Development of a Traceless Directing Group: Cp*-Free Cobalt-Catalyzed C-H Activation/Annulations to Access Isoquinolinones

Article abstract of DOI:10.1021/acs.joc.9b03073

A new traceless directing group, 2-(hydroxymethyl)pyridine, has been reported for the Cp*-free cobalt-catalyzed C-H activation/annulation reaction to synthesize isoquinolinones. The reaction exhibits good functional group tolerance, affording products in good to excellent isolated yields under mild conditions. Notably, the directing group can be removed directly in situ along the catalytic process.

Full text of DOI:10.1021/acs.joc.9b03073

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Article
Development of a Traceless Directing Group: Cp*-Free Cobalt-
Catalyzed C–H Activation/Annulations to Access Isoquinolinones
Minghui Liu, Jun-Long Niu, Dandan Yang, and Mao-Ping Song
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03073 • Publication Date (Web): 12 Feb 2020
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Development of a Traceless Directing Group: Cp*-Free
Cobalt-Catalyzed C–H Activation/Annulations to Access
Isoquinolinones
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Minghui Liu, Jun-Long Niu, Dandan Yang* and Mao-Ping Song*
Green Catalysis Center, and College of Chemistry, Zhengzhou University,
Zhengzhou 450001, China
Graphic abstract
O
R2
R1
O
[Co]
NH
R2
O
Ar/
Het
N
+
Ar/
Het
N
H
H
R1
new traceless directing group
mild reaction conditions
Cp*-free cobalt catalyzed
34 examples, up to 94% yield




ABSTRACT: A new traceless directing group, 2-(hydroxymethyl)pyridine, has been
reported for the Cp*-free cobalt-catalyzed C–H activation/annulation reaction to
synthesize isoquinolinones. The reaction exhibits good functional group tolerance,
affording products in good to excellent isolated yields under mild conditions. Notably,
the directing group can be removed directly in situ along the catalytic process.
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INTRODUCTION
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Research on efficient and convenient synthesis of heterocyclic compounds has
increased significantly over the past decades. Among them, nitrogen-containing
heterocyclic aromatic hydrocarbons, especially isoquinolinone and its derivatives,
have aroused eager attention due to their remarkable pharmacological importance
ranging from anticancer and antihypertensive.1 Alternatively, transition-metal
catalyzed C–H activation/annulations have emerged as an effective method for
concise synthesis of heterocycles in recent years.2
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In general, transition metal-catalyzed C–H activation relies mainly on precious
metal (such as Ru3, Rh4, or Pd5) catalysts. In spite of their high catalytic activity, these
metals are less abundant. So it would be advantageous if more-abundant first-row
metal catalysts could emulate the reactivity of a noble-metal catalyst and enable
comparable catalytic efficacy. To this, cobalt salts entered the focus of attention in C–
H activation chemistry due to its low cost, low toxicity, unique reactivity, and
abundant availability from the natural sources.6 Recently, the groups of Daugulis,7
Ackermann,8 Song,9 and others10 have reported that air-stable commercially available
CoII/CoIII salts were applied to C(sp2)–H activation/annulation assisted by a bidentate
directing group.
On the other hand, the directing group was seen as the key to reaction
acceleration control. It was also believed that bidentate auxiliaries could generate
stable metallacycles and promote C–H activation. Nevertheless, the directing groups
are generally difficult to remove after the catalytic procedure. For example, Daugulis
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described that a methoxy group mounted on 8-aminoquinoline makes removal of the
directing groups possible, while it is expensive and requires harsh reaction
conditions.7b The multiple chemical steps involving removal of directing groups also
mean low step economy and limit the application. Therefore, traceless directing
groups, which can be removed directly in situ along the catalytic process, exhibit
great potential in the bidentate directing group systems.11 However, the functional
groups that could be employed as the traceless directing groups remain relatively
rare.12 More recently, Cp*Co(III) catalyzed N-O or N-N bond cleavage type reactions
had been well established for heterocycles synthesis.13 It would be advantageous for
the C−H activation/annulation using more cheaper and readily available Cp*-free
cobalt salts based on a traceless directing group.
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Guided by the aforementioned progress and our previous work,14 we have
attempted to develop novel protocols for concise synthesis of heterocycles using
cheap and earth abundant cobalt catalyst. Herein, we report an efficient
cobalt-catalyzed C(sp2)–H bond activation/annulation based on a new traceless
bidentate directing group to synthesize isoquinolinone derivatives. In this reaction,
2-(hydroxymethyl)pyridine was firstly used as a non-marking guide group, which
could be removed directly in situ along the catalytic process.
RESULT AND DISCUSSION
We commenced our study by exploring reaction conditions with
N-(pyridin-2-ylmethoxy)benzamide 1a and diphenylacetylene 2a (Table 1). Initially,
the desired product 3aa was observed in 22% isolated yield in the presence of
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Co(OAc)24H2O, AgOAc in HFIP at 110 °C for 10 h (entry 1). Among the solvents
examined, TFE exhibited the best transformation, giving the product 3aa in 36% yield
(entries 1-4). Encouraged by the solvent-change results, we then screened some bases
or acids for the reaction. It was gratifying that, the yield rapidly increased to 64%
when PivOH was added (entries 5-9). Meanwhile, the addition of KOAc also gave
good yield of 62%, which indicated that reaction might require a large amount of
acetate or pivalate for ligand exchange in the catalytic progress. Subsequent
investigations indicated that a change of cobalt salts could not improve the reaction
efficiency (entries 10-12).
