Synthesis of Isoquinolones by Sequential Suzuki Coupling of 2-Halobenzonitriles with Vinyl Boronate Followed by Cyclization

Article abstract of DOI:10.1021/acs.joc.1c00472

A novel, facile, and expeditious two-step synthesis of 3,4-unsubstituted isoquinolin-1(2H)-ones from a Suzuki cross-coupling between 2-halobenzonitriles and commercially available vinyl boronates followed by platinum-catalyzed nitrile hydrolysis and cyclization is described.

Full text of DOI:10.1021/acs.joc.1c00472

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Synthesis of Isoquinolones by Sequential Suzuki Coupling of
2‑Halobenzonitriles with Vinyl Boronate Followed by Cyclization
Saul Jaime-Figueroa, Michael J. Bond, J. Ignacio Vergara, Jake C. Swartzel, and Craig M. Crews*
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ABSTRACT: A novel, facile, and expeditious two-step synthesis of 3,4-unsubstituted isoquinolin-1(2H)-ones from a Suzuki cross-
coupling between 2-halobenzonitriles and commercially available vinyl boronates followed by platinum-catalyzed nitrile hydrolysis
and cyclization is described.
he isoquinolone scaffold is a privileged structural motif
T
present in many natural products1,2 and small molecules
with pharmacological and biological activities. Compounds of
this class are known for their antitumor,3−5 antihypertensive,6,7
antithrombotic,8 anti-inflammatory,9 and analgesic proper-
ties.10 The isoquinolin-1(2H)-one scaffold is present in a
wide variety of small-molecule ligands that bind kinases,7 ion
channels,10 folate-dependent enzymes,11 tissue factors,8
glucocorticoid receptors,9 and several other pharmacologically
relevant protein classes (Figure 1).
As a result, several synthetic methodologies have been
developed to synthesize this important building block. These
approaches include classical methods,12 typically multistep
syntheses that use harsh reaction conditions, and the recently
developed elegant syntheses of isoquinolones from benzoic
acid derivatives using metal-catalyzed ortho-C−H activa-
tion,13−28 which require a directing group on the carboxylic
moiety. Unfortunately, the latter are not applicable to the
synthesis of 3,4-unsubstituted isoquinolones. Furthermore,
they rely on elaborate noncommercial starting materials and
lack regioselectivity (Scheme 1).
On the other hand, current synthetic approaches for 3,4-
unsubstituted isoquinolones are scarce and consist of mainly
multistep processes.12,14,29,30 Therefore, there is still a need for
additional methodologies to access this important chemical
scaffold. In this work, we report an improvement of our
previously published method,31 consisting of an expeditious
two-step synthesis of 3,4-unsubstituted isoquinolones from 2-
halobenzonitriles that use a vinyl boronate as an “acetylene
equivalent”, which is installed by a Suzuki coupling (Scheme
2).
Figure 1. Examples of approved and/or experimental drugs
containing the isoquinolone motif.
Received: February 25, 2021
Published: May 28, 2021
https://doi.org/10.1021/acs.joc.1c00472
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 8479−8488
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Scheme 1. Current Transition-Metal-Catalyzed C−H Activation Methods to Prepare Isoquinolones
Scheme 2. Synthesis of 3,4-Unsubstituted Isoquinolones by a Suzuki Cross-Coupling Followed by Cyclization
Scheme 3. Synthesis of 3,4-Unsubstituted Isoquinolin-1(2H)-ones via a Putative Amide−Aldehyde Intermediate
As part of a current research project, we had to synthesize a
library of 3,4-unsubstituted isoquinolones and therefore
needed a robust, short, efficient, and versatile synthetic
approach. We envisioned that 2-bromobenzonitriles could be
an excellent synthon to replace the N-tert-butylbenzamides that
we used in our previous work31 with the advantage of avoiding
an extra step and the harsh conditions needed to deprotect the
final cyclic N-tert-butylisoquinolone as well as being scalable if
required. Additionally, there are a wide variety of inexpensive,
commercially available 2-bromobenzonitriles to facilitate rapid
derivatization.
proved to be a very robust and general protocol. Thus, the
Suzuki coupling reaction between a range of 2-bromo or 2-
iodobenzonitriles 1, and the simple, commercially available
vinyl boronate ester 4 provides the corresponding vinyl ether
intermediates 2 in moderate to high yields (51−88% yield,
Tables 1 and 2). For the second step, we hypothesized that the
hydrolysis of the nitrile and the vinyl ether could be achieved
simultaneously by heating 2 in an aqueous solvent under the
appropriate conditions. We envisioned that the amide−
aldehyde intermediate 2′ generated would cyclize sponta-
neously to give isoquinolone 3 under these reaction conditions
(Scheme 3). To facilitate this transformation, we chose the
Parkins catalyst,32,33 an air-stable hydride−platinum(II)
complex. This platinum-catalyzed process offers mild con-
For the first step in this new approach, the palladium-
catalyzed cross-coupling reaction, we used the same optimized
reaction conditions described in our previous work,31 which
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Table 1. Substrate Scope of the Synthesis of Isoquinolones from ortho-X-benzonitriles
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Table 1. continued
*
In some cases, small amounts of the Z-isomer were formed (detected by NMR).
Encouraged by this result, we next examined the impact of
the electronics of the substituents present on the starting
benzonitrile core. Our synthesis proved to be robust, as vinyl
ether intermediates bearing both strong electron-donating
groups (2d−f) and strong electron-withdrawing groups (2g,
2i, and 2l) were prepared and converted into their
corresponding isoquinolones in moderate to excellent yield
(47−91%). Of note, we were able to greatly improve the yield
of 6-dimethylamine isoquinolone 3e from 16% in previous
methodologies14 to 82% in the present study. The high yields
for 3d and 3e highlight the ability of our method to efficiently
generate isoquinolones substituted with amine functionalities
as useful chemical handles for further derivatization. Addition-
ally, we also examined the use of ortho-chloro and ortho-triflate-
benzonitriles to further expand the availability of the starting
benzonitriles, especially if the latter can be prepared from the
corresponding phenols. We demonstrated that the vinyl ethers
2a can also be prepared from ortho-chloro and ortho-triflate-
benzonitriles in good yields (entries 3, 4, 14, and 17 on Table
1). Remarkably, when we use 2,5-dichlorobenzonitrile as
starting material, we mainly obtained the desired ortho-
substituted vinyl ether and just traces of the 5-substitued
product (<7% by NMR, entry 17 on Table 1).
Table 2. Synthesis of Benzo- and Aza-3,4-unsubstituted
Isoquinolin-1(2H)-ones
In previous reports of 3,4-unsubstituted isoquinolone
syntheses, a major challenge was obtaining good product
yields from ortho-substituted starting materials.14,30,31,34
Excitingly, our new strategy was able to efficiently generate
5- and 8-substituted isoquinolones 3b and 3n in moderate to
good yield (55 and 81%, respectively). Previous attempts at
synthesizing 8-methoxyisoquinolones had failed,14 making the
successful synthesis of 3n noteworthy. Another issue
encountered by other synthetic routes has been regioselectivity
when generating 5- or 7-substituted isoquinolones.30 Since our
methodology does not rely on an ortho-directing group on the
carboxylic moiety, the regioselectivity of the reaction is fully
dictated by the position of the halo substituent in the starting
benzonitrile. Therefore, we were able to synthesize 5- or 7-
substituted isoquinolones (3b, 3k, and 3l) in a regiospecific
manner and in good yields (80−83%).
*
In some cases, small amounts of the Z-isomer were formed (detected
by NMR).
ditions, high reactivity, and compatibility with many chemical
functionalities like aldehydes, alcohols, acetals, azides, and
most protecting groups.33 Fortunately, efficient hydrolysis of
both the nitrile and the vinyl ether on the parent unsubstituted
compound 2a, followed by cyclization of the carboxamide−
aldehyde intermediate 2′, provided the corresponding 3,4-
unsubstituted isoquinolone 3a in the same reaction step (87%
yield, Table 1 and Scheme 3).
To further demonstrate the versatility of our novel process,
we applied the same approach to the synthesis of other
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Scheme 4. Synthetic Approach to Give Isoquinolone 3o
heterocycles, by using ortho-halo-cyano-arenes other than
ortho-halobenzonitriles as starting materials (Table 2). In our
previous work, we were able to produce diazaheterocycles;
however, the isolated products in every case were N-tert-
butylazaisoquinolones that required harsh conditions of neat
TFA at 150 °C (microwave) to remove the tert-butyl group.31
Our new approach bypasses the N-tert-butylisoquinolone
intermediates to give a variety of nitrogenous heterocycles
(7a−d) in moderate to good yield (60−91%). Two of these
heterocycles, 7c and 7d, could not be prepared with our
previous method because of the high stability of the
corresponding N-tert-butylisoquinolones.31 Therefore, this
work is a substantial improvement over our previous
methodology, since it enables the formation of complex
isoquinolones bearing acid-sensitive functional groups.
A major advantage of our new synthetic approach is that the
mild reaction conditions are compatible with a wide array of
functional groups that can be used to further derivatize the
isoquinolone products. We successfully synthesized 3,4-
unsubstituted isoquinolones bearing amine (3d and 3e),
carbaldehyde (3g), hydroxyl (3h), and BOC-protecting groups
(3o). Previous strategies generated only trace amounts of 3h,14
further highlighting the power of our two-step synthesis. To
underscore the potential utility of our synthetic approach in
generating diverse libraries of isoquinolones, we heated 6-
fluoro-2H-isoquinolin-1-one (3j) in neat pyrrolidine for 48 h
to form the SNAr product 6-pyrrolidin-1-yl-2H-isoquinolin-1-
one in excellent yield (94%, fully characterized as 3d). Finally,
the versatility of this methodology was further demonstrated in
an ongoing project in our lab when we prepared large
quantities of compound 3o, which was a critical starting
material for the construction of a library of 6-substituted
isoquinolones (Scheme 4).
intermediate by LC−MS and 1H NMR, which contained
prominent amide and vinyl ether peaks.
In conclusion, we developed an efficient and expeditious
synthesis of 3,4-unsubstituted isoquinolin-1(2H)-ones using
mild conditions with simple, affordable starting materials in
two steps. The wide availability of the starting materials, the
mild neutral reaction conditions, and experimental simplicity
allow the present methodology to have rapid access to these
very important isoquinolone scaffolds, some of which were not
accessible using previous methodologies.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise indicated, common
reagents or starting materials were obtained from a commercial
source and used without further purification. The Parkins catalyst was
purchased from Strem Cheimcals Inc. (Newburyport, MA). Flash
column chromatography was performed using silica gel 60 (230−400
mesh). Preparative and analytical thin-layer chromatography (PTLC
and TLC) was carried out on Merck silica gel plates with a QF-254
indicator and visualized by UV or KMnO4. 1H and 13C NMR spectra
were recorded on an Agilent DD2 500 (500 MHz 1H; 125 MHz 13C),
Agilent DD2 600 (600 MHz 1H; 150 MHz 13C), or Agilent DD2 400
1
(400 MHz H; 100 MHz 13C) spectrometer at room temperature.
Chemical shifts were reported in ppm relative to the residual CDCl3
1
1
(δ 7.26 ppm H; δ 77.0 ppm 13C), CD3OD (δ 3.31 ppm H; δ 49.0
ppm 13C), or DMSO-d6 (δ 2.50 ppm H; δ 39.5 ppm 13C). NMR
1
chemical shifts were expressed in ppm relative to internal solvent
peaks, and coupling constants were measured in Hz (bs = broad
signal). Mass spectrometric measurements were obtained using
electrospray ionization (ESI) and performed with a Shimadzu
Scientific Instruments QToF 9030 LC−MS system, equipped with
a Nexera LC-40D xs UHPLC, consisting of a CBM-40 Lite system
controller, a DGU-405 degasser unit, two LC-40D XS UHPLC
pumps, a SIL-40C XS autosampler, and a column oven CTO-40S. UV
data was collected with a Shimadzu Nexera HPLC/UHPLC
photodiode array detector SPD M-40 in the range of 190−800 nm.
Mass spectra were subsequently recorded with the quadrupole time-
of-flight (QToF) 9030 mass spectrometer.
Synthesis of tert-Butyl-((1-(5-bromo-4-cyano-2-fluorophenyl)-
pyrrolidin-3-yl)methyl)carbamate (1o). tert-Butyl-N-(pyrrolidin-3-
ylmethyl)carbamate (463 mg, 2.31 mmol) was added to a solution
of 2-bromo-4,5-difluorobenzonitrile (462 mg, 2.12 mmol) in MeCN
(4.00 mL, 0.53 M) at room temperature. The orange solution was
stirred for 12 h at room temperature and then concentrated in vacuo,
and the residue was purified by flash chromatography (SiO2-100g,
Although we did not perform a comprehensive mechanistic
study of our novel synthetic route, we hypothesize that
isoquinolones generated through this strategy undergo a
sequential hydrolysis of the nitrile followed by hydrolysis of
the vinyl ether to the aldehyde, after which cyclization to the
isoquinolone is spontaneous. This is inferred from the isolation
of the primary amide of 7d′ (for structure see Figure S88 in the
SI) that retains the intact vinyl ether moiety during the
uncomplete reaction to produce 7d. We verified this
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gradient Hex/EtOAc, 95:5 to 7:3 in 20 min) to afford 585 mg of the
desired product (67% yield) as a light-yellow oil. 1H NMR (400 MHz,
CDCl3) δ 7.13 (dd, J = 13.5, 1.9 Hz, 1H), 6.70 (dd, J = 8.0, 2.1 Hz,
1H), 4.66 (bs, 1H), 3.72−3.40 (m, 3H), 3.32−3.01 (m, 3H), 2.60−
2.35 (m, 1H), 2.16−1.99 (m, 1H), 1.82−1.56 (m, 1H), 1.43 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 155.9, 148.9 (d, J = 243.6 Hz), 140.9
(d, J = 9.9 Hz), 121.3 (d, J = 2.3 Hz), 120.7 (d, J = 25.7 Hz), 117.9
(d, J = 5.9 Hz), 117.7 (d, J = 1.7 Hz), 79.6, 53.0 (d, J = 5.7 Hz), 49.1
(d, J = 5.7 Hz), 42.7, 39.2, 28.7, 28.3. 19F NMR (376 MHz, CDCl3) δ
−130.08. HRMS (ESI) m/z [M + H]+: Calcd for C17H22BrFN3O2
398.0879; Found 398.0896 and 400.0877.
General Procedure for the Synthesis of (E)-2-(2-Ethoxyvin-
yl)-nitriles (2) and (6). To a solution of the ortho-substituted-
benzonitrile compound (1) or (5) (1.15 mmol) and 2-[(E)-2-
ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (228 mg, 1.15
mmol) in dioxane (15 mL, 0.08 M) was added K2CO3 (476 mg, 3.44
mmol) followed by water (5 mL, 0.02 M). The reaction mixture was
degassed under vacuum and purged with argon (5×). Then, PCy3
(0.11 mmol) and Pd(dba)2 (0.05 mmol) were added. The reaction
mixture was heated in an oil bath with vigorous stirring at 80 °C for 2
to 4 h. The reaction mixture was diluted with EtOAc (50 mL) and
filtered over a Celite pad. The filtrate was diluted with EtOAc (50
mL), washed with an aqueous saturated solution of NaCl (30 mL),
dried (Na2SO4), and concentrated in vacuo. The crude material was
purified by flash column chromatography (gradient Hex/EtOAc 1:0
to 8:2) or PTLC to give the product (2) or (6).
(E)-2-(2-Ethoxyvinyl)benzonitrile (2a). This compound was
prepared following the procedure described above to give 160 mg
(81% yield) of pure product as a light-yellow oil. 1H NMR (400 MHz,
DMSO-d6) δ 7.70 (dd, J = 7.9, 1.4 Hz, 2H), 7.62−7.40 (m, 2H), 7.27
(t, J = 7.6 Hz, 1H), 5.99 (d, J = 12.7 Hz, 1H), 3.98 (q, J = 7.0 Hz,
2H), 1.28 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (151 MHz, DMSO-d6)
δ 152.8, 140.0, 133.1, 132.8, 125.8, 124.0, 118.1, 108.1, 101.4, 66.0,
14.6. HRMS (ESI) m/z: [M + H]+ Calcd for C11H12NO 174.0918;
Found 174.0920.
141.5, 134.2, 120.4, 111.5, 109.7, 106.4, 103.2, 65.7, 40.2, 14.8.
HRMS (ESI) m/z: [M + H]+ Calcd for C13H17N2O 217.1340; Found
217.1355.
2-[(E)-2-Ethoxyvinyl]-4-methoxybenzonitrile (2f). This compound
was prepared following the procedure described above to give 90 mg
(88% yield) of pure product as a light-yellow oil. 1H NMR (400 MHz,
DMSO-d6) δ 7.68−7.44 (m, 2H), 7.17 (d, J = 2.5 Hz, 1H), 6.80 (dd, J
= 8.7, 2.5 Hz, 1H), 5.90 (d, J = 12.7 Hz, 1H), 3.94 (q, J = 7.0 Hz,
2H), 3.80 (s, 3H), 1.25 (t, J = 7.0 Hz, 4H). 13C{1H} NMR (101
MHz, DMSO-d6) δ 163.1, 153.6, 142.6, 135.0, 119.0, 113.3, 108.9,
102.0, 100.8, 66.5, 56.1, 15.1. HRMS (ESI) m/z: [M + H]+Calcd for
C12H14NO2 204.1024; Found 204.1028.
2-[(E)-2-Ethoxyvinyl]-4-formylbenzonitrile (2g). This compound
was prepared following the procedure described above to give 304 mg
(66% yield) as a white amorphous solid and was characterized as a
mixture of isomers (E:Z ratio ≈ 3:1). E-isomer: 1H NMR (600 MHz,
DMSO-d6) δ 10.15 (s, 1H), 8.09 (dd, J = 7.7, 1.4 Hz, 1H), 8.05 (dd, J
= 7.8, 1.5 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 12.8 Hz, 1H),
6.36 (d, J = 12.8 Hz, 1H), 4.04 (q, J = 7.0 Hz, 2H), 1.31 (t, J = 7.0 Hz,
3H). 13C{1H} NMR (151 MHz, CDCl3) δ 190.5, 156.4, 143.0, 137.9,
134.2, 133.3, 126.3, 117.7, 113.0, 98.0, 66.6, 14.6. Z-isomer: 1H NMR
(600 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.08 (dd, J = 7.7, 1.5 Hz, 1H),
7.99 (dd, J = 7.8, 1.4 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 6.84 (d, J =
6.9 Hz, 1H), 5.72 (d, J = 6.8 Hz, 1H), 3.96 (q, J = 7.1 Hz, 2H), 1.14
(t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 190.9, 150.7,
141.4, 137.1, 134.0, 131.5, 127.0, 117.4, 113.4, 97.9, 69.5, 15.0.
HRMS (ESI) m/z: [M + H]+ Calcd for C12H12NO2 202.0868; Found
202.0878.
2-[(E)-2-Ethoxyvinyl]-4-(hydroxymethyl)benzonitrile (2h). This
compound was prepared following the procedure described above
to give 85 mg (71% yield) of pure product as a gray amorphous solid.
1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.0 Hz, 1H), 7.45−7.42
(m, 1H), 7.21 (d, J = 12.8 Hz, 1H), 7.15 (dt, J = 8.0, 1.0 Hz, 1H),
6.11 (d, J = 12.8 Hz, 1H), 4.72 (s, 2H), 3.97 (q, J = 7.0 Hz, 2H), 1.91
(s, 1H), 1.37 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 151.8, 146.0, 141.0, 133.3, 123.8, 121.7, 118.6, 108.5, 102.3, 66.1,
(E)-2-(2-Ethoxyvinyl)-3-methylbenzonitrile (2b). This compound
64.6, 14.8. HRMS (ESI) m/z: [M
+
H]+ Calcd for
was prepared following the procedure described above to give 190 mg
1
(80% yield) of pure product as a yellow oil. H NMR (400 MHz,
C12H14NO2204.1024; Found 204.1023.
CDCl3) δ 7.49−7.43 (m, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.13 (t, J =
7.7 Hz, 1H), 6.97 (d, J = 13.0 Hz, 1H), 5.84 (d, J = 12.9 Hz, 1H),
3.98 (q, J = 7.0 Hz, 2H), 2.32 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 152.8, 139.0, 137.2, 134.3,
131.3, 126.0, 119.8, 110.6, 101.0, 66.2, 20.9, 14.9. HRMS (ESI) m/z:
[M + H]+ Calcd for C12H13NO 188.1075; Found 188.1082.
4-Chloro-2-[(E)-2-ethoxyvinyl]benzonitrile (2c). This compound
was prepared following the procedure described above to give 98 mg
(82% yield) of pure product as a light-yellow oil. 1H NMR (400 MHz,
CDCl3) δ 7.48 (d, J = 8.3 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.19 (d, J
= 12.8 Hz, 1H), 7.15 (dd, J = 8.3, 2.0 Hz, 1H), 6.06 (d, J = 12.8 Hz,
1H), 3.99 (q, J = 7.0 Hz, 2H), 1.38 (t, J = 7.0 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 152.7, 142.5, 139.4, 134.2, 126.0, 124.0,
117.8, 108.0, 101.4, 66.3, 14.7. HRMS (ESI) m/z: [M + H]+ Calcd
for C11H11ClNO 208.0529; Found 208.0534.
2-[(E)-2-Ethoxyvinyl]-4-(trifluoromethyl)benzonitrile (2i). This
compound was prepared following the procedure described above
to give 393 mg (73% yield) of pure product as a yellow oil. 1H NMR
(600 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.79
(d, J = 12.5 Hz, 1H), 7.58 (dd, J = 8.2, 1.7 Hz, 1H), 6.02 (d, J = 12.6
Hz, 1H), 4.03 (q, J = 7.0 Hz, 2H), 1.29 (t, J = 7.0 Hz, 3H). 13C{1H}
NMR (151 MHz, DMSO-d6) δ 155.5, 141.9, 134.6, 133.4 (q, J = 32.2
Hz), 123.8 (q, J = 273.4 Hz), 122.3 (q, J = 3.8 Hz), 121.0 (q, J = 3.8
Hz), 117.5, 111.97, 101.19, 67.1, 15.2. 19F NMR (376 MHz, DMSO-
d6) δ −62.05. HRMS (ESI) m/z: [M + H]+ Calcd for C12H10F3NO
242.0793; Found 242.0786.
4-Fluoro-2-[(E)-2-ethoxyvinyl]benzonitrile (2j). This compound
was prepared following the procedure described above to give 90 mg
1
(77% yield) of pure product as a colorless oil. H NMR (400 MHz,
CDCl3) δ 7.55 (dd, J = 8.6, 5.7 Hz, 1H), 7.19 (d, J = 12.9 Hz, 1H),
7.10 (dd, J = 10.2, 2.5 Hz, 1H), 6.88 (ddd, J = 8.7, 7.8, 2.5 Hz, 1H),
6.09 (dd, J = 12.8, 1.4 Hz, 1H), 3.99 (q, J = 7.0 Hz, 2H), 1.38 (t, J =
7.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.3, 163.8,
152.5, 143.8, 143.7, 135.3, 135.2, 117.7, 113.5, 113.2, 110.7, 110.5,
105.7, 105.7, 101.5, 101.5, 66.1, 14.6. 19F NMR (471 MHz, CDCl3) δ
−103.75. HRMS (ESI) m/z: [M + H]+ Calcd for C11H11FNO
192.0824; Found 192.0825.
(E)-2-(2-Ethoxyvinyl)-4-(pyrrolidin-1-yl)benzonitrile (2d). This
compound was prepared following the procedure described above
1
to give 98 mg (64% yield) of pure product as a yellow oil. H NMR
(500 MHz, DMSO-d6) δ 7.42 (d, J = 12.7 Hz, 1H), 7.39 (d, J = 8.7
Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H), 6.39 (dd, J = 8.8, 2.6 Hz, 1H), 5.89
(d, J = 12.7 Hz, 1H), 3.94 (q, J = 7.0 Hz, 2H), 3.42−3.00 (m, 4H),
2.08−1.66 (m, 4H), 1.27 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (126
MHz, DMSO-d6) δ 152.1, 150.3, 141.0, 134.1, 120.5, 110.3, 106.2,
102.8, 94.1, 66.2, 47.6, 25.3, 15.1. HRMS (ESI) m/z: [M + H]+ Calcd
for C15H19N2O 243.1497; Found 243.1504.
(E)-2-(2-Ethoxyvinyl)-5-fluorobenzonitrile (2k). This compound
was prepared following the procedure described above to give 326 mg
1
(76% yield) of pure product as a colorless oil. H NMR (400 MHz,
CDCl3) δ 7.39 (dd, J = 8.9, 5.1 Hz, 1H), 7.29−7.22 (m, 1H), 7.18
(ddd, J = 9.0, 7.9, 2.8 Hz, 1H), 7.10 (d, J = 12.9 Hz, 1H), 6.07 (d, J =
12.9 Hz, 1H), 3.97 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 159.9 (d, J = 247.7 Hz), 151.5
(d, J = 1.8 Hz), 137.2 (d, J = 3.6 Hz), 126.0 (d, J = 7.9 Hz), 120.8 (d,
J = 21.6 Hz), 119.2 (d, J = 24.3 Hz), 117.3 (d, J = 2.9 Hz), 110.5 (d, J
= 9.0 Hz), 101.3, 66.0, 14.7. 19F NMR (471 MHz, DMSO-d6) δ
4-(Dimethylamino)-2-[(E)-2-ethoxyvinyl]benzonitrile (2e). This
compound was prepared following the procedure described above
to give 250 mg (87% yield) of pure product as a yellow oil. 1H NMR
(400 MHz, CDCl3) δ 7.38 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 12.9 Hz,
1H), 6.55 (d, J = 2.5 Hz, 1H), 6.47 (dd, J = 8.8, 2.5 Hz, 1H), 6.05 (d,
J = 12.9 Hz, 1H), 3.95 (q, J = 7.0 Hz, 2H), 3.02 (s, 6H), 1.36 (t, J =
7.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 152.6, 150.8,
8484
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Note
−115.94. HRMS (ESI) m/z: [M + H]+ Calcd for C11H11FNO
192.0824; Found 192.0829.
(E)-2-(2-Ethoxyvinyl)-5-nitrobenzonitrile (2l). This compound was
99.2, 67.8, 15.0. HRMS (ESI) m/z: [M + H]+ Calcd for
C9H10N3O,176.0823; Found, 176.0835.
5-[(E)-2-Ethoxyvinyl]pyrimidine-4-carbonitrile (6d). This com-
pound was prepared following the procedure described above to
give 240 mg (72%) of pure product as a white solid. H NMR (400
prepared following the procedure described above to give 326 mg
(64% yield) of pure product as a yellow oil. H NMR (600 MHz,
1
1
MHz, CDCl3) δ 9.01 (s, 1H), 8.92 (s, 1H), 7.35 (d, J = 13.0 Hz, 1H),
5.93 (d, J = 13.0 Hz, 1H), 4.05 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 7.0 Hz,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.6, 154.2, 154.0, 136.2,
134.1, 115.0, 96.5, 66.9, 14.7. HRMS (ESI) m/z: [M + H]+ Calcd for
C9H9N3O, 176.0823; Found 176.0833.
General Procedure for the Synthesis of Isoquinolin-1(2H)-
ones (3) and (7). To a solution of 2-[(E)-3-ethoxyallyl]benzonitrile
(2) or (6) (0.74 mmol) in a mixture of EtOH/water (3:2 mL, 0.49
M/0.74 M) was added Parkins catalyst (0.02 mmol). The solution
was heated at reflux temperature in an oil bath with vigorous stirring
until the starting material was fully consumed (12 to 48 h). The
reaction mixture was concentrated in vacuo and crude product was
purified by flash column chromatography (gradient DCM/MeOH,
1:0 to 9:1) or PTLC to give the product (3) or (7).
DMSO-d6) δ 8.60 (d, J = 2.5 Hz, 1H), 8.32 (dd, J = 9.0, 2.5 Hz, 1H),
7.98 (d, J = 9.1 Hz, 1H), 7.89 (d, J = 12.5 Hz, 1H), 6.06 (d, J = 12.5
Hz, 1H), 4.09 (q, J = 7.0 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H). 13C{1H}
NMR (151 MHz, DMSO-d6) δ 157.6, 146.9, 144.1, 128.7, 127.5,
124.3, 116.3, 108.3, 100.8, 67.3, 14.7. HRMS (ESI) m/z: [M + Na]+
Calcd for C11H10N2O3Na 241.0589; Found 241.0557.
(E)-5-Chloro-2-(2-ethoxyvinyl)benzonitrile (2m). This compound
was prepared following the procedure described above to give 53 mg
(51% yield) of pure product as a light-yellow oil. 1H NMR (400 MHz,
DMSO-d6) δ 7.86 (d, J = 2.3 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.62
(dd, J = 8.7, 2.4 Hz, 1H), 7.56 (d, J = 12.7 Hz, 1H), 5.94 (d, J = 12.7
Hz, 1H), 3.98 (q, J = 7.0 Hz, 2H), 1.28 (t, J = 7.0 Hz, 3H). 13C{1H}
NMR (101 MHz, DMSO-d6) δ 154.1, 139.6, 133.7, 132.4, 130.1,
126.0, 117.3, 109.9, 101.0, 66.7, 15.0. HRMS (ESI) m/z: [M + H]+
Calcd for C9H7ClNO 180.0216; Found 180.0219.
2-[(E)-2-Ethoxyvinyl]-6-methoxybenzonitrile (2n). This com-
pound was prepared following the procedure described above to
give 291 mg (64% yield) of pure product as a white amorphous solid.
1H NMR (600 MHz, DMSO-d6) δ 7.53−7.36 (m, 2H), 7.22 (d, J =
8.0 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 5.90 (d, J = 12.7 Hz, 1H), 3.94
(q, J = 7.0 Hz, 2H), 3.84 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H). 13C{1H}
NMR (151 MHz, DMSO-d6) δ 161.4, 153.2, 141.7, 134.1, 115.8,
115.6, 108.0, 101.5, 97.7, 66.1, 56.2, 14.7, 14.7. HRMS (ESI) m/z: [M
+ H]+ Calcd for C12H13NO2 204.1024; Found 204.1035.
Isoquinolin-1(2H)-one (3a). This compound was prepared
following the procedure described above to give 95 mg (87% yield)
1
of pure product as a white amorphous solid. H NMR (400 MHz,
DMSO-d6) δ 11.22 (bs, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.67 (dt, J =
15.1, 7.6 Hz, 2H), 7.47 (t, J = 8.0 Hz, 1H), 7.16 (t, 1H), 6.54 (d, J =
7.1 Hz, 1H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 161.8, 137.8,
132.2, 128.9, 126.6, 126.2, 126.1, 126.0, 104.6. HRMS (ESI) m/z: [M
+ H]+ Calcd for C9H8NO 146.0605; Found 146.0606.
5-Methyl-2H-isoquinolin-1-one (3b). This compound was pre-
pared following the procedure descried above to give 24 mg (81%
1
yield) of pure product as a white amorphous solid. H NMR (400
tert-Butyl-(E)-((1-(4-cyano-5-(2-ethoxyvinyl)-2-fluorophenyl)-
pyrrolidin-3-yl)methyl)carbamate (2o). This compound was pre-
pared following the procedure described above to give 226 mg (85%
yield) of pure product as a colorless oil. 1H NMR (400 MHz, DMSO-
d6) δ 7.41−7.24 (m, 2H), 6.97 (t, J = 5.8 Hz, 1H), 6.65 (d, J = 8.8 Hz,
1H), 5.82 (d, J = 12.7 Hz, 1H), 3.91 (q, J = 7.0 Hz, 1H), 3.54−3.35
(m, 3H), 3.22−3.15 (m, 1H), 2.99−2.90 (m, 2H), 2.32 (p, J = 6.9 Hz,
1H), 1.95 (h, J = 6.6 Hz, 1H), 1.69−1.56 (m, 1H), 1.34 (s, 9H), 1.24
(t, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 155.8,
151.8, 147.8 (d, J = 240.1 Hz), 140.2 (d, J = 9.2 Hz), 137.5 (d, J = 1.9
Hz), 119.2 (d, J = 24.5 Hz), 118.6 (d, J = 2.0 Hz), 109.2 (d, J = 5.6
Hz), 101.5, 93.6 (d, J = 8.9 Hz), 77.6, 65.8, 52.8 (d, J = 5.9 Hz), 48.7
(d, J = 5.0 Hz), 42.2, 38.4, 28.2, 14.7. 19F NMR (376 MHz, DMSO-
d6) δ −131.37. HRMS (ESI) m/z: [M + H]+ Calcd for C21H29FN3O3,
390.2192; Found 390.2218.
MHz, DMSO-d6) δ 11.28 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.52 (d, J
= 7.2 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 6.57
(d, J = 7.4 Hz, 1H), 2.47 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ
162.5, 137.1, 133.6, 133.3, 129.1, 126.7, 126.3, 125.1, 101.7, 19.1.
HRMS (ESI) m/z: [M + H]+ Calcd for C10H10NO 160.0762; Found
160.0765.
6-Chloroisoquinolin-1(2H)-one (3c). This compound was pre-
pared following the procedure descried above to give 15 mg (91%
1
yield) of pure product as a white amorphous solid. H NMR (400
MHz, DMSO-d6) δ 11.35 (s, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.74 (d, J
= 2.1 Hz, 1H), 7.44 (dd, J = 8.6, 2.1 Hz, 1H), 7.20 (d, J = 7.1 Hz,
1H), 6.49 (d, J = 7.1 Hz, 1H). 13C{1H} NMR (101 MHz, DMSO-d6)
δ 161.3, 139.5, 137.3, 130.7, 129.0, 126.5, 125.3, 124.6, 103.8. HRMS
(ESI) m/z: [M + H]+ Calcd for C9H7ClNO 180.0216; Found
180.0219.
6-(Pyrrolidin-1-yl)isoquinolin-1(2H)-one (3d). This compound
was prepared following the procedure described above to give 28
mg (88% yield) of pure product as a light-yellow amorphous solid. 1H
NMR (600 MHz, DMSO-d6) δ 10.63 (s, 1H), 7.94 (d, J = 8.9 Hz,
1H), 6.97 (t, J = 6.4 Hz, 1H), 6.73 (d, J = 8.9 Hz, 1H), 6.49 (s, 1H),
6.30 (d, J = 7.1 Hz, 1H), 3.57−2.93 (m, 4H), 2.17−1.67 (m, 4H).
13C{1H} NMR (151 MHz, DMSO-d6) δ 161.8, 149.9, 139.5, 128.7,
128.1, 115.1, 112.5, 104.5, 104.4, 47.2, 24.9. HRMS (ESI) m/z: [M +
H]+ Calcd for C13H15N2O 215.1184; Found 215.1173.
(E)-1-(2-Ethoxyvinyl)-2-naphthonitrile (6a). This compound was
prepared following the procedure described above to give 132 mg
1
(69% yield) of pure product as a colorless oil. H NMR (400 MHz,
DMSO-d6) δ 7.70 (dd, J = 7.9, 1.4 Hz, 2H), 7.62−7.40 (m, 2H), 7.27
(t, J = 7.6 Hz, 1H), 5.99 (d, J = 12.7 Hz, 1H), 3.98 (q, J = 7.0 Hz,
2H), 1.28 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (151 MHz, DMSO-d6)
δ 152.8, 140.0, 133.1, 132.8, 125.8, 124.0, 118.1, 108.1, 101.4, 66.0,
14.6. HRMS (ESI) m/z: [M + H]+ Calcd for C15H14NO, 224.1075;
Found 224.1089.
3-[(E)-2-Ethoxyvinyl]pyridine-2-carbonitrile (6b). This compound
was prepared following the procedure described above to give 271 mg
(68% yield) of pure product as an orange amorphous solid. 1H NMR
(600 MHz, DMSO-d6) δ 8.42 (dd, J = 4.5, 1.5 Hz, 1H), 8.14 (dd, J =
8.3, 1.5 Hz, 1H), 7.60 (d, J = 12.7 Hz, 1H), 7.56 (ddd, J = 8.4, 4.5, 0.6
Hz, 1H), 5.91 (d, J = 12.7 Hz, 1H), 3.99 (q, J = 7.0 Hz, 3H), 1.26 (t, J
= 7.0 Hz, 3H). 13C{1H} NMR (151 MHz, DMSO-d6) δ 154.8, 147.9,
137.4, 131.9, 128.6, 127.4, 116.8, 98.6, 98.3, 66.4, 14.6. HRMS (ESI)
m/z: [M + H]+ Calcd for C10H11N2O, 175.0871; Found, 175.0878.
3-[(E)-2-Ethoxyvinyl]pyrazine-2-carbonitrile (6c). This compound
was prepared following the procedure described above to give 331 mg
6-(Dimethylamino)-2H-isoquinolin-1-one (3e). This compound
was prepared following the procedure described above to give 20 mg
(82% yield) of pure product as a white amorphous solid. H NMR
(400 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.94 (d, J = 9.0 Hz, 1H), 6.99
(t, J = 6.3 Hz, 1H), 6.90 (dd, J = 9.0, 2.6 Hz, 1H), 6.66 (d, J = 2.5 Hz,
1H), 6.32 (d, J = 7.2 Hz, 1H), 3.01 (s, 6H). 13C{1H} NMR (101
MHz, DMSO-d6) δ 161.8, 152.6, 139.5, 128.8, 128.0, 115.6, 112.4,
105.0, 104.6. HRMS (ESI) m/z: [M + H]+ Calcd for C11H12N2O
189.1028; Found 189.1039.
1
6-Methoxy-2H-isoquinolin-1-one (3f). This compound was
prepared following the procedure described above to give 9 mg
(47% yield) of pure product as a white amorphous solid along with
1
(83% yield) of pure product as an off-white amorphous solid. H
1
NMR (600 MHz, DMSO-d6) δ 8.69 (d, J = 2.3 Hz, 1H), 8.47 (d, J =
2.3 Hz, 1H), 7.93 (d, J = 12.1 Hz, 1H), 6.03 (d, J = 12.1 Hz, 1H),
4.09 (q, J = 7.0 Hz, 2H), 1.28 (t, J = 7.0 Hz, 3H). 13C{1H} NMR
(151 MHz, DMSO-d6) δ 159.0, 154.6, 147.9, 142.5, 124.7, 116.3,
35% recovered starting material. H NMR (400 MHz, DMSO-d6) δ
11.03 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.13−7.06 (m, 2H), 7.00 (dd,
J = 8.9, 2.6 Hz, 1H), 6.43 (d, J = 7.1 Hz, 1H), 3.82 (s, 3H). 13C{1H}
NMR (101 MHz, DMSO-d6) δ 162.6, 162.0, 140.5, 130.0, 129.1,
8485
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Note
1
120.2, 116.2, 107.5, 104.9, 55.9. HRMS (ESI) m/z: [M + H]+ Calcd
for C10H9NO2 176.0711; Found 176.0718.
1-Oxo-2H-isoquinoline-6-carbaldehyde (3g). This compound was
(55% yield) of pure product as an off-white amorphous solid. H
NMR (600 MHz, DMSO-d6) δ 10.84 (s, 1H), 7.52 (t, J = 8.1 Hz,
1H), 7.08 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.91 (d, J =
8.1 Hz, 1H), 6.35 (d, J = 7.0 Hz, 1H), 3.79 (s, 3H). 13C{1H} NMR
(151 MHz, DMSO-d6) δ 160.8, 160.8, 141.4, 133.4, 129.9, 118.6,
115.9, 108.6, 104.7, 56.1. HRMS (ESI) m/z[M + H]+ Calcd for
C10H10NO2 176.0711; Found 176.0709.
prepared following the procedure described above to give 26 mg (52%
1
yield) of pure product as a white amorphous solid. H NMR (600
MHz, DMSO-d6) δ 11.60 (s, 1H), 10.33 (s, 1H), 8.51 (d, J = 8.0 Hz,
1H), 8.29 (dd, J = 7.5, 1.6 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.65 (d, J
= 7.3 Hz, 1H), 7.39 (dd, J = 7.5, 5.9 Hz, 1H). 13C{1H} NMR (151
MHz, DMSO-d6) δ 194.0, 161.7, 139.8, 137.3, 133.4, 132.8, 130.3,
127.5, 126.4, 100.8. HRMS (ESI) m/z: [M + H]+ Calcd for
C10H8NO2 174.0555; Found 174.0557.
tert-Butyl-((1-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-6-yl)-
pyrrolidin-3-yl)methyl)carbamate (3o). This compound was pre-
pared following the procedure described above using 216 mg (0.55
mol) of 2o to give 157 mg (78% yield) of pure product as a white
amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ 10.87 (bs, 1H),
7.63 (dd, J = 14.9, 2.1 Hz, 1H), 7.20−6.87 (m, 2H), 6.70 (d, J = 8.5
Hz, 1H), 6.36 (d, J = 7.0 Hz, 1H), 3.60−3.38 (m, 3H), 3.27−3.15 (m,
1H), 3.13−2.84 (m, 2H), 2.44−2.31 (m, 1H), 2.10−1.91 (m, 1H),
1.75−1.61 (m, 1H), 1.38 (s, 9H). 13C{1H} NMR (101 MHz, DMSO-
d6) δ 160.9 (d, J = 3.3 Hz), 155.8, 150.5 (d, J = 242.8 Hz), 140.7 (d, J
= 10.8 Hz), 136.2, 128.3, 115.8 (d, J = 6.8 Hz), 112.2 (d, J = 22.2
Hz), 109.1 (d, J = 5.1 Hz), 103.8, 77.5, 53.0 (d, J = 5.5 Hz), 48.9 (d, J
= 5.4 Hz), 42.3, 38.4, 28.3, 28.2. 19F NMR (376 MHz, DMSO-d6) δ
−127.33. HRMS (ESI) m/z: [M + H]+ Calcd for C19H25FN3O3
362.1879; Found 362.1869.
6-(Hydroxymethyl)-2H-isoquinolin-1-one (3h). This compound
was prepared following the procedure described above to give 14 mg
1
(82% yield) of pure product as a white amorphous solid. H NMR
(400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.56
(d, J = 1.7 Hz, 1H), 7.41 (dd, J = 8.3, 1.6 Hz, 1H), 7.14 (dd, J = 7.1,
5.1 Hz, 1H), 6.52 (d, J = 7.1 Hz, 1H), 5.40 (t, J = 5.7 Hz, 1H), 4.63
(d, J = 5.2 Hz, 2H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 161.8,
147.2, 137.9, 129.0, 126.6, 124.7, 123.0, 104.8, 62.6. HRMS (ESI) m/
z: [M + H]+ Calcd for C10H9NO2 176.0711; Found 176.0701.
6-(Trifluoromethyl)-2H-isoquinolin-1-one (3i). This compound
was prepared following the procedure described above to give 22 mg
1
Benzo[f ]isoquinolin-4(3H)-one (7a). This compound was pre-
(47% yield) of pure product as a white amorphous solid. H NMR
pared following the procedure described above to give 60 mg (91%
yield) of pure product as a white amorphous solid. H NMR (500
(400 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.32 (dd, J = 8.5, 1.2 Hz,
1H), 8.09 (s, 1H), 7.71 (dd, J = 8.4, 1.8 Hz, 1H), 7.28 (dd, J = 7.1, 4.8
Hz, 1H), 6.68 (d, J = 7.1 Hz, 1H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 161.1, 138.1, 132.1 (q, J = 32.0 Hz), 130.8, 128.4, 128.0,
123.9 (q, J = 273.1 Hz), 123.7 (q, J = 4.0 Hz), 121.9 (q, J = 3.4 Hz),
104.4. 19F NMR (376 MHz, DMSO-d6) δ −61.57. HRMS (ESI) m/z:
[M + H]+ Calcd for C10H7F3NO 214.0479; Found, 214.0487.
6-Fluoroisoquinolin-1(2H)-one (3j). This compound was prepared
following the procedure descried above to give 16 mg (79% yield) of
pure product as a white amorphous solid. 1H NMR (400 MHz,
DMSO-d6) δ 11.30 (s, 1H), 8.22 (dd, J = 8.9, 6.0 Hz, 1H), 7.47 (dd, J
= 10.1, 2.6 Hz, 1H), 7.30 (td, J = 8.9, 2.6 Hz, 1H), 7.22 (d, J = 7.2 Hz,
1H), 6.53 (d, J = 7.2 Hz, 1H). 13C{1H} NMR (101 MHz, DMSO-d6)
δ 165.6, 163.1, 161.2, 140.4, 140.3, 130.5, 130.2, 130.1, 123.0, 122.9,
114.9, 114.6, 111.0, 110.8, 104.2, 104.1. 19F NMR (471 MHz,
DMSO-d6) δ −107.46. HRMS (ESI) m/z: [M + H]+ Calcd for
C9H7FNO 164.0511; Found 164.0510.
1
MHz, DMSO-d6) δ 11.64 (bs, 1H), 8.64 (d, J = 8.0 Hz, 1H), 8.18 (d,
J = 8.8 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H),
7.79−7.58 (m, 2H), 7.43 (t, J = 6.2 Hz, 2H). 13C{1H} NMR (126
MHz, DMSO-d6) δ 161.7, 136.4, 134.3, 130.5, 128.5, 128.4, 128.1,
126.9, 126.4, 124.4, 123.3, 122.8, 100.3. HRMS (ESI) m/z: [M + H]+
Calcd for C13H10NO 196.0762; Found 196.0766.
7H-1,7-Naphthyridin-8-one (7b). This compound was prepared
following the procedure described above to give 26 mg (69% yield) of
pure product as a yellow amorphous solid. 1H NMR (400 MHz,
DMSO-d6) δ 11.55 (s, 1H), 8.72 (dd, J = 4.3, 1.7 Hz, 1H), 8.07 (dd, J
= 8.1, 1.7 Hz, 1H), 7.63 (dd, J = 8.1, 4.3 Hz, 1H), 7.23 (d, J = 7.1 Hz,
1H), 6.50 (d, J = 7.0 Hz, 1H). 13C{1H} NMR (101 MHz, DMSO-d6)
δ 161.2, 149.3, 142.4, 135.2, 134.8, 130.4, 127.2, 103.7. HRMS (ESI)
m/z: [M + H]+ Calcd for C8H7N2O 147.0558; Found 147.0557.
6H-Pyrido[3,4-b]pyrazin-5-one (7c). This compound was prepared
following the procedure described above to give 33 mg (80% yield) of
pure product as a orange amorphous solid. 1H NMR (400 MHz,
DMSO-d6) δ 11.83 (s, 1H), 8.90 (d, J = 2.1 Hz, 1H), 8.76 (d, J = 2.1
Hz, 1H), 7.50 (d, J = 6.5 Hz, 1H), 6.59 (d, J = 7.3 Hz, 1H). 13C{1H}
NMR (101 MHz, DMSO-d6) δ 161.4, 150.6, 149.6, 144.3, 137.8,
134.5, 105.2. HRMS (ESI) m/z: [M + H]+ Calcd for C7H5N3O
148.0510; Found, 148.0512.
7-Fluoroisoquinolin-1(2H)-one (3k). This compound was pre-
pared following the procedure described above to give 17 mg (83%
1
yield) of pure product as a white amorphous solid. H NMR (400
MHz, DMSO-d6) δ 11.37 (bs, 1H), 7.83 (dd, J = 9.6, 2.8 Hz, 1H),
7.76 (dd, J = 8.8, 5.4 Hz, 1H), 7.60 (td, J = 8.7, 2.8 Hz, 1H), 7.16 (dd,
J = 6.2, 2.6 Hz, 2H), 6.59 (d, J = 7.1 Hz, 1H). 13C{1H} NMR (126
MHz, DMSO-d6) δ 160.4 (d, J = 244.3 Hz), 161.0 (d, J = 3.5 Hz),
134.7 (d, J = 1.8 Hz), 129.1 (d, J = 8.0 Hz), 128.2 (d, J = 2.3 Hz),
127.4 (d, J = 7.5 Hz), 121.0 (d, J = 23.5 Hz), 111.2 (d, J = 22.2 Hz),
104.1. 19F NMR (376 MHz, DMSO-d6) δ −113.97. HRMS (ESI) m/
z: [M + H]+ Calcd for C9H7FNO, 164.0511; Found 164.0496.
7-Nitroisoquinolin-1(2H)-one (3l). This compound was prepared
following the procedure described above to give 26 mg (80% yield) of
pure product as a white amorphous solid. 1H NMR (400 MHz,
DMSO-d6) δ 11.76 (s, 1H), 8.88 (d, J = 2.5 Hz, 1H), 8.43 (dd, J =
8.8, 2.5 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 7.2, 4.8 Hz,
1H), 6.72 (d, J = 7.1 Hz, 1H). 13C{1H} NMR (151 MHz, DMSO-d6)
δ 161.1, 145.0, 142.8, 133.5, 128.1, 126.1, 125.6, 122.6, 104.1. HRMS
(ESI) m/z: [M + H]+ Calcd for C9H7N2O3 191.0456; Found
191.0452.
7H-Pyrido[3,4-d]pyrimidin-8-one (7d). This compound was
prepared following the procedure described above to give 10 mg
1
(60% yield) of pure product as a white amorphous solid. H NMR
(400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.35 (d, J = 2.0 Hz, 1H), 9.26
(d, J = 2.0 Hz, 1H), 7.39 (t, J = 5.2 Hz, 1H), 6.61 (dd, J = 7.0, 2.2 Hz,
1H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 160.0, 158.7, 155.6,
145.7, 132.1, 130.8, 100.6. HRMS (ESI) m/z [M + H]+: Calcd for
C7H5N3O 148.0510; Found 148.0514.
(E)-5-(2-Ethoxyvinyl)pyrimidine-4-carboxamide (7d′). Small
amounts of this compound (white amorphous solid) were obtained
1
from the uncomplete reaction to produce 7d. H NMR (400 MHz,
CDCl3) δ 8.96 (s, 1H), 8.91 (s, 1H), 7.90 (bs, 1H), 7.08 (d, J = 13.3
Hz, 1H), 7.02 (d, J = 13.3 Hz, 1H), 5.66 (bs, 1H), 4.01 (q, J = 7.0 Hz,
2H), 1.37 (t, J = 7.0 Hz, 3H). HRMS (ESI) m/z: [M + H]+ Calcd for
C9H12N3O2 194.0929; Found 194.0933.
Alternative Synthesis of 6-(Pyrrolidin-1-yl)isoquinolin-
1(2H)-one (3d). This compound was alternatively prepared by
dissolving 4-fluoro-2-[(E)-2-ethoxyvinyl]benzonitrile (3j) (5.00 mg,
0.03 mmol) in pyrrolidine (1 mL). The reaction was heated at reflux
in an oil bath and stirred for 48 h, after which pyrrolidine was
removed in vacuo. The crude product was purified by PTLC to yield
6.2 mg (94% yield) of the desired product as a light-yellow
amorphous solid. The 1H NMR matched that described for (3d)
7-Chloroisoquinolin-1(2H)-one (3m). This compound was pre-
pared following the procedure described above to give 29 mg (79%
1
yield) of pure product as a white amorphous solid. H NMR (400
MHz, DMSO-d6) δ 11.43 (s, 1H), 8.11 (s, 1H), 7.87−7.46 (m, 1H),
7.33−7.01 (m, 1H), 6.58 (d, J = 6.9 Hz, 1H). 13C{1H} NMR (101
MHz, DMSO-d6) δ 160.7, 136.6, 132.4, 130.8, 129.5, 128.5, 127.2,
125.6, 104.1. HRMS (ESI) m/z: [M+1]+ Calcd for
C9H7ClNO180.0216; Found 180.0219.
8-Methoxy-2H-isoquinolin-1-one (3n). This compound was
prepared following the procedure described above to give 24 mg
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The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(fully characterized above). 1H NMR (400 MHz, DMSO-d6) δ 10.64
(s, 1H), 7.94 (d, J = 8.9 Hz, 1H), 6.97 (t, 1H), 6.73 (d, J = 8.9 Hz,
2H), 6.49 (s, 1H), 6.30 (d, J = 7.2 Hz, 1H), 3.50−3.16 (m, 4H),
2.08−1.82 (m, 4H).
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00472.
■
sı
1
NMR spectra for all compounds: H, 13C{1H}, and 19F
where applicable (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Craig M. Crews − Department of Molecular, Cellular &
Developmental Biology, Department of Pharmacology, and
Department of Chemistry, Yale University, New Haven,
Connecticut 06511, United States; orcid.org/0000-0002-
8456-2005; Email: craig.crews@yale.edu
Authors
Saul Jaime-Figueroa − Department of Molecular, Cellular &
Developmental Biology, Yale University, New Haven,
Connecticut 06511, United States
Michael J. Bond − Department of Pharmacology, Yale
University, New Haven, Connecticut 06511, United States
J. Ignacio Vergara − Department of Chemistry, Yale
University, New Haven, Connecticut 06511, United States
Jake C. Swartzel − Department of Chemistry, Yale University,
New Haven, Connecticut 06511, United States
(11) Fales, K. R.; Njoroge, F. G.; Brooks, H. B.; Thibodeaux, S.;
Torrado, A.; Si, C.; Toth, J. L.; Mc Cowan, J. R.; Roth, K. D.;
Thrasher, K. J.; Frimpong, K.; Lee, M. R.; Dally, R. D.; Shepherd, T.
A.; Durham, T. B.; Margolis, B. J.; Wu, Z.; Wang, Y.; Atwell, S.; Wang,
J.; Hui, Y. H.; Meier, T. I.; Konicek, S. A.; Geeganage, S. Discovery of
N-(6-Fluoro-1-oxo-1,2-dihydroisoquinolin-7-yl)-5-[(3R)-3-hydroxy-
pyrrolidin-1-yl]t hiophene-2-sulfonamide (LSN 3213128), a Potent
and Selective Nonclassical Antifolate Aminoimidazole-4-carboxamide
Ribonucleotide Formyltransferase (AICARFT) Inhibitor Effective at
Tumor Suppression in a Cancer Xenograft Model. J. Med. Chem.
2017, 60, 9599−9616.
(12) Glushkov, V. A.; Shklyaev, Y. Synthesis of 1(2H)-
isoquinolones. Chem. Heterocycl. Compd. 2001, 37, 663−687.
(13) Zhu, H. J.; Zhuang, R. X.; Zheng, W. Y.; Fu, L. P.; Zhao, Y. K.;
Tu, L. P.; Chai, Y. T.; Zeng, L. H.; Zhang, C.; Zhang, J. K. Synthesis
of isoquinolone via rhodium(III)-catalyzed C-H activation with 1,4,2-
dioxazol-5-ones as oxidizing directing group. Tetrahedron 2019, 75,
3108−3112.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00472
Notes
The authors declare the following competing financial
interest(s): C.M.C. is founder, shareholder, and consultant to
Arvinas, Inc. and Halda, LLC, which support research in his
laboratory.
ACKNOWLEDGMENTS
■
C.M.C. is funded by the NIH (R35CA197589) and is
supported by an American Cancer Research Professorship.
M.J.B. acknowledges support from the NIH (F31CA232477
and 5T32GM067543). We would like to thank the Yale
Chemical and Biophysical Instrumentation Center, especially
Dr. Fabian Menges for his assistance with obtaining the HRMS
data. Additionally, we would like to thank Dr. Andy Crew for
many helpful discussions and critiques during the preparation
of this manuscript.
(14) Sun, R.; Yang, X.; Li, Q.; Xu, K.; Tang, J.; Zheng, X.; Yuan, M.;
Fu, H.; Li, R.; Chen, H. Divergent Synthesis of Isoquinolone and
Isocoumarin Derivatives by the Annulation of Benzoic Acid with N-
Vinyl Amide. Org. Lett. 2019, 21, 9425−9429.
(15) Potter, T. J.; Li, Y.; Ward, M. D.; Ellman, J. A. RhIII-Catalyzed
Synthesis of Isoquinolones and 2-Pyridones via Annulation of N-
Methoxyamides and Nitroalkenes. Eur. J. Org. Chem. 2018, 2018,
4381−4388.
(16) Shi, L.; Yu, K.; Wang, B. Regioselective synthesis of
multisubstituted isoquinolones and pyridones via Rh(III)-catalyzed
annulation reactions. Chem. Commun. 2015, 51, 17277−17280.
(17) Sagara, P. S.; Siril, P. F.; Ravikumar, P. C. N-Amino-7-azaindole
as the N,N’-Bidentate Directing Group: Ruthenium-Catalyzed
Oxidative Annulation of N-(7-Azaindole)benzamides with Alkynes
via C-H Bond Activation. J. Org. Chem. 2019, 84, 12314−12323.
(18) Sharma, N.; Bahadur, V.; Sharma, U. K.; Saha, D.; Li, Z.;
Kumar, Y.; Colaers, J.; Singh, B. K.; Van der Eycken, E. V. Microwave-
Assisted Ruthenium-Catalysed ortho-C-H Functionalization of N-
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