Protocol for the Direct Conversion of Lactones to Lactams Mediated by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene: Synthesis of Pyridopyrazine-1,6-diones

Article abstract of DOI:10.1021/acs.joc.7b02079

We present an operationally simple lactone-to-lactam transformation utilizing diverse amine nucleophiles. The key steps of amidation, alcohol activation, and cyclization are all mediated by one reagent (TBD) in a single vessel at room temperature. We illustrate the convenience of this protocol by synthesizing a wide range of N-alkyl, N-aryl, and N-hetereoaryl pyridopyrazine-1,6-diones, an important class of medicinally significant lactams. Furthermore, the reported methodology can be applied to the synthesis of milligram to hundred gram quantities of pyridopyrazine-1,6-diones without the use of specialized equipment.

Full text of DOI:10.1021/acs.joc.7b02079

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Note
A Protocol for the Direct Conversion of Lactones to Lactams Mediated by
1,5,7-Triazabicyclo[4.4.0]dec-5-ene: Synthesis of Pyridopyrazine-1,6-diones
Danica A Rankic, Cory M. Stiff, Christopher W. am Ende, and John M. Humphrey
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02079 • Publication Date (Web): 19 Oct 2017
Downloaded from http://pubs.acs.org on October 20, 2017
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A Protocol for the Direct Conversion of Lactones to Lactams Mediꢀ
ated by 1,5,7ꢀTriazabicyclo[4.4.0]decꢀ5ꢀene: Synthesis of Pyridopyraꢀ
zineꢀ1,6ꢀdiones
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Danica A. Rankic,* Cory M. Stiff, Christopher W. am Ende, and John M. Humphrey
Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
danica.rankic@pfizer.com
Supporting Information Placeholder
ABSTRACT: We present an operationally simple lactoneꢀtoꢀlactam transformation utilizing diverse amine nucleophiles. The key
steps of amidation, alcohol activation and cyclization are all mediated by one reagent (TBD) in a single vessel at room temperature.
We illustrate the convenience of this protocol by synthesizing a wide range of Nꢀalkyl, Nꢀaryl and Nꢀhetereoaryl pyridopyrazineꢀ
1,6ꢀdiones, an important class of medicinally significant lactams. Furthermore, the reported methodology can be applied to the synꢀ
thesis of milligram to hundred gram quantities of pyridopyrazineꢀ1,6ꢀdiones without the use of specialized equipment.
Lactams are important substructures in natural products and
biologically active compounds.1 Although multiple methods
for lactam synthesis exist, a highly atom and step economical
approach is the direct conversion of a lactone to its correꢀ
sponding cyclic amide via reaction with amines. This strategy
is efficient for rapidly accessing structural diversity as nitroꢀ
gen substitution of the final lactam can be varied with different
amine nucleophiles. However, few methodologies have been
reported for the mild conversion of a lactone to a lactam in a
single vessel.2 Most methods for the synthesis of cyclic amides
from lactones in a unit operation rely on extreme reaction
temperatures (>200 ˚C) and/or high pressures,3 expensive stoiꢀ
chiometric additives or solvents,4 or multistep reactions.2b We
herein describe a step economical and operationally simple,
single vessel synthesis of pyridopyrazineꢀ1,6ꢀdiones, a class of
lactams critical to the development of neurokininꢀ1 (NK1)
receptor antagonists,5 HIVꢀ1 integrase inhibitors6 and γꢀ
secretase modulators (GSMs) – potential treatments for Alzꢀ
heimer’s disease (Scheme 1a).7
DABALꢀMe3, an air stable DABCO/AlMe3 complex, as a
Lewis acid (Scheme 1c).9−11 The intermediate amido alcohol
was then be converted to the pyridopyrazineꢀ1,6ꢀdione (lacꢀ
tam) by activation of the alcohol and subsequent baseꢀ
mediated ring closure using a strong organic base such as
DBU or 1,5,7ꢀtriazabicyclo[4.4.0]decꢀ5ꢀene (TBD).
Scheme 1. Pyridopyrazineꢀ1,6ꢀdiones: valuable lactam subꢀ
structures in medicinal chemistry
A number of strategies have been employed to generate pyriꢀ
dopyrazineꢀ1,6ꢀdiones6,8 such as amidation of picolinic acids
with amino alcohols and their subsequent cyclization6a and Nꢀ
alkylation of an Nꢀunsubstituted pyridopyrazineꢀ1,6ꢀdione6c
which are complicated by challenges such as custom amino
alcohol synthesis and competing elimination reactions, respecꢀ
tively (Scheme 1b). A key approach that we utilized while
progressing our GSM program was a lactoneꢀtoꢀlactam conꢀ
version strategy. In this effort, a critical lactone (pyridooxaꢀ
zineꢀ1,6ꢀdione) intermediate was reacted with amines in order
to generate an amido alcohol intermediate (Scheme 1c). To
effect lactone aminolysis, we employed stoichiometric
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[a] All reactions were performed on a 0.25 mmol scale with 1 equiv. of
lactone and 1 equiv. of benzylamine unless otherwise stated. [b] 1,3,5ꢀ
trimethoxybenzene was used as an internal standard. [c] 1.3 equiv. of
lactone and 1 equiv. of benzylamine.
During the course of these early studies, we identified the
side product 4 in the crude reaction mixture, a result of acylaꢀ
tion of intermediate amido alcohol 3 with the extraction solꢀ
vent ethyl acetate during workꢀup (Scheme 2).13 Although
compound 4 was inert to baseꢀpromoted cyclization, we surꢀ
mised that replacement of the “acetate” with an electronꢀpoor
surrogate (e.g. trifluoroacetate) might set the stage for an effiꢀ
cient oneꢀpot, direct lactoneꢀtoꢀlactam conversion.14 In this
way, TBD would serve as a catalyst for lactone amidation, a
mediator of transesterification (for alcohol activation) as well
as a base for the subsequent intramolecular Nꢀalkylation.
The lactoneꢀtoꢀlactam conversion strategy proved effective for
both nonꢀhindered and hindered amines, enabling the preparaꢀ
tion of a variety of pyridopyrazineꢀ1,6ꢀdione GSMs from an
easily handled crystalline lactone intermediate. However, reꢀ
quired isolation of the intermediate amido alcohol prior to
cyclization was time consuming, added to the stepꢀcount and
generated additional waste. Furthermore, scaleꢀup of the lacꢀ
tone amidation chemistry is complicated by methane offꢀ
gassing upon quenching of the stoichiometric DABALꢀMe3
that is used in stoichiometric quantities. In order to address
these challenges, we sought alternative reaction conditions to
generate the key intermediate amido alcohol (Scheme 1c).
