A facile, scalable preparation of 4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbonitriles

Article abstract of DOI:10.1016/j.tetlet.2008.09.107

We report a new synthesis of thieno[2,3-b]pyridine-5-carbonitriles from 2-aminothiophene-3-carboxylate esters. The key step of the synthesis is a thermally promoted elimination/decarboxylation followed by nucleophilic cyclization to give 4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbonitriles. The reactions proceed in good yield and generally require no chromatographic purification. These compounds are easily transformed in two steps to 4-chloro-2-iodothieno[2,3-b]pyridine-5-carbonitriles which are key intermediates in the synthesis of various kinase inhibitors.

Full text of DOI:10.1016/j.tetlet.2008.09.107

Tetrahedron Letters 49 (2008) 6850–6852
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A facile, scalable preparation of 4-oxo-4,7-dihydrothieno[2,3-b]pyridine-
5-carbonitriles
*
L. Nathan Tumey , Niala Bhagirath, Biqi Wu, Diane H. Boschelli
Wyeth Research, Chemical and Screening Sciences, 401 N. Middletown Road, Pearl River, NY 10965, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a new synthesis of thieno[2,3-b]pyridine-5-carbonitriles from 2-aminothiophene-3-carboxyl-
ate esters. The key step of the synthesis is a thermally promoted elimination/decarboxylation followed by
nucleophilic cyclization to give 4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbonitriles. The reactions
proceed in good yield and generally require no chromatographic purification. These compounds are easily
transformed in two steps to 4-chloro-2-iodothieno[2,3-b]pyridine-5-carbonitriles which are key interme-
diates in the synthesis of various kinase inhibitors.
Received 28 August 2008
Revised 11 September 2008
Accepted 12 September 2008
Available online 21 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
O
Cl
N
1. Introduction
CN
CN
a,b,c
d,e
CN
I
NO2
4-Oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbonitriles such
as 1 are important intermediates in the synthesis of thieno[2,3-b]-
pyridine-5-carbonitrile kinase inhibitors.1–3 Compound 1 can be
transformed in two steps to 2, a versatile intermediate whose
unique structure allows for complementary addition of nucleo-
philes to the 2-position and to the 4-position of the thieno[2,3-b]-
pyridine by palladium-catalyzed addition and SNAr addition,
respectively.
S
S
S
S
N
H
2
1
1
O
CO2Me
NH2
?
S
N
H
3
Scheme 1. Reagents and conditions: (a) Sn, HCl; (b) EMCA, pyridine; (c) PhOPh,
255 °C; (d) POCl3; (e) LDA then I2, À78 °C.
The previously reported synthesis of 2 began with tin-mediated
reduction of 2-nitrothiophene followed by nucleophilic addition to
ethyl ethoxymethylenecyanoacetate (EMCA) and electrophilic ring
closure to gave 14 (Scheme 1). Chlorination (POCl3)5 followed by
nucleophilic iodination1 gave the key intermediate 2 in 13% overall
yield. In addition to the low yield, this sequence has several inher-
ent drawbacks. First, the commercial 2-nitrothiophene is contam-
inated with small amounts (10–20%) of 3-nitrothiophene,
creating purification issues through the sequence. Second, large
amounts of toxic reagents such as tin and EMCA (a sensitizer) are
required early in the reaction sequence. Finally, substituted
2-nitrothiophenes are not commercially available. This creates
limitations on the SAR that may be readily explored at the 2 and
3 position of the thieno[2,3-b]pyridone.
Following literature precedent for a related anthranilic ester,8
the aminothiophene 3 was treated with excess dimethylformam-
ide dimethylacetal (DMF–DMA) at 100 °C overnight. Evaporation
gave the dimethylamidine which was dissolved in tert-butanol
and treated with t-butyl cyanoacetate (Scheme 2). Enamine 4
slowly crystallized out of the reaction solution over a period of 4
days in approximately 50% yield. Partial concentration of the
mother liquor resulted in additional crystallization (over several
days) to give a combined yield of 78%. Unexpectedly, the NMR
analysis of 4 indicated the presence of only a single alkene isomer.
With these issues in mind, we desired a route to compound 1
that would begin with 2-aminothiophene-3-carboxylate esters,
such as 3. Substituted 2-aminothiophene-3-carboxylate esters are
widely available commercially and are easily synthesized by the
classic Gewald reaction.6,7 Therefore, such a synthetic method
would presumably allow for a straightforward synthesis of substi-
tuted analogs of compound 1.
