Preparation, X-ray structure and propylaminolysis of 7,7-dichloro-5,7- dihydro-thieno[3,4-b]pyridin-5-one

Article abstract of DOI:10.3184/030823407X225392

Refluxing 2-methylpyridine-3-carboxylic acid with thionyl chloride for 6-7 h gave (～50%) title compound dichlorothienolactone 2 as was confirmed by a X-ray structure analysis. The propylaminolysis of 2 provides a new and convenient access to highly functi

Full text of DOI:10.3184/030823407X225392

JOURNAL OF CHEMICAL RESEARCH 2007
JUNE, 373–376
RESEARCH PAPER 373
Preparation, X-ray structure and propylaminolysis of 7,7-dichloro-
5,7-dihydro-thieno[3,4-b]pyridin-5-one
Theodorus van Esa, Benjamin Staskunb,c* and Manuel A. Fernandesb
aDepartment of Biochemistry and Microbiology, Cook College, Rutgers, The State University of New Jersey, 08903-0231, USA
bSchool of Chemistry, University of the Witwatersrand, P.O.Wits, 2050, South Africa
cHonorary Associate, Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW 2109, Australia
Refluxing 2-methylpyridine-3-carboxylic acid with thionyl chloride for 6–7 h gave (~50%) title compound
dichlorothienolactone 2 as was confirmed by a X-ray structure analysis. The propylaminolysis of 2 provides a new
and convenient access to highly functionalised pyrrolo[3,4-b]pyridine derivatives.
Keywords: 7,7-dichloro-5,7-dihydrothieno[3,4-b]pyridin-5-one, X-ray structure, 3,3-dichloro-4-ethylthieno[3,4-b]quinoline-1,
9-dione, derivatives, reaction mechanisms
The alkylaminolysis of 3,3,9-trichlorothieno[3,4-b]quinolin-
1-one 1 is a convenient new methodology for accessing
highly functionalised pyrrolo[3,4-b]quinoline derivatives.1
Here we describe the preparation and structure of a
hitherto undocumented pyridine analogue of 1, namely,
title compound 2, and the outcomes stemming from its
propylaminolysis which offers an alternate and convenient
access to a variety of functionalised pyrrolo[3,4-b]pyridine
derivatives. Of the 10 isomeric methylpyridinecarboxylic
acds, six cannot be converted by thionyl chloride to a
corresponding dichlorothiolactone derivative owing to
structural considerations. To date, only 4-methylpyridine-
3-carboxylic acd has provided such a compound, namely 3,2
while from 2,6-dimethyl-4-(3-thieny)pyridine-3,5-dicarb-
oxylicacd was obtained the dichlorothiolactone product
5.3 The product(s) generally isolated from the various
methylpyridinecarboxylic acds has/(have) been either the
appropriate methylpyridinecarboxylic acd chloride4 and/or
other chlorinated material.5,6 There is, however, a dearth of
relevant follow-up research in this area.
Here, we show that refluxing (79°C) 2-methylpyridine-
3-carboxylic acd with (excess of) SOCl2 affords title
dichlorothiolactone derivative 2, the yield increasing to
~56% after 6 h, via initial production of 2-methylpyridine-3-
carboxylic acd chloride 4 which transforms during heating
with the reagent to end-product 2. It is noteworthy that little
if any change is effected on 4 at 50°C for 5 h4 or at 60°C for
3.5 h. Structure 2 was unambiguously established from X-ray
crystallographic analysis (Fig.1).
Fig.1 Ortep diagram (50% ellipsoids) for 2, showing the
labelling of the non-hydrogen atoms.
