Accessing 4-oxy-substituted isoquinolinones via C-H activation and regioselective migratory insertion with electronically biased ynol ethers

Article abstract of DOI:10.1039/C8OB02622J

The rhodium-catalyzed C-H activation and annulation with ynol ethers to directly provide 4-oxy substituted isoquinolinones is reported. The polarized nature of ynol ethers provides an electronic bias for controlling the regioselectivity of the migratory insertion process. While the highly reactive nature of ynol ethers presents a challenge, mild conditions were found to provide product in moderate to good yield. Utility was demonstrated by application in the synthesis of a prolyl-4-hydroxylase inhibitor framework.

Full text of DOI:10.1039/C8OB02622J

Organic &
Biomolecular Chemistry
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PAPER
Accessing 4-oxy-substituted isoquinolinones via
C–H activation and regioselective migratory
insertion with electronically biased ynol ethers†
Cite this: Org. Biomol. Chem., 2018,
16, 8639
Brandon L. Coles-Taylor, a Maximilian S. McCallum, a J. Scott Lee b and
a
Brian W. Michel
*
The rhodium-catalyzed C–H activation and annulation with ynol ethers to directly provide 4-oxy substi-
tuted isoquinolinones is reported. The polarized nature of ynol ethers provides an electronic bias for con-
trolling the regioselectivity of the migratory insertion process. While the highly reactive nature of ynol
ethers presents a challenge, mild conditions were found to provide product in moderate to good yield.
Utility was demonstrated by application in the synthesis of a prolyl-4-hydroxylase inhibitor framework.
Received 8th August 2018,
Accepted 24th October 2018
DOI: 10.1039/c8ob02622j
rsc.li/obc
ambient temperature.8 Recently, more readily available metals,
such as cobalt9 and ruthenium,10 have been used as catalysts.
Introduction
Throughout the last decade, C–H activation has been a thriv-
Application of these technologies to target-directed synth-
ing field of organic research yielding new transformations that eses, such as the synthesis of biologically active species, would
have the ability to rapidly functionalize relatively simple sub- be facilitated by methods that deliver products with predict-
strates or to functionalize late stage intermediates.1 Chelation able regioselectivity and manipulable handles. There are a few
assisted C–H activation, in particular, is a common strategy general preferences that are observed depending on the nature
that has facilitated a rapid assembly of biologically relevant of the alkyne substituents (Fig. 2a): (1) If R1 is aryl and R2 is
frameworks such as isoquinoline, isoquinolinone, pyridine, alkyl, then the aryl group is observed proximal to the nitrogen;
and other N-containing scaffolds.2 In the context of these (2) if both R1 and R2 are alkyl, then the more sterically
N-containing heterocycles, Guimond and Fagnou3 as well as demanding group is observed distal to the nitrogen; (3) term-
Satoh, Miura and coworkers4 built upon the work of Jones and inal alkynes, when tolerated, provide products with substi-
coworkers5 to contemporaneously develop RhIII-catalyzed oxi-
dative cyclizations preparing isoquinolines via C–H activation
of imine substrates and annulation with disubstituted alkynes.
Following this early work with imines, Rovis and coworkers
demonstrated the competence of benzamides as coupling part-
ners in the synthesis of isoquinolinones with the use of an
external oxidant to turn over the RhIII catalyst in 2010 (Fig. 1).6
Fagnou and coworkers expanded upon this work in 2010, and
developed a catalytic system that utilized an internal oxidant
in the N-methoxy group, and afforded isoquinolinones in
excellent yields.7 Fagnou later found in 2011 that by changing
the internal oxidant they could retain the efficacy of isoquinoli-
none synthesis while reducing catalyst loading, and reacting at
aDepartment of Chemistry and Biochemistry, University of Denver, Denver, CO,
80210, USA. E-mail: Brian.Michel@du.edu
bMucosal Inflamation Program, University of Colorado, Anschutz Medical Campus,
Aurora, CO, 80045, USA
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data, 1H and 13C spectra of all new compounds. See
DOI: 10.1039/c8ob02622j
Fig. 1 Previous work synthesizing isoquinolinones via RhIII catalyzed
C–H activation.
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participating as migratory insertion substrates. Palladium cata-
lyzed hydroarylation and hydroalkenylation reported by Zhu
and coworkers is a notable exception to this (Fig. 2d).17 We
hypothesized that ynol ethers could undergo selective
migratory insertion due to the polarized nature of the alkyne.
Herein we report the highly regioselective synthesis of isoqui-
nolinones using electronically biased ynol ethers (Fig. 2e).
Results and discussion
Our efforts began with utilizing N-pivaloyloxy benzamide 1a
and 1-phenoxyhexyne 2a as our model substrates. Initial reac-
tion conditions of 2.5 mol% [Cp*RhCl2]2 and 25 mol% NaOAc
in 1,2-dichloroethane provided isoquinolinone 3aa in a 55%
yield after 4 hours. As preliminary studies indicated potential
degradation of the ynol ether substrate, 1.2 equivalents of
1-phenoxyhexyne 2a were added in three equal aliquots
(Table 1, entry 1) or via syringe pump addition of ynol ether
solution. Evaluation of other solvents did not lead to signifi-
cant increases in yield. However, methanol provided 3aa in
acceptable 42% yield, which has proven useful for polar sub-
strates (entry 2). Upon screening a range of additives (entries
3–6) the yield using 1,2-dichloroethane as the solvent could be
improved to 82% with the use of tetrabutylammonium acetate
(entry 6). Using these conditions, slow or batch-wise addition
was no longer found to be necessary and when 2a was added
in a single addition a 94% yield was observed (entry 7).
