Thermal synthesis of 3-bromothieno[3,2-c]pyridin-4-(5h)-one: A telescoped procedure with tributylamine

Article abstract of DOI:10.1002/jhet.1981

3-Bromothieno[3,2-c]pyridine-4-(5H)-one (1) was prepared from (2E)-3-(4-bromo-2-thienyl)-2- propenoic acid (3) by the Eloy-Deryckere thermal benzo/heteropyridinone synthesis. A telescoped procedure was developed, which reduces some of the risk associated with the classic procedure. Use of tributylamine as an additive in this process was shown to facilitate E/Z-isomerization of the intermediate vinyl isocyanate and lower the temperature necessary for the overall thermal process.

Full text of DOI:10.1002/jhet.1981

Month 2014
Thermal Synthesis of 3-Bromothieno[3,2-c]pyridin-4-(5H)-one: A
Telescoped Procedure with Tributylamine
*
Eric E. Boros and Istvan Kaldor
GlaxoSmithKline Research & Development, Five Moore Drive, Research Triangle Park, NC 27709
*
E-mail: eric.e.boros@gsk.com
Received July 18, 2012
DOI 10.1002/jhet.1981
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
3-Bromothieno[3,2-c]pyridine-4-(5H)-one (1) was prepared from (2E)-3-(4-bromo-2-thienyl)-2-
propenoic acid (3) by the Eloy–Deryckere thermal benzo/heteropyridinone synthesis. A telescoped proce-
dure was developed, which reduces some of the risk associated with the classic procedure. Use of
tributylamine as an additive in this process was shown to facilitate E/Z-isomerization of the intermediate
vinyl isocyanate and lower the temperature necessary for the overall thermal process.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
electrocyclization sequence in Scheme 2 (E-5 ! 6) are
very high (e.g. 220–240ꢀC). In fact, compound 1 may
degrade under such forcing reaction conditions [5].
Catalysis studies with mercuric acetate suggest that
alkene isomerization is the rate-limiting step [9] in this
pathway. In fact, both iodine [11,12] and mercuric acetate
[9] can reduce temperatures by about 50–60ꢀC for this
process (e.g. 170–180ꢀC). Addition of tributylamine as
an additive is also known to increase yields of cyclized
product [13] but at temperatures similar to those reported
for the non-catalyzed process [2,6,13]. To our knowledge,
the exact role of tributylamine in this process is not
described, although we assumed it facilitates alkene
isomerization (E ! Z) of the isocyanate intermediate (5).
Use of tributylamine as an additive was intriguing to us,
owing to its moderate reactivity, low toxicity, and high
boiling point (214–216ꢀC). This article reports on the
results of our investigations into the role of tributylamine
in this process. In addition, we describe a telescoped proce-
dure for converting carboxylic acid 3 to thienopyridinone 1
that alleviates some of the safety concerns associated with
the synthesis.
3-Bromothieno[3,2-c]pyridine-4-(5H)-one (1) is widely
employed as an intermediate for synthesis of medicinally
relevant 3-aryl-4-aminothieno[3,2-c]pyridines of general
structure 2 (Scheme 1), including potassium channel
blockers [1] and kinase inhibitors [2–4]. Recently, two
new routes to 1 were described [5], including both
Friedel–Crafts and reductive cyclization protocols.
Even so, the classic “thermal” synthesis of Eloy and
Deryckere [6] continues to be applied [7,8] for the prepa-
ration of benzopyridinones (and thienopyridinones) owing
to procedural ease (for small scale) and inexpensive
starting materials.
We recently performed a laboratory scale-up of 1 for use
as an intermediate to support kinase inhibitor lead optimi-
zation programs in our laboratories. In the course of this
work, we developed a simple procedure that mitigates
some of the risks associated with the thermal route. In
addition, some insight was gained into the role of
tributylamine as an additive in this process. The details of
this study are described herein.
We originally prepared acyl azide 4 by published methods
[3]. Preliminary stability studies with 4 showed that decom-
position (by Curtius degradation) began at 75–80ꢀC; for this
reason, multi-gram operations with this material were
performed in solution at RT. Two NMR sample solutions
of 4 (~0.05M) in d4-1,2-dichlorobenzene were prepared.
Both samples were heated in the same 100ꢀC oil bath for
30min, which effected complete conversion to E-5. One of
the NMR samples containing E-5 was subsequently treated
with tributylamine (~2 equiv), and both samples were re-
heated at 100ꢀC for an additional 30 min. The NMR
RESULTS AND DISCUSSION
The reaction path for the thermal route [9] (Scheme 2)
involves conversion of the thiophene acrylic acid 3 to acyl
azide 4 [10] followed by Curtius degradation to the vinyl
isocyanate E-5. Double-bond isomerization of E-5 to Z-5
sets up a 6p electrocyclization to afford hydropyridinone
intermediate 6, which undergoes a sigmatropic hydrogen
shift to yield the desired product (1). The temperatures
generally reported for the alkene isomerization and
© 2014 HeteroCorporation