O
O
O
c,d
X
CN
a.b
OMe
NH2
OMe
H
3JHC = 5.6 Hz
CN
78%
S
N
H
N
S
S
H
1
3
CO2tBu
3JHC = 10.1 Hz
4
* Corresponding author. Tel.: +1 845 602 1876; fax: +1 845 602 5561.
E-mail address: tumeyn@wyeth.com (L. N. Tumey).
Scheme 2. Reagents and conditions: (a) DMF–DMA, 100 °C; (b) t-Bu-cyanoacetate,
t-BuOH; (c) TfOH; (d) DBU.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.107

L. N. Tumey et al. / Tetrahedron Letters 49 (2008) 6850–6852
6851
Table 1
O
O
O
Reagents: (a) DMF–DMA, 100 °C, 2 h; (b) t-Bu-cyanoacetate, t-BuOH, 2–8 days; (c)
PhOPh, 255 °C, 2 h
OMe
OMe
CN
a
b
CN
CN
N
N
S
S
quant.
S
H
CO2tBu
N
H
H
5
O
O
4
1
O
R2
R2
R1
OR3
NH2
R2
1:1 mixture of isomers
OR3
CN
a.b
c
CN
b
R1
R1
N
S
S
S
91%
N
H
H
CO2tBu
II
I
Scheme 3. Reagents and conditions: (a) PhOPh or C6H4Cl2, 180 °C; (b) PhOPh,
255 °C, 2 h.
R1
R2
R3
Yield Ia (%)
Yield II (%)
H
H
H
H
Me
i-Pr
H
H
H
H
Me
4-F–Ph
4-F–Ph
4-Cl–Ph
4-Br–Ph
4-OMe–Ph
2-Furyl
Me
Et
Et
Me
Et
Et
Me
Me
Et
Me
Et
Et
Me
Et
4, 78
1, 91
Ia, 64
Ib, 73
Ic, 53
Id, 33
Ie, 53
If, 70
Ig, 69
Ih, 23
Ii, 76
IIa, 85
IIb, 78
IIc, 86
IId, 88
IIe, 90
IIf, 79
IIg, 91
IIh, 87
IIi, 64
IIj, 72
IIk, 77
IIl, 99
IIm, 77
1H–13C HSQMBC experiments indicated that the JCCCH between the
olefinic proton and the carbonyl carbon was significantly greater
than the JCCCH between the olefinic proton and the nitrile carbon.
This strongly suggests that the obtained isomer is the shown (Z)
isomer. The previous work on related quinolones had shown that
triflic acid-promoted removal of the t-butyl group followed by
basification with DBU would give the desired thieno[2,3-b]pyri-
done 1.8 While the triflic acid-promoted dealkylation proceeded
as expected, numerous byproducts were observed following DBU
treatment and only a trace of 1 was obtained.
Me
Et
Ph
Bn
Me
H
Me
H
H
Ij, 70
Ik, 41
Il, 32b
Im, 55b
H
H
Alternatively, compound 4 could be heated in dichlorobenzene
or diphenyl ether to 180 °C to affect the thermal elimination of the
t-butyl and concomitant decarboxylation to give enamine 5 as a
mixture of regiomers (Scheme 3). Once again, literature precedent
for the synthesis of quinolones suggested that the ring closure to
form 1 should be trivial. Analogous quinolone ring closures have
been performed under basic conditions.9,10 However, both base
(DBU, LDA, NaOH, NaOMe) and acid (HOAc, TsOH) failed to affect
the cyclization of 5. Only starting material or polymerized material
was obtained. Interestingly however, refluxing 5 in diphenyl ether
promoted a nearly quantitative conversion to the desired thie-
no[2,3-b]pyridone 1 (Scheme 3). To the best of our knowledge,
thermal ring closure of enamines onto esters to form pyridone-
containing scaffolds is unprecedented in the literature.
Given that both the decarboxylation and ring closure reactions
are promoted thermally, we attempted to perform these two reac-
tions in a single operation. To our satisfaction, we found that
slowly adding 4 to refluxing diphenyl ether followed by heating
at reflux for approximately 2 h then cooling the reaction and pour-
ing into hexanes gave a 91% isolated yield of thieno[2,3-b]pyridone
1. Extending the reaction beyond 2 h resulted in gradually de-
creased yields due to thermal decomposition of the desired prod-
uct. In spite of the high temperature, this reaction was easily
scalable and was conducted successfully up to a 0.5 mol scale.
(CAUTION: On a large scale, compound 4 must be added to the
refluxing diphenyl ether in portions over a 30 min period due to
the vigorous release of 1 M equiv each of CO2, isobutylene, and
methanol gas during the cyclization.)
a
Yield over two steps.
