 (380 mg,
1.17 mmol) followed by BnBr (1 M solution in DMF; 1.50 mL,
1.50 mmol). The mixture was stirred for 18 h at rt and then diluted
with water (10 mL) and extracted with EtOAc (2 × 15 mL). The
combined organic extracts were washed with brine (2 × 10 mL),
dried (MgSO4) and evaporated. The residual oil was subjected to
flash column chromatography (10 : 1 CH2Cl2–Et2O) to afford the
title compound (105 mg; 78%) as a colourless powder.
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CH(CH3)2), 3.41 (1 H, sept, J 6.9, CH(CH3)2), 6.74 (1 H, dt, J6 ,4
1.4, J6 ,5 6.9, J6 ,7 6.9, H-6ꢁ), 7.10 (1 H, d, J 9.8, H-4), 7.13 (1 H,
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ddd, J5 ,7 1.1, J5 ,6 6.9, J5 ,4 9.0, H-5ꢁ), 7.57 (1 H, d, J 9.8, H-5),
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7.72 (1 H, dt, J4 ,5 9.0, J4 ,6 1.2, J4 ,7 1.2, H-4ꢁ), 8.45 (1 H, dt, J7 ,6
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6.9, J7 ,5 1.1, J7 ,4 1.1, H-7ꢁ), 13.21 (1 H, br s, NH); dC (101 MHz;
CDCl3) 22.8 (CH(CH3)2), 27.0 (CH(CH3)2), 103.9 (C-3ꢁ), 112.3
(CH-6ꢁ), 117.4 (CH-4ꢁ), 125.2 (CH-5ꢁ), 128.8 (CH-7ꢁ), 130.0 (CH-
4), 134.2 (CH-5), 139.1 (C-3aꢁ), 142.3 (C-6), 159.5 (C), 161.8 (C);
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+
m/z (EI) 254 (64%, M+), 239 (31%, M+ − Me), 43 (100%, C3H7 );
(found: M+, 254.1167. C14H14N4O requires 254.1168); (found C,
65.99; H, 5.43; N, 21.88. C14H14N4O requires: C, 66.13; H, 5.55;
N, 22.03%).¶¶
Method 2.
A
stirred mixture of 1-aminopyridinium
mesitylenesulfonate12 (350 mg, 1.19 mmol), 22 (304 mg,
1.20 mmol) and powdered K2CO3 (335 g, 2.40 mmol) in DMF
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(12 mL) was heated at 120 ◦C for 24 h. Additional pyridinium
salt (354 mg, 1.20 mmol) and K2CO3 (323 mg, 2.33 mmol) were
then added and heating continued for a further 24 h. The mixture
was subsequently evaporated to dryness and the resulting residue
partitioned between CH2Cl2 (30 mL) and water (20 mL). The
organic phase was separated, washed with water (20 mL) followed
by brine (2 × 20 mL), dried (MgSO4) and evaporated. The resulting
residue was subjected to flash column chromatography (gradient
elution from 3 : 7 to 3 : 2 EtOAc–light petroleum), affording the
starting alkyne (129 mg, 511 lmol; 43%) followed by the title
compound (109 mg, 316 lmol; 26%) as a pale yellow powder: mp
172–173 ◦C (from EtOAc); mmax(KBr)/cm−1 3088, 2968, 1662, 1589,
1533, 1506, 1321, 1030, 845, 746, 700; dH (400 MHz; CDCl3) 1.36
(6 H, d, J 6.9, CH(CH3)2), 3.34 (1 H, sept, J 6.9, CH(CH3)2), 5.40
6-(3-Methylbut-1-ynyl)pyridazin-3(2H)-one (21)
Chloropyridazine 20 (6.07 g, 33.6 mmol) was heated in a mixture
of AcOH (140 mL), water (18 mL) and NaOAc·3H2O (5.30 g)
at 100 ◦C for 15 h. The mixture was then cooled and decanted
into an ice-cooled solution of NaOH (100 g) in water (700 mL).
The resulting alkaline solution was washed with CH2Cl2 (2 ×
200 mL) and the organic phase discarded. The pH of the aqueous
mixture was adjusted to ∼6 by addition of conc. hydrochloric
acid and it was extracted with CH2Cl2 (3 × 200 mL). The
combined organic extract was dried (MgSO4) and evaporated.