Scheme 2. Observation of acetylated side product 4 upon
workup
Literature reports of TBD being used to mediate direct ester
amidation led us to investigate this reagent in our system.12
Toward this end, we reacted benzyl amine (2) and lactone 1 in
the presence of TBD in a variety of solvents (Table 1). Of the
solvents utilized, DMF afforded the greatest conversions to
amido alcohol 3 at a concentration of 1 M, and a full molar
equivalent of TBD proved more effective than subꢀ
stoichiometric amounts (Table 1, entries 5 and 6). Additionalꢀ
ly, the reaction was complete in only 1 hour, providing the
desired ringꢀopened product 3 in 83% yield (Table 1, entry 7).
Further improvements in yield were realized when excess lacꢀ
tone 1 was employed (Table 1, entry 8, 95% yield). This is
attributed to lactone 1 being prone to baseꢀmediated hydrolysis
and therefore, a slight excess of lactone was enough to overꢀ
come adventitious water.
To test our hypothesis, the lactone aminolysis reaction (Taꢀ
ble 1, entry 8) was run to completion at which point ethyl triꢀ
fluoroacetate (ETFA) was added. Gratifyingly, the desired
lactam was generated in 40% NMR yield (Scheme 3). The low
yield was later attributed to insufficient quantities of the stoiꢀ
chiometric base required for the final ring closure. Increasing
the amount of TBD from 1 equiv. to 1.5 equiv. afforded the
desired pyridopyrazineꢀ1,6ꢀdione 5 in 80% 1H NMR yield.
Table 1. TBD amidation of lactone 1 with benzylamine
Scheme 3. Evaluation of conditions for the oneꢀpot synthesis
of pyridopyrazineꢀ1,6ꢀdione 5.15
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With these results in hand, we proceeded to examine the
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scope of amine nucleophiles that would be competent in this
transformation. Benzyl amines containing electron withdrawꢀ
ing and electron donating groups perform well as nucleophiles
in this reaction, providing the corresponding lactams in excelꢀ
lent yields (Table 2, examples 7−9). Aliphatic amines such as
allyl and propargyl amine as well as, amines with αꢀ
substitution (cyclopropyl, cyclohexyl and αꢀmethyl benzylaꢀ
mine) were well tolerated, providing the desired lactams in
52–92% yield (examples 10−14). tertꢀButyl amine, however,
did not provide the desired pyridopyrazineꢀ1,6ꢀdione 15. We
attribute this to the inability of the sterically encumbered actiꢀ
vated intermediate amido alcohol to undergo deprotonation or
cyclization. This hypothesis is supported by the isolation of
the intermediate amido alcohol in 89% yield, indicating that
tertꢀbutyl amine is a viable nucleophile in the amidation step.16
We also found that tryptamine could be employed as a nuꢀ
cleophile without requiring a nitrogen protecting group on the
indole (Table 2, example 16). Furthermore, aniline is also a
competent substrate in this transformation, providing access to
Nꢀphenyl pyridopyrazineꢀ1,6ꢀdione 17. This result prompted
us to investigate the use of amino heterocycles in this transꢀ
formation. Thus, amino heterocycles such as 2ꢀ and 4ꢀamino
pyridines were employed as potential substrates for the oneꢀ
pot synthesis of pyridopyrazineꢀ1,6ꢀdiones; however, we
found that these amines lacked the nucleophilicity needed to
engage in the TBD amidation step. On the other hand, 2ꢀ
ethoxyꢀ4ꢀamino pyridine and other electron rich 5ꢀmembered
amino heterocycles were found to be sufficiently nucleophilic
to afford the corresponding Nꢀheteroaryl pyridopyrazineꢀ1,6ꢀ
diones in 45−81% yield (Table 3, examples 18−22). Again,
yields were highly dependent on the nucleophilicity of the
amino group, with more electron rich systems providing highꢀ
er yields. This is exemplified by the comparison of amino
isoxazole and Nꢀmethyl amino pyrazole (examples 19 and 20).
[a] All reactions were performed on a 1 mmol scale with 1.3 equiv. of
lactone and 1 equiv. of amine unless otherwise stated. [b] All yields reꢀ
ported are isolated yields. [c] Performed on a 1.3 mmol scale with 2 equiv.
of TBD. [d] Intermediate amido alcohol was isolated in 89% yield and no
ring closure was observed.16
In addition to its broad substrate scope, the TBDꢀ
mediated oneꢀpot synthesis of pyridopyrazineꢀ1,6ꢀdiones
proved highly effective on elevated scales required for explorꢀ
atory toxicology studies. We demonstrated this with the synꢀ
thesis of 25, a highly potent and selective γꢀsecretase modulaꢀ
tor (Scheme 4).17 Lactone 23 was subjected to TBDꢀmediated
aminolysis with cyclopropyl chromane amine 24. Consumpꢀ
tion of amine 24 and presence of the intermediate amido alcoꢀ
hols was observed after 1 h and at this time ETFA was added
to the reaction mixture. After an additional 4 hours, full conꢀ
version to racꢀ25 was observed. By simply diluting the reacꢀ
tion mixture with water, the desired product was precipitated
from the reaction mixture and could be collected by vacuum
filtration. After washing the collect solids with water, azeoꢀ
troping with toluene and drying, 89 grams of racꢀ25 were obꢀ
tained as a white solid in 93% yield.
Table 2. Evaluation of primary amine scope for the oneꢀpot
synthesis of pyridopyrazineꢀ1,6ꢀdiones.[a], [b]
Table 3. Evaluation of amino heterocycle nucleophiles in the
oneꢀpot synthesis of Nꢀheteroaryl pyridopyrazineꢀ1,6ꢀ
diones.[a], [b]
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tored by TLC (TLC plates F254, Merck) or UPLCꢀMS analysis
1
(Waters Acquity, ESCI +/−, APCI +/−). H NMR and 13C NMR
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3
spectra were obtained using deuterated solvent on a Varian or
Bruker 400 MHz instrument. All H NMR shifts are reported in δ
1
units (ppm) relative to the signals for chloroform (7.27 ppm) or
methanol (3.31 ppm). All 13C shifts are reported in δ units (ppm)
relative to the signals for chloroform (77.0 ppm) or methanol
(49.1 ppm) with 1Hꢀdecoupled observation. All coupling constants
(J values) are reported in hertz (Hz). NMR abbreviations are as
follows: br, broadened; s, singlet; d, doublet; t, triplet; q, quartet;
p, pentuplet; m, multiplet; dd, doublet of doublets; ddd, doublet of
doublet of doublets. Highꢀresolution mass spectra (HRMS) were
acquired on an Agilent model 6220 MS (ESIꢀTOF). Column
chromatography was carried out on silica gel 60 (32ꢀ60 mesh, 60
Ǻ) or on preꢀpacked Biotage™ or ISCO columns.