Variations in temperature (entries 8 and 9) and additive load-
ings (entry 10) did not provide improved product yields. Under
the optimized conditions starting material was consumed after
2.5 hours (entry 11). It should be noted that no ketene side
Fig. 2 (a) General selectivity guidelines for regioselective annulations;
(b) polarization of ynol ethers; (c) thermal rearrangement to ketenes; (d)
limited examples of migratory insertion with ynol ethers; and (e) syn-
thesis of 4-oxy isoquinolinones.
tution proximal to the nitrogen. Good selectivity is observed
from the benzamide/benzhydroxamic acid substrates; though
mixtures of regioisomeric products are observed from acryl-
amides and related challenging substrates.11,12 Predictable
annulation products with potential for further manipulation
remains a challenge.
As part of our efforts to prepare the biologically active 4-oxy
substituted isoquinoline framework,13 we hypothesized that
highly polarized ynol ethers (Fig. 2b) could override other
selectivity biases to provide a single cyclization product and
address a key limitation in current C–H activation/annulation
methodology by providing heteroatom functionalization of the
4-position. Indeed, You and co-workers observed 4-amino-
Table 1 Optimization of reaction conditions
isoquinolone
derivatives
from
the
cyclization
of
N-methylbenzamides and ynesulfonamides.14 While most
alkyne substrates had an aryl group, reinforcing the generally
observed pattern of product isomers, ynesulfonamides bearing
alkyl groups including a bulky tBu group delivered the
4-amino products with regioisomeric selectivity. Owing to the
success of ynesulfonamides in C–H activated isoquinolinone
synthesis, we were optimistic that ynol ethers would provide a
similar selectivity profile.
In contrast to their amino cousins bearing acyl or sulfonyl
groups to attenuate polarization of the triple bond, ynol ethers
are generally less stable and more difficult to handle.15 In fact,
much of the reported chemistry of ynol ethers takes advantage
of a relatively facile thermal isomerization to ketenes via a
hydride shift from the alkyl side of ynol ethers (Fig. 2c).16
Further, there are relatively limited examples of ynol ethers
Entry
Solvent
Additive
Temp. (°C)
% yielda
1
2
3
4
DCE
MeOH
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
NaOAc
NaOAc
CsOAc
NaOPiv
NH4OAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAcc
Bu4NOAc
30
30
30
30
30
30
30
45
75
30
30
55
42
57
45
76
82
94
57
5
6
7b
8
9
Trace
79
96
10
11d
a % yield determined by 1H NMR referenced to 2,4,5-trichloropyrimi-
dine as an internal standard. b Single addition of 2a. c 50 mol%
Bu4NOAc. d Reaction time was reduce to 2.5 h. For a more extensive
optimization table see ESI.
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products or products derived from interception of ketene side was found that protection of the alcohol as an acetate ester
products was observed. combined with slow addition of the ynol ether provided 3ah in
With general reaction conditions set, a variety of ynol 52% yield. The methoxy variant 3ai was afforded in 26% yield
ethers were evaluated (Table 2). While there are a number of under these conditions, but the yield could be increased to
methods for preparing ynol ethers, in our hands the most 66% yield with NaOAc as the additive.
reliable methods were preparation either from an alkoxide and
Using ynol ether 2b, a variety of electronically disparate
trichloroethylene or from the acetal of chloroacetaldehyde N-pivaloxybenzamide substrates were evaluated (Table 3). The
corresponding to the desired alkyl ether partner. In general annulation reaction with ynol ethers appears to have a signifi-
aryl and alkyl groups were compatible as ynol ether substitu- cant dependence on the electronic nature of the arene ring
ents and our optimization substrate provided 3aa in 85% iso- with a 4-OMe substituent providing a poor 11% yield of 3bb,
lated yield. Of note, a neopentyl group lacks the β-hydrogens while electron neutral and electron poor substrates generally
necessary for rearrangement to a ketene and provided 3ab in provided moderate to good yields (3cb–3gb). Interestingly
71% yield. The installation of a terminal trimethylsilyl group heterocyclic substrate 3hb did not provide product, while the
on the ynol-ether was well tolerated (3ae) and is useful as a isomeric 3ib was isolated in 74% yield. The discrepancy in
terminal alkyne surrogate or a handle for further modification yields for these benzamide derivatives likely stems from
via reactions such as a Fleming–Tamao oxidation18 or a attenuation of the rate or equilibrium position of the C–H acti-
Hiyama cross-coupling.19 Interestingly, a O-silyl ynol ether did vation process.
not react under these reaction conditions (3af). A free pro-
The success of propargylic acetate ynol-ethers as substrates
pargylic alcohol was not well-tolerated under the reaction con- in a one-step synthesis of a highly functionalized isoquinoli-
ditions, as rhodium rapidly facilitated a Meyer–Schuster none offered a unique opportunity to demonstrate a direct
rearrangement to give acrylate products.20 While slow addition route towards the synthesis of a class of biologically active iso-
could alleviate this competing reaction to some extent (3ag), it quinolines. These isoquinolines have inhibitory activity
against prolyl-4-hydroxylase domain (PHD) enzymes, which
Table 2 Scope evaluation of various ynol ethers
Table 3 Scope evaluation of various benzamides
a Isolated yields are averages of at least 2 separate experiments. b Ynol
ether showed no reaction or degredation. c 2.5 mol% [Cp*RhCl2]2,
25 mol% NaOAc, MeOH, syringe pump addition over 2.5 h, 4 h.
d Yields are reported as NMR yields using 2,4,5-trichloropyrimidine as
an internal standard. e 1.8 mmol scale, 25 mol% NaOAc, MeOH, a Isolated yields are averages of at least 2 separate experiments,
syringe pump addition over 2.5 h, 4 h total.