The title compound (4.73 g; 87%) was isolated from the resulting
residue as a colourless solid by flash column chromatography
(50% EtOAc–light petroleum) followed by crystallisation from
◦
CHCl3–light petroleum: mp 96–97 C (CHCl3–light petroleum);
(2 H, s, CH2Ph), 6.74 (1 H, dt, J6 ,4 1.4, J6 ,5 6.9, J6 ,7 6.9, H-6ꢁ),
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mmax(KBr)/cm−1 3468, 2976, 2925, 2233, 1682, 1648, 1585, 1547,
1442, 1005, 849, 657, 638; dH (200 MHz; CDCl3) 1.27 (6 H, d, J 6.9,
CH(CH3)2), 2.79 (1 H, sept, J 6.9, CH(CH3)2), 6.95 (1 H, d, J 9.7,
H-4), 7.28 (1 H, d, J 9.7, H-5), 12.65 (1 H, br s, NH); dC (50 MHz;
CDCl3) 21.0 (CH(CH3)2), 22.4 (CH(CH3)2), 75.0 (C≡CCH), 98.9
(C≡CCH), 129.6 (CH-4), 133.3 (C-6), 136.2 (CH-5), 161.5 (C-
3); EIMS: m/z (EI) 162 (83%, M+), 161 (100%, M+ − H), 147
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7.02 (1 H, d, J4,5 9.6, H-4), 7.11 (1 H, ddd, J5 ,7 1.1, J5 ,6 6.9, J5 ,4
9.0, H-5ꢁ), 7.27–7.37 (3 H, complex overlapping m, Ph meta-H
and para-H), 7.44–7.49 (3 H, complex overlapping m, H-4ꢁ and
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Ph ortho-H), 7.45 (1 H, d, J5,4 9.6, H-5), 8.41 (1 H, dt, J7 ,6 6.9,
J7 ,5 1.1, J7 ,4 1.1, H-7ꢁ); dC (101 MHz; CDCl3) 22.7 (CH(CH3)2),
26.9 (CH(CH3)2), 55.1 (CH2Ph), 104.1 (C-3ꢁ), 112.1 (CH-6ꢁ), 117.1
(CH-4ꢁ), 125.0 (CH-5ꢁ), 127.9 (Ph para-CH), 128.6 (2× Ph meta-
CH), 128.8 (CH-7ꢁ), 129.1 (2× Ph ortho-CH), 130.3 (CH-4), 132.6
(CH-5), 136.7 (Ph C), 139.0 (C-3aꢁ), 141.1 (C-6), 159.2 (C-3), 159.5
(C-2ꢁ); m/z (EI) 344 (100%, M+), 253 (10%, M+ − Bn), 91 (23%,
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(71%, M+ − CH3), 133 (38%, M+ − C2H5), 119 (33%, M+
−
C3H7); (found: C, 66.44; H, 6.19; N, 17.31. C9H10N2O requires C,
66.65; H, 6.21; N, 17.27%).¶¶
+
C7H7 ); (found: C, 73.06; H, 5.77; N, 16.32. C21H20N4O requires
2-Benzyl-6-(3-methylbut-1-ynyl)pyridazin-3(2H)-one (22)
C, 73.23; H, 5.85; N, 16.27%).¶¶
Method 1. To a stirred solution of 21 (3.92 g, 24.1 mmol) in
anhydrous DMF (50 mL) was added powdered K2CO3 (13.5 g,
97.7 mmol) followed after 5 min by BnBr (3.50 mL, 29.4 mmol).
After 30 min the mixture was diluted with water (850 mL) and
extracted with EtOAc (3 × 200 mL). The combined organic extract
was dried (MgSO4) and evaporated. The residual oil was subjected
to flash column chromatography (4 : 7 EtOAc–light petroleum).
Fractions containing the target material were evaporated and the
resulting yellow solid crystallised from EtOAc–hexane to afford
the title compound (4.98 g; 82%) as colourless needles.
3-Chloro-6-(3-methylbut-1-ynyl)pyridazine (20)
A sealable, heavy-walled flask (∼750 mL capacity) was charged
with 3,6-dichloropyridazine (41.6 g, 279 mmol), Bu4NI (37.0 g,
100 mmol), CuI (1.30 g, 6.83 mmol), Pd(PPh3)4 (1.66 g,
1.44 mmol), anhydrous THF (400 mL), 3-methyl-1-butyne (9.50 g,
140 mmol) and iPr2NH (20.0 mL, 143 mmol). The flask was sealed
and the mixture stirred magnetically in an oil bath thermostatted
at 90 ◦C for 24 h [SAFETY SCREEN]. The flask was then
cooled and opened; the mixture was diluted with light petroleum
(600 mL) and passed through a column of Merck kieselgel 60H
(120 mm diameter × 90 mm length), eluting with 1 : 1 EtOAc–light
petroleum (2 L). The eluate was evaporated and the resulting dark
brown residue subjected to flash column chromatography (30%
EtOAc–light petroleum). Fractions containing the target material
were evaporated and the resulting light brown powder crystallised
from Et2O–light petroleum to afford the title compound (13.4 g;