Mechanistic considerations
We currently assume that dichlorothiolactone 2 forms
via mechanistic events similar to those proposed2 for
dichlorothiolactone 3 and likewise involve the production
and intramolecular cyclisation of an appropriate thioacyl
chloride intermediate 11 (from 2-methylpyridine-3-carbonyl
chloride 4, Scheme 3A). An additional and crucal factor
in the reactions of both the 2- and 4-methylpyridine-3-
carboxylic acds with SOCl2 in forming 2 and 3, respectively,
may be considered, viz., a tautomerism in the initially
formed acd chloride, corresponding to the enolisation8 in 3-
phenylpropanoyl chloride, thereby faclitating the addition of
SOCl2 to a methylene double bond8 and the production of a
thioacyl intermediate (Scheme 3A).
Compound
2
when treated with propylamine (as
representative amine) provided different products, the
nature and yields of which were determined by the reaction
conditions: Thus: (i) stirring 2 with PrNH2 (in slight molar
excess) in dioxan solution at 0°C for a relatively short time
(~20 min), gave (67%) N-propyl-2-[(propylamino)thioxo-
methyl]pyridine-3-carboxamide 6 (Scheme 1), while (ii)
stirring 2 with neat propylamine (in large molar excess) at room
temperature for 12 h provided (68%) 6-propyl-6,7-dihydro-7-
(propylimino)pyrrolo[3,4-b]pyridin-5-one 7 as end-product. In
subsequent transformations: (i) acd-catalysed cyclisation of
6 gave 6-propyl-6,7-dihydro-7-thioxopyrrolo[3,4-b]pyridin-
5-one 8, (ii) propylamine converted compounds 6 and 8
each to end-product 7, and (iii) acd hydrolysis of 7 gave
(85%) 6-propyl-6,7-dihydropyrrolo[3,4-b]pyridine-5,7-dione 9.
Possible reaction transformations and sequences giving rise to
the aforementioned transformations are outlined in Scheme 2.
The known7 thieno[3,4-b]pyridine-5,7-dione 10 was isolated
from the mother liquor of crystallisation of title compound 2.
Although the Wenkert2 mechanism shows no role for the
pyridine N, an imine-enamine tautomerism also may be
envisaged to complement/replace the aforementioned one
(Scheme 3B). However, this possibility is unlikely in the
instance of 1-ethyl-2-methyl-4-oxoquinoline-3-carboxylic
acd 12 which with SOCl2 yields the 3,3-dichlorothieno[3,4-b]
quinoline derivative 17 (Scheme 3B) at room temp.9 It is
noteworthy that 17 forms more readily than does 2, on account
perhaps of more tautomeric possibilities being available in
carboxylic acd chloride 13.
Consideration of the above suggested the following
possibilities: (i) were 2-methyl-3-nitrobenzoyl chloride to
exhibit the requisite tautomerism(s), its reaction with SOCl2
might result in the novel dichlorothiolactone derivative 19
(Scheme 3C). (ii) Imidoyl chloride 20 bears a close structural
and chemical reactivity relationship to acd chloride 13,
and in reaction with SOCl2 might provide the unusual 3,3-
dichloro-1-phenylimino-thieno[3,4-b]quinoline derivative 18
(Scheme 3B).