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Synthesis of Lactone 1: 3,4-dihydropyrido[2,1-c][1,4]oxazine-
1,6-dione (1): To 6ꢀoxoꢀ1,6ꢀdihydropyridineꢀ2ꢀcarboxylic acid
(5.00 g, 34.1 mmol, 95% purity) in anhydrous DMSO (18 mL)
was added cesium carbonate (17.6 g, 53.9 mmol) followed by 1,2ꢀ
dibromoethane (16.0 g, 85.4 mmol). The resultant slurry was
heated to 85 °C for 1.5 h, and the resultant dark solution was then
cooled to rt and partitioned between dichloromethane (4 × 40 mL)
and 10% saturated sodium bicarbonate (1 × 40 mL). The comꢀ
bined cloudy extracts were treated with solid sodium chloride (5.0
g) and decolorizing carbon (3.4 g) with stirring for 20 min. The
mixture was filtered through celite and the dichloromethane was
removed under reduced pressure to afford a slurry of product in
residual DMSO. The slurry was triturated with ethanol (4 mL) in
an ice bath for 20 min, and the solid was collected via filtration
and rinsed with ethyl ether to afford 4.77 g (85%) of the title
compound as an offꢀwhite crystalline solid. The material may be
recrystallized from ethyl acetate to afford offꢀwhite prisms. m.p.
178.2 – 180.4 ˚C; LCMS m/z 166 [M + H]+; IR (thin film) νmax
1649 (C=O) cm−1; 1H NMR (400 MHz, DMSOꢀd6) δ 7.59 (dd, J =
7.0, 9.4 Hz, 1H), 7.08 (dd, J = 1.2, 7.0 Hz, 1H), 6.76 (dd, J = 1.2,
[a] All reactions were performed on a 1 mmol scale with 1.3 equiv. lacꢀ
tone and 1 equiv. of amine unless otherwise stated. [b] All yields reported
are isolated yields.
Scheme 4. Large scale pyridopyrazineꢀ1,6ꢀdione synthesis
9.4 Hz, 1H), 4.64 (t, J = 5.1 Hz, 2H), 4.15 (t, J = 5.1 Hz, 2H); 13
C
NMR (100 MHz, DMSOꢀd6) 159.4, 159.0, 138.6, 133.4, 124.9,
65.6, 38.4; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C8H8NO3
166.0498, found 166.0496.
Synthesis and characterization of intermediate amido alcoꢀ
hol 3. N-benzyl-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-2-
carboxamide (3): To a suspension of lactone 1 (215.0 mg, 1.3
mmol) and TBD (220.0 mg, 1.5 mmol) in DMF (1.0 mL) was
added benzylamine (0.11 mL, 1.00 mmol) and the reaction mixꢀ
ture was stirred at room temperature for 2 h. The reaction was
partitioned between water and EtOAc and the layers were separatꢀ
ed. The aqueous layer was extracted with EtOAc (3 × 5 mL). The
combined EtOAc layers were washed with water, brine and then
dried over Na2SO4, filtered and evaporated. The resulting residue
was purified by silica gel chromatography (0 – 5% MeOH in
DCM) to afford the product as a white solid (0.207 g, 0.76 mmol,
76%). LCMS m/z 273.5 [M + H]+; 1H NMR (400 MHz, CDCl3) δ
7.42 – 7.28 (m, 6H), 7.00 (s, 1H), 6.61 (dd, J = 9.2, 1.3 Hz, 1H),
6.36 (dd, J = 6.8, 1.4 Hz, 1H), 4.59 (d, J = 5.8 Hz, 2H), 4.26 (dd,
J = 5.6, 4.4 Hz, 2H), 3.95 (dd, J = 5.6, 4.4 Hz, 2H), 3.64 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 163.6, 163.1, 144.3, 138.7, 137.0,
128.9, 128.0, 127.9, 122.3, 122.3, 106.8, 60.5, 48.9, 44.2.; IR
(thin film) νmax 3199 (O–H), 1644 (C=O), 1053 (C–O) cm−1;
HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C15H16N2O3Na
295.1053, found 295.1049.
In conclusion, we have developed a mild, single vessel
lactoneꢀtoꢀlactam conversion for the synthesis of pyridopyraꢀ
zineꢀ1,6ꢀdiones utilizing TBD to mediate all key steps in this
transformation: lactone amidation, alcohol activation with
ETFA and deprotonative cyclization. The described transforꢀ
mation has a broad substrate scope that is capable of generatꢀ
ing Nꢀsubstituted pyridopyrazineꢀ1,6ꢀdiones from a wide variꢀ
ety of amines including branched and unbranched aliphatic
amines, anilines and amino heterocycles. Furthermore, this
method was found to be highly scalable, generating cycloproꢀ
pyl chromane γꢀsecretase modulator 26 on an 89 g scale, withꢀ
out the need for specialized equipment, liquidꢀliquid extraction
or chromatography.
General procedure for the synthesis of N-alkyl, Nꢀaryl and
Nꢀheteroaryl pyridopyrazineꢀ1,6ꢀdiones. Note that this general
procedure was followed unless otherwise stated. To a suspension
of lactone 1 (215.0 mg, 1.3 mmol) and TBD (220.0 mg, 1.5
mmol) in DMF (1.0 mL) was added nitrogen nucleophile (1.00
mmol) and the reaction mixture was stirred at room temperature.
Experimental Section
General. All solvents and reagents were obtained from commerꢀ
cial sources and were used as received. All reactions were moniꢀ
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The reaction was monitored by LCMS for consumption of nitroꢀ
silica gel chromatography (0 – 5% MeOH in DCM) to afford the
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8
gen nucleophile and the presence of the corresponding intermediꢀ
ate amido alcohol. ETFA (0.24 mL, 2.00 mmol) was added to the
reaction mixture and stirring was continued at room temperature.
The ring closure was monitored by LCMS for consumption of
amido alcohol intermediate and presence of pyridopyrazineꢀ1,6ꢀ
dione. The reaction was quenched with aqueous 1N NaOH (2 mL)
and extracted into either DCM or EtOAc (3 × 5 mL). The comꢀ
bined organic layers were washed with water and brine and then
dried over MgSO4, filtered and evaporated. The resulting residue
was purified by silica gel chromatography.