53%) as a colourless solid: mp 49–51 ◦C (Et2O–light petroleum);
mmax (CHCl3 film)/cm−1 3099, 3067, 2981, 2238, 1560, 1395, 1145,
1067, 857; dH (200 MHz; CDCl3) 1.28 (6 H, d, J 6.9, CH(CH3)2),
2.83 (1 H, sept, J 6.9, CH(CH3)2), 7.44 (2 H, app. s, H-4 and H-5);
dH (200 MHz; C6D6) 1.03 (6 H, d, J 6.9, CH(CH3)2), 2.48 (1 H, sept,
J 6.9, CH(CH3)2), 6.32 (1 H, d, J 8.8, H-4), 6.51 (1 H, d, J 8.8,
H-5); dC (50 MHz; CDCl3) 21.2 (CH(CH3)2), 22.2 (CH(CH3)2),
75.9 (C≡CCH), 102.7 (C≡CCH), 127.6 (CH-4), 131.7 (CH-5),
147.5 (C-6), 154.6 (C-3); dC (50 MHz; C6D6) 21.5 (CH(CH3)2),
22.4 (CH(CH3)2), 77.2 (C≡CCH), 101.7 (C≡CCH), 126.8 (CH-
4), 131.0 (CH-5), 147.6 (C-6), 154.7 (C-3); m/z (EI) 180 (35Cl;
100%, M+), 179 (35Cl; 64%, M+ − H), 145 (37%, M+ − Cl); (found:
C, 59.87; H, 4.94; N, 15.55. C9H9ClN2 requires C, 59.84; H, 5.02;
N, 15.51%).¶¶
Method 2. A sealable, heavy-walled flask (∼100 mL capacity)
was charged with 2415 (4.03 g, 18.3 mmol), Bu4NI (6.99 g,
18.9 mmol), CuI (211 mg, 1.11 mmol), Pd(PPh3)4 (841 mg,
728 lmol), anhydrous THF (40 mL), 3-methyl-1-butyne (1.89 g,
i
27.7 mmol) and Pr2NH (4.00 mL, 28.5 mmol). The flask was
sealed and the mixture stirred magnetically in an oil bath
thermostatted at 80 ◦C for 4 h [SAFETY SCREEN]. The flask
was then cooled and opened; the mixture was evaporated to
afford a residue that was dissolved in EtOAc (30 mL). The
resulting solution was washed with water (2 × 20 mL), dried
(MgSO4) and evaporated. The residue was subjected to flash
column chromatography (gradient elution from 1 : 9 to 1 : 4
EtOAc–light petroleum). Fractions containing the target material
were evaporated and the resulting light brown residue crystallised
from EtOAc–light petroleum to afford the title compound (3.83 g;
83%) as colourless needles: mp 85–87 ◦C (from EtOAc–light
petroleum); mmax(KBr)/cm−1 3055, 2974, 2222, 1661, 1591, 1490,
1301, 1151, 938, 842, 731, 696; dH (200 MHz; CDCl3) 1.26 (6 H,
d, J 6.9, CH(CH3)2), 2.78 (1 H, sept, J 6.9, CH(CH3)2), 5.30
(2 H, s, CH2Ph), 6.84 (1 H, d, J 9.6, H-4), 7.17 (1 H, d, J 9.6,
H-5), 7.22–7.46 (5 H, complex overlapping m, Ph); dC (50 MHz;
182 | Org. Biomol. Chem., 2008, 6, 175–186
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CDCl3) 21.2 (CH(CH3)2), 22.5 (CH(CH3)2), 55.9 (CH2Ph), 75.3
(C≡CCH), 98.7 (C≡CCH), 128.0 (Ph CH), 128.7 (2× Ph CH),
128.8 (2× Ph CH), 129.7 (CH-4), 132.3 (Ph C), 135.1 (CH-5),
136.0 (C-6), 159.2 (C-3); m/z (EI) 252 (100%, M+), 237 (36%, M+ −
195 (7%, M+ − C3H7), 77 (100%, C6H5 ); (found: M+, 238.1106.
+
C15H14N2O requires 238.1106).
6-(2-Isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-phenylpyridazin-
3(2H)-one (29)
CH3), 91 (79%, C7H7 ); (found: M+, 252.1265. C16H16N2O requires
+
252.1263); (found: C, 75.86; H, 6.35; N, 11.10. C16H16N2O requires
C, 76.16; H, 6.39; N, 11.10%).¶¶
A stirred mixture of 1-aminopyridinium mesitylenesulfonate12
(753 mg, 2.56 mmol), 28 (500 mg, 2.10 mmol) and powdered
K2C◦O3 (597 mg, 4.32 mmol) in DMF (10 mL) was heated at
120 C for 9 h. Additional pyridinium salt (506 mg, 1.72 mmol)
and K2CO3 (535 mg, 3.87 mmol) were then added and heating
continued for a further 12 h. The mixture was then evaporated
to dryness and the resulting residue partitioned between EtOAc
(75 mL) and water (40 mL). The organic phase was separated,
washed with water (2 × 40 mL) followed by brine (4 × 40 mL),
dried (Na2SO4) and evaporated. The residue was subjected to flash
column chromatography (1 : 1 EtOAc–light petroleum) to afford
the title compound (346 mg; 50%)◦as a pale yellow powder: mp 174–