* Correspondent. E-mail: benmina@optusnet.com.au
PAPER: 07/4595

374 JOURNAL OF CHEMICAL RESEARCH 2007
Cl
O
O
O
Pr
Cl
Cl
O
Pr
O
S
8
5
9
4
N
-HCl
PrNH2
N
H
Cl
1
5
S
7
S
H
O
S
SH
Cl
N
N
N
Cl
Cl
3
Cl
N
S
N
1
N
Cl
Cl
Cl
Cl
1
2
PrNH2
-HCl
1
2
3
S
O
O
O
N
O
O
Pr
Pr
H
O
N
O
3
H
3
N
Pr
N
Pr
H
Cl
N
N
O
H
2
2
N
N
N
N
S
N
1
N
1
S
S
Pr
H
N
S
4
-H2S
Cl
Cl
O
6
8
6
7
5
-PrNH2
O
O
4
O
4
PrNH2
4
5
5
N
Pr
N
7
Pr
N
Pr
N
Pr
Pr
7
N
1
N
N
N
1
1
N
N
H
S
O
Pr
HS
7
8
9
O
Scheme 2
4
O
OH
10
S
O
N
1
Cl
Cl
S
O
Cl
(A)
(B)
2
N
N
N
Scheme 1
Cl
Cl
O
4
11
O
The experimental outcomes were as follows: (i) Refluxing
(79°C) a mixture of 2-methyl-3-nitrobenzoic acd, SOCl2
and pyridine catalyst (the latter to promote8 enolisation/
tautomerism in the anticpated acd chloride) for up to
65 h merely furnished (>90%) 2-methyl-3-nitrobenzoyl
chloride, indicative perhaps of the absence of the requisite
tautomerism(s) in this particular acd chloride. (ii) 1-
Ethyl-1,4-dihydro-2-methyl-4-oxo-N-phenylquinoline-3-
carboxamide 14 was selected for in situ conversion in SOCl2
to the representative imidoyl chloride 20 and was prepared as
follows: Acd 12 was reacted with 1,11-carbonyldiimidazole10
in DMF to form acylimidazole 21. Heating (~120°C) the latter
with aniline provided anilide 14 [in comparison to forming
the N-methyl carboxamide 15 from 21 and (the more basic)
methylamine at room temperature].
It was found that acylimidazole 21 itself reacted with
SOCl2 to give dichlorothiolactone 17 at room temperature,
and trichlorothiolactone 1 at reflux temperature, the outcomes
presumably stemming from initial production of acd chloride
13 followed on by the Wenkert2 events (Scheme 3). In
support, acd chloride 13 was formed when hydrogen chloride
was bubbled into a dioxan solution of acylimidazole 21 at
room temperature. A similar explanation accounts also for the
production of trichlorothiolactone 1 on refluxing methyl ester
16 with SOCl2.
O
N
X
O
Cl
R
S
N
N
H
Cl
Cl
15 R=NHMe
16 R=OMe
17 X=O
12 R=OH
13 R=Cl
18 X=NC6H5
14 R=NHC6C5
O
O
O
1
Cl
Cl
S
(C)
2
3
Cl
Cl
N
O
N
N
OH
O
O
O
O
19
O
N
O
NC6H5
O
Cl
N
(D)
N
N
20
21
Scheme 3
events leading to 22 is outlined in Scheme 4, but details of
this reaction remain to be clarified.
Contrary to expectations, anilide 14 on heating (79°C) with
SOCl2 for 2.5 h furnished 9-chloro-2-phenylpyrrolo[3,4-b]
quinoline-1,3-dione 22 (53%) as major product. The MS
of the 22 contained a minor peak at m/z 324 attributable to
a proposed thioxo intermediate 23 (Scheme 4). With the
knowledge that dichlorothienolactone 17 will form prior to
trichlorothienolactone 1,9 and that the MS of the (the slightly
impure) 22 contained a minor peak at m/z 324 attributable to
a (proposed) thioxo intermediate 23 a tentative sequence of
In summary, the recently developed aminolysis
methodology1 with 2-methylquinoline-3-carboxylic acds has
been extended to a pyridine analogue viz., 2-methylpyridine-3-
carboxylic acd to now provide an alternative and convenient
access to highly functionalised thieno- and pyrrolo[3,4-b]
pyridine derivatives suitable for further synthetic procedures
and biological testing.
PAPER: 07/4595

JOURNAL OF CHEMICAL RESEARCH 2007 375
O
temperature. The comparatively pure title product was filtered off
(80 mg, 67%) and crystallised from EtOAc/hexane; m.p. 69–70°C.