Chromatography was required to isolate compound I cleanly.
b
of the reaction solution over a period of several days. This depen-
dence upon the crystallinity and poor solubility of Ia–m may ac-
count for some of the lower yields obtained in this reaction. In
almost all cases, intermediate I was obtained as a single regiomer
presumed to be of the (Z) configuration based on the NMR studies
of compound 4. The second step of the sequence, the thermal-pro-
moted cyclization to form II, proceeded with generally high yield
(64–99% isolated yield).
Surprisingly, two substrates closely related to 4 failed to under-
go the cyclization reaction (Scheme 4). The 3-aminothiophene-2-
carboxylate 6 failed to cyclize to compound 7. Likewise, anthrani-
late 9 failed to undergo ring closure to form 10. In both cases, the
major product resulted from loss of the t-butyl ester resulting in 8
and 11, respectively. The reason for this unexpected result remains
unclear.
Having developed a suitable method for the transformation of
2-aminothiophene-3-carboxylates into the desired 4-oxo-4,7-
dihydrothieno[2,3-b]pyridines, we next turned our attention to
the synthesis of 4-chloro-2-iodothieno[2,3-b]pyridine-5-carbo-
nitriles (2). The previous synthetic methodology (Scheme 1)
employed POCl3 in order to form 4-chlorothieno[2,3-b]pyridine-
5-carbonitrile. This compound proved to be resistant to electro-
philic iodination, and therefore was deprotonated with LDA at
low temperatures and quenched with iodine. We reasoned that
Having successfully worked out conditions for the conversion of
methyl 2-aminothiophene-3-carboxylate (3) to pyridone 1, we set
about exploring the utilization of 4-substituted and 5-substituted
2-aminothiophene-3-carboxylate esters. We found that numerous
substituted 2-aminothiophene-3-carboxylates were able to be suc-
cessfully transformed in three steps to the desired 4-oxo-4,7-dihy-
drothieno[2,3-b]pyridines (IIa–m) (Table 1). The isolated yields of
the intermediate cyanoacrylate esters I were generally modest
(23–73%). In all but two examples, compound I crystallized out
O
CO2Me
CO2Me
PhOPh, reflux
X
CN
CN
S
S
S
CN
CN
CN
N
H
N
H
N
H
CO2tBu
8
6
7
O
CO2Me
CO2Me
PhOPh, reflux
X
A similar reaction was reported in which a 2,2-disubstituted enamine closes onto
a carboxylic acid to form a pyridone. However, the reaction proceeds via decarbox-
ylation of the aryl carboxylic acid followed by an electrophilic addition to the
thiophene by one of the esters attached to the enamine. See Ref. 11. Also, a similar
microwave-promoted reaction was described recently. However few experimental
details were provided. See Ref. 12.
CN
N
H
11
N
H
9
N
H
CO2tBu
10
Scheme 4.

6852
L. N. Tumey et al. / Tetrahedron Letters 49 (2008) 6850–6852
2.2. General procedure for the thermal cyclization of I to form II
O
O
R3
Cl
R3
R3
CN
CN
CN
a or b
c
I
The t-butyl acrylate obtained above is slowly added in portions
to refluxing diphenyl ether (ꢀ0.5 M). Nitrogen is gently blown over
the top of the refluxing solvent during the course of the reaction.
After heating at reflux for approximately 2 h, the reaction solution
is cooled and poured over excess hexanes. The product (a brown
precipitate) is filtered and washed extensively with hexanes in or-
der to remove residual solvent. CAUTION: The starting material
must be added to the refluxing diphenyl ether in portions over a
30 min period due to the vigorous gas evolution during the
cyclization.
I
S
N
H
S
S
N
H
N
2 (R3=H), 96%
12 (R3=H), 92%i or 75%j
1 (R3=H)
15 (R3=Me), 95%k
16 (R3=iPr), 59%
13 (R3=Me)i
IIa (R3=Me)
IIb (R3=iPr)
14 (R3=iPr), 78%j
Scheme 5. Reagents and conditions: (a) I2, (CF3CO2)2PhI, CHCl3; (b) ICl, MeOH; (c)
POCl3, DMF (cat). using I2 method; using ICl method; yield over two steps.
i
j
k
the intermediate thieno[2,3-b]pyridone 1 may be more electron
rich in nature, and therefore more susceptible to electrophilic
attack. Gratifyingly, compound 1 was iodinated at the 2-position
to give 12 in 92% yield (using I2/(CF3CO2)2PhI or 75% (using
iodine monochloride). Compound 12 was readily chlorinated
with POCl3 to give 2 in 96% yield (Scheme 5). The overall 5-step
yield from commercial material 3 was 62%. Two other analogs
(IIa and IIb) were subjected to the same conditions and trans-
formed to the 3-methyl and 3-isopropyl analogs of 2, namely
15 and 16, in good yield.