3-(6-Chloropyridazin-3-yl)-2-isopropylpyrazolo[1,5-a]pyridine (25)
A stirred mixture of 1-aminopyridinium mesitylenesulfonate12
(1.32 g, 4.47 mmol), 20 (254 mg, 1.41 mmol) and powdered K2CO3
(1.12 g, 8.08 mmol) in DMF (15 mL) was heated at 120 ◦C for
30 h. The mixture was then evaporated to dryness and the residue
partitioned between EtOAc (50 mL) and water (50 mL). The
organic phase was separated, washed with brine (50 mL), dried
(MgSO4) and evaporated. The resulting residue was subjected
to flash column chromatography (2 : 3 EtOAc–light petroleum)
to afford the title compound (78.0 mg; 20%) as a pale yellow
◦
176 C (from petroleum 60–80 C); mmax(KBr)/cm−1 3053, 2969,
◦
powder: mp 147–148 C (from hexane–EtOAc); mmax(KBr)/cm−1
1670, 1590, 1527, 1476, 1310, 1043, 852, 745, 695; dH (400 MHz;
3080, 2969, 1632, 1576, 1543, 1531, 1506, 1465, 1400, 1359, 1214,
1146, 1092, 771, 754; dH (200 MHz; CDCl3) 1.38 (6 H, d, J 6.9,
CH(CH3)2), 3.48 (1 H, sept, J 6.9, CH(CH3)2), 6.79 (1 H, dt, J6,4
1.4, J6,5 6.9, J6,7 6.9, H-6), 7.20 (1 H, ddd, J5,7 1.1, J5,6 6.8, J5,4 9.0,
CDCl3) 1.43 (6 H, d, J 6.9, CH(CH3)2), 3.46 (1 H, sept, J 6.9,
CH(CH3)2), 6.79 (1 H, dt, J6 ,4 1.4, J6 ,5 6.9, J6 ,7 6.9, H-6ꢁ), 7.15
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(1 H, d, J4,5 9.7, H-4), 7.20 (1 H, ddd, J5 ,7 1.1, J5 ,6 6.8, J5 ,4 9.0,
H-5ꢁ), 7.38–7.42 (1 H, complex m, Ph para-H), 7.48–7.53 (2 H,
complex m, 2× Ph meta-H), 7.56 (1 H, d, J5,4 9.7, H-5), 7.70–
H-5), 7.49 (1 H, d, J5 ,4 9.0, H-5ꢁ), 7.62 (1 H, d, J4 ,5 9.0, H-4ꢁ),
7.99 (1 H, dt, J4,5 9.0, J4,6 1.2, J4,7 1.2, H-4), 8.43 (1 H, dt, J7,6 6.9,
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7.72 (3 H, complex overlapping m, H-4ꢁ and 2× Ph ortho-H), 8.45
ꢁ
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J
7,5 1.1, J7,4 1.1, H-7); dC (50 MHz; CDCl3) 22.6 (CH(CH3)2), 27.0
(1 H, dt, J7 ,6 7.0, J7 ,5 1.0, J7 ,4 1.0, H-7 ); dC (50 MHz; CDCl3) 22.8
(CH(CH3)2), 27.2 (CH(CH3)2), 103.9 (C-3ꢁ), 112.4 (CH-6ꢁ), 117.2
(CH-4ꢁ), 125.4 (2× ortho-CH and CH-5ꢁ), 128.2 (Ph para-CH),
128.9 (2× Ph meta-CH and CH-7ꢁ), 131.5 (CH-4), 132.8 (CH-5),
139.2 (C-3aꢁ), 141.7 (C-6), 141.9 (Ph C), 159.2 (C-3), 159.7 (C-2ꢁ);
m/z (EI) 330 (36%, M+), 315 (9%, M+ − CH3), 197 (100%); (found:
C, 72.48; H, 5.52; N, 16.69. C20H18N4O requires C, 72.71; H, 5.49;
N, 16.96%).¶¶
(CH(CH3)2), 104.4 (C-3), 112.8 (CH-6), 118.0 (CH-4), 125.9 (CH-
5), 127.5 (CH-4ꢁ), 128.0 (CH-5ꢁ), 128.8 (CH-7), 139.6 (C-3a), 153.2
(C-6ꢁ), 155.6 (C-3ꢁ), 160.1 (C-2); m/z (EI) 272 (35Cl; 19%, M+), 271
(35Cl; 18%, M+ − H), 237 (44%, M+ − Cl), 69 (100%); (found: C,
61.69; H, 4.69; N, 20.78. C14H13ClN4 requires C, 61.65; H, 4.80;
N, 20.54%).
6-(3-Methylbut-1-ynyl)-2-phenylpyridazin-3(2H)-one (28)
6-(2-Isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-phenyl-4,5-
dihydropyridazin-3(2H)-one (30)
A sealable, heavy-walled flask (∼50 mL capacity) was charged
with 2717 (1.06 g, 5.13 mmol), Bu4NI (2.08 g, 5.64 mmol), CuI
(58.6 mg, 0.31 mmol), Pd(PPh3)4 (232 mg, 201 lmol), anhydrous
THF (16 mL), 3-methyl-1-butyne (927 mg, 13.6 mmol) and iPr2NH
(1.00 mL, 7.13 mmol) under argon. The flask was sealed and the
mixture was stirred magnetically in an oil bath thermostatted at
A mixture of Zn dust (51.6 mg, 789 lmol) and 29 (250 mg,
757 lmol) in AcOH (12 mL) was boiled for 37 h, adding further
zinc dust (145 mg, 2.22 mmol) in increments until TLC indicated
consumption of 29. The mixture was then cooled, filtered through
celite and evaporated to afford a residue that was partitioned
between EtOAc (30 mL) and saturated NaHCO3 solution (10 mL).