Synthesis and characterization of pyridopyrazineꢀ1,6ꢀdiones
5, 7−14, 16ꢀ22: 2-benzyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-
1,6-dione (5): The general procedure was followed using benzylꢀ
amine (0.11 mL, 1.00 mmol) and the reaction mixture was stirred
at room temperature for 1 h. ETFA was added and the reaction
was stirred for 1 h prior to work up using DCM and 1N NaOH as
described. The resulting residue was purified by silica gel chroꢀ
matography (0 – 5% MeOH in DCM) to afford the title compound
as a white solid (0.241 mg, 0.95 mmol, 95%). The spectral data
matched that reported in the literature.8a LCMS m/z 255.1 [M +
H]+; 1H NMR (400 MHz, CDCl3) δ 7.46 (t, J = 8.1 Hz, 1H), 7.40
– 7.29 (m, 5H), 7.22 (d, J = 6.8 Hz, 1H), 6.76 (d, J = 8.9 Hz, 1H),
4.77 (s, 2H), 4.26 – 4.11 (m, 2H), 3.54 (dd, J = 6.7, 5.1 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 160.9, 158.3, 138.7, 136.8, 135.5,
129.0, 128.2, 124.1, 109.3, 50.7, 43.3, 39.0.
title compound as an offꢀwhite solid (0.177 g, 0.69 mmol, 69%).
LCMS m/z 256.1 [M + H]+; 1H NMR (400 MHz, CDCl3) δ 8.66 –
8.55 (m, 3H), 7.47 (ddd, J = 8.7, 7.1, 1.1 Hz, 1H), 7.25 (d, J = 5.2
Hz, 2H), 7.22 (d, J = 6.9 Hz, 1H), 6.79 (d, J = 9.3 Hz, 1H), 4.78
(s, 2H), 4.26 (t, J = 5.9 Hz, 2H), 3.60 (t, J = 5.8 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 160.8, 158.6, 150.1, 145.0, 138.6,
136.2, 124.6, 122.8, 109.5, 50.0, 44.1, 38.9.; IR (thin film) νmax
1633 (C=O) cm−1; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C14H14N3O2 256.1081, found 256.1076.
9
2-allyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (10):
The general procedure was followed using allyl amine (57.1 mg,
1.0 mmol) and the reaction mixture was stirred at room temperaꢀ
ture for 10 min. ETFA was added and the reaction was stirred
overnight prior to work up using DCM and 1N NaOH as deꢀ
scribed. The resulting residue was purified by silica gel chromaꢀ
tography (50 – 100% EtOAc in heptane) to afford the title comꢀ
pound as an offꢀwhite solid (0.188 g, 0.92 mmol, 92%). LCMS
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1
m/z 205.1 [M + H]+; H NMR (400MHz, CDCl3) δ 7.45 (dd, J =
7.0, 9.2 Hz, 1H), 7.18 (dd, J = 1.4, 7.0 Hz, 1H), 6.77 (dd, J = 1.4,
9.2 Hz, 1H), 5.88 − 5.76 (m, 1H), 5.34 − 5.31 (m, 1H), 5.29 (qd, J
= 1.3, 8.0 Hz, 1H), 4.29 − 4.23 (m, 2H), 4.19 (td, J = 1.4, 6.1 Hz,
2H), 3.62 − 3.56 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 160.9,
158.0, 138.6, 136.7, 131.4, 124.1, 119.2, 109.1, 49.7, 43.3, 39.0.;
IR (thin film) νmax 1632 (C=O) cm−1; HRMS (ESIꢀTOF) m/z: [M
+ H]+ Calcd for C11H13N2O2 205.0972, found 205.0966.
2-(4-methoxybenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-
1,6-dione (7): The general procedure was followed using 4ꢀ
methoxybenzyl amine (137.0 mg, 1.0 mmol) and the reaction
mixture was stirred at room temperature for 1 h. ETFA was added
and the reaction was stirred overnight prior to work up using
DCM and 1N NaOH as described. The resulting residue was puriꢀ
fied by silica gel chromatography (50 – 100% EtOAc in heptane)
to afford the title product as a thick oil that slowly solidified to an
offꢀwhite solid (0.281 g, 0.99 mmol, 99%). LCMS m/z 285.1 [M
2-(prop-2-yn-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-
dione (11): The general procedure was followed using propargylꢀ
amine (55.1 mg, 1.0 mmol) and the reaction mixture was stirred at
room temperature for 30 min. ETFA was added and the reaction
was stirred overnight prior to work up using DCM and 1N NaOH
as described. The resulting residue was purified by silica gel
chromatography (50 – 100% EtOAc in heptane) to afford the title
compound as an offꢀwhite solid (0.155 g, 0.77 mmol, 77%).
1
LCMS m/z 203.4 [M + H]+; H NMR (400 MHz, CDCl3) δ 7.46
1
+ H]+; H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 9.0, 7.1 Hz,
(dd, J = 9.2, 6.9 Hz, 1H), 7.19 (d, J = 7.5 Hz, 1H), 6.79 (d, J = 9.2
Hz, 1H), 4.43 (d, J = 2.5 Hz, 2H), 4.34 – 4.26 (m, 2H), 3.84 –
3.72 (m, 2H), 2.34 (t, J = 2.5 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 160.8, 157.9, 138.6, 136.3, 124.5, 109.4, 76.8, 73.5,
43.1, 38.9, 36.1.; IR (thin film) νmax 3232, 2125, 1633 (C=O)
cm−1; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C11H11N2O2
203.0815, found 203.0808.
1H), 7.25 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 7.2 Hz, 1H), 6.89 (d, J
= 7.9 Hz, 2H), 6.76 (d, J = 9.2 Hz, 1H), 4.70 (s, 2H), 4.18 (t, J =
5.9 Hz, 2H), 3.82 (d, J = 1.5 Hz, 3H), 3.52 (t, J = 5.7 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 160.9, 159.5, 158.2, 138.6, 136.8,
129.7, 127.6, 124.1, 114.3, 109.2, 55.3, 50.0, 43.0, 39.0.; IR (thin
film) νmax 1636 (C=O) cm−1; HRMS (ESIꢀTOF) m/z: [M + H]+
Calcd for C16H17N2O3 ([M + H]+) 285.1234, found 285.1231.
2-(4-(trifluoromethyl)benzyl)-3,4-dihydro-2H-pyrido[1,2-
2-(1-phenylethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-
dione (12): To a suspension of lactone 1 (280.0 mg, 1.7 mmol) in
DMF (1.3 mL) was added αꢀmethyl benzylamine (0.17 mL, 1.3
mmol) followed by TBD (272.0 mg, 1.95 mmol). The reaction
mixture was stirred at room temperature for 2 h after which ethyl
trifluoroacetate (0.24 mL, 1.3 mmol) was added to the reaction
mixture and stirring was continued at room temperature for an
additional 1 h. TLC analysis revealed that major product was the
intermediate amido alcohol. An additional portion of ethyl triꢀ
fluoroacetate (0.54 mL, 5.2 mmol) was added to the reaction mixꢀ
ture and stirring was continued overnight. TLC analysis revealed
that some intermediate amido alcohol still remained. An additionꢀ
al portion of TBD (90.6 mg, 0.65 mmol) was added and complete
conversion was realized by TLC analysis after 2 h. The reaction
was quenched with aqueous 1N NaOH (2 mL) and stirred for 15
min. The mixture was partitioned between water and ethyl acetate.