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Table 1. Optimization of the Reaction Conditionsa
O
Ph
O
NH
Ph
[Co]
110 oC, 10 h, air
O
+
N
H
N
Ph
2a
Ph
3aa
1a
Entry
Catalyst
Oxidant
Acid/Base
Solvent
Yields (%)
1
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Ag2CO3
AgOTf
AgTFA
AgOAc
AgOAc
AgOAc
HFIP
TFE
EtOH
CH3CN
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
22
36
33
29
62
53
35
55
64
59
41
40
43
trace
7
Co(OAc)24H2O
Co(OAc)24H2O
Co(OAc)24H2O
Co(OAc)24H2O
Co(OAc)24H2O
Co(OAc)24H2O
Co(OAc)24H2O
Co(OAc)24H2O
Co(OAc)24H2O
CoCl26H2O
2
3
4
5
KOAc
6
AcOH
7
PhCOOH
1-AdCOOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
8
9
10
11
12
13
14
15
16c,d
17c,d,e
18c,e,f
CoC2O44H2O
Cp*Co(CO)I2
b
Co(OAc)24H2O
Co(OAc)24H2O
Co(OAc)24H2O
Co(OAc)24H2O
Co(OAc)24H2O
Co(OAc)24H2O
72
79
87
aReaction conditions: substrate 1a (0.2 mmol), 2 (0.3 mmol), Co(OAc)24H2O (20 mol%), Oxidant
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(2.0 equiv), Acid/Base (2.0 equiv), air atmosphere, solvent (1 mL), 10 h, isolated yields. bAg2CO3
c
d
e
(1.0 eq). Co(OAc)24H2O (40 mol%). AgOAc (1.5 eq). 4-octyne instead of diphenylacetylene.
fAgOAc (1.0 eq).
7
8
9
Changing the type of oxidant caused a decrease in yields (entries 13-15). The yield
had no enhance after adding various additives (see SI). Therefore, we had to increase
the amount of catalyst to 40 mol% and the yield rose to 72%. Considering the steric
hindrance of diphenylacetylene which may inhibit the alkyne coordination to the
metal center, 4-octyne 2b was employed instead of diphenylacetylene 2a. As a result,
we obtained the target product 3ab in 79% yield (entry 17). Reducing the amount of
oxidant from 1.5 equiv to 1.0 equiv improved the reaction yield significantly (87%,
entry 18).
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According to previous studies,15 we speculate that the high catalyst loading (40
mol%) required for this reaction is due to the coordination of metal with the
2-(hydroxymethyl)pyridine formed by the reaction which may reduce the catalytic
activity of Co catalyst. In order to verify this speculation, we performed the reaction
of 1a and 2b with additional 2-(hydroxymethyl)pyridine under the optimized reaction
conditions. The yield of product 3ab indeed decreased gradually with increasing the
amount of 2-(hydroxymethyl)pyridine (Table 2).
Table 2. Effect of the Concentration of 2-(Hydroxymethyl)pyridine on the Yield
of 3aba
N
O
nPr
OH
O
H
NH
nPr
(x mol%)
Standard conditions
O
+
N
H
N
nPr
nPr
1a
2b
3ab
Entry
Additive (x mol%)
Yield (%)
1
2
20
40
72
45
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80
31
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100
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aReaction conditions: substrate 1a (0.2 mmol), 2b (0.3
mmol), Co(OAc)24H2O (40 mol%), TFE (1.0 mL), AgOAc
(1.0 equiv), PivOH (2.0 equiv), additive (x mol%), air
atmosphere, 10 h, isolated yields.
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In addition, the influences of directing group for the reaction were discussed as
follows (see Figure 1). The results indicated that substrate 1a (as for D) exhibited a
preferable reactivity for the reaction under identical conditions. No expected products
were obtained when substrates A-C, F were used, and the substrate E gave 3ab in
relatively low yield.
O
O
O
O
OH
OMe
O
NH2
N
N
N
N
H
H
H
A,
B,
C,
D,
87%
N.R.
O
N.R.
N.R.
O
O
O
N
N
N
N
H
H
O
E,
F,
N.R.
63%
Figure 1. The influences of directing group for the reaction.
The optimized synthetic conditions allowed us to explore the substrate scope.
Therefore, we first investigated the substrate scope of this reaction between various
substrate 1 derivatives and 4-octyne 2b. As shown in Table 3, a wide variety of
functionalized N-(pyridin-2-ylmethoxy)benzamides were well tolarated by the cobalt
catalyst to deliver the targeted products 3. For example, benzamides with the
electron-donating groups at the para position, such as methyl, ethyl, tert-butyl, and
phenyl promoted this transformation smoothly. The desired products (3bb−3db, 3lb)
were obtained in excellent yields (79%−83%). para-Methoxy substituted benzamide
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gives the desired product (3eb) in a relatively-low yield. In contrast, benzamides
substituted with electron-withdrawing groups, such as -F, -Cl, -Br, -I, -CF3, and
-COOMe also reacted with 2b smoothly, giving the corresponding products in
45-75% yields (3fb−3kb). When the -F substitution exists on the meta position, the
reaction gave a regioisomeric mixture in good yields (3ob). With the steric hindrance
of the
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Table 3. Co(III)-Catalyzed Synthesis of Isoquinolinone Derivativesa
O
nPr
O
Co(OAc)2·4H2O (40 mol%)
O
NH
nPr
AgOAc (1 equiv)
Ar/
Het
Ar/
Het
N
H
N
+
PivOH (2 equiv)
TFE, 110 °C
nPr
H
nPr
2b
1
3
b
O
O
3ab:
3bb:
3cb:
3db:
3eb:
3fb:
3gb:
3hb:
3ib:
3jb:
R = H, 87% (61%)
R = Me, 82%
R = F, 71%
R = Cl, 75%
R = Br, 71%
R = I, 72%
NH
NH
nPr
R = Et, 83%
R
nPr
R = Bu, 79%
R
t
R = CF3, 45%
nPr
nPr
O
R = OMe, 36%
O
O
3mb:
3nb:
3ob:
3pb:
3qb:
R = Me, 86%
R = OMe, 64%
R = F, 76% (2.4:1)
R = Cl, 72%
2
NH
R
NH
nPr
NH
nPr
c
Ph
nPr
MeOOC
6
nPr
83%
nPr
nPr
O
R = CF3, 37%
3kb,
60%
3lb,
F
O
O
O
Ph
S
NH
nPr
NH
nPr
NH
nPr
NH
nPr
nPr
nPr
nPr
3ub,
nPr
d
3sb,
3tb,
56%
46%
67%
3rb,
46%
O
O
O
Ph
NH
Ph
NH
Ph
O
Ph
Ph
e
f
e
3ua,
4
67%
, 23%
3va,
64%
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aReaction conditions: substrate 1 (0.2 mmol), 2b (0.3 mmol), Co(OAc)24H2O (40
mol%), TFE (1.0 mL), AgOAc (1.0 equiv), PivOH (2.0 equiv), air atmosphere, 10 h,
b
c
isolated yields. Yield of 1.0 mmol scale. The regioisomeric ratio was given in
parentheses (C6:C2
2.4:1). d14 h. eDiphenylacetylene instead of 2b.