The organic phase was separated, washed with additional volumes
of NaHCO3 solution (2 × 10 mL) followed by brine (3 ×
10 mL), dried (Na2SO4) and evaporated. The resulting residue
was subjected to flash column chromatography (3 : 2 Et2O–
light petroleum) to afford the title compound (212 mg; 84%) as
a pale yellow powder: mp 129–130 ◦C (from petroleum 60–80 ◦C–
EtOAc); mmax(CHCl3 film)/cm−1 3019, 2975, 1670, 1634, 1523,
1496, 1357, 1216, 753, 669; dH (200 MHz; CDCl3) 1.42 (6 H, d, J
6.9, CH(CH3)2), 2.75–2.83 (2 H, complex m, CH2), 3.10–3.18 (2 H,
complex m, CH2), 3.52 (1 H, sept, J 6.9, CH(CH3)2), 6.78 (1 H, dt,
◦
80 C for 19 h [SAFETY SCREEN]. The flask was then cooled
and opened; the mixture was filtered and the filtrate evaporated to
afford a residue that was dissolved in EtOAc (15 mL). The resulting
solution was washed with water (2 × 10 mL) followed by brine (2 ×
10 mL), dried (Na2SO4) and evaporated. The residue was subjected
to flash column chromatography (1 : 1 Et2O–light petroleum
gradient elution). Fractions containing the target material were
evaporated to afford the title compound (1.22 g; 99%) as a buff
powder: mmax(KBr)/cm−1 3300, 3045, 2970, 2237, 1677, 1589, 1312,
1198, 1022, 851, 767, 692; dH (200 MHz; CDCl3) 1.26 (6 H, d, J
6.9, CH(CH3)2), 2.78 (1 H, sept, J 6.9, CH(CH3)2), 6.97 (1 H, d,
J 9.6, H-4), 7.26 (1 H, d, J 9.6, H-5), 7.33–7.59 (5 H, complex
overlapping m, Ph); dC (50 MHz; CDCl3) 21.2 (CH(CH3)2), 22.5
(CH(CH3)2), 75.2 (C≡CCH), 99.2 (C≡CCH), 125.7 (2× Ph ortho-
CH), 128.6 (Ph para-CH), 129.0 (2× Ph meta-CH), 130.7 (CH-4),
132.8 (C-6), 135.0 (CH-5), 141.4 (Ph CH), 159.0 (C-3); m/z (EI)
238 (65%, M+), 223 (29%, M+ − CH3), 209 (11%, M+ − C2H5),
J6 ,4 1.4, J6 ,5 6.9, J6 ,7 6.9, H-6ꢁ), 7.20 (1 H, ddd, J5 ,7 1.1, J5 ,6 6.8,
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J5 ,4 9.0, H-5ꢁ), 7.21–7.30 (1 H, complex m, Ph para-H), 7.37–7.46
ꢁ
ꢁ
(2 H, complex m, 2× Ph meta-H), 7.58–7.65 (2 H, complex m, 2×
Ph ortho-H), 7.80 (1 H, dt, J4 ,5 9.0, J4 ,6 1.2, J4 ,7 1.2, H-4ꢁ), 8.42
ꢁ
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(1 H, dt, J7 ,6 6.9, J7 ,5 1.1, J7 ,4 1.1, H-7ꢁ); dC (101 MHz; CDCl3)
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Org. Biomol. Chem., 2008, 6, 175–186 | 183
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22.8 (CH(CH3)2), 25.9 (CH2), 27.7 (CH(CH3)2), 28.5 (CH2), 105.2
(C-3ꢁ), 112.4 (CH-6ꢁ), 118.3 (CH-4ꢁ), 124.9 (2× Ph ortho-CH),
125.5 (CH), 126.5 (CH), 128.6 (2× Ph meta-CH), 129.0 (CH),
139.3 (C-3aꢁ), 141.4 (Ph C), 149.7 (C-6), 160.4 (C-2ꢁ), 165.4 (C-
3); m/z (EI) 332 (100%, M+), 303 (23%, M+ − C2H5); (found: C,
72.09; H, 5.99; N, 16.58; C20H20N4O requires C, 72.27; H, 6.06; N,
16.86%).