The layers were separated and the organic layer was washed with
brine and dried over MgSO4. Filtered and evaporated to afford a
colorless oil that was purified by silica gel chromatography (100%
EtOAc). The title compound was obtained as an offꢀwhite solid
(0.180 g, 0.68 mmol, 52%). The spectral data matched that reportꢀ
a]pyrazine-1,6-dione (8): The general procedure was followed
using 4ꢀ(trifluoromethyl)benzylamine (175 mg, 1.00 mmol) and
the reaction mixture was stirred at room temperature for 1 h.
ETFA was added and the reaction was stirred for an additional
hour prior to work up using EtOAc and 1N NaOH as described.
The resulting residue was purified by silica gel chromatography (0
– 10% MeOH in DCM) to afford the title product as a white solid
(0.306 g, 0.95 mmol, 95%). LCMS m/z 323.4 [M + H]+; 1H NMR
(400 MHz, CD3OD) δ 7.63 (d, J = 8.2 Hz, 2H), 7.62 − 7.57 (m,
1H), 7.51 (d, J = 8.2 Hz, 2H), 7.20 (dd, J = 1.6, 7.0 Hz, 1H), 6.72
(dd, J = 1.2, 9.0 Hz, 1H), 4.81 (s, 2H), 4.24 − 4.15 (m, 2H), 3.70 −
3.61 (m, 2H).; 13C NMR (100 MHz, CD3OD) δ 163.1, 160.3,
2
142.1, 141.0, 138.5, 131.2 (q, JC−F = 32.1 Hz), 129.8, 126.9 (q,
1
3JC−F = 3.51 Hz), 125.8 (q, JC−F = 271.1 Hz), 124.6, 111.1, 51.4,
45.1, 40.7; IR (thin film) νmax 1641 (C=O) cm−1; HRMS (ESIꢀ
TOF) m/z: [M + H]+ Calcd for C16H14F3N2O2 323.1002, found
323.1000.
2-(pyridin-4-ylmethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-
1,6-dione (9): The general procedure was followed using 4ꢀ
pyridine methanamine (108 mg, 1.0 mmol) and the reaction mixꢀ
ture was stirred at room temperature for 2 h. ETFA was added and
the reaction was stirred for 2 h prior to work up using DCM and
1N NaOH as described. The resulting residue was purified by
1
ed in the literature.8a LCMS m/z 269.5 [M + H]+; H NMR (400
MHz, CDCl3) δ 7.46 (dd, J = 9.2, 6.9 Hz, 1H), 7.30 – 7.42 (m,
5H), 7.23 (dd, J = 6.9, 1.4 Hz, 1H), 6.75 (dd, J = 9.2, 1.4 Hz, 1H),
6.11 (q, J = 7.1 Hz, 1H), 4.28 (ddd, J = 14.2, 6.4, 3.9 Hz, 1H),
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3.88 (ddd, J = 14.2, 8.9, 4.0 Hz, 1H), 3.45 (ddd, J = 13.0, 8.9, 3.9
2H), 4.11 – 4.04 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 160.8,
1
2
3
4
5
6
7
8
Hz, 1H), 3.18 (ddd, J = 13.4, 6.5, 4.0 Hz, 1H), 1.61 (d, J = 7.1 Hz,
3H).
157.8, 141.1, 138.7, 137.1, 129.3, 127.3, 124.6, 124.4, 109.7,
47.2, 39.5.; IR (thin film) νmax 1640 (C=O) cm−1; HRMS (ESIꢀ
TOF) m/z: [M + H]+ Calcd for C14H13N2O2 241.0972, found
241.0969.
2-(cyclopropylmethyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-
1,6-dione (13): The general procedure was followed using cycloꢀ
propylamine (57.1 mg, 1.0 mmol) and the reaction mixture was
stirred at room temperature for 2 h. ETFA was added and the
reaction was stirred for 2 h prior to work up using DCM and 1N
NaOH as described. The resulting residue was purified by silica
gel chromatography (0 – 5% MeOH in DCM) to afford the title
compound as an offꢀwhite solid (0.173 g, 0.85 mmol, 85%).
2-(6-ethoxypyridin-3-yl)-3,4-dihydro-2H-pyrido[1,2-
a]pyrazine-1,6-dione (18): The general procedure was followed
using 6ꢀethoxypyridinꢀ3ꢀamine (138.0 mg, 1.0 mmol) and the
reaction mixture was stirred at room temperature for 6 h. ETFA
was added and the reaction was stirred overnight prior to work up
using DCM and 1N NaOH as described. The resulting residue was
purified by silica gel chromatography (0% – 10% MeOH in
DCM) to afford the title compound as a pink solid (0.162 g, 0.57
9
1
LCMS m/z 205.1 [M + H]+; H NMR (400 MHz, CDCl3) δ 7.46
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(dd, J = 8.8, 7.1 Hz, 1H), 7.19 (d, J = 6.9 Hz, 1H), 6.77 (d, J = 9.2
Hz, 1H), 4.23 (t , J = 5.9 Hz, 2H), 3.63 (t, J = 5.9 Hz, 2H), 2.91
(dt, J = 7.4, 3.6 Hz, 1H), 0.98 (q, J = 6.6 Hz, 2H), 0.83 – 0.75 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 160.9, 159.8, 138.7, 137.0,
124.0, 108.9, 44.6, 39.6, 30.3, 7.0.; IR (thin film) νmax 1637 (C=O)
cm−1; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C11H12N2O2
205.0972, found 205.0966.
1
mmol, 57%). LCMS m/z 286.4 [M + H]+; H NMR (400 MHz,
CDCl3) δ 8.14 (d, J = 2.7 Hz, 1H), 7.61 (dd, J = 8.9, 2.8 Hz, 1H),
7.48 (dd, J = 9.2, 6.9 Hz, 1H), 7.22 (dd, J = 6.9, 1.3 Hz, 1H), 6.84
– 6.74 (m, 2H), 4.44 – 4.33 (m, 5H), 4.05 – 4.00 (m, 2H), 1.40 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.4, 160.7,
158.1, 142.8, 138.6, 136.7, 135.7, 131.5, 124.5, 111.3, 109.8,
62.2, 47.5, 39.3, 14.5.; IR (thin film) νmax 1648 (C=O) cm−1;
HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C15H16N3O3
286.1186, found 286.1184.