=
f7-Oxabenzonorbornadiene instead of 2b.
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meta-substituent increasing, the reaction occured only in the less obstructed position,
exhibiting good regioselectivity (3mb, 3nb, 3pb, 3qb). For instance, 3mb was
generated in an excellent yield of 86%. When a sterically hindered ortho-fluoro
substituted N- (pyridin-2-ylmethoxy)benzamide was employed, the annulated product
was given in moderate yield (3rb). This indicated that the steric hindrance of
ortho-substitution had a significant effect on the efficiency of the reaction. In
addition, the 1s derived from a bicyclic system was smoothly converted to the
corresponding benzo[h]-isoquinolinone 3sb. It should be noted that the heteroarene
and terminal olefins substrates were still compatible in this transformation (3tb, 3ub,
3ua, 3va). To further reinforce the generality and practicality of the directing group,
we targeted 7-oxabenzonorbornadiene with 1a in the optimal conditions. Surprisingly,
an unexpected five-membered [3+2] annulation product 4 was obtained in 23%
yield.15
Table 4. Substrate Scope for Alkynesa
O
R2
Co(OAc)2·4H2O (40 mol%)
O
H
AgOAc (1 equiv)
NH
R2
O
+
N
H
N
PivOH (2 equiv)
TFE, 110 °C
R1
R1
1a
2
3
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O
O
O
O
5
NH
NH
NH
NH
6
7
8
F
Cl
9
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F
3ad,
Cl
3ae,
b
3aa,
3ac,
83%
82%
NH
67%
NH
57%
NH
O
O
O
O
NH
Br
CF3
COOEt
Br
3af,
CF3
COOEt
3ag,
3ah,
3ai,
70%
64%
74%
O
44%
O
O
O
NH
NH
NH
OMe
NH
F
MeO
F
3aj,
3ak,
3al/3al'
= 2:1, 94%
48%
74%
aReaction conditions: substrate 1a (0.2 mmol), 2 (0.3 mmol), Co(OAc)24H2O (40
mol%), TFE (1.0 mL), AgOAc (1.0 equiv), PivOH (2.0 equiv), air atmosphere, 10 h,
isolated yields.
Subsequently, we investigated the scope of alkynes and experimental results are
illustrated in Table 4. To our delight, we extended the length of the alkyl chain and
the desirable target product was still obtained in 82% yield (3ac). The reaction gave
product 3aa in pleasant yield 83% under optimal conditions. Using 1.5 equiv of
AgOAc as oxidant gave lower yield 72% (entry 16, Table 1). Phenylacetylenes with a
para-substituent on the benzene ring such as -F (3ad), -Cl (3ae), -Br (3af), -CF3 (3ag),
and -COOEt (3ah) groups were also well tolerated, providing ample opportunities for
further derivatization of the products. Furthermore, the desired products were
obtained in good yields for meta-substituted tolanes, such as methyl (3ai, 74%),
methoxy (3aj, 48%), and fluoro (3ak, 74%) groups. In addition, unsymmetrical
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internal aryl alkyne, 1-phenylpropyne 2l, was tested as substrate, giving a
regioisomeric mixture (3al:3alʹ = 2:1) in 94% total yield. In addition, terminal
alkynes (such as: 1-octyne or phenylacetylene) were employed under standard
conditions, but no target product was detected.
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In order to gain further insight into the nature of the present reaction, the
following experiments were performed to probe the reaction mechanism (Scheme 1).
The competition experiment between 1b/1k and 2b was performed and revealed the
preferred reaction for electron-rich 1b (3bb/3kb = 1.49, Scheme 1a). An
intermolecular kinetic isotope effect (KIE) experiment was carried out between
benzamide 1a and isotopically labelled substrate [D5]-1a (Scheme 1b), resulting in a
KIE value of approximately 2.0, suggesting that the formation of organometallic
intermediates in the catalytic cycle might be affected by the H/D isotope. Then, a
kinetic isotope effect (KIE) value of 1.25 was observed between 1a or [D5]-1a with
2b in the parallel experiments. Furthermore, no H/D exchange could be detected in
both the reaction of isotopically labeled substrates [D5]-1a and 1a/D2O under standard
reaction conditions without 2b, indicating presumable irreversibility of the C–H
cobaltation step (Scheme 1c).
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a) Intermolecular competitive experiments
O
5
6
7
8
O
NH
nPr
O
N
H
N
nPr
nPr
1b
3bb, 52%
Standard conditions
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O
O
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O
nPr
2b
N
H
N
NH
nPr
MeOOC
MeOOC
1k
nPr
3bb/3kb = (52/35) = 1.49
3kb, 35%
b) KIE studies
1a
1a
/[D5]- = 1:1
Standard conditions
3ab
3ab
3ab
+ [D4]-
1 h
KIE = 2.0
2b
1a
1a
or [D5]-
Standard conditions
3ab
or [D4]-
90-135 min
KIE = 1.25
2b
c) H/D exchange experiment
D98%
D
D
O
DH O
Co(OAc)2·4H2O (40 mol%)
D
D
O
D
D
O
AgOAc (1 equiv)
N
N
N
N
H
H
PivOH (2 equiv)
TFE, air, 110 oC, 6 h
D
DH
D
-1a
[D5]
H98%
Co(OAc)2·4H2O (40 mol%)
AgOAc (1 equiv)
HD
O
O
O
N
D2O (10 equiv)
O
N
N
N
H
PivOH (2 equiv)
TFE, air, 110 °C, 6 h
H
HD
1a
Scheme 1. Mechanistic studies.