E. E. Boros and I. Kaldor
Vol 000
Scheme 1
yield zwitterionic intermediates 8 and 9, respectively. Rotation
of the requisite carbon–carbon bond in these intermediates,
followed by elimination of tributylamine, would effect
interconverion of E-5 and Z-5. Assuming alkene
isomerization is rate-limiting in the absence of additive,
tributylamine effectively facilitates electrocyclization at a
lower temperature (similar to mercuric acetate catalysis [9]).
A change in mechanism for hydrogen migration is also
plausible (from a 1,5-shift to a 1,3-shift) under tributylamine
base catalysis [16].
Scheme 2
A modified procedure for conversion of 3–1 was subse-
quently devised. We chose p-cymene as solvent owing to its
high bp (177ꢀC), low density (relative to water), and low
freezing point relative to diphenyl ether (the most common
solvent employed for this process). The desired compound
(1) also crystallizes from hot p-cymene on cooling [17].
Telescoping the title synthesis simply entailed
generating the acyl azide from the carboxylic acid with
diphenylphosphoryl azide and tributylamine in p-cymene at
RT. This stage was performed on a 1.29-mol scale of 3 in a
6-L fixed glass jacketed lab reactor. Following acyl azide
formation, multiple washing with NaOH (1.0 M) removed
the diphenylphosphoric acid by-product, without detriment
to the acyl azide, and avoided solvent exchange and charging
of tributylamine prior to the critical high temperature stage.
The organic phase containing 4 and tributylamine was
separated, dried, filtered, and split into two separate batches
(~0.64mol each) for further processing.
Metered addition of the p-cymene solution of 4 and
tributylamine to neat p-cymene at 165–170ꢀC was
performed over 3 h. Azide addition by pump from a rela-
tively remote position (as opposed to an overhead dropping
funnel) minimized risk of accidental spillage over the hot
reaction vessel. This reverse addition at temperatures well
above that required for Curtius degredation, alkene isomer-
ization, and electrocyclization enabled control of both
reactive inventory (acyl azide) and nitrogen production.
To ensure complete reaction, the mixture was stirred for
2.5 h at 170ꢀC following the addition.
spectrum of the sample containing tributylamine [Fig. 1(A)]
showed a new pair of AB-doublets consistent with ~50%
isomerization to Z-5 (d 5.85 and 5.83 ppm, J = 7.4 Hz).
Heating this sample for an additional 90 min at 147ꢀC
effected conversion to 1 [Fig. 1(B)].
Conversely, after 30min at 100ꢀC, the NMR spectra of the
sample without tributylamine added showed only the AB
pattern of vinylic doublets corresponding to E-5 [Fig. 1(C):
d 6.15 and 6.10 ppm, J = 13 Hz]. Heating this sample for an
additional 90 min at 147ꢀC produced minimal changes in
the spectrum [Fig. 1(D)], although a very small multiplet at
d 5.84ppm corresponding to Z-5 was observed. Additional
resonances also appeared, which we assigned to carbamoyl
thienopyridinone 7 (in analogy to a previously described
benzopyridinone syntheses [9,13]). Heating the sample
without tributylamine for 60min at 180ꢀC completed the
cyclization to 1.
Our results support the supposition that tributylamine
facilitates vinyl isocyanate isomerization in the Eloy–
Deryckere (benzo/hetero)pyridinone synthesis and in turn
enables electrocyclization at lower temperature. Moreover,
telescoping the acyl azide and thienopyridinone syntheses
Two possible pathways for tributylamine-mediated E/Z-
isomerization of 5 involve reversible Michael [14] or
isocyanate [15] addition-elimination pathways, which would
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Thermal Synthesis of 3-Bromothieno[3,2-c]pyridin-4-(5H)-one: A Telescoped
Procedure with Tributylamine
Figure 1. 1H NMR spectra (400MHz; 7.2–5.8ppm) from solutions isocyanate E-5 in d4-dichlorobenzene after heating with (A and B) and without (C and D)
tributylamine. Solvent peaks (S) are labeled (7.20 and 6.94 ppm).
(M + 1), 232 (M + 1); 1H NMR (400 MHz, DMSO-d6) d 6.83