2-cyclohexyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione
(14): The general procedure was followed using cyclohexylamine
(99.2 mg, 1.0 mmol) and the reaction mixture was stirred at room
temperature for 2 h. ETFA was added and the reaction was stirred
overnight prior to work up using DCM and 1N NaOH as deꢀ
scribed. The resulting residue was purified by silica gel chromaꢀ
tography (0 – 5% MeOH in DCM) to afford the title compound as
an offꢀwhite solid (0.201 g, 0.82 mmol, 82%). LCMS m/z 247.1
2-(isoxazol-3-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-
dione (19): The general procedure was followed using 3ꢀamino
isoxazole (84.1 mg, 1.0 mmol) and the reaction mixture was
stirred at room temperature overnight. ETFA was added and the
reaction was stirred for 1.5 h prior to work up using DCM and 1N
NaOH as described. Due to the presence of residual DMF, the
resulting residue was taken up in DCM and the solution was reꢀ
washed with water then brine. The resulting solution was dried
over Na2SO4, filtered and evaporated to afford the title compound
as a white solid (0.105 g, 0.45 mmol, 45%). LCMS m/z 232.3 [M
1
[M + H]+; H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 9.2, 6.9
Hz, 1H), 7.16 (d, J = 6.9 Hz, 1H), 6.75 (d, J = 9.2 Hz, 1H), 4.68 –
4.41 (m, 1H), 4.21 (dd, J = 6.7, 4.9 Hz, 2H), 3.54 (dd, J = 6.7, 4.9
Hz, 2H), 1.95 – 1.81 (m, 2H), 1.81 – 1.68 (m, 3H), 1.55 – 1.34
(m, 4H), 1.20 – 1.06 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
160.9, 157.6, 138.8, 137.3, 123.7, 109.1, 53.1, 39.4, 38.7, 29.8,
25.4, 25.3.; IR (thin film) νmax 1635 (C=O) cm−1; HRMS (ESIꢀ
TOF) m/z: [M + H]+ Calcd for C14H19N2O2 247.1441, found
247.1436.
1
+ H]+; H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 1.8 Hz, 1H),
7.49 (dd, J = 9.2, 6.9 Hz, 1H), 7.27 – 7.23 (m, 2H), 6.84 (dd, J =
9.2, 1.3 Hz, 1H), 4.45 – 4.33 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 160.5, 159.6, 159.0, 156.8, 138.4, 136.1, 125.3, 110.5,
100.6, 43.7, 38.7; IR (thin film) νmax 1651 (C=O) cm−1; HRMS
(ESIꢀTOF) m/z: [M + H]+ Calcd for C11H10N3O3 232.0717, found
232.0709.
2-(2-(1H-indol-3-yl)ethyl)-3,4-dihydro-2H-pyrido[1,2-
a]pyrazine-1,6-dione (16): The general procedure was followed
using tryptamine (0.160 g, 1.00 mmol) and the reaction mixture
was stirred at room temperature for 1 h. ETFA was added and the
reaction was stirred for 1 h prior to work up using EtOAc and 1N
NaOH as described. The resulting beige solid was recrystallized
from EtOAc to afford the title compound as a crystalline white
solid (0.196 g, 0.64 mmol, 64%). m.p. 209.0 – 214.1 ˚C (deꢀ
comp.); LCMS m/z 308.4 [M + H]+; 1H NMR (500 MHz, DMSOꢀ
d6) δ 10.84 (br. s., 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.54 (dd, J = 7.0,
9.2 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H),
7.12 − 7.04 (m, 1H), 7.02 − 6.93 (m, 2H), 6.62 (dd, J = 1.2, 9.3
Hz, 1H), 4.03 − 3.97 (m, 2H), 3.77 − 3.66 (m, 2H), 3.65 − 3.56
(m, 2H), 2.99 (t, J = 7.6 Hz, 2H); 13C NMR (125 MHz, DMSOꢀ
d6) δ 159.9, 157.3, 138.9, 137.4, 136.3, 127.1, 123.0, 122.7, 121.0,
118.3, 118.2, 111.5, 111.0, 107.3, 47.9, 43.8, 38.6, 22.8; IR (thin
film) νmax 3281 (N–H), 1639 (C=O) cm−1; HRMS (ESIꢀTOF) m/z:
[M + H]+ Calcd for C18H18N3O2 308.1394, found 308.1390.
2-phenyl-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione
(17): The general procedure was followed using aniline (0.09 mL,
93.1 mg, 1.0 mmol) and the reaction mixture was stirred at room
temperature overnight. ETFA was added and the reaction was
stirred for 2 h prior to work up using DCM and 1N NaOH as deꢀ
scribed. The resulting residue was purified by silica gel chromaꢀ
tography (0 – 5% MeOH in DCM) to afford an offꢀwhite solid
containing residual DMF. The solid was azeotroped with heptane
(3 × 20 mL) to afford the title compound as an offꢀwhite solid
(0.120 g, 0.50 mmol, 50%). LCMS m/z 241.5 [M + H]+; 1H NMR
(400 MHz, CDCl3) δ 7.54 – 7.43 (m, 3H), 7.41 – 7.36 (m, 2H),
7.35 – 7.29 (m, 1H), 7.26 (partially obscured by solvent, dd, J =
9.2, 1.4 Hz, 1H), 6.82 (dd, J = 9.2, 1.4 Hz, 1H), 4.47 – 4.39 (m,
2-(1-methyl-1H-pyrazol-3-yl)-3,4-dihydro-2H-pyrido[1,2-
a]pyrazine-1,6-dione (20): The general procedure was followed
using 1ꢀmethylꢀ1Hꢀpyrazolꢀ3ꢀamine (84.1 mg, 1.0 mmol) and the
reaction mixture was stirred at room temperature overnight. ETFA
was added and the reaction was stirred for 5 h prior to work up
using DCM and 1N NaOH as described. The resulting residue was
purified by silica gel chromatography (0% – 10% MeOH in
DCM) to afford the title compound as a white solid (0.155 g, 0.64
1
mmol, 64%). LCMS m/z 245.1 [M + H]+; H NMR (400 MHz,
CDCl3) δ 7.47 (dd, J = 9.2, 6.9 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H),
7.23 (dd, J = 7.0, 1.3 Hz, 1H), 6.88 (d, J = 2.3 Hz, 1H), 6.78 (dd,
J = 9.2, 1.3 Hz, 1H), 4.39 – 4.29 (m, 4H), 3.85 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 160.8, 156.3, 148.0, 138.6, 137.1, 131.2,
124.2, 109.5, 99.4, 43.3, 39.0.; IR (thin film) νmax 1644 (C=O)
cm−1; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C12H13N4O2
245.1033, actual 245.1034.