2-Benzyl-4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)phthalizin-
1(2H)-one (34)
A stirred mixture of 1-aminopyridinium mesitylenesulfonate12
(498 mg, 1.69 mmol), 33 (503 mg, 1.66 mmol) and powdered
K2CO3 (457 mg, 3.31 mmol) in DMF (16 mL) was heated at
100 ◦C for 20 h. Additional pyridinium salt (515 mg, 1.75 mmol)
and K2CO3 (470 mg, 3.40 mmol) were then added and heating
continued for a further 20 h. The mixture was then evaporated
to dryness and the resulting residue partitioned between EtOAc
(30 mL) and water (20 mL). The organic phase was separated,
washed with water (20 mL) followed by brine (2 × 20 mL),
dried (Na2SO4) and evaporated. The residue was subjected to flash
column chromatography (gradient elution from light petroleum to
1 : 9 Et2O–light petroleum), affording the starting alkyne (194 mg;
39%) followed by the title compound (262 mg; 40%) as a colourless
powder: mp 198–199 ◦C (from MeOH); mmax(KBr)/cm−1 3040,
2958, 1651, 1581, 1532, 1350, 1302, 1256, 1158, 992, 766, 702;
dH (200 MHz; CDCl3) 1.24 (3 H, d, J 6.9, CH(CH3)), 1.28 (3 H, d,
J 6.9, CH(CH3)), 3.11 (1 H, sept, CH(CH3)2), 5.36 (1 H, AB d, Jgem
13.8, CHHPh), 5.62 (1 H, AB d, Jgem 13.9, CHHPh), 6.77 (1 H,
2-Benzyl-4-chlorophthalazin-1(2H)-one (32)
Phthalazinedione 3117 (4.93 g, 19.5 mmol) was boiled in POCl3
(70 mL). After 5 h the POCl3 was removed by distillation. The
residue was dissolved in EtOAc (30 mL) and washed with saturated
NaHCO3 (3 × 30 mL). The organic layer was then washed with
brine (3 × 30 mL), dried (Na2SO4) and evaporated to give a brown
solid that was subjected to flash column chromatography (1 : 9
EtOAc–light petroleum) to afford the title compound (905 mg;
17%) as a colourless powder: mp 99–101 ◦C (from EtOH);
mmax(KBr)/cm−1 3033, 2958, 1656, 1578, 1495, 1344, 1295, 1128,
1074, 998, 767, 752, 682; dH (200 MHz; CDCl3) 5.37 (2 H, s,
CH2Ph), 7.26–7.38 (3 H, complex overlapping m), 7.46–7.52 (2 H,
complex m), 7.77–7.90 (2 H, complex overlapping m), 7.95–8.00
(1 H, complex m), 8.42–8.47 (1 H, complex m); dC (50 MHz;
CDCl3) 55.0 (CH2Ph), 125.8 (CH), 127.7 (CH + C), 128.1 (CH),
128.7 (2× CH), 128.9 (2× CH), 132.7 (CH), 133.8 (CH), 136.4
(2× C), 137.8 (C), 158.9 (C); m/z (EI) 270 (35Cl; 19%, M+), 235
ddd, J6 ,7 7.0, J6 ,5 5.9, J6 ,4 2.2, H-6ꢁ), 7.03–7.17 (2 H, complex
overlapping m), 7.23–7.38 (3 H, complex overlapping m), 7.45–
7.53 (3 H, complex overlapping m), 7.70 (1 H, td, J 7.2 and 1.6,
H-6 or H-7), 7.78 (1 H, td, J 7.2 and 1.4, H-6 or H-7), 8.49 (1 H,
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dt, J7 ,6 7.0, J7 ,5 1.0, J7 ,4 1.0, H-7ꢁ), 8.53–8.58 (1 H, complex
m, H-8); dC (50 MHz; CDCl3) 22.5 (CH(CH3)), 23.0 (CH(CH3)),
27.1 (CH(CH3)2), 54.9 (CH2Ph), 102.8 (C-3ꢁ), 111.9 (CH-6ꢁ), 116.8
(CH-4ꢁ), 124.5 (CH), 126.7 (CH), 127.5 (CH), 127.8 (CH), 128.5
(C), 128.6 (2× Ph CH), 128.8 (CH), 128.9 (2× Ph CH), 130.4 (C),
131.7 (CH), 133.1 (CH), 137.2 (C), 140.1 (C), 140.8 (C), 159.2 (C),
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(44%, M+ − Cl), 91 (38%, C7H7 ); (found: C, 66.50; H, 4.09; N,
+
10.14. C15H11ClN2O requires C, 66.55; H, 4.03; N, 10.35%).
2-Benzyl-4-(3-methylbut-1-ynyl)phthalazin-1(2H)-one (33)
160.8 (C); m/z (EI) 394 (100%, M+), 91 (56%, C7H7 ); (found: M+,
+
A sealable, heavy-walled flask (∼100 mL capacity) was charged
with 32 (3.07 g, 11.3 mmol), Bu4NI (4.39 g, 11.9 mmol), CuI
(141 mg, 740 lmol), Pd(PPh3)4 (524 mg, 453 lmol), anhydrous
THF (50 mL), 3-methyl-1-butyne (2.74 g, 40.2 mmol) and iPr2NH
(3.00 mL, 21.4 mmol). The flask was sealed and the mixture
stirred magnetically in an oil bath thermostatted at 80 ◦C for
21 h [SAFETY SCREEN]. The flask was then cooled and opened;
the mixture was evaporated to afford a residue that was dissolved
in CH2Cl2 (30 mL). The resulting solution was washed with water
(2 × 20 mL) followed by brine (2 × 20 mL), dried (Na2SO4)
and evaporated. The residue was subjected to flash column
chromatography (gradient elution from light petroleum to 1 : 9
EtOAc–light petroleum) to afford the title compound (3.12 g;
91%) as a colourless powder: mp 82–83 ◦C (from EtOAc–light
petroleum); mmax(KBr)/cm−1 3090, 2972, 2873, 2230, 1661, 1607,
1582, 1454, 1348, 1301, 1112, 778, 701; dH (200 MHz; CDCl3) 1.36
(6 H, d, J 6.9, CH(CH3)2), 2.92 (1 H, sept, J 6.9, CH(CH3)2), 5.41
(2 H, s, CH2Ph), 7.25–7.36 (3 H, complex overlapping m), 7.43–
7.50 (2 H, complex m), 7.70–7.86 (2 H, overlapping m), 7.99–8.04
(1 H, complex m), 8.37–8.42 (1 H, complex m, CH); dC (50 MHz;
CDCl3) 21.4 (CH(CH3)2), 22.7 (CH(CH3)2), 55.5 (CH2Ph), 73.6
(C≡CCH), 101.5 (C≡CCH), 126.4 (CH), 127.0 (CH), 127.6 (C),
127.8 (CH), 128.6 (2× Ph CH), 128.7 (2× Ph CH), 130.4 (C),
131.8 (CH), 132.7 (C), 133.4 (CH), 136.8 (C), 159.0 (C); m/z
394.1793. C25H22N4O requires 394.1778); (found: C, 75.78; H, 5.52;
N, 14.18. C25H22N4O requires C, 76.12; H, 5.62; N, 14.20%).