In conclusion, we developed a 5-step route for the synthesis
of 4-chloro-2-iodothieno[2,3-b]pyridine-5-carbonitrile (2) and
related analogs. The yield of the overall sequence is 62% and
thus represents a significant advance over the previously re-
ported 6-step route, which provided a 13% yield. No chromato-
graphic purification is necessary and the reactions have been
performed up to a 0.5 mol scale. The synthesis begins with
readily available 2-aminothiophene-3-carboxylate esters which
allows for the facile incorporation of substituents at the C-2
and C-3 positions of the thieno[2,3-b]pyridone. An alternative
iodination protocol was developed which negates the need for
the previously reported low temperature lithiation. This se-
quence has enabled synthesis-substituted thieno[2,3-b]pyri-
dine-5-carbonitrile kinase inhibitors that were not readily
accessible with existing methodology.
2.3. General procedure for the iodination and chlorination of II
The thieno[2,3-b]pyridone II is stirred as a suspension in CHCl3
(.05 M) and treated sequentially with [bis(trifluoroacetoxy)-
iodo]benzene (1.5 equiv) and iodine (1.5 equiv). After stirring at
rt for 24 h, the mixture is concentrated to approximately ½ volume
and the resulting solid is filtered and washed with hexanes. The so-
lid thus obtained is treated with POCl3 (ꢀ10 equiv) and DMF (cat).
After heating to 70 °C overnight, the reaction is carefully quenched
over ice and the resulting product is filtered and washed with
water.
Acknowledgments
We thank the Wyeth Chemical Technologies department for
spectroscopic characterization, Drs. Joe Ashcroft and Melissa Lin
for 1H–13C HSQMBC analysis, and Drs. Tarek Mansour and Janis
Upeslacis for management support.
References and notes
1. Boschelli, D. H.; Wu, B.; Barrios Sosa, A. C.; Durutlic, H.; Ye, F.; Raifeld, Y.; Golas,
J. M.; Boschelli, F. J. Med. Chem. 2004, 47, 6666.
2. Boschelli, D. H.; Wu, B.; Barrios Sosa, A. C.; Chen, J.; Asselin, M.; Cole, D. C.; Lee,
J.; Yang, X.; Chaudhary, D. Bioorg. Med. Chem. Lett. 2008, 18, 2850.
3. Tumey, L. N.; Boschelli, D. H.; Lee, J.; Chaudhary, D. Bioorg. Med. Chem. Lett.
2008, 18, 4420.
2. Experimental details
4. Khan, M. A.; Guarconi, A. E. J. Heterocycl. Chem. 1977, 14, 807.
5. Khan, M.; Guarconi, A. E. Heterocycles 1977, 6, 727.
6. Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J. Heterocycl. Chem. 1999, 36,
333.
7. Gewald, K.; Schinke, E.; Boettcher, H. Chem. Ber. 1966, 99, 94.
8. Duncan, S. M.; Pagan, M. A.; Floyd, M. B.; (Wyeth Holdings Corporation, USA)
WO2004092138.
9. Stern, E.; Millet, R.; Depreux, P.; Henichart, J.-P. Tetrahedron. Lett. 2004, 45,
9257.
10. Atkins, R. J.; Breen, G. F.; Crawford, L. P.; Grinter, T. J.; Harris, M. A.; Hayes, J. F.;
Moores, C. J.; Saunders, R. N.; Share, A. C.; Walsgrove, T. C.; Wicks, C. Org.
Process Res. Dev. 1997, 1, 185.
2.1. General procedure for the synthesis of intermediates I
The 2-aminothiophene-3-carboxylate ester is treated with
DMF–DMA (4 equiv) and heated to 100 °C overnight. The resulting
solution is cooled and concentrated under vacuum. The crude res-
idue is dissolved in t-butanol (0.5–1 M) and treated with t-butyl
cyanoacetate (1.5 equiv). After stirring for an extended period (2–
8 days), the resulting precipitate is collected by filtration and
washed with t-butanol until the washings run nearly clear. Further
product can often be obtained by concentrating the mother liquor
and allowing the reaction to stand for a few additional days.
11. Bacon, E. R.; Daum, S. J. J. Heterocycl. Chem. 1991, 28, 1953–1955.
12. Almazroa, S.; Elnagdi, M. H.; Salah El-Din, A. M. J. Heterocycl. Chem. 2004, 41,
267–272.