On the basis of the bove mechanistic studies and related reports,7a, 8, 12b, 14a, 16
a
plausible Co(III)/Co(I) catalytic cycle is illustrated in Scheme 2. Initially,
Co(OAc)2·4H2O coordinates to the substrate 1a, leading to the formation of
intermediate A accompanied by release of one equivalent of acetic acid. Next, the
Co(II) can be oxidized to Co(III) by the silver salt, and Co(III) can activate the aryl
C-H bond through a CMD type process to generate intermediate B. Subsequently, the
coordination of the Co(III) center of intermediate B with alkyne 2b forms
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intermediate C. Then, migratory insertion of alkyne into the C-Co bond of
intermediate C gives the seven-membered cobaltacyclic intermediate D. After that,
cross-redox cyclization of intermediate D affords intermediate E. The Co(I) insert to
the N-O bond forming intermediate F. Demetallization of intermediate F delivers the
desired product 3ab and affords the putative cobalt(III) species G. The catalytically
active cobalt(III) complex G coordinated with the benzylamide 1a to give
intermediate H. Finally, intermediate H generates intermediate B through a CMD
type process for a new catalytic cycle.
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1a
3ab
N
OH
CoIIILn+3
O
2 HOAc or HOPiv
G
O
N
CoIII
L
N
H
L
O
N
O
CoIII
N
L
nPr
F
nPr
O
O
1a
AgI
Ag0
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O
N
N
Co(OAc)2·4H2O
CoII
CoIII
N
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L
HOAc
HOAc
A
B
L = OAc, or OPiv
nPr
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O
CoI
N
O
N
nPr
L
nPr
O
2b
nPr
oIII
C
E
N
L
nPr
O
nPr
O
N
C
C
oIII
N
nPr
D
L
nPr
Scheme 2. Proposed mechanistic pathway
CONCLUSION
In conclusion, an efficient cobalt-catalyzed C(sp2)–H bond activation/annulation
strategy using a new traceless bidentate directing group to synthesize isoquinolinones
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has been developed. In the reaction, 2-(hydroxymethyl)pyridine was first used as a
non-marking directing group and could be removed directly in situ along the catalytic
process. The reaction exhibits a broad substrate scope, affording the products in good
isolated yields. Moreover, mechanical investigation experiments provide a clearer
experimental process. Further applications of the directing group strategy in other
related types of C−H functionalization and detailed mechanistic studies are actively
ongoing in our laboratory.
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EXPERIMENTAL SECTION
General information. Unless otherwise mentioned, all materials were commercially
obtained and used without further purification, and all the reactions were performed
under the ambient air. Substrates 1a-1v were synthesized from benzohydroxamate17
13
19
according to the literature method.18 1H NMR, C NMR and F NMR spectra were
recorded on 400 MHz or 600 MHz, 101 MHz or 151 MHz, and 376 MHz or 565 MHz
respectively on a Bruker DPX instrument19. High resolution mass spectra (HRMS) for
new compounds were measured on a Waters Q-Tof Micro MS/MS System ESI
spectrometer. Melting points were tested on a WC-1 instrument and uncorrected.
Chemical shift multiplicities are reported as follows: (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, dd = doublet of doublet, dt = doublet of triplet, td =
triplet of doublet).
General procedure for preparation of substrates 1. According to the literature
method18, a 250 mL round-bottom flask was charged with benzohydroxamate (13
mmol, 1.3 equiv), potassium hydroxide (13 mmol, 1.3 equiv) and methanol (50 mL).
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The reaction mixture was heated to reflux and refluxing was continued for 30 min in
an oil bath. After slowly cooling to room temperature, the sodium carbonate (15
mmol, 1.5 equiv) and water (50 mL) were added. Then 2-chloromethylpyridine (10
mmol, 1.0 equiv) was added dropwise at 0 oC and stirred at room temperature for 3 h.
The reaction mixture was heated to 100 oC for 2 h in an oil bath. Excess methanol was
removed under reduced pressure and the mixture extracted with dichloromethane,
dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification
by column chromatography gave pure substrates.
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General procedure for the synthesis of isoquinolinone derivatives 3. A 15 mL dry
screw cap vial was equipped with a magnetic stir bar and charged with substrate 1
(0.2 mmol, 1.0 equiv), alkynes 2 (0.3 mmol, 1.5 equiv), Co(OAc)24H2O (40 mol%,
0.08 mmol), AgOAc (0.2 mmol, 1.0 equiv), PivOH (0.4 mmol, 2.0 equiv), and TFE
(1.0 mL). The vessel was heated at 110 oC for 10 h in an oil bath, and cooled down to
room temperature. Next, the reaction mixture was diluted with 25 mL of DCM, and
the organic layer was washed with saturated aqueous NaHCO3 solution (30 mL). The
aqueous phase was washed with DCM (3 x 10 mL). After that, the combined organic
layer was dried over Na2SO4 and concentrated under reduced pressure. Then product
was purified by preparative TLC on silica gel using DCM/EA as eluent to afford 3.
Procedure for the synthesis of product 4.
A 15 mL dry screw cap vial was equipped with a magnetic stir bar and charged with
substrate 1a (0.2 mmol, 1.0 equiv), 7-oxabenzonorbornadiene (0.3 mmol, 1.5 equiv),
Co(OAc)24H2O (0.08 mmol, 0.4 equiv,), AgOAc (0.2 mmol, 1.0 equiv), PivOH (0.4
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mmol, 2.0 equiv), and TFE (1.0 mL). The vessel was heated at 110 C for 10 h in an
oil bath, and cooled down to room temperature. Next, the reaction mixture was diluted
with 25 mL of DCM, and the organic layer was washed with saturated aqueous
NaHCO3 solution (30 mL). The aqueous phase was washed with DCM (3 x 10 mL).
After that, the combined organic layer was dried over Na2SO4 and concentrated under
reduced pressure. Then product was purified by preparative TLC on silica gel using
DCM/EA as eluent to afford 4.