2-(3-Methylbut-1-ynyl)pyridine (35)
A sealable, heavy-walled flask (∼100 mL capacity) was charged
with CuI (1.08 g, 5.67 mmol), Pd(PPh3)4 (227 mg, 196 lmol),
anhydrous THF (50 mL), 2-bromopyridine (1.20 mL, 12.6 mmol),
i
3-methyl-1-butyne (1.08 g, 15.9 mmol) and Pr2NH (3.00 mL,
21.4 mmol). The flask was sealed and the mixture stirred mag-
netically in an oil bath thermostatted at 70 ◦C for 40 h [SAFETY
SCREEN]. The flask was then cooled and opened; the mixture
was evaporated to afford a residue that was partitioned between
CH2Cl2 (75 mL) and water (75 mL). The organic phase was
separated and washed with water (2 × 75 mL) followed by brine
(2 × 20 mL), dried (MgSO4) and evaporated. The residue was
subjected to flash column chromatography (15 : 40 : 45 CH2Cl2–
Et2O–pentane) to afford the title compound (750 mg; 41%) as
a pale yellow oil: mmax(neat)/cm−1 3053, 2972, 2933, 2235, 1584,
1464, 1428, 1322, 1149, 991, 780; dH (200 MHz; CDCl3) 1.25
(6 H, d, J 6.9, CH(CH3)2), 2.77 (1 H, sept, J 6.9, CH(CH3)2),
7.13 (1 H, ddd, J5,4 7.6, J5,6 4.9, J5,3 1.2, H-5), 7.33 (1 H, dt,
J3,4 7.8, J3,5 1.1, J3,6 1.1, H-3), 7.56 (1 H, td, J4,3 7.7, J4,5 7.7,
J4,6 1.8, H-4), 8.50 (1 H, ddd, J6,5 4.9, J6,4 1.7, J6.3 0.9, H-6);
dC (50 MHz; CDCl3) 21.0 (CH(CH3)2), 22.7 (CH(CH3)2), 79.6
(C≡CCH), 96.1 (C≡CCH), 122.3 (CH-5), 126.8 (CH-3), 136.1
(CH-4), 143.9 (C-2), 149.8 (CH-6); m/z (ESI) 146 (96%, M+ + H),
+
(EI) 302 (100%, M+), 287 (4%, M+ − CH3), 91 (40%, C7H7 ), 77
(9%, C6H5 ); (found: M+, 302.1451. C20H18N2Orequires 302.1419);
+
(found: C, 79.05; H, 5.89; N, 9.19. C20H18N2O requires C, 79.44; H,
6.00; N, 9.26%).
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130 (21%, M+ − CH3), 118 (93%, M+ − CHN), 78 (70%, C5H4N+);
fractions were combined, evaporated and the resulting residue
triturated with 2 : 1 CH2Cl2–Et2O to afford the title salt (146 mg;
39%) as a buff coloured powder: mmax(thin film)/cm−1 3019, 2972,
1632, 1530, 1216, 756, 754; dH (400 MHz; CDCl3) 1.23 (3 H, d, J
6.9, CHCH3), 1.30 (3 H, d, J 6.9, CHCH3), 2.97 (1 H, sept, J 6.9,
(found: M+, 145.0903. C10H11N requires 145.0892).