δH 0.94 (3H, t J = 7.4), 1.05 (3H, t, J = 7.4), 1.65 (2H, m), 1.76 (2H,
m), 3.35 (2H, m), 3.75 (2H,m), 7.53 (1H,m), 8.0–8.2 (~3H, m), 8.6
(1H, m). Found: C,58.43; H,7.12; N, 15.42; m/z 265 (M+, 20%), 206
[M-59, 100%), corresponding (to loss of propylamine) to thioxo
derivative 8]. C13H19N3OS requires C, 58.84; H, 7.22; N, 15.84%; M,
265. Acd-sensative 6 underwent cyclisation to thiolactone 8 in the
course of chromatography on (acdic) silica gel (vide infra).
O
N
NHC6H5
Cl
SOCl2
14
S
6-Propyl-5,7-dihydro-7-(propylimino)pyrrolo[3,4-b]pyridin-5-one
7: Dichloro compound 2 (313 mg, 1.42 mmol) was slowly added
(over ~ 10 min) with stirring to neat propylamine (5 ml) cooled in
ice. The solution was kept at room temperature overnight and treated
with CHCl3/H2O. Evaporation of the CHCl3 extract gave (crude) title
compound 7 (320 mg), which were washed with hexane (cooled to –
80°C) to provide crystals (100 mg) of 7, m.p. 43–44°C; concentration
of the mother liquor and chilling to ~80°C afforded a further 125 mg
of product 7 (total yield, 225 mg, 69%). δH 0.94 (3H,t, J = 7.5), 1.01
(3H, t, J = 7.4), 1.71 (2H, m), 1.78 (2H, m), 3.81 (2H,t, J = 7.3), 4.43
(2H, t, J = 7.0), 7.46 (1H, m, 3-H), 8.14 (1H, m, 2-H), 8.85 (1H,m,
4-H). Found: C, 67.33; H, 7.35; N, 17.81; m/z 231, M+, 100%; 216,
M-15, 35%; 202, M-29, 40%, 174, M-57, 50%. C13H17N3O requires
C, 67.51; H, 7.41; N, 18.17%; M, 231.
O
Cl
N
O
O
N
C6H5
N
C6H5
N
S
X
22 X=O
23 X=S
Scheme 4
6-Propyl-5,7-dihydro-7-thioxopyrrolo[3,4-b]pyridin-5-one 8: (a)
A mixture of amide 6 (43 mg, 0.16 mmol) and 2 ml glacal HOAc was
warmed at 50°C for 30 min. The solution was diluted with ice-H2O
and the red (crude 8) solid which had separated (30 mg, 90%) was
collected by filtration and crystallised from EtOAc (m.p.103–104°C).
δH 0.99 (3H, t, J = 7.4), 1.79 (2H, sextet), 4.09 (2H, t, J = 7.4), 7.62
(1H, m, 3-H), 8.13 (1H, m, 2-H), 8.96 (1H, m, 4-H). Found: C, 57.86;
H,4.76; N, 13.21%; m/z, 206(M+, 100%), 191 (M-15, 20%),178
(M-28, 35%). C10H10N2OS requires C,58.23; H, 4.89; N, 13.58%;
M, 206.
(b) Dichlorolactone 2 (550 mg, 2.49 mmol) was added over 5 min
in portions to ice-cold stirred propylamine (5 ml) and the reaction
continued for a further 15 min. following addition of CHCl3/H2O,
the CHCl3 extract was dried and evaporated to a residue (690 mg)
which was applied to a column (silica gel, 15% acetone in benzene)
to give imine 7 (94 mg, 16%), crystals from hexane, m.p. 43–44°C)
and title compound 8 (244 mg, 48%), crystals from EtOAc/hexane,
m.p. 103–104°C). Also eluted (74 mg, 11%) was amide 6.