2-(1H-pyrrol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-
dione (21): The general procedure was followed using 1ꢀamino
pyrrole (82.1 mg, 1.0 mmol) and the reaction mixture was stirred
at room temperature overnight. ETFA was added and the reaction
was stirred for 1.5 h. The reaction was quenched with aqueous 1N
NaOH (1 mL) and stirred for 10 min upon which a white precipiꢀ
tate formed. Water (1 mL) was added to the slurry and stirring
continued for 5 min. The slurry was filtered on a glass frit. The
filter cake was washed with water, ether and heptane and allowed
to dry on the frit to afford the title product as a white powder
(0.143 g, 0.62 mmol, 62%). LCMS m/z 230.4 [M + H] +; 1H NMR
(400 MHz, CDCl3) δ 7.48 (dd, J = 9.3, 6.9 Hz, 1H), 7.25 (dd, J =
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The Journal of Organic Chemistry
6.9, 1.4 Hz, 1H), 6.84 (dd, J = 9.3, 1.4 Hz, 1H), 6.74 (t, J = 2.3
Supporting Information
Experimental details including H and 13C NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
2
3
4
5
6
7
8
1
Hz, 2H), 6.26 (t, J = 2.3 Hz, 2H), 4.50 (t, J = 5.8 Hz, 2H), 4.09 (t,
J = 5.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 160.7, 157.7,
138.7, 135.8, 125.4, 119.5, 110.4, 108.7, 49.8, 40.0; IR (thin film)
νmax 1651 (C=O) cm−1; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd
for C12H12N3O2 230.0924, found 230.0923.
AUTHOR INFORMATION
2-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-
dione (22): The general procedure was followed using 2ꢀamino
thiazole (100.0 mg, 1.0 mmol) and the reaction mixture was
stirred at room temperature for 1 h. ETFA was added and the
reaction was stirred for 2 h prior to work up using DCM and 1N
NaOH as described. The resulting residue was purified by silica
gel chromatography (30 – 100% EtOAc in heptane) to afford the
title compound as a white solid (0.20 g, 0.8 mmol, 80%). LCMS
Corresponding Author
*Eꢀmail: danica.rankic@pfizer.com
Author Contributions
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The manuscript was written through contributions of all authors
and all authors have given approval to the final version of the
manuscript.
1
m/z 248.4 [M + H] +; H NMR (400 MHz, CDCl3) δ 7.60 (d, J =
3.5 Hz, 1H), 7.52 (dd, J = 9.3, 6.9 Hz, 1H), 7.32 (dd, J = 6.9, 1.3
Hz, 1H), 7.17 (d, J = 3.6 Hz, 1H), 6.87 (dd, J = 9.2, 1.3 Hz, 1H),
4.73 – 4.62 (m, 2H), 4.47 – 4.40 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 160.5, 158.0, 156.5, 138.5, 137.6, 135.6, 125.5, 116.4,
110.5, 43.7, 38.8. IR (thin film) νmax 1640 (C=O) cm−1; HRMS
(ESIꢀTOF) m/z: [M + H]+ Calcd for C11H10N3O2S 248.0488,
found 248.0481.
Notes
The authors have no competing financial interests.
ACKNOWLEDGMENT
The authors would like to thank Martin Pettersson, Akshay Shah,
Christopher Helal, Patrick Verhoest, Anabella Villalobos and
Prof. E. J. Corey for their useful discussions and feedback during
the preparation of this manuscript.
Synthesis and characterization of intermediate amido alcoꢀ
hol 15a – precursor to targeted pyridopyrazineꢀ1,6ꢀdione 15:
N-(t-butyl)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-2-
carbox-amide (15a): To a suspension of lactone 1 (215.0 mg, 1.3
mmol) and TBD (220.0 mg, 1.5 mmol) in DMF (1.0 mL) was
added tertꢀbutyl amine (0.11 mL, 1.00 mmol) and the reaction
mixture was stirred at room temperature for 24 h. The reaction
was partitioned between water and EtOAc and the layers were
separated. The aqueous layer was extracted with EtOAc (3 × 5
mL). The combined EtOAc layers were washed with water, brine
and then dried over Na2SO4, filtered and evaporated. The resulting
residue was purified by silica gel chromatography (0 – 5% MeOH
in DCM) to afford the product as a white solid (0.213 g, 0.89
mmol, 89%). 1H NMR (400 MHz, CDCl3) δ 7.32 (dd, J = 9.2, 6.8
Hz, 1H), 6.64 (dd, J = 9.2, 1.4 Hz, 1H), 6.29 (dd, J = 6.7, 1.4 Hz,
1H), 6.27 (br s, 1H, N–H), 4.31 – 4.22 (m, 2H), 4.00 (q, J = 4.8
Hz, 2H), 3.84 (t, J = 5.0 Hz, 1H, O–H), 1.46 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 163.1, 145.2, 138.7, 122.1, 105.9, 60.7, 52.8,
49.0, 28.5.; IR (thin film) νmax 3200 (O–H), 1647 (C=O), 1053
(C–O) cm−1; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C12H19N2O3 239.1390, found 239.1385.
REFERENCES
(1) (a) Ogliaruso, M. A.; Wolfe, J. F. In Synthesis of Lactones and
Lactams (1993); John Wiley & Sons, Inc.; West Sussex, England,
2010; p 1ꢀ268. (b) Natural Lactones and Lactams; Synthesis, Occur-
rence and Biological Activity; Janecki, T., Ed WileyꢀVCH: Weinꢀ
heim, Germany, 2013.
(2) (a) For an Irꢀcatalyzed hydrogen autotransfer/transamidation
approach, see: Kim, K.; Hong, S. H. J. Org. Chem. 2015, 80, 4152.
(b) For an approach using solid supported reagents and scavengers,
see: Kawahata, N. H.; Brookes, J.; Makara, G. M. Tetrahedron
Lett.2002, 43, 7221.
(3) (a) Decker, M.; Nguyen, T. T. H.; Lehmann, J. Tetrahedron 2004,
60, 4567. (b) Zienty, F. B.; Steahly, G. W. J. Am. Chem. Soc. 1947,
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2727.
(4) Orrling, K. M.; Wu, X.; Russo, F.; Larhed, M. J. Org. Chem.
2008, 73, 8627.
(5) Natsugari, H.; Ikeura, Y.; Kamo, I.; Ishimaru, T.; Ishichi, Y.;
Fuishima, A.; Tanaka, T.; Kasahara, F.; Kawada, M.; Doi, T. J. Med.
Chem. 1999, 42, 3982.
(6) Wai, J. S.; Kim, B.; Fisher, T. E.; Zuang, L.; Embrey, M. W.;
Williams, P. D.; Staas, D. D.; Culberson, C.; Lyle, 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.
(7) For recent reviews on γꢀsecretase modulators as potential theraꢀ
peutics in Alzheimer’s Disease including examples of pyridopyrazineꢀ
1,6ꢀdiones see: (a) Johnson, D. S.; Pettersson, M. Top. Med. Chem.