0.25 mmol scale.
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Scheme 1 Synthesis of prolyl-4-hydroxylase domain inhibitors.
play a key role in the regulation of hypoxia inducible factor.13
Inhibition of this enzyme is potentially therapeutic in the
treatment of chronic kidney disease, cancer-associated
Experimental
General procedure for the synthesis of isoquinolinones (3)
anemia, and inflammatory bowel diseases. Utilizing our annu- To a round bottom flask 1a (0.25 mol), cyclopentadienyl
lation with an appropriate ynol ether would allow for the direct rhodium chloride dimer (1.25–2.5 mol%), and Bu4NOAc
installation of the requisite 4-oxy functionality and potentially (25 mol%) were added. The flask was evacuated and refilled
provide a route with opportunity for late stage modifications.
with N2 gas. 1,2-Dichloroethane (1.0 mL) was added to the
We began the synthesis with the rhodium-catalyzed annula- flask, and the mixture was heated to 30 °C. Then, a solution of
tion to provide 3ai in a 66% yield (Scheme 1). POCl3 was used ynol ether (0.30 mmol) in 1,2-dichlorethane (1.0 mL) was
to chlorinate the carbonyl and convert to the isoquinoline 4 in added via syringe. The reaction mixture was then stirred for
50% yield. Notably 1-halo isoquinolines can be further functio- 2.5 h. The reaction mixture was concentrated, loaded directly
nalized via cross-coupling if desired.21 Next, basic methanol onto silica and purified by flash chromatography (CH2Cl2/
hydrolyzed the acetate and the resulting primary alcohol was MeOH). Products were verified by 1H, and 13C-NMR. Isolated
oxidized to aldehyde 5 in a 63% yield over two steps without yields are reported below.
purification of the intermediate alcohol. Further oxidation to
the carboxylic acid 6 in 84% yield was followed by amide coup-
ling with glycine tert-butyl ester, which provided isoquinoline
7 in an 88% yield. Palladium on carbon and ammonium
3-Butyl-4phenoxyisoquinoline-1(2H)-one (3aa)
This compound was prepared according to the general pro-
cedure. Molecular formula: C19H19NO2. Yellow solid, 62.9 mg
formate were used to hydrogenate the 1-position of the ring
1
quantitatively.22 A LiCl-TsOH tandem brought about both de-
and 60.1 mg (85% yield). H NMR (500 MHz, Chloroform-d) δ
methylation of the aromatic methoxy group23 and hydrolysis of
11.90 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 8.1, 7.0, 1H),
7.55 (d, J = 7.7 Hz, 1H), 7.50 (dd, J = 8.2, 7.0 Hz, 1H), 7.29 (dd,
J = 8.9, 7.4 Hz, 2H), 7.04 (dd, J = 7.4, 7.4 Hz, 1H), 6.96 (d, J =
the tBu ester to afford the desired isoquinoline in 86% yield
with the correct functionalization at the 3- and 4-positions. In
just eight steps, compound 8 was isolated in 15% overall yield
with minimal optimization of conditions.
7.8 Hz, 2H), 2.69 (t, J = 7.8 Hz, 2H), 1.74 (tt, J = 7.8, 7.4 Hz,
2H), 1.43 (qt, J = 7.4, 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13C
NMR (126 MHz, Chloroform-d) δ 163.6, 158.8, 134.9, 134.7,
132.7, 130.2, 129.7, 127.7, 126.3, 125.0, 122.0, 121.5, 114.9,
30.2, 27.7, 22.4, 13.7; HRMS (ESI): 292.1338 m/z [M]− calcu-
lated for C19H18NO2−, 292.1346 m/z observed.
Conclusions
In conclusion, ynol ethers have been demonstrated as viable
annulation partners in rhodium catalyzed C–H activation reac-
3-Buytyl-4-neopentoxyisoquin-1(2H)-one (3ab)
tions to provide isoquinolinone products as single isomers in This compound was prepared according to the general pro-
moderate to good yields. The polarized nature of the ynol cedure. Molecular formula: C18H25NO2. Yellow solid, 54.0 mg
1
ether is presumed to provide the controlling element for and 48.0 mg (71%). H NMR (500 MHz, Chloroform-d) δ 11.87
selectivity during the migratory insertion step as none of the (s, 1H), 8.43 (d, J = 8.0, 1H), 7.79 (d, J = 8.0, 1H), 7.72 (dd, J =
other insertion isomer has been observed. Finally, this 8.0, 7.0, 1H), 7.49 (dd, J = 8.0, 7.0, 1H), 3.54 (s, 2H), 2.76 (t, J =
approach was demonstrated to enable the rapid assembly of 7.4 Hz, 2H), 1.80 (m, 2H), 1.51 (m, 2H), 1.18 (s, 9H), 1.01 (t, J =
PHD inhibitors. Current efforts are focused on evaluating ynol 7.4 Hz, 3H); 13C NMR (126 MHz, Chloroform-d) δ 163.3, 135.3,
ethers in other alkyne difunctionalization reactions.
134.6, 133.6, 132.3, 127.8, 125.8, 125.0, 120.8, 84.2, 32.5, 30.8,
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27.4, 26.7, 22.7, 13.8; HRMS (ESI): 286.1807 m/z [M]− calc’d for (4-(Neopentyloxy)-1-oxo-1,2-dihydroisoquinolin-3-yl)methyl
C18H24NO2−, 286.1811 m/z observed.
acetate (3ah)
To a septum-fitted 1-dram vial 1a (9.0 mg, 0.05 mmol, 1.0
equiv.), cyclopentadienyl rhodium chloride dimer (0.8 mg,
1.25 µmol, 2.5 mol%), and NaOAc (1.0 mg, 12.5 µmol,
25 mol%) were added. The flask was evacuated and refilled
with N2 gas. Methanol (0.2 mL) was added to the flask, and
the mixture was heated to 30 °C. A solution of 3-(neopentyloxy)
prop-2-yn-1-yl acetate (16.8 mg, 0.1 mmol, 2 equiv.) in 0.2 mL
of methanol was added while heating at 30 °C over 4 hours via
syringe pump; bringing the total concentration of the reaction
to (0.125 M). The reaction mixture stirred for 30 minutes after
the addition was completed and was concentrated under
reduced pressure. An internal standard of 2,4,5-trichloropyri-
midine was added (26.2 µmol, 3.0 µL) and the yield was deter-
mined by integrating the internal standard in the 1H-NMR
(8.62 ppm) and comparing that to the integrated value for a
single proton in the product peak (8.41 ppm). 38% yield.
3-Methyl-4(neopentyloxy)isoquinolin-1(2H)-one (3ac)
This compound was prepared according to the general pro-
cedure. Molecular formula: C15H19NO2. Yellow solid, 20.2 mg
1
and 21.0 mg (34%). H NMR (500 MHz, Chloroform-d) δ 11.33
(s, 1H), 8.43 (d, 7.7 Hz, 1H), 7.78 (dd, J = 8.3, 1.4 Hz, 1H), 7.72
(ddd, J = 8.3, 7.0, 1.4 Hz, 1H), 7.49 (ddd, J = 8.1, 7.0, 1.2 Hz,
1H), 3.52 (s, 2H), 2.42 (s, 3H), 1.18 (s, 8H); 13C NMR (126 MHz,
Chloroform-d) δ 163.1, 135.3, 134.9, 132.5, 129.0, 127.8, 125.9,
124.8, 120.6, 83.6, 32.5, 26.7, 13.6; HRMS (ESI): 246.1494 m/z
+
[M + H]+ calc’d for C15H20NO2 , 246.1497 m/z observed.
3-Butyl-4isobutoxyisoquinolin-1(2H)-one (3ad)
This compound was prepared according to the general pro-
cedure. Molecular formula: C17H23NO2. Yellow solid, 49.4 mg
1
and 47.8 mg (71%). H NMR (500 MHz, Chloroform-d) δ 11.67
(s, 1H), 8.42 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.72
(dd, J = 8.0, 7.3 Hz, 1H), 7.49 (dd, J = 8.0, 7.0 Hz, 1H), 3.65 (d,
J = 6.3 Hz, 2H), 2.77 (t, J = 7.7 Hz, 2H), 2.2 (m, 1H), 1.79 (m,
2H), 1.5 (m, 2H), 1.2 (d, J = 6.7 Hz, 6H), 1.0 (t, J = 7.4 Hz, 3H);
13C NMR (126 MHz, Chloroform-d) δ 162.9, 135.2, 134.9,
133.2, 132.4, 127.8, 125.9, 125.0, 120.9, 81.0, 30.7, 29.3, 27.4,
22.6, 19.4, 13.8; HRMS (ESI): 274.1807 m/z [M + H]+ calc’d for
(4-Methoxy-1-oxo-dihydroisoquinolin-3-yl)methyl acetate (3ai)
To a round bottomed flask N-(pivaloxy)benzhydroxamic acid
(0.398 g, 1.8 mmol, 1.0 equiv.), NaOAc (36.9 mg, 2.1 mmol,
0.25 equiv.), and (Cp*RhCl2)2 (11.5 mg, 0.18 mmol, 0.01
equiv.) were added, and the flask was evacuated and refilled
with N2 gas. Methanol (12 mL) was then added to the round
bottomed flask. A solution of 3-methoxyprop-2-yn-1-yl acetate
(2i) (240 mg, 2.1 mmol, 1.2 equiv.) in 2 mL of methanol was
added while heating at 30 °C over 4 hours via syringe pump;
bringing the total concentration of the reaction to (0.125 M).
The reaction stirred for 30 minutes after the addition was com-
plete and the reaction mixture was concentrated under
reduced pressure. The crude product was purified by flash
chromatography (gradient: 2–5% MeOH in CH2Cl2, retention
time = 9.5 min). Molecular formula: C13H13NO4. Pale yellow
solid, 0.293 g (1.18 mmol, 66% yield). 1H NMR (500 MHz,
Chloroform-d) δ 9.24 (s, 1H), 8.43 (d, J = 7.9 Hz, 1H), 7.83 (d,
J = 7.9 Hz, 1H, 7.78 (ddd, 7.9, 7.2, 1.0 Hz 1H), 7.58 (ddd, J =
8.1, 7.0, 1.1 Hz, 1H)), 5.21 (s, 2H), 3.91 (s, 3H), 2.19 (s, 3H);
13C NMR (126 MHz, Chloroform-d) δ 171.1, 162.5, 138.1,
+
C17H24NO2 , 274.1820 m/z observed.
3-(Trimethylsilyl)-4-ethoxyisoquinolin-1(2H)-one (3ae)
This compound was prepared according to the general pro-
cedure. Molecular formula: C15H19NO2Si. Yellow solid, 65.4 mg
and 60.7 mg (97%). 1H NMR (500 MHz, Chloroform-d) δ 9.08
(s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.71 (m, 2H), 7.53 (m, 1H), 3.94
(q, J = 7.0 Hz, 2H), 1.50 (t, J = 7.0 Hz, 3H), 0.44 (s, 9H);
13C NMR (126 MHz, Chloroform-d) δ 162.5, 145.4, 134.0,
132.3, 131.7, 128.1, 127.3, 126.7, 121.3, 70.9, 15.4, 1.37; HRMS
(ESI): 262.1263 m/z [M + H]+ calc’d for C15H20NO2Si+, 262.1260
m/z observed.
3-(Hydroxylmethyl)-4-(neopentyloxy)isoquinolin-1(2H)-one (3ag)
134.0, 132.7, 128.0, 127.5, 126.4, 126.3, 121.5, 63.1, 58.0, 20.9;
To a septum-fitted 1-dram vial 1a (9.0 mg, 0.05 mmol, 1.0
equiv.), cyclopentadienyl rhodium chloride dimer (0.8 mg,
1.25 µmol, 2.5 mol%), and NaOAc (1.0 mg, 12.5 µmol,
25 mol%) were added. The flask was evacuated and refilled
with N2 gas. Methanol (0.2 mL) was added to the flask, and
HRMS (ESI): 246.0766 m/z [M]− calc’d for C13H12NO4
246.0763 m/z observed.
,
−
3-Butyl-4-neopentoxy-6-methoxyisoquinolin-1(2H)-one (3bb)
the mixture was heated to 30 °C. A solution of 3-(neopentoxy) This compound was prepared according to the general pro-
prop-2-yn-1-ol (28.4 mg, 0.2 mmol, 4.0 equiv.) in 0.2 mL of cedure. Molecular formula: C19H27NO3. Yellow solid, 11.0 mg
methanol was added while heating at 30 °C over 4 hours via and 6.3 mg (11%). 1H NMR (500 MHz, Chloroform-d) δ 11.4 (s,
syringe pump; bringing the total concentration of the reaction 1H), 8.31 (d, J = 8.9 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.05 (dd,
to (0.125 M). The reaction mixture was stirred for 30 minutes J = 8.9, 2.4 Hz, 1H), 3.93 (s, 3H), 3.52 (s, 2H), 2.72 (t, J = 7.8 Hz,
after the addition was completed and was concentrated under 2H), 1.75 (dd, J = 7.8, 7.5 Hz, 2H), 1.48 (dt, J = 7.4, 7.4 Hz, 2H),
reduced pressure. An internal standard of 2,4,5-trichloropyri- 1.18 (s, 9H), 1.00 (t, J = 7.4 Hz, 3H); 13C NMR (126 MHz,
midine was added (26.2 µmol, 3.0 µL) and the yield was deter- Chloroform-d) δ 163.2, 162.3, 137.3, 134.3, 133.5, 130.0,
mined by integrating the internal standard in the 1H-NMR 118.65, 115.9, 101.8, 83.8, 55.4, 32.5, 30.6, 27.3, 26.6, 22.5,
(8.62 ppm) and comparing that to the integrated value for a 13.8; HRMS (ESI): 316.1913 m/z [M]− calc’d for C19H26NO3
,
−
single proton in the product peak (8.41 ppm). 19% yield.
316.1906 m/z observed.
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3-Butyl-4-neopentoxy-6-bromoisoquinolin-1(2H)-one (3cb)
(s, 1H), 8.47 (d, J = 8.3 Hz, 1H), 8.06 (s, 1H), 7.67 (d, J = 8.2 Hz,
1H), 3.51 (s, 2H), 2.75(t, J = 7.9 Hz, 2H), 1.77 (tt, J = 7.8, 7.4.
Hz, 2H), 1.5 (qt, J = 7.4, 7.4 Hz, 2H), 1.19 (s, 9H), 1.02 (t, J =
7.4 Hz, 3H); 13C NMR (126 MHz, Chloroform-d) δ 161.9, 135.7,
135.5, 133.7, 129.0, 127.7, 127.1, 126.1, 118.5, 116.1, 84.7, 32.6,
30.6, 27.5, 26.6, 22.5, 13.8; HRMS (ESI): 311.1760 m/z [M]−
calc’d for C19H23N2O2−, 311.1763 m/z observed.
This compound was prepared according to general procedure.
Molecular formula: C18H24NO2Br. Yellow solid, 60.6 mg and
1
55.5 mg (64%). H NMR (500 MHz, Chloroform-d) δ 11.21 (s,
1H), 8.24 (d, J = 8.6 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.56 (dd,
J = 8.6, 1.9 Hz, 1H), 3.50 (s, 2H). 2.72 (t, J = 7.9 Hz, 2H), 1.76
(m, 2H), 1.48 (dt, J = 7.4, 7.4 Hz, 2H), 1.2 (s, 9H), 1.00 (t, J =
7.4 Hz, 3H); 13C NMR (126 MHz, Chloroform-d) δ 162.7, 136.7,
135.1, 133.6, 129.6, 129.2, 127.9, 123.7, 123.5, 84.3, 32.6, 30.7,
27.4, 26.6, 22.6, 13.8; HRMS (ESI): 364.0912 m/z [M]− calc’d for
C18H23BrO2−, 364.0914 m/z observed.
3-Butyl-4-(neopentyloxy)-2,6-naphthyridin-1(2H)-one (3ib)
This compound was prepared according to the general pro-
cedure. Molecular formula: C17H24N2O2. Yellow solid, 61.6 mg
1
and 46.1 mg (74%). H NMR (500 MHz, Chloroform-d) δ 11.90
(s, 1H), 9.23 (s, 1H), 8.70 (d, J = 5.3 Hz, 1H), 8.14 (d, J = 5.3 Hz,
1H), 3.57 (s, 2H), 2.75 (t, J = 7.9 Hz, 2H), 1.78 (tt, J = 7.4,
7.8 Hz, 2H), 1.52 (qt, J = 7.4, 7.4 Hz, 2H), 1.17 (s, 9H), 1.02 (t,
J = 7.4 Hz, 3H); 13C NMR (126 MHz, Chloroform-d) δ 162.1,
145.6, 145.6, 135.5, 133.5, 129.6, 129.5, 119.7, 84.9, 32.6, 30.7,
27.3, 26.6, 22.6, 13.8; HRMS (ESI): 287.1760 m/z [M]− calc’d for
C17H23N2O2−, 287.1768 m/z observed.
3-Butyl-4-neopentoxy-6-flouroisoquinolin-1(2H)-one (3db)
This compound was prepared according to the general pro-
cedure. Molecular formula: C18H24NO2F. Yellow solid, 44.0 mg
1
and 40.2 mg (56%). H NMR (500 MHz, Chloroform-d) δ 12.03
(s, 1H), 8.42 (dd, J = 8.9, 8.8 Hz, 1H), 7.38 (d, J = 10.0 1H), 7.17
(dd, J = 8.6, 8.4 Hz, 1H), 3.51 (s, 2H), 2.75 (t, J = 7.9 Hz, 2H),
1.80 (m, 2H), 1.51 (m, 2H), 1.17 (s, 9H), 1.01 (t, J = 7.4 Hz, 3H);
13C NMR (126 MHz, Chloroform-d) δ 166.6, 164.6, 162.7, 137.8
(d, J = 9.8 Hz), 135.3, 134.1 (d, J = 3.2 Hz), 131.0 (d, J = 10.0
Hz), 121.5, 114.6 (d, J = 24.0 Hz), 106.1 (d, J = 23.3 Hz), 84.1,
32.5, 30.8, 27.4, 22.6, 13.8′ HRMS (ESI): 304.1713 m/z [M]−
calc’d for C18H23FO2−, 304.1725 m/z observed.
3-Butyl-4-neopentoxy-6-methylisoquinolin-1(2H)-one (3jb)
This compound was prepared according to the general pro-
cedure. Molecular formula: C19H27NO2. Yellow solid, 35.1 mg
and 45.2 mg (52%). 1H NMR (500 MHz, Chloroform-d) δ 11.16 (s,
1H), 8.30 (d, J = 8.2 Hz, 1H), 7.55 (s, 1H), 7.29 (d, J = 10.1 Hz,
1H), 3.52 (s, 2H), 2.72 (t, J = 7.9 Hz, 2H), 2.53 (s, 3H), 1.76 (tt, J =
7.8, 7.4 Hz, 2H), 1.48 (qt, J = 7.4, 7.4 Hz, 2H), 1.18 (s, 9H), 1.00 (t,
J = 7.4 Hz, 3H); 13C NMR (126 MHz, Chloroform-d) δ 163.0,
142.8, 135.3, 134.4, 133.4, 127.8, 127.5, 122.8, 120.6, 84.0, 32.6,
30.8, 27.4, 26.7, 22.6, 22.3, 13.8; HRMS (ESI): 300.1964 m/z [M]−
calc’d for C19H26NO2−, 300.1973 m/z observed.
3-Butyl-4-neopentoxy-6-(trifluoromethyl)isoquinolin-1(2H)-one
(3eb)
This compound was prepared according to the general pro-
cedure. Molecular formula: C19H24NO2F3. Yellow solid,
1
44.9 mg and 46.7 mg (52%). H NMR (500 MHz, Chloroform-d)
δ 11.64 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.08 (s, 1H), 7.67 (d,
J = 8.4, 1H), 3.53 (s, 2H), 2.77 (t, J = 7.4 Hz, 2H), 1.80 (tt, J = 7.9, 1-Chloro-3-methylacetate-4-methoxyisoquinoline (4)
7.5 Hz, 2H), 1.51 (qt, J = 7.4, 7.4 Hz, 2H), 1.19 (s, 9H), 1.02 (t,
To a 250 mL round bottomed flask (4-methoxy-1-oxo-dihydroi-
soquinolin-3-yl)methyl acetate (220 mg, 0.89 mmol, 1.0 equiv.)
and DMF (60 mL) were added. Next, POCl3 (0.33 mL,
3.6 mmol, 4.0 equiv.) was added at room temperature, and the
reaction mixture was heated 110 °C for 4 hours. The reaction
mixture was cooled to room temperature and then poured over
J = 7.4 Hz, 3H); 13C NMR (126 MHz, Chloroform-d) δ 162.3,
135.3 (d, J = 17.4 Hz), 134.3, 134.2 128.9, 126.9, 124.9, 122.8,
121.9, 118.5, 84.5, 32.6, 30.7, 27.4, 26.6, 22.6, 13.8; HRMS
(ESI): 354.1681 m/z [M]− calc’d for C19H23F3NO2−, 354.1692 m/z
observed.
ice water. The aqueous mixture was extracted three times with
CH2Cl2. The combined organic layer was washed five times with
3-Butyl-4-neopentoxy-6-nitroisoquinolin-1(2H)-one (3fb)
This compound was prepared according to the general pro-
cedure. Molecular formula: C18H24N2O4. Yellow solid, 35.3 and
40.5 mg (45%). H NMR (500 MHz, Chloroform-d) δ 10.94 (s,
1H), 8.67 (s, 1H), 8.54 (d, J = 10.4 Hz, 1H), 8.23 (d, J = 8.7 Hz,
1H), 3.5 (s, 2H), 2.77 (t, J = 7.1 Hz, 2H), 1.78 (tt, J = 8.1, 7.1 Hz,
2H), 1.50 (qt, J = 7.3, 7.1 Hz, 2H), 1.22 (s, 9H), 1.03 (t, J =
7.2 Hz, 3H); 13C NMR (126 MHz, Chloroform-d) δ 161.5, 150.7,
136.0, 135.7, 134.3, 130.0, 128.3, 119.6, 117.0, 84.8, 32.6, 30.5,
27.5, 26.6, 22.5, 13.8; HRMS (ESI): 331.1658 m/z [M]− calc’d for
C18H23N2O4−, 331.1658 m/z observed.
water and dried over anhydrous Na2SO4. The organic layer was
concentrated under reduced pressure, and was purified by flash
chromatography (gradient: 0–6% MeOH in CH2Cl2, retention
time = 13.0 min). Molecular formula: C13H12NO3Cl. White solid,
0.138 g (0.52 mmol, 50% yield). 1H NMR (500 MHz, Chloroform-d)
δ 11.40 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H),
7.82 (dd, J = 7.8, 7.4 Hz, 1H), 7.72 (dd, J = 7.8, 7.4 Hz, 1H), 5.35
(s, 2H), 4.00 (s, 3H), 2.14 (s, 3H); 13C NMR (126 MHz,
Chloroform-d) δ 170.8, 150.3, 145.8, 139.3, 133.0, 131.3, 129.0,
128.0, 126.9, 122.1, 63.6, 62.2, 21.0; HRMS (ESI): 288.0403 m/z
[M − Na]+ calc’d for NaC13H12NO3Cl+, 288.0408 m/z observed.
1
3-Butyl-4-neopentoxy-6-cyanoisoquinolin-1(2H)-one (3gb)
1-Chloro-4-methoxyisoquinolin-3-carbaldehyde (5)
This compound was prepared according to the general pro-
cedure. Molecular formula: C19H24N2O2 Yellow solid, 32.0 mg To a 25 mL round bottomed flask 1-chloro-3-methylacetate-
1
and 32.4 mg (41%). H NMR (500 MHz, Chloroform-d) δ 11.29 4-mehtoxyisoquinoline (131 mg, 0.5 mmol, 1.0 equiv.), K2CO3
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(170 mg, 1.2 mmol, 2.5 equiv.), and MeOH (7 mL) were added. with CH2Cl2, and washed five times with DI water, & once with
The reaction mixture was stirred at room temperature for brine. The organic layer was dried over anhydrous Na2SO4 and
30 minutes. The reaction mixture was diluted with EtOAc, and purified by flash chromatography (gradient: 5–10% MeOH in
washed with brine. The organic layer was dried over anhydrous CH2Cl2, retention time
= 4.0 min). Molecular formula:
Na2SO4. The volatile solvents were evaporated under reduced C17H19N2O4Cl. White solid, 65.0 mg (0.19 mmol, 100% yield).
pressure, and the pale solid was dissolved in CH2Cl2 (0.5 M). 1H NMR (500 MHz, Chloroform-d) δ 8.34 (dd, J = 7.9, 7.8 Hz,
Activated MnO2 (424 mg, 2.9 mmol, 10.0 equiv.) was added 2H), 8.31 (s, 1H), 7.87 (dd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.81 (ddd,
and the mixture was stirred for 30 min at room temperature. J = 8.2, 7.0, 1.5 Hz, 1H), 4.20 (d, J = 5.50 Hz, 3H), 4.16 (s, 3H),
The reaction mixture was filtered through Celite and was 1.53 (s, 9H); 13C NMR (126 MHz, Chloroform-d) δ 169.0, 163.1,
rinsed through with MeOH. The volatile solvents were evapor- 153.1, 144.0, 134.6, 132.5, 131.5, 130.3, 129.3, 126.7, 123.5,
ated under reduced pressure and the crude product was puri- 82.2, 63.8, 42.1, 28.1; HRMS (ESI): 373.0931 m/z [M + Na]+
fied by flash chromatography (gradient: 30–100% EtOAc in calc’d for NaC17H19N2O4Cl+, 373.0950 m/z observed.
Hexanes, retention time = 3.5 min). Molecular formula:
C11H8NO2Cl. White solid, 68 mg (0.31 mmol, 63% yield).
1H NMR (500 MHz, Chloroform-d) δ 10.34 (s, 1H), 8.41
2-(5-Hydroxyisoquinoline-3carboxamido)acetic acid (8)
(m, 2H), 7.93 (m, 2H), 4.20 (s, 3H); 13C NMR (126 MHz, (1) To a 25 mL round bottomed flask (1-chloro-4-methoxyiso-
Chloroform-d) δ 189.3, 155.5, 146.2, 135.9, 133.4, 131.9, 131.7, quinoline-3-carboxamid)acetate (28.5 mg, 0.08 mmol, 1.0
129.9, 127.0, 123.8, 64.8; HRMS (ESI): 244.0141 m/z [M − Na]+ equiv.), Pd/C (8.5 mg, 0.08 mmol, 1.0 equiv.), ammonium
calc’d for NaC11H8NO2Cl+, 244.0145 m/z observed.
formate (7.5 mg, 0.12 mmol, 1.5 equiv.), and EtOAc (10 mL)
were added. The reaction mixture was refluxed for 1 hour. The
crude mixture was filtered through a silica plug to remove the
1-Chloro-4-methoxyisoquinolin-3-carboxylic acid (6)
To a 50 mL round bottomed flask 1-chloro-4-methoxyisoqui- palladium, and the volatile solvents was evaporated under
noli-3-carbaldehyde (64 mg, 0.29 mmol, 1.0 equiv.), 2-methyl- reduced pressure. The crude product was purified by flash
2-butene (1.45 ml, 0.2 M), and tBuOH (6 ml, 0.05 M) were chromatography (gradient: 25–50% EtOAc in hexanes, reten-
added. Then, a solution of NaClO2 (262.2 mg, 2.9 mmol, tion time = 8.5 min) to afford tert-butyl-2-(4-methoxyisoquino-
10.0 equiv.) and NaH2PO4 monohydrate (276 mg, 2.0 mmol, line-3-carboxamido)acetate. Molecular formula: C17H20N2O4.
7.0 equiv.) in H2O (3.0 ml, 0.1 M) was added dropwise over White solid, 25.3 mg (0.08 mmol, 100% yield). 1H NMR
10 minutes. The mixture was stirred at room temperature over- (500 MHz, Chloroform-d) δ 9.00 (s, 1H), 8.60 (s, 1H), 8.33 (d,
night. The reaction mixture was diluted with EtOAc and the J = 8.3 Hz, 1H), 8.04 (d, J = 8.25 Hz, 1H), 7.81 (ddd, J = 8.3, 6.9,
organic layer was washed once with 1 M HCl. The aqueous 1.3 Hz, 1H), 7.73 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 4.23 (d, J =
layer was extracted three times with EtOAc. The organic layers 5.4 Hz, 2H), 4.16 (s, 3H), 1.53 (s, 9H); 13C NMR (126 MHz,
were combined and dried over anhydrous Na2SO4, and volatile Chloroform-d) δ 169.3, 164.4, 153.2, 146.4, 133.8, 132.6, 131.3,
solvents were removed under reduced pressure. The crude 130.7, 129.1, 127.4, 122.8, 82.1, 63.5, 42.1, 28.1; HRMS (ESI):
product was purified via flash chromatography (gradient: 317.1501 m/z [M + H]+ calc’d for C17H21N2O4+, 317.1501 m/z
6–16% MeOH in CH2Cl2, retention time = 4.5 min). Molecular observed.
formula: C11H8NO3Cl. White solid, 58 mg (0.24 mmol, 84%
(2) To a 10 mL round bottomed flask tert-butyl-2-(4-methox-
yield). Note: This substrate proved difficult to completely yisoquinoline-3-carboxamido)acetate (25.3 mg, 0.08 mmol, 1.0
1
purify, and the H-NMR spectra show these minor impurities. equiv.), p-toluenesulfonic acid monohydrate (33.9 mg,
1H NMR (500 MHz, Chloroform-d) δ 10.43 (s, 1H), 8.38 (m, 0.8 mmol, 10.0 equiv.), LiCl (10.0 equiv.), and N-methyl-2-pyr-
2H), 7.92 (m, 2H), 4.20 (s, 3H); 13C NMR (126 MHz, rolidone (1 mL) were added. The reaction mixture was heated
Chloroform-d) δ 162.5, 155.4, 144.2, 134.5, 132.3, 131.5, 130.0, to 180 °C for 1 hour. The reaction was quenched with water,
128.9, 126.9, 123.9, 64.0; HRMS (ESI): 236.0114 m/z [M]− calc’d and the aqueous layers was extracted three times with EtOAc.
for C11H7ClNO3−, 236.0119 m/z observed.
The organic layer was washed once with brine, dried over
Na2SO4 and the volatile solvents were evaporated under
reduced pressure. The crude product was purified by flash
column (gradient: 0–3% AcOH in EtOAc, retention time =
tert-Butyl 2-(1-chloro-4methoxyisoquinoline-3-carboxamido)
acetate (7)
To a 25 mL round bottomed flask1-chloro-4-methoxyisoquino- 3.5 min) to yield. Molecular formula: C12H10N2O4. White solid,
lin-3-carboxylic acid (44.0 mg, 0.19 mmol, 1.0 equiv.), HATU 17 mg (0.07 mmol, 86% yield). The 13C NMR spectrum was
(77.2 mg, 0.20 mmol, 1.1 equiv.), and DMF (4 mL) were added. obtained in acetone-d6 due to better solubility, however better
The mixture was stirred at room temperature for 10 minutes. 1H-NMR resolution was obtained in DMSO-d6. 1H NMR
Then, glycine tert-butyl ester (73.7 mg, 0.56 mmol, 3.0 equiv.) (500 MHz, DMSO-d6) δ 12.83 (s, 1H), 9.37 (s, 1H), 8.90 (s, 1H),
in 2.0 mL of DMF was added bring the total reaction concen- 8.29 (d, J = 7.9 Hz, 1H), 8.21 (d, J = 7.5 Hz, 1H), 7.89 (m, 2H),
tration to 0.04 M. The reaction was stirred at room temperature 7.13 (br s, 1H), 4.05 (d, J = 6.2 Hz, 2H); 13C NMR (126 MHz,
for 20 minutes, then diisopropylethylamine (0.10 mL, acetone-d6) δ 209.1, 170.2 169.9, 154.4, 142.3, 131.6, 130.2,
0.54 mmol, 2.9 equiv.) was added. The reaction was stirred 129.9, 127.5, 122.1, 68.4, 40.1; HRMS (ESI): 245.0562 m/z [M]−
−
overnight under a N2 atmosphere. The reaction was diluted calc’d for C12H9N2O4
.
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Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
Financial support from the University of Denver and the Knoebel
Institute for Healthy Aging is gratefully acknowledged.
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