Experimental
General procedure
Melting points were recorded on a hot-stage microscope apparatus
and are uncorrected. TLC was performed on aluminium-backed
plates, precoated with 0.25 mm silica gel. Column chromatography
was carried out on silica gel. HPLC solvent generally used to elute:
hexane: isopropyl alcohol; 450:50. 1H NMR spectra were determined
in CDCl3 using a Bruker DRX (399.900 MHz specrometer. J values
are in Hz. High-resolution mass spectra were recorded on a VG 70
SEQ mass spectrometer. Extracts were dried over anhydrous sodium
sulfate.
Several of the compounds formed in the propylaminolysis
reaction(s) were very similar by TLC while analytical HPLC showed
a number of compounds to have similar retention times. Therefore
several of the compounds were difficult to separate cleanly by column
(silica gel) chromatography. Moreover, several of the products
such as thioamide 6 and thioxo derivative 8 reacted further with
propylamine (and at different rates). Accordingly, in order to isolate
a specfic product, reaction conditions such as time, temperature and
concentration, had to be manipulated to afford the desired compound
in satisfactory yield. We have not attempted to optimise yields in
every instance.
7,7-Dichloro-5,7-dihydrothieno[3,4-b]pyridin-5-one 2: A mixture
of 2-methylpyridine-3-carboxylic acd (548 mg, 4.0 mmol) and
thionyl chloride (5 ml) was refluxed (79°C) for various periods up to
24 h with TLC monitoring. The reaction mixture from 6.5 h estimated
as containing an optimum yield of 2 was evaporated and the residue
kept in a a vacuum dessicator (over solid KOH) to ensure the removal
of all the SOCl2. The crude material (~750 mg) was applied to a silica
gel column using 15% acetone/benzene to obtain title compound
2 (412 mg, 1.87 mmol, 47%). Crystals (from EtOAc/hexane),
m.p. 154–155°C. δH 7.60 (1H, m), 8.15 (1H, m), 9.06 (1H, m). Found:
C,37.99; H, 1.50; N,6.17. C7H3Cl2NOS requires C, 38.20; H, 1.37;
N, 6.36%. Also isolated from the column was 80 mg of thiolactone
10 (vide infra).
2-Methylpyridine-3-carbonyl chloride 4: Keeping a mixture of
2-methylpyridine-3-carboxylic acd (140 mg, 1.02 mmol) and SOCl2
(5 ml) at 0°C, at room temperature up to 24 h, or even at 60°C for
5 h, followed by evaporation, gave in each instance, a residue of the
known4 title compound 4 as evidenced by treatment with methanol to
form the methyl ester, identical (TLC) with authentic (commercal)
ester. Refluxing (79°C) 4 with SOCl2 for an extended time provided
dichlorothiolactone 2 (vide supra).
Preparation of 6-Propyl-5,7-dihydropyrrolo[3,4-b]pyridine-5,7-
dione 9: A solution of propylimino compound
7 (156 mg,
0.68 mmol) in (1:1) glacal HOAc/H2O (3 ml) was kept overnight at
room temperature after which the reaction was allowed to evaporate.
The residue was treated with H2O and the crude title product 9 was
collected by filtration (110 mg, 85%). Crystals from EtOAc/hexane,
m.p. 100–101°C. δH 0.96 (3H, t, J = 7.4), 1.73 (2H, sextet, J = 7.4),
3.72 (2H, t, J = 7.4), 7.61 (1H, m, 3-H), 8.16 (1H, m, 2-H), 8.96 (1H,
m, 4-H). Found: C, 62.90; H, 5.34; N, 14.45; m/z 190 (M+, 60%, 161
(M-29, 100%). C10H10N2O2 requires C, 63.15; H, 5.30; N, 14.73%;
M, 190.
Thieno[3,4-b]pyridine-5,7-dione 10: The mother liquor of
crystallised 2 (vide supra) was evaporated and the residue applied to
a silica gel column (15% acetone in benzene). Appropriate fractions
were combined and evaporated to obtain 10. Crystals (from EtOAc/
hexane); m.p. 84–86°C (lit7. m.p. 91°C). Found: m/z 165, (M+, 100%,
105, 90%, 77, 90%). C7H3NO2S requires M, 165.