2-Isopropyl-3-(pyridin-2-yl)pyrazolo[1,5-a]pyridine (36)
A stirred mixture of 1-aminopyridinium mesitylenesulfonate12
(596 mg, 2.02 mmol), 35 (158 mg, 1.09 mmol) and powdered
K2CO3 (570 mg, 4.12 mmol) in DMF (12 mL) was heated at
80 ◦C for 40 h. The mixture was then evaporated to dryness
and the residue partitioned between EtOAc (20 mL) and water
(20 mL). The organic phase was separated, washed with brine
(20 mL), dried (MgSO4) and evaporated. The resulting residue was
subjected to flash column chromatography (gradient elution from
light petroleum to 7 : 3 EtOAc–light petroleum) to recover starting
alkyne (83.0 mg; 53%) and afford the title compound (24.6 mg;
10%) as a pale yellow powder: mp 82–83 ◦C (from CHCl3–hexane),
mmax(thin film)/cm−1 3019, 2972, 1635, 1590, 1533, 1216, 756, 669;
dH (400 MHz; CDCl3) 1.42 (6 H, d, J 6.9, CH(CH3)2), 3.63 (1 H,
sept, J 6.9, CH(CH3)2), 6.75 (1 H, td, J6,5 6.9, J6,7 6.9, J6,4 1.4, H-6),
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CH(CH3)2), 4.30 (3 H, s, NMe), 6.94 (1 H, td, J6 ,5 6.9, J6 ,7 6.9,
J6 ,4 1.3, H-6ꢁ), 7.36 (1 H, ddd, J5 ,4 8.9, J5 ,6 6.9, J5 ,7 1.1, H-5ꢁ),
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7.71 (1 H, dt, J4 ,5 8.9, J4 ,6 1.1, H-4ꢁ), 7.87 (1 H, dd, J3,4 7.9, J3,5
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1.4, H-3), 8.14 (1 H, ddd, J5,4 7.7, J5,6 6.3, J5,3 1.4, H-5), 8.48 (1 H,
d6, J7 6, 7.0, J7 ,4 1.0, J7 ,5 1.0, H-7ꢁ), 8.55 (1 H, td, J4,3 7.9, J4,5
7.9, J4,6 1.2, H-4), 9.62 (1 H, br d, J6,5 6.2, H-6); dC (101 MHz;
CDCl3) 22.6 (CHCH3), 22.9 (CHCH3), 27.0 (CH(CH3)2), 47.2
(NMe), 98.9 (C-3ꢁ), 113.7 (CH-6ꢁ), 117.0 (CH-4ꢁ), 126.9 (CH-
5), 127.6 (CH-5ꢁ), 129.2 (CH-7ꢁ), 131.5 (CH-3), 139.3 (C-3aꢁ),
145.2 (CH-4), 148.5 (CH-6), 149.3 (C-2), 159.9 (C-2ꢁ); m/z
(+ve ion ESI) 252 (100%, C16H18N+); m/z (−ve ion ESI) 127
(100%, I−); (found: organic cation, 252.1494. C16H18N+ requires
252.1495).¶¶
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7.13–7.17 (2 H, overlapping m, H-5 and H-5ꢁ), 7.48 (1 H, br d, J3 ,4
ꢁ
ꢁ
8.0, H-3ꢁ), 7.74 (1 H, td, J4 ,3 7.8, J4 ,5 7.8, J4 ,6 1.9, H-4 ), 7.91 (1 H,
ꢁ
Acknowledgements
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dt, J4,5 9.0, J4,6 1.2, J4,6 1.7, H-4), 8.44 (1 H, dt, J7,6 7.0, J7,4 1.1, J7,5
We thank the EPSRC Mass Spectrometry Centre at Swansea for
mass spectra.
1.1, H-7), 8.71 (1 H, br d, J6 ,5 4.8, H-6ꢁ); dC (101 MHz; CDCl3)
22.9 (CH(CH3)2), 26.7 (CH(CH3)2), 109.2 (C-3), 112.0 (CH-6),
118.1 (CH-4), 120.5 (CH-5ꢁ), 123.0 (CH-3ꢁ), 124.6 (CH-5), 128.6
(CH-7), 136.4 (CH-4ꢁ), 139.6 (C-3a), 149.9 (CH-6ꢁ), 153.8 (C-2ꢁ),
159.5 (C-2); m/z (EI) 237 (91%, M+), 236 (100%, M+ − H), 222
(74%, M+ − CH3), 194 (26%, M+ − C3H7), 78 (16%, C5H4N+);
(found: M+, 237.1252. C15H15N3 requires 237.1266); (found: C,
75.97; H, 6.34; N, 17.65. C15H15N3 requires C, 75.92; H, 6.37; N,
17.71%).‡,¶¶
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Notes and references
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1-Methyl-2-(3-methylbut-1-ynyl)pyridinium iodide (37)
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1.38 mmol) in dry THF (2 mL) was heated at 60 ◦C for 1.5 h.
Upon cooling and standing the mixture separated into two phases.
The upper phase was decanted off and the lower phase pumped
(0.1 mm Hg) to afford the title salt (283 mg; 72%) as a brown oil:
mmax(neat)/cm−1 3041, 2974, 2223, 1618, 1509, 1457, 1270, 1180,
754; dH (200 MHz; CDCl3) 1.21 (6 H, d, J 6.9, CH(CH3)2), 2.87
(1 H, sept, J 6.9, CH(CH3)2), 4.42 (3 H, s, NCH3), 7.89–8.00
(2 H, overlapping m, H-3 and H-5), 8.52 (1 H, br td, J4,3 8.0, J4,5
8.0, J4,6 0.8, H-4), 9.42 (1 H, br d, J6,5 5.7, H-6); dC (50 MHz;
CDCl3) 21.6 (CH(CH3)2), 21.7 (CH(CH3)2), 47.9 (NCH3), 71.4
(C≡CCH), 117.0 (C≡CCH), 126.6 (CH), 131.5 (CH), 138.0 (C-
2), 145.3 (CH-4), 147.2 (CH-6); m/z (+ve ion ESI) 160 (100%,
C11H14N+), 117 (22%, C11H14N+ − C3H7); m/z (−ve ion ESI) 127
(100%, I−); (found: organic cation, 160.1120. C11H14N+ requires
160.1121).¶¶
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