(d, 1H, J = 7 Hz), 7.24 (d, 1H, J = 7 Hz), 7.63 (br s, 1H), 11.46
(br s, 1H) [5].
with tributylamine in p-cymene avoids both isolation of
azide 4 and charging of tributyl amine prior to the high
temperature stage. The modified procedure affords the title
compound in good yield (71%) and purity (>98% by
LCMS). Spectral data of 1 were in agreement with
literature values [5].
REFERENCES AND NOTES
[1] Ford, J.; Madge, D. J.; Payne, H. J.; Knight, J. D. PCT Interna-
tional Patent Application WO 2007/066127 A2, 2007, Chem Abstr 2007,
147, 72734.
EXPERIMENTAL
[2] Abbott, L.; Betschmann, P.; Burchat, A.; Calderwood, D. J.;
Davis, H.; Hrnciar, P.; Hirst, G. C.; Li, B.; Morytko, M.; Mullen, K.;
Yang, B. Bioorg Med Chem Lett 2007, 17, 1167.
[3] Miyazaki, Y.; Nakano, M.; Sato, H.; Truesdale, A. T.; Stuart,
J. D.; Nartey, E. N.; Hightower, K. E.; Kane-Carson, L. Bioorg Med
Chem Lett 2007, 17, 250.
[4] Heyman, H. R.; Frey, R. R.; Bousquet, P. F.; Cunha, G. A.;
Moskey, M. D.; Ahmed, A. A.; Soni, N. B.; Marcotte, P. A.; Pease, L.
J.; Glaser, K. B.; Yates, M.; Bouska, J. J.; Albert, D. H.; Black-Schaefer,
C. L.; Dandliker, P. J.; Stewart, K. D.; Rafferty, P.; Davidsen, S. K.;
Michaelides, M. R.; Curtin, M. L. Bioorg Med Chem Lett 2007,
17, 1246.
[5] Engstrom, K. M.; Baize, A. L.; Franczyk, T. S.; Kallemeyn,
J. M.; Mulhern, M. M.; Rickert, R. C.; Wagaw, S. J Org Chem 2009,
74, 3849.
[6] Eloy, F.; Deryckere, A. Helv Chim Acta 1970, 53, 645.
[7] Zhao, L.; Zhang, Y.; Dai, C.; Guzi, T.; Wiswell, D.; Seghezzi, W.;
Parry, D.; Fischmann, T.; Siddiqui, M. A. Bioorg Med Chem Lett 2010, 20,
7216.
[8] Gentile, G.; Bernasconi, G.; Pozzan, A.; Merlo, G.;
Marzorati, P.; Bamborough, P.; Bax, B.; Bridges, A.; Brough, C.;
Carter, P.; Cutler, G.; Neu, M.; Takada, M. Bioorg Med Chem Lett
2011, 21, 4823.
3-Bromo-thieno[3,2-c]pyridin-4-(5H)-one (1).
Diphenyl
phosphorylazide (390 g, 1.42 mol) was added drop wise to a
stirred solution of (2E)-3-(4-bromo-2-thienyl)-2-propenoic acid
(300 g, 1.29 mol) and tributylamine (286g, 1.54 mol) in p-cymene
(2.2 L) at RT, and the reaction mixture was stirred overnight.
The reaction mixture was basified with 1N NaOH. The phases
were separated, and the organic layer was washed with 1N
NaOH (2 ꢁ 2L) to remove the diphenylphosphoric acid by-
product. The organic phase was washed with brine, dried over
MgSO4, and filtered. The p-cymene filtrate containing 4 and
tributylamine was split into two equal volumes and used in
separate batches without further purification. This solution
(0.64 mol of 4) was added by pump over 3h (flow rate 8 mL/min)
to stirred p-cymene (2 L) at 165ꢀC internal temperature. Following
the addition, the reaction mixture was maintained at 170ꢀC for an
additional 2.5h and then allowed to cool to ambient temperature
overnight. The slurry was diluted with heptane (700 mL), cooled
to ꢂ10ꢀC, and the product (1) was collected by filtration as a light
beige solid (105g, 71% yield): LCMS purity >98%; m/z 230
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. E. Boros and I. Kaldor
Vol 000
[9] Chuang, T. H.; Wu, P. L.
53, 413.
J
Chin Chem Soc 2006,
[14] For Michael addition/elimination mechanisms involving
tributylamine and iodoacrylates, see: Maw, G.; Thirsk, C.; Whiting, A.
Tetrahedron Lett 2001, 42, 8387.
[15] Tertiary amine-isocyanate complexes are described, see:
Burkus, J. J Org Chem 1961, 26, 779.
[16] Woodward, R. B.; Hoffmann, R. Angew Chem Int Ed 1969, 8, 781.
[17] p-Cymene is a potentially bio-renewable solvent from eucalyp-
tus oil, see: Leita, B. A.; Warden, A. C.; Burke, N.; O’Shea, M. S.;
Trimm, D. Green Chem 2010, 12, 70.
[10] For a detailed calorimetric investigation and scale-up of a
Curtius rearrangement, see: am Ende, D. J., DeVries, K. M.; Clifford,
P. J.; Brenek, S. J. Org Process Res Dev 1998, 2, 382.
[11] Ajao, J. F.; Bird, C. W. J Het Chem 1985, 22, 329.
[12] Mikol, G. J.; Boyer, J. H. J Org Chem 1972, 37, 724.
[13] Showalter, H. D. H.; Sercel, A. D.; Stier, M. A.; Turner, W. R.
J Het Chem 2001, 38, 961.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet