Synthesis of pyridopyrazine-1,6-diones from 6-hydroxypicolinic acids via a one-pot coupling/cyclization reaction

Article abstract of DOI:10.1021/ol303463e

A facile one-pot synthesis of 3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6(2H)- diones (pyridopyrazine-1,6-diones) has been developed which employs a sequential coupling/cyclization reaction of 6-hydroxypicolinic acids and β-hydroxylamines. The transformation proceeds in good yield under mild conditions using O-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) to both carry out the amide formation and activate the hydroxyl group for intramolecular alkylation.

Full text of DOI:10.1021/ol303463e

ORGANIC
LETTERS
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Vol. XX, No. XX
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Synthesis of Pyridopyrazine-1,6-diones
from 6‑Hydroxypicolinic Acids via
a One-Pot Coupling/Cyclization Reaction
Tuan P. Tran,*,† Patrick B. Mullins,† Christopher W. am Ende,† and
Martin Pettersson*,‡
Neuroscience Medicinal Chemistry, Pfizer Worldwide Research and Development,
Eastern Point Road, Groton, Connecticut 06340, United States, and Neuroscience
Medicinal Chemistry, Pfizer Worldwide Research and Development, 700 Main Street,
Cambridge, Massachusetts 02139, United States
tuan.tran@pfizer.com; martin.pettersson@pfizer.com
Received December 18, 2012
ABSTRACT
A facile one-pot synthesis of 3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6(2H)-diones (pyridopyrazine-1,6-diones) has been developed which employs
a sequential coupling/cyclization reaction of 6-hydroxypicolinic acids and β-hydroxylamines. The transformation proceeds in good yield under
mild conditions using O-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) to both carry out the amide
formation and activate the hydroxyl group for intramolecular alkylation.
In the context of a recent medicinal chemistry program,
we sought to convert a series of amides 1 into the corre-
sponding conformationally restricted pyridopyrazine-1,6-
dione derivatives 2 (Figure 1).1 Introduction of conforma-
tional constraint is a common strategy in medicinal chemistry
to improve potency by locking the molecule in its putative
pharmacologically active conformation as well as to improve
permeability and bioavailability by reducing the number of
rotatable bonds.2
High lipophilicity has been linked not only to increased risk
of toxicity4 but also to poor pharmacokinetic properties.5,6
Therefore, given the increased polarity of pyridopyrazine-
1,6-dione 2 relative to pyridyl amide 1, this bicyclic ring
system represents a potentially valuable structural motif in
medicinal chemistry.
Several recent analyses have highlighted the importance
of controlling physicochemical properties in drug design,
in particular, reducing the lipophilicity of drug molecules.3
† Pfizer, Groton, Connecticut.
‡ Pfizer, Cambridge, Massachusetts.
(1) Pfizer Inc. WO12131539; 2012.
Figure 1. Genesis of the pyridopyrazine-1,6-dione ring system.
(2) Veber, D. F.; Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward,
K. W.; Kopple, K. D. J. Med. Chem. 2002, 45, 2615–2623.
(3) Leeson, P. D.; Springthorpe, B. Nat. Rev. Drug Discovery 2007, 6,
881–890.
(4) Hughes, J. D.; Blagg, J.; Price, D. A.; Bailey, S.; DeCrescenzo,
G. A.; Devraj, R. V.; Ellsworth, E.; Fobian, Y. M.; Gibbs, M. E.; Gilles,
R. W.; Greene, N.; Huang, E.; Krieger-Burke, T.; Loesel, J.; Wager, T.;
Whiteley, L.; Zhang, Y. Bioorg. Med. Chem. Lett. 2008, 18, 4872–4875.
(5) Wager, T. T.; Chandrasekaran, R. Y.; Hou, X.; Troutman, M. D.;
Verhoest, P. R.; Villalobos, A.; Will, T. ACS Chem. Neurosci. 2010, 1,
420–434.
Surprisingly, a survey of the literature revealed only two
distinct approaches related to thisparticularbicyclicsystem.
Both methods start with a piperazinone intermediate onto
which the aromatic portion is constructed and require
(6) Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. ACS Chem.
Neurosci. 2010, 1, 435–449.
r
10.1021/ol303463e
XXXX American Chemical Society

multistep syntheses that proceed in low overall yield.7,8
The lack of a general and efficient synthesis of the
pyridopyrazine-1,6-dione scaffold provided an impetus
for the development of a new synthetic approach to this
potentially valuable but relatively unexplored heterocyclic
ring system. Herein, we report a novel one-pot coupling/
cyclization reaction for the efficient assembly of pyrido-
pyrazine-1,6-diones 2.
We envisioned two potential approaches to construct
the pyridopyrazine-1,6-dione system starting from a series
of readily available 6-hydroxypicolinic acids (e.g., 6) that
would allow access to a diverse set of these compounds
(Scheme 1). Acids 6 proved to be versatile building blocks,
as a number of these are commercially available or can
be easily prepared by demethylation of the corresponding
6-methoxy-picolinic acids.9 Thus, one approach would
be to prepare amide-alcohol intermediate 4 via amide
coupling of acid 6 with β-hydroxylamine 5. Subsequently,
conversion of the primary hydroxyl group to a suitable
leaving group followed by intramolecular alkylative
cyclization would provide product 2 in a manner similar
to those reported in the syntheses of cytisine and proto-
berberines.10,11 Alternatively, N-alkylation of pyridone
8 would give rise to intermediate 7. Deprotection and
intramolecular amidation would then theoretically afford
the same product. We opted to focus our efforts on the
former approach to avoid potential complications result-
ing from competitive N-/O-alkylation of ethyl picolinate 8.
11 but also the cyclized product 12a along with unreacted
acid 1012 in an approximately 1:2:2 ratio as indicated by
LC/MS. Upon purification via column chromatography,
intermediate 11 and pyridopyrazine-1,6-dione 12a were
isolated in 21% and 34% yield, respectively.
Formation of 12a as a major product indicated that
the cyclization step may in fact be promoted by the
coupling reagent, and the observed distribution of pro-
ducts suggested that the initial amide coupling is likely
the slowest step in the overall process. Consequently, we
treated purified amide-alcohol 11 with HATU and DIEA
and observed virtually complete conversion to the desired
pyridopyrazine-1,6-dione 12a as evidenced by TLC and
LC/MS. It is important to note that the addition of DIEA
is required for this transformation to proceed. The forma-
tion of 12a under these reaction conditions was particu-
larly interesting because tothe best of our knowledge, there
has been no report of N-alkylation of a heterocycle with
an alcohol promoted by HATU or other peptide coupling
reagents.13 To firmly establish the role of HATU in the
cyclization step, amide-alcohol 11 was subjected to a
variety of conditions (thermal, acidic, basic, and exposure
to silica) in the absence of HATU, and no formation of
product 12a was observed.
Scheme 2. Formation of Pyridopyrazine-1,6-dione 12a via a
One-Pot Coupling/Cyclization Reaction
Scheme 1. Retrosynthesis of Pyridopyrazine-1,6-diones 2
These preliminary results inspired us to pursue a one-pot
synthesis of the pyridopyrazine-1,6-diones directly from
the acid 10. Toward this end, the yield of the tandem
coupling/cyclization reaction was improved to 55% by
increasing the amount of HATU to 2.3 equiv. Further
optimization revealed that warming the reaction mixture
to reflux in methylene chloride resulted in complete con-
sumption of acid 10 and increased the isolated yield of 12a
to 75%. Using these improved conditions, amide-alcohol
11 was not observed in any appreciable amount and was
not recovered after column chromatography. With these
optimized conditions in hand, we began to explore the
In our initial attempts to generate the amide-alcohol
intermediate 11 (Scheme 2) utilizing standard peptide
coupling protocols, we were surprised to find that using
1.2 equiv of the coupling reagent HATU and excess
diisopropylethyl amine (DIEA) provided not only alcohol
(7) Kawahara, N.; Nakajima, T. Heterocycles 1983, 20, 1721–1725.
(8) Wai, J. S.; Kim, B.; Fisher, T. E.; Zhuang, L.; Embrey, M. W.;
Williams, P. D.; Staas, D. D.; Culberson, C.; Lyly, T. A.; Vacca, J. P.;
Hazuda, D. J.; Felock, P. J.; Schleif, W. A.; Gabryelski, L. J.; Jin, L.;
Chen, I.-W.; Ellis, J. D.; Mallai, R.; Young, S. D. Bioorg. Med. Chem.
Lett. 2007, 17, 5595–5599.
(9) Representative examples: (a) Leznoff, C. C.; Svirskaya, P. I.;
Yedidia, V.; Miller, J. M. J. Heterocycl. Chem. 1985, 22, 145–147. (b)
Ulbricht, T. L. V. J. Chem. Soc. 1961, 3345–3348. (c) McElroy, W. T.;
DeShong, P. Tetrahedron 2006, 62, 6945–6954.
(12) While 2-pyridones and 2-hydroxypyridines exist as a tautomeric
equilibrium in solution, the oxo-form predominates in polar solvents
and in the solid state; see: Wong, M. W.; Wiberg, K. B.; Frisch, M. J.
J. Am. Chem. Soc. 1992, 114, 1645–1652.
(13) The reaction below was attempted, but no alkylation product
was observed.
(10) O’Neill, B. T.; Yohannes, D.; Bundesmann, M. W.; Arnold,
E. P. Org. Lett. 2000, 2, 4201–4204.
(11) Le, T. N.; Gang, S. G.; Cho, W.-J. J. Org. Chem. 2004, 69, 2768–
2772.
B
Org. Lett., Vol. XX, No. XX, XXXX

scope and limitations of this transformation, the results of
which are presented in Table 1.
In addition to HATU, we explored a select number of
alternative peptide coupling reagents including N-(3-
dimethylaminopropyl)-N0-ethylcarbodiimide (EDCI), 1,3-
dicyclohexylcarbodiimide (DCC), 1-propanphosphoric acid
cyclic anhydride (T3P), and O-(1,2-dihydro-2-oxo-pyridyl)-
1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU).
Among these reagents, only TPTU afforded the desired
product 12a, albeit in moderate yield (46%). This brief
survey showed that HATU is clearly superior in the one-
pot synthesis of pyridopyrazine-1,6-diones as compared
to the other common coupling reagents that we examined.
We also sought to expand the scope of the coupling/
cyclization reaction to include the formation of medium-
sized rings. Thus, coupling of 10 with amino-alcohol 13
gave the seven-membered ring analogue 15 in 39% yield
(Scheme 3). Intramolecular formation of seven-membered
rings is typically not an efficient process, so, not surpris-
ingly, this yield was reduced considerably as compared to
12a. An attempt to expand to the eight-membered ring
with our standard conditions failed to afford the desired
product 16, but rather gave 17 in 40% yield. This side
product stems from activation of the primary hydroxyl
group with the azabenzotriazole component of HATU. In
fact, we were pleased to be able to isolate HOAt-ether 17,
as this provides further mechanistic support for the role of
HATU in the cyclization step in this sequence.
The tandem coupling/cyclization reaction was found to
proceed in good to excellent yields when using unhindered
amino alcohols (12aꢀc). However, substrates bearing
substitutionadjacenttothe reactingmoietiestypicallygave
the corresponding products in lower yields, as highlighted
by 12e and 12f. The presence of a methyl substituent at the
carbon atom adjacent to the hydroxyl group reduced the
yield from 75% to 29% (12e), while substitution near the
amino group reduced the yield to 45% (12f). Interestingly,
an R-methyl group on the ethylene linker adjacent to the
nitrogen did not impede product formation as seen with
12d, which was isolated in 69% yield. Not surprisingly,
attempts to prepare 12g from the corresponding amine 5g
did not afford any appreciable amount of the product by
LC/MS and none could be isolated. Instead, the main
identifiable side product was the ester arising from prefer-
ential coupling of the primary alcohol over the amino
moiety (not isolated).
Table 1. Scope and Limitations of the One-Pot Pyridopyrazine-
1,6-dione Synthesis
Scheme 3. Attempts To Form Medium-Size Rings
Discovery and isolation of 17 prompted us to examine
the formation of HOAt-ethers by treating various alcohols
with HATU and DIEA. Indeed, we were able to form the
HOAt adducts 18ꢀ20 in high yields (Scheme 4). Addition-
ally, single crystal X-ray analysis of 18 enabled unambig-
uous assignment of its regiochemistry. To the best of our
knowledge, this transformation has not previously been
reported.
While the initial reaction conditions for the coupling/
cyclization reaction provided the 7-bromopyridopyrazine
diones in good yields, inconsistent results were obtained
in the synthesis of corresponding des-bromo analogues
starting from acid 23. Typically the intermediate amide-
alcohols (analogous to 11) were observed as the major
products, whereas the desired pyridopyrazine diones were
generally obtained in low yields. Postulating that the
differences in pKa’s of the pyridone NH of picolinic acids
10 and 23 could be an important factor, we found that
a Reaction at rt gave the product in a 55% yield; TPTU gave a 46%
yield.
Org. Lett., Vol. XX, No. XX, XXXX
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Table 2. Results with Cs2CO3/MeCN Condition
Scheme 4. Formation of HOAt Adducts and ORTEP Diagram
of X-ray Crystal Structure of 18
substituting 1,5-diaza-bicyclo[4.3.0]-5-nonene (DBN), which
has a conjugate acid pKa of 13.5 and is more basic than
DIEA (conjugate acid pKa: 11.4), increased the yield of 24c
from 27% to 46% (Table 2).
a Reaction with DIEA/CH2Cl2/reflux gave product in 27% yield;
DBN gave a 46% yield.
Figure 2. Effect of 5-substituent on pKa.
one-pot process are mediated by HATU and proceed
under mild reaction conditions to afford a series of pyr-
idopyrazine-1,6-diones in good yields. Given the limited
precedent for the construction of these bicyclic systems,
our approach provides an efficient route to compounds of
this class. Additionally, during these studies we discovered
that alcohols readily form HOAt ethers by refluxing in
CH2Cl2 in the presence of HATU and DIEA. Further
results and applications in medicinal chemistry will be
reported in due course.
To confirm the differences in pKa as a result of the
bromo substituent in the 5-position, we prepared the two
standards shown in Figure 2 and measured their pKa’s
according to a published procedure.14 The pKa’s of com-
pounds 21 and 22 were found to be 7.47 and 8.94,
respectively, in an aqueous medium. Indeed, the presence
of the bromide increases the acidity of the hydroxypicoli-
namide, lowering its pKa by approximately 1.5 log units.
As a result of this observation, a screen of various bases
and solvents was undertaken.
Acknowledgment. The authors thank the Pfizer Neuro-
science Chemistry Leadership Team (Pfizer, Cambridge,
MA) for their support of this work; Dr. Andrew Flick
(Pfizer, Groton, CT) for insightful chemistry discussions
and helpful comments on this manuscript; Dr. Gregory
Kauffman (Pfizer, Cambridge, MA) and Marina Shalaeva
(Pfizer, Groton, CT) for discussions and measurement of
pKa’s; Brian Samas(Pfizer, Groton, CT) for determination
of X-ray crystal structures; and Matthew Teague (Pfizer,
Groton, CT) for obtaining HRMS data.
Ultimately, cesium carbonate in acetonitrile at 50 °C
gave results that were comparable to those obtained for
the bromo-anologues 12aꢀf. Using these optimized con-
ditions, 7-H analogues24a, 24c, 24d, and 24f wereobtained
in good yields as shown in Table 2. Additionally, prepara-
tion of 12a was repeated using these conditions and it was
obtained in 67% yield. Thus, careful consideration of the
pKa of the starting material and selection of the suitable
reaction conditions were crucial for successful optimization
of this one-pot synthesis of pyridopyrazine-1,6-diones.
In conclusion, a new tandem coupling/cyclization ap-
proach to form 3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6-
(2H)diones starting from 6-hydroxypicolinic acids and
β-hydroxyamines has been developed. Both steps in the
Supporting Information Available. Experimentaldetails,
1H and 13C NMR spectra, and crystal structure data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(14) Shalaeva, M.; Kenseth, J.; Lombardo, F.; Bastin, A. J. Pharm.
Sci. 2008, 97, 2581–2606.
The authors declare no competing financial interest.
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