2017, 24, 87. (b) Bursavich, M. G.; Harrison, B. A.; Blain, J.ꢀF. J.
Med. Chem. 2016, 59, 7389.
(8) (a) Tran, T. P.; Mullins, P. B.; am Ende, C. W.; Pettersson, M.
Org. Lett. 2013, 15, 642. (b) Janssen Pharmaceuticals, Inc. WO
2014096212; 2014 (c) Janssen Pharmaceuticals, Inc. WO
2014111457 A1; 2014 (d) for related cyclization with bis (2ꢀ
chloroethyl amine) see: Pettersson, M.; Johnson, D. S.; Subramanꢀ
yam, C.; Bales, K. R.; am Ende, C. W.; Fish, B. A.; Green, M. A.;
Kauffman, G. W.; Mullins, P. B.; Navaratnam, T.; Sakya, S. M.; Stiff,
C. M.; Tran, T. P. Xie, L.; Zhang, L.; Pustilnik, L. R.; Vetelino, B. C.;
Wood, K. M.; Pozdnyakov, N.; Verhoest, P. R.; O’Donnell, C. J. J.
Med. Chem. 2014, 57, 1046.
Procedure for the large scale preparation of γꢀsecretase
modulator racꢀ25: To a suspension of lactone 2310b (60.6 g,
0.247 mol) and amine 2417 (53.3 g, 0.186 mol) in DMF (200 mL)
was added TBD (39.9 g, 0.278 mol) and the reaction mixture was
stirred at room temperature. After 1 h, LCMS analysis revealed
consumption of amine 24 and the presence of the corresponding
intermediate amido alcohol. ETFA (55 mL, 0.460 mol) was added
dropwise to the reaction mixture over 30 minutes and stirring was
continued at room temperature for an additional hour. The reacꢀ
tion was quenched with aqueous 1N NaOH (200 mL). The resultꢀ
ing suspension was stirred at room temperature for 30 min and
then filtered. The obtained solids were washed with water, azeoꢀ
troped with toluene (3 × 500 mL) and dried under vacuum to afꢀ
ford the product as a white solid (88.9 g, 173 mmol, 93% yield).
Analytical data matched that reported in the literature.17 LCMS
1
m/z 515.2 (M + H)+; H NMR (400 MHz, CD3ODꢀd4) δ 8.29 (s,
1H), 7.77 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.26 – 7.33 (m, 2H),
6.95 (d, J = 9.8 Hz, 1H), 6.78 (d, J = 8.6 Hz, 1H), 5.11 (d, J =
14.8 Hz, 1H), 4.20 – 4.26 (m, 2H), 3.77 – 3.84 (m, 2H), 3.01 (d, J
= 14.8 Hz, 1H), 2.23 (s, 3H), 2.02 (t, J = 7.2 Hz, 1H), 1.50 (s,
3H), 1.28 (s, 3H), 1.08 (d, J = 7.4 Hz, 2H).
(9) A number of conditions were evaluated for efficient lactone amiꢀ
dation. Of these, two reagents were found to be superior: DABALꢀ
Me3 (which even outperformed related AlMe3) and triazabicyclodeꢀ
cene (TBD). Direct aminolysis with amines at elevated temperatures
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was successful, with the caveat that a large excess of amine was reꢀ
quired to drive the reaction beyond ~60% conversion. While acceptaꢀ
ble for simple and readily available amines, an alternative approach is
required when both coupling partners are precious.
1
2
3
(10) For examples of lactone amidation with DABALꢀMe3 see: (a)
Pettersson, M.; Johnson, D. S.; Humphrey, J. M.; am Ende, C. W.;
Evrard, E.; Efremov, I.; Kauffman, G. W.; Stepan, A. F.; Stiff, C. M.;
Xie, L.; Bales, K. R.; HajosꢀKorcsok, E.; Murrey, H. E.; Pustilnik, L.
R.; Steyn, S. J.; Wood, K. M.; Verhoest, P. R. Bioorg. Med. Chem.
Lett. 2015, 25, 908. (b) Pettersson, M.; Johnson, D. S.; Humphrey, J.
M.; Butler, T. W.; am Ende, C. W.; Fish, B. A.; Green, M. E.; Kauffꢀ
man, G. W.; Mullins, P. B.; O’Donnell, C. J.; Stepan, A. F.; Stiff, C.
M.; Subramanyam, C.; Tran, T. P.; Vetelino, B. C.; Yang, E.; Xie, L.;
Bales, K. R.; Pustilnik, L. R.; Steyn, S. J.; Wood, K. M.; Verhoest, P.
R. ACS Med Chem Lett. 2015, 6, 596. (c) Pfizer, Inc.US9193726 B2.
(11) (a) For an initial report of DABALꢀMe3 see: Bradford, A. M.;
Bradley, D. C.; Hursthouse, M. B.; Motevalli, M. Organometallics
1992, 11, 111. (b) For a review on the initial discovery and uses of
DABALꢀMe3 as a reagent that can be used in the absence of an inert
atomosphere see: Woodward, S. Synlett 2007, 10, 1490. (c) For the
use of DABALꢀMe3 in amide bond formation see: Novak, A.; Humꢀ
phreys, L. D.; Walker, M. D.; Woodward, S. Tetrahedron Lett. 2006,
47, 5767.
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(12) Sabot, C.; Kumar, K. A.; Meunier, S.; Mioskowski, C.;
Tetrahedron Lett.2007, 48, 3863.
(13) TBD is known to mediate transesterification, see: Pratt, R. C.;
Lohmeijer, B. G. G.; Long, D. A.; Waymouth, R. M.; Hedrick, J. L. J.
Am. Chem. Soc. 2006, 128, 4556.
(14) It has previously been demonstrated that the amido alcohol actiꢀ
vation with trifluoromethyl acetic anhydride and subsequent deprotoꢀ
nation with DBU mediates lactam formation. See reference 10b for
more details.
(15) 1,3,5ꢀtrimethoxy benzene was used as a standard for reported 1H
NMR yields.
(16) See supporting information for more detail.
(17) Pettersson, M.; Johnson, D. S.; Rankic, D. A.; Kauffman, G. W.;
am Ende, C. W.; Butler, T. W.; Boscoe, B.; Evrard, E.; Helal, C. J.;
Humphrey, J. M.; Stepan, A. F.; Stiff, C. M.; Yang, E.; Xie, L.; Bales,
K. R.; HajosꢀKorcsok, E.; Jenkinson, S.; Pettersen, B.; Pustilnik, L.
R.; Ramirez, D. S.; Steyn, S. J.; Wood, K. M.; Verhoest, P. R. Med-
ChemCommun. 2017, 8, 730.
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