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Procedure for the synthesis of product 3aa on a 1 mmol scale. A 35 mL dry screw
cap vial was equipped with a magnetic stir bar and charged with substrate 1a (1
mmol, 228.5 mg ), alkynes 2b (1.5 mmol, 220 μl, 1.5 equiv), Co(OAc)24H2O (0.4
mmol, 100 mg, 40 mol%), AgOAc (1 mmol, 167 mg, 1 equiv), PivOH (2 mmol, 235
o
μl, 2 equiv), and TFE (5.0 mL). The vessel was heated at 110 C for 10 h in an oil
bath, and cooled down to room temperature. After general treatment for the synthesis
of isoquinolinone derivatives 3, the product was purified by preparative TLC on silica
gel (DCM/EA = 3:1) to yield 3ab (181 mg, 61%) as a white solid.
Experiments for determination of electronic effect on the isoquinolinones
synthesis. A 15 mL dry screw cap vial was equipped with a magnetic stir bar and
charged with substrate 1b (0.1 mmol, 24.2 mg), 1k (0.1 mmol, 28.7 mg), alkynes 2b
(0.1 mmol, 11.4 mg), Co(OAc)24H2O (0.08 mmol, 20 mg), AgOAc (0.2 mmol, 33.4
o
mg), PivOH (0.4 mmol, 47 μl), and TFE (1.0 mL). The vessel was heated at 110 C
for 10 h in an oil bath, and cooled down to room temperature. After general treatment
for the synthesis of isoquinolinone derivatives 3, the residue was purified by
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preparative TLC on silica gel with DCM/EA as the eluent to yield 3bb (12.6 mg,
52%) and 3kb (10 mg, 35%).
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Experiments for independent initial rate comparison kH/kD. A 15 mL dry screw
cap vial was equipped with a magnetic stir bar and charged with substrate 1a (0.2
mmol, 45.7 mg), alkynes 2b (0.3 mmol, 33.1 mg), Co(OAc)24H2O (0.08 mmol, 20
mg), AgOAc (0.2 mmol, 33.4 mg), PivOH (0.4 mmol, 47 μl) and TFE (1.0 mL). The
vessel was heated at 110 oC for 90, 105, 120, 135 min in an oil bath, and immediately
quenched separately with 2.0 mL EA. Next, the reaction mixture was diluted with 25
mL of EA, and filtered through a celite pad. The reaction solution was concentrated in
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1
vacum and H NMR was taken using anisole (0.2 mmol, 21.6 mg) as the internal
standard. The KIE was determined as kH /kD = 0.0822/0.0657 ≈ 1.25.
Experiments for intermolecular kinetic isotope effects. A 15 mL dry screw cap vial
was equipped with a magnetic stir bar and charged with substrate 1a (0.1 mmol, 22.9
mg), [D5]-1a (0.1 mmol, 23.4 mg), alkynes 2b (0.3 mmol, 33.1 mg), Co(OAc)24H2O
(0.08 mmol, 20 mg), AgOAc (0.2 mmol, 33.4 mg), PivOH (0.4 mmol, 47 μl) and TFE
(1.0 mL). The vessel was heated at 110 oC for 1 h in an oil bath, and cooled down to
room temperature. After general treatment for the synthesis of isoquinolinone
derivatives 3, the residue was purified by preparative TLC on silica gel (DCM/EA =
3/1) to afford the target products of 3ab and [D4]-3ab in 15% total yield. A mixture of
1
3ab and [D4]-3ab was determined on the basis of H NMR analysis. Based on the
integrations related to different hydrogen resonances, the kinetic isotope effect is
calculated to be kH /kD = 2.0 (kH/kD = 0.669/(1-0.669) = 2.0).
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Deuterium labeled experiments.
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(a) A 15 mL dry screw cap vial was equipped with a magnetic stir bar and charged
with substrate [D5]-1a (0.2 mmol, 46.7 mg), Co(OAc)24H2O (0.08 mmol, 20 mg),
AgOAc (0.2 mmol, 33.4 mg), PivOH (0.4 mmol, 47 μl), and TFE (1.0 mL). The
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vessel was heated at 110 C for 6 h in an oil bath, and cooled down to room
temperature. Next, the reaction mixture was diluted with 25 mL of DCM, and the
organic layer was washed with saturated aqueous NaHCO3 solution (30 mL). The
aqueous phase was washed with DCM (3 x 10 mL). After that, the combined organic
layer was dried over Na2SO4 and concentrated under reduced pressure. The residue
was purified by preparative TLC on silica gel with DCM/EA as the eluent to afford
substrate [D5]-1a. The H/D exchange (D/H ≥ 98%) was calculated by 1 H NMR.
(b) A 15 mL dry screw cap vial was equipped with a magnetic stir bar and charged
with substrate 1a (0.2 mmol, 45.7 mg), Co(OAc)24H2O (40 mol%, 20 mg), AgOAc
(0.2 mmol, 33.4 mg), D2O(2.0 mmol, 36.2 μl), PivOH (0.4 mmol, 47 μl), and TFE
(1.0 mL). The vessel was heated at 110 oC for 6 h in an oil bath, and cooled down to
room temperature. Next, the reaction mixture was diluted with 25 mL of DCM, and
the organic layer was washed with saturated aqueous NaHCO3 solution (30 mL). The
aqueous phase was washed with DCM (3 x 10 mL). After that, the combined organic
layer was dried over Na2SO4 and concentrated under reduced pressure. The residue
was purified by preparative TLC on silica gel with DCM/EA as the eluent to afford
1
substrate 1a.. The H/D exchange (H/D ≥ 98%) was calculated by H NMR. No
obvious deuterium incorporation was detected.
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Reactions in the presence TEMPO, BHT or BQ. A 15 mL dry screw cap vial was
equipped with a magnetic stir bar and charged with substrate 1a (0.2 mmol, 45.7 mg),
alkynes 2b (0.3 mmol, 33.1 mg), Co(OAc)24H2O (0.08 mmol, 20 mg), AgOAc (0.2
mmol, 1.0 equiv), PivOH (0.4 mmol, 2.0 equiv), TEMPO (1 equiv, BHT 1 equiv or
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BQ 1 equiv) and TFE (1.0 mL). The vessel was heated at 110 C for 10 h in an oil
bath, and cooled down to room temperature. Next, the reaction mixture was diluted
with 25 mL of EA, and filtered through a celite pad. The reaction solution was
detected by TLC. The addition of a radical quencher, either TEMPO, BHT, or BQ,
under standard reaction conditions, suppressed the formation of 3ab, suggesting that
the reaction likely proceeds through radical intermediates in some steps of the
mechanism.9d, 16a
Characterizations of Substrates 1
N-(pyridin-2-ylmethoxy)benzamide (1a): white solid (1.18 g, 52% yield). Rf = 0.20
(PE:EA, 1:1). mp 69–70 oC. 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.57 (d,
J = 4.3 Hz, 1H), 7.86 (s, 1H), 7.75 (d, J = 5.9 Hz, 2H), 7.64 (s, 1H), 7.55 (s, 1H), 7.47
(t, J = 7.5 Hz, 2H), 7.40–7.30 (m, 1H), 5.04 (d, J = 2.6 Hz, 2H). 13C{1H} NMR (101
MHz, DMSO-d6) δ 164.5, 155.8, 149.0, 136.7, 132.2, 131.6, 128.4, 123.2, 122.8,
77.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C13H13N2O2 229.0972; Found
229.0971.
4-methyl-N-(pyridin-2-ylmethoxy)benzamide (1b): white solid (1.40 g, 58% yield). Rf
o
= 0.18 (PE:EA, 1:1). mp 107–108 C. 1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H),
8.54 (d, J = 4.4 Hz, 1H), 7.71 (td, J = 7.7, 1.7 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.46
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(d, J = 7.8 Hz, 1H), 7.26–7.17 (m, 3H), 5.17 (s, 2H), 2.38 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 156.3, 149.2, 137.0, 129.3, 127.1, 123.2, 122.7, 78.0, 21.5. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C14H15N2O2 243.1128; Found 243.1127.
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4-ethyl-N-(pyridin-2-ylmethoxy)benzamide (1c): white solid (1.25 g, 49% yield). Rf =
o
0.18 (PE:EA, 1:1). mp 75–76 C. 1H NMR (400 MHz, CDCl3) δ 10.18 (s, 1H), 8.52
(dd, J = 7.9, 4.7 Hz, 1H), 7.82–7.57 (m, 3H), 7.49 (t, J = 14.7 Hz, 1H), 7.22 (d, J =
6.9 Hz, 3H), 5.16 (s, 2H), 2.67 (q, J = 7.5 Hz, 2H), 1.43–0.98 (m, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 166.4, 156.3, 149.2, 137.0, 128.1, 127.3, 123.2, 122.8, 78.0,
28.8, 15.3. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H17N2O2 257.1285; Found
257.1284.
4-(tert-butyl)-N-(ptyridin-2-ylmehoxy)benzamide (1d): white solid (1.70 g, 60%
yield). Rf = 0.21 (PE:EA, 1:1).mp 87–88 oC. 1H NMR (400 MHz, CDCl3) δ 10.23 (s,
1H), 8.51 (s, 1H), 7.73 (dd, J = 26.3, 8.4 Hz, 3H), 7.47 (d, J = 7.8 Hz, 1H), 7.41 (d, J
13
= 7.3 Hz, 2H), 7.25–7.20 (m, 1H), 5.17 (s, 2H), 1.31 (s, 9H). C{1H} NMR (101
MHz, CDCl3) δ 156.3, 155.5, 149.2, 149.1, 137.0, 129.0, 127.0, 125.6, 123.2, 122.8,
77.9, 34.9, 31.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17H21N2O2 285.1598;
Found 285.1601.
4-methoxy-N-(pyridin-2-ylmethoxy)benzamide (1e): white solid (1.06 g, 41% yield).
o
Rf = 0.18 (PE:EA, 1:1). mp 96–97 C. 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H),
8.59–8.48 (m, 1H), 7.77–7.66 (m, 3H), 7.46 (d, J = 7.8 Hz, 1H), 7.26–7.19 (m, 1H),
13
6.95–6.82 (m, 2H), 5.16 (s, 2H), 3.84 (s, 3H). C{1H} NMR (101 MHz, CDCl3) δ
162.5, 156.3, 149.2, 136.9, 129.0, 123.2, 122.8, 113.9, 78.0, 55.4. HRMS (ESI-TOF)
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m/z: [M+H]+ Calcd for C14H15N2O3 259.1077; Found 259.1078.
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4-fluoro-N-(pyridin-2-ylmethoxy)benzamide (1f): white solid (1.11 g, 45% yield). Rf
= 0.20 (PE:EA, 1:1). mp 81–82 oC. 1H NMR (400 MHz, CDCl3) δ 10.72 (s, 1H), 8.47
(d, J = 3.1 Hz, 1H), 7.82–7.75 (m, 2H), 7.71 (td, J = 7.7, 1.6 Hz, 1H), 7.46 (d, J = 7.8
Hz, 1H), 7.26–7.19 (m, 1H), 7.10–6.99 (m, 2H), 5.15 (s, 2H). 13C{1H} NMR (101
MHz, CDCl3) δ 164.9 (JC-F = 257.4 Hz), 155.9, 149.0, 137.2, 129.6 (JC-F = 8.5 Hz),
128.0, 123.4, 123.1, 115.7 (JC-F = 21.9 Hz), 77.9. 19F{1H} NMR (376 MHz, CDCl3) δ
-107.12. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C13H12FN2O2 247.0877; Found
247.0876.
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4-chloro-N-(pyridin-2-ylmethoxy)benzamide (1g): white solid (1.1 g, 42% yield). Rf =
0.23 (PE:EA, 1:1). mp 131–132 oC. 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.49
(dd, J = 21.3, 4.5 Hz, 1H), 7.79–7.64 (m, 3H), 7.39 (dt, J = 14.8, 7.9 Hz, 3H), 7.26–
13
7.14 (m, 1H), 5.16 (s, 2H). C{1H} NMR (101 MHz, CDCl3) δ 156.1, 149.1, 137.1,
128.9, 128.6, 123.3, 122.9, 77.8. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C13H12ClN2O2 263.0582; Found 263.0583.
4-bromo-N-(pyridin-2-ylmethoxy)benzamide (1h): white solid (1.77 g, 58% yield). Rf
o
1
= 0.19 (PE:EA, 1:1). mp 139–140 C. H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H),
8.58 (d, J = 4.9 Hz, 1H), 7.74 (td, J = 7.7, 1.7 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.56
(d, J = 8.5 Hz, 2H), 7.41 (d, J = 7.8 Hz, 1H), 7.31–7.26 (m, 1H), 5.17 (s, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 156.3, 149.2, 137.1, 131.9, 128.7, 123.3, 122.7, 77.2.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C13H12BrN2O2 307.0077; Found 307.0076.
4-iodo-N-(pyridin-2-ylmethoxy)benzamide (1i): white solid (1.95 g, 55% yield). Rf =
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0.20 (PE:EA, 1:1). mp 132–133 oC. 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 8.52
(dd, J = 4.8, 0.6 Hz, 1H), 7.80–7.69 (m, 3H), 7.44 (d, J = 7.8 Hz, 1H), 7.26–7.21 (m,
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1H), 7.13–7.02 (m, 2H), 5.16 (s, 2H). C{1H} NMR (101 MHz, CDCl3) δ 166.2,
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163.6, 156.1, 149.2, 137.1, 129.5, 123.3, 122.9, 115.8, 115.6, 77.9. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C13H12IN2O2 354.9938; Found 354.9934.
N-(pyridin-2-ylmethoxy)-4-(trifluoromethyl)benzamide (1j): white solid (1.53 g, 53%
o
1
yield). Rf = 0.20 (PE:EA, 1:1). mp 112–113 C. H NMR (600 MHz, CDCl3) δ 11.3
(s, 1H), 8.36 (s, 1H), 7.88 (s, 2H), 7.64 (d, J = 19.9 Hz, 3H), 7.46 (s, 1H), 7.12 (s,
1H), 5.16 (s, 2H). 13C{1H} NMR (151 MHz, CDCl3) δ 164.0, 155.8, 148.9, 137.2,
135.2, 133.2 (JC-F = 33.0 Hz), 127.7, 125.4, 123.6 (JC-F = 273.3 Hz), 123.4, 123.2,
77.8. 19F{1H} NMR (565 MHz, CDCl3) δ -63.05. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C14H12F3N2O2 297.0845; Found 297.0846.
methyl 4-((pyridin-2-ylmethoxy)carbamoyl)benzoate (1k): white solid (1.72 g, 60%
yield). Rf = 0.23 (PE:EA, 1:1). mp 86–87 oC. 1H NMR (400 MHz, CDCl3) δ 10.45 (s,
1H), 8.53 (d, J = 4.1 Hz, 1H), 8.07 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.1 Hz, 2H), 7.73
(td, J = 7.7, 1.6 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.25 (s, 1H), 5.19 (s, 2H), 3.93 (s,
13
3H). C{1H} NMR (101 MHz, CDCl3) δ 156.2, 149.2, 137.1, 128.8, 128.6, 123.3,
122.8, 77.2, 52.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H15N2O4 287.1026;
Found 287.1027.
N-(pyridin-2-ylmethoxy)-[1,1'-biphenyl]-4-carboxamide (1l): white solid (1.49 g,
o
1
49% yield). Rf = 0.16 (PE:EA, 1:1). mp 104–105 C. H NMR (400 MHz, CDCl3) δ
10.88 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.73–7.65 (m, 3H), 7.61–7.53 (m, 4H), 7.51–
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7.34 (m, 4H), 7.19 (m, 1H), 5.19 (s, 2H). C{1H} NMR (101 MHz, CDCl3) δ 166.2,
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8
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156.2, 149.1, 144.7, 139.9, 137.0, 130.7, 128.9, 128.1, 127.8, 127.2, 123.3, 123.0,
78.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H17N2O2 305.1285; Found
305.1286.
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3-methyl-N-(pyridin-2-ylmethoxy)benzamide (1m): light yellow liquid (1.36 g, 56%
1
yield). Rf = 0.22 (PE:EA, 1:1). H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.54 (s,
1H), 7.72 (t, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.49 (dd, J = 17.9, 7.3 Hz, 2H), 7.36–7.27
(m, 2H), 7.25 (d, J = 7.1 Hz, 1H), 5.17 (s, 2H), 2.36 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 156.2, 149.2, 138.5, 137.1, 132.7, 128.5, 128.2, 127.9, 124.4, 123.3,
122.9, 78.0, 21.3. HRMS (positive ESI) Calcd. For C14H14N2O2 [M+H]+, 243.1128,
Found: 243.1130. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H15N2O2 243.1128;
Found 243.1128.
3-methoxy-N-(pyridin-2-ylmethoxy)benzamide (1n): white solid (1.08 g, 42% yield).
o
Rf = 0.21 (PE:EA, 1:1). mp 50–51 C. 1H NMR (400 MHz, CDCl3) δ 10.71 (s, 1H),
8.54–8.43 (m, 1H), 7.70 (td, J = 7.7, 1.7 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.38–7.27
13
(m, 3H), 7.25–7.18 (m, 1H), 7.07–6.95 (m, 1H), 5.15 (s, 2H), 3.76 (s, 3H). C{1H}
NMR (101 MHz, CDCl3) δ 159.7, 155.8, 149.0, 137.2, 129.6, 123.4, 123.2, 119.2,
118.2, 112.3, 77.9, 55.4, 55.3. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H15N2O3
259.1077; Found 259.1079.
3-fluoro-N-(pyridin-2-ylmethoxy)benzamide (1o): white solid (1.06 g, 43% yield). Rf
= 0.25 (PE:EA, 1:1). mp 45-47 oC. 1H NMR (400 MHz, CDCl3) δ 10.91 (s, 1H), 8.45
(t, J = 4.3 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 10.0
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Hz, 2H), 7.37 (t, J = 7.9 Hz, 1H), 7.27–7.13 (m, 2H), 5.17 (s, 2H). C{1H} NMR
(151 MHz, CDCl3) δ 162.6 (JC-F = 252.3 Hz), 156.0, 149.1, 137.1, 134.2, 130.3,
130.2, 123.3, 123.0, 122.7, 118.8 (JC-F = 20.1 Hz),114.5 (JC-F = 21.7 Hz), 77.9.
19F{1H} NMR (565 MHz, CDCl3) δ -115.47. HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C13H12FN2O2 247.0877; Found 247.0876.
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3-chloro-N-(pyridin-2-ylmethoxy)benzamide (1p): white solid (0.92 g, 35% yield). Rf
= 0.16 (PE:EA, 1:1). mp 56–57 oC. 1H NMR (400 MHz, CDCl3) δ 11.01 (s, 1H), 8.46
(t, J = 9.0 Hz, 1H), 7.76 (t, J = 1.7 Hz, 1H), 7.71 (td, J = 7.7, 1.7 Hz, 1H), 7.63 (t, J =
8.4 Hz, 1H), 7.47 (ddd, J = 10.3, 2.6, 1.2 Hz, 2H), 7.31 (t, J = 7.9 Hz, 1H), 7.26–7.17
(m, 1H), 5.15 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.8, 149.0, 137.2, 134.7,
133.6, 131.8, 129.9, 127.5, 125.3, 123.4, 123.2, 77.9. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C13H12ClN2O2 263.0582; Found 263.0583.
N-(pyridin-2-ylmethoxy)-3-(trifluoromethyl)benzamide (1q): white solid (1.48 g, 50%
yield). Rf = 0.19 (PE:EA, 1:1). mp 90–91 oC. 1H NMR (400 MHz, CDCl3) δ 10.83 (s,
1H), 8.47 (d, J = 4.4 Hz, 1H), 8.05 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.73 (td, J = 7.8,
1.7 Hz, 2H), 7.54 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.24 (dd, J = 7.1, 5.4
Hz, 1H), 5.18 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.0, 149.1, 137.2, 132.7,
131.3 (JC-F = 34.1 Hz), 130.4, 129.2, 128.3, 124.2, 123.6 (JC-F = 273.2 Hz), 123.4,
123.0, 77.7. 19F{1H} NMR (376 MHz, CDCl3) δ -62.83. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C14H12F3N2O2 297.0845; Found 297.0846.
2-fluoro-N-(pyridin-2-ylmethoxy)benzamide (1r): white solid (1.06 g, 43% yield). Rf
= 0.16 (PE:EA, 1:1). mp 109–110 C. 1H NMR (400 MHz, CDCl3) δ 10.17 (s, 1H),
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8.60 (s, 1H), 8.07 (s, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.54–7.40 (m, 2H), 7.27–7.24 (m,
2H), 7.17–6.98 (m, 1H), 5.19 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.2 (JC-F
= 249.5 Hz), 155.8, 149.4, 137.0, 133.7 (JC-F = 8.7 Hz), 131.8, 125.0 (JC-F = 2.99 Hz),
123.2, 122.6, 119.0 (JC-F = 13.5 Hz), 116.0 (JC-F = 24.1 Hz), 78.3. 19F{1H} NMR (376
MHz, CDCl3) δ -110.43. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C13H12FN2O2
247.0877; Found 247.0878.
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N-(pyridin-2-ylmethoxy)-2-naphthamide (1s): white solid (1.70 g, 61% yield). Rf =
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0.22 (PE:EA, 1:1). mp 89–90 C. H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.52
(dd, J = 10.7, 4.9 Hz, 1H), 8.28 (s, 1H), 7.91–7.76 (m, 4H), 7.71 (tdd, J = 7.3, 5.3, 1.7
Hz, 1H), 7.60–7.43 (m, 3H), 7.23 (dd, J = 11.8, 6.7 Hz, 1H), 5.23 (s, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 156.3, 149.2, 137.0, 134.9, 132.5, 128.9, 128.5, 127.8,
126.8, 123.5, 123.3, 122.9, 78.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C17H15N2O2 279.1128; Found 279.1129.
N-(pyridin-2-ylmethoxy)thiophene-2-carboxamide (1t): white solid (1.38 g, 59%
yield). Rf = 0.17 (PE:EA, 1:1). mp 83–84 oC. 1H NMR (400 MHz, CDCl3) δ 10.83 (s,
1H), 8.47 (d, J = 4.5 Hz, 1H), 7.77–7.58 (m, 2H), 7.48 (t, J = 6.4 Hz, 2H), 7.24–7.18
13
(m, 1H), 7.04 (dd, J = 4.8, 3.9 Hz, 1H), 5.14 (s, 2H). C{1H} NMR (101 MHz,
CDCl3) δ 161.7, 155.8, 149.1, 137.1, 135.0, 130.8, 127.6, 123.3, 123.0, 78.3. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C11H11N2O2S 235.0536; Found 235.0537.
2-phenyl-N-(pyridin-2-ylmethoxy)acrylamide (1u): white solid (1.42 g, 56% yield).
o
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Rf= 0.16 (PE:EA, 1:1). mp 91–92 C. H NMR (400 MHz, CDCl3) δ 9.51 (s, 1H),
8.45 (d, J = 4.2 Hz, 1H), 7.70 (td, J = 7.7, 1.7 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.33
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(s, 5H), 7.25–7.17 (m, 1H), 6.04 (s, 1H), 5.66 (s, 1H), 5.09 (s, 2H). 13C{1H} NMR
(101 MHz, CDCl3) δ 155.9, 149.2, 142.3, 136.9, 136.0, 128.6, 127.8, 123.2, 122.8,
122.1, 78.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H15N2O2 255.1128; Found
255.1130.
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N-(pyridin-2-ylmethoxy)