Effect of SOCl2 on 2-Methyl-3-nitrobenzoic acd: A mixture
of the (commercal) acd (0.50 g, 2.76 mmol), SOCl2 (5 ml) and
pyridine catalyst (several drops) was refluxed for ~65 h [with TLC
(benzene) monitoring]. Exhaustive evaporation of solvent (under
vacuo) yielded a residue (450 mg, TLC benzene; one spot) of (crude)
2-methyl-3-nitro-benzoyl chloride, m.p. 59–60°C. Lassaigne sodium
fusion: positive for Cl, negative for S. Treatment of the product with
H2O in dioxan gave crystals of (crude) title acd, m.p. 179–181°C.,
mixture m.p. with substrate acd unchanged). Warming the acd
chloride product with methanol formed the methyl ester; crystals
(from EtOAc/hexane), m.p. 64°C. In each instance the product m.p.
corresponded to the literature value.
1-Ethyl-1,4-dihydro-2-methyl-4-oxoquinolin-3-oyl-N-imidazole:
21: A stirred mixture of acd 1211 (909 mg, 3.94 mmol), 1,11-
carbonyldiimidazole10 (910 mg, 5.48 mmol) and DMF (5 ml) was
heated at 100°C for 2 h and afterwards chilled in ice. The precpitate
was collected, washed with EtOAc and then with Et2O, and dried in
vacuo to provide crude acylimidazole derivative 21 (960 mg, 87%).
Crystals (from CHCl3/EtOAc), mp 236°C. δH 1.60 (3H, t, J = 7.2),
2.68 (3H, s), 4.43 (2H, q, J = 7.2), 7.38 (1H, m), 7.54 (1H, m), 7.65
(1H, m), 7.78 (1H, m), 7.83 (1H, m), 8.39 (1H, m), 8.84 (1H, m).
N-Propyl-2-[(propylamino)thioxomethyl]pyridine-3-carboxamide
6: The reaction of 2 in neat propylamine is comparatively fast and
results in mixtures of 6, 7 and 8 and, eventually in end-product, 7 (vide
infra). To prepare title compound 6 the reaction rate was reduced by
conducting the propylaminolysis in 10% w/w propylamine in dioxan,
at 0°C: 1.20 g PrNH2/dioxan solution (120 mg PrNH2, 2.0 mmol)
cooled in ice was slowly added with stirring to dichlorothiolactone 2
(100 mg, 0.45 mmol). The reaction progress was monitored by TLC
(solvent), and after 20 min (when the yield of 6 was estimated as
optimum) the reaction was extracted with CHCl3/H2O. Evaporation
of the CHCl3 under reduced pressure and temperature gave crude
title compound 6 (120 mg.) which was stirred with hexane at room
PAPER: 07/4595

376 JOURNAL OF CHEMICAL RESEARCH 2007
Found: C, 68.84; H, 5.42; N, 14.86. C16H15N3O2 requires: C, 68.31;
H, 5.37; N, 14.94.
of width 0.3°. Data reduction was carried out using the program
SAINT + (Bruker, 1999).12 The crystal structure was solved by
direct methods using SHELXTL (Bruker, 1999).13 Diagrams and
publication material were generated using SHELXTL and PLATON
+(Spek, 2003).14
1-Ethyl-1,4-dihydro-2,N-dimethyl-4-oxoquinoline-3-carboxamide
15: A mixture of acylimidazole 21 (500 mg, 1.78 mmol) and
methylamine gas (1.0 g, ~ 30 mmol) dissolved in DMF (6 ml) was
stirred at room temperature for 3 h. The resulting reaction was chilled
in ice, and the solid was collected and washed with EtOAc to give
the crude title amide 15 (390 mg, 90%). Crystals (from EtOAc), m.p.
220°C. Found: C, 68.69; H, 6.57; N, 11.37. C14H16N2O2 requires: C,
68.79; H, 6.60; N, 11.47%.
1-Ethyl-1,4-dihydro-2-methyl-4-oxo-N-phenylquinoline-3-
carboxamide 14:Amixture of acylimidazole 21 (319 mg, 1.14 mmol),
aniline (197 mg, 2.1 mmol) and pyridine catalyst (1.5 ml) was heated
(~120°C) for 24 h. The reaction was evaporated under reduced
pressure and the residue (190 mg, 54%) of crude title amide 14 was
crystallised from methanol; m.p. 214–215°C. Found: C,74.27; H,
6.00; N, 9.14. C19H18N2O2 requires C, 74.49; H, 5.92; N, 9.14%.
3,3-Dichloro-4-ethylthieno[3,4-b]quinoline-1,9-dione 17 from
SOCl2 acting on acylimidazole 21: A mixture of 21 (325 mg,
1.16 mmol) and SOCl2 (5 ml) was stirred at room temperature
with TLC monitoring which revealed a slow transformation of 21
to dichlorothiolactone 17 accompanied by increasing darkening
of the reaction. After 4 days the solution was evaporated and the
residue was washed with aqueous NaHCO3, and extracted into
CHCl3. Evaporation gave a dark, tarry solid (230 mg) which was
chromatographed (silica gel, 20% EtOAc/CHCl3) to obtain 17
(150 mg, 48%), m.p. 187–189°C, identified by comparison (mixture
m.p., TLC and HPLC) with authentic9 compound 17.
3,3,9-Trichlorothieno[3,4-b]quinolin-1-one 1 from SOCl2 acting
on acylimidazole 21 and on methyl ester 16: A mixture of 21 (330
mg, 1.17 mmol) and SOCl2 (5 ml) was refluxed for 1.5 h. Evaporation
gave a residue which was extracted into CHCl3. Removal of solvent
gave a dark gummy material which was extracted with boiling EtOAc
to give crystals of title compound 1 (200 mg, 56%), m.p. 200–202°C
(from dioxan), identified by mixture m.p., TLC and HPLC comparison
with authentic9 1: Refluxing a mixture of methyl ester 16 (150 mg,
0.61 mmol) and SOCl2 (5 ml) for 1.5 h also provided thiolactone 1
(30 mg, 16%), m.p. 198–201°C, likewise identified
Action of hydrogen chloride on acylimidazole 21: Acylimidazole
21 (51 mg, 0.18 mmol) was added with stirring to a dioxan solution
[10 ml, containing ~10% (by weight) hydrogen chloride gas].
Monitoring of the reaction (at room temperature) by TLC (30%
acetone and 5% Et3N in benzene) showed little remaining substrate
21 after ~10 min. The sticky product which had separated was
filtered (45 mg) and treated with aqueous NaHCO3 to provide acd 12
(25 mg, 60%) and some unchanged acylimidazole 21.
Crystal data for 2.
EF C7H3Cl2NOS, FW 220.06, crystal system: orthorhombic, space
group: Pnma, unit cell dimensions: a = 11.407(2)Å, b = 6.861(5)Å,
c = 10.382(2)Å, volume: 812.5(6)Å3, Z = 4, Dcalc = 1.799 Mg m-3,
μ = 0.996 mm-1, T = 293(2)K, F(000) = 440, crystal size = 0.40 ¥
0.27 ¥ 0.22 mm, unique reflections 1062[R(int) = 0.0226]. The final
refinement converged to R1 = 0.0298 and wR2 = 0.0726 for observed
data and R1 = 0.0341, wr2 = 0.756 for all data with residuals (max.
peak/hole) of 0.486 and –0.348 eÅ-3. Full crystallographic details for
structure 2 have been deposited at the Cambridge Crystallographic
Data Centre (deposition number: CCDC 640183). Any request to the
CCDC for this material should quote the full literature ctation.
The authors thank Dr Isla Hains for the acquisition of the
1H NMR spectra.
Received 15 March 2007; accepted 12 June 2007
Paper 07/4595 doi: 10.3184/030823407X225392
References
1
T. van Es, B. Staskun and S. van Vuuren, S. Afr. J. Chem., 2005, 58, 74,
and refs therein.
2
3
E. Wenkert, F. Haglid and S.L. Mueller, J. Org. Chem., 1969, 34, 247.
F. Heude, M. Cugnon de Sevricourt, S. Rault and M. Robba, Heterocycles,
1987, 26, 1535.
4
5
6
See for example: N. Douja, M. Besson, P. Gallezot and C. Pinel, J. Mol.
Catalysis A: Chemical, 2002, 186, 145.
H. Vörbruggen, Advances in Heterocyclic Chemistry, Ed. A.R. Katritzky,
1990, 9,129. Academic Press, San Diego.
More recently, K. Nagarajan, P.J. Rodrigues, M. Nethaji, M. Vohler
and W. von Philipsborn, Helv. Chimica. Acta., 1994, 77, 155, claim
that 4-methylpyridine-3-carboxylic acd and SOCl2 stirred at 0°C for
6 h and then kept at 30°C for 14 h followed by filtration of the mixture
and evaporation of the filtrate at 90°C in vacuo gave (>50%) crude
4-chloromethypyridine-3-carboxylic acd chloride; no mention is made of
thiolactone 32.
7
A. Bigotto, V. Galasso, F.P. Colonna, G. Distefano, G.C. Pappalardo and
G. Scarlata, J. Chem. Soc., Perkin Trans.2., 1978, 1194.
A.J. Krubsack and T. Higa, Tetrahedron Lett., 1968, 49, 5149.
D.C. Levendis, J. Moffit, B. Staskun and T. van Es, J. Chem. Research(S),
1999, 614.
9-Chloro-2-phenylpyrrolo[3,4-b]quinoline-1,3-dione 22: A mixture
of N-phenylquinoline-3-carboxamide 14 (116 mg, 0.38 mmol) and
SOCl2 (5 ml) was refluxed for 2.5 h. Evaporation gave a residue
which was chromatographed (silica gel, 10% acetone in CHCl3) to
give (62 mg, 53%) product 22 containing minor impurities. Crystals
(from EtOAc), m.p.242–244°C. δH 7.45–7.60 (5H, m), 7.91 (1H, m),
8.03 (1H, m), 8.48 (1H, m), 8.55 (1H, m). Found: m/z 308 (100%,
Cl isotopic ratio, ~3:1), 324 (~5%,Cl isotopic ratio: ca 3:1). M,
308.03587. C17H9ClN2O2 requires: M, 308.03525.
8
9
10 M.P. Wentland, R.B. Perni, P.H. Dorff, R.P. Brundage, M.J. Castaldi,
T.R. Bailey, P.M. Carabateas, E.R. Bacon, D.C. Young, M.G. Woods,
D. Rosi, M.L. Drozd, R.K. Kullnig and F.J. Dutko, J. Med. Chem., 1993,
36, 1580.
11 T. van Es and B. Staskun, S. Afr. J. Chem., 1998, 51, 121.
12 Bruker (1999). SAINT + . Version 6.02 (includes XPREP and SADABS).
Bruker AXS Inc., Madison, Wisconsin, USA.
X-ray crystallographic analysis for 2
Intensity data were collected on a Bruker SMART IK CCD area
detector diffractometer with graphite monochromatated Mo Kα
radiation (50kV, 30 mA). The collection method involved ω-scans
13 Bruker (1999). SHELXTL. Version 5.1. (includes XS, Xl, XP, XSHELL)
Bruker AXS Inc., Madison, Wisconsin, USA.
14 A.L. Spek, J. Appl. Cryst. 2003, 36, 7.
PAPER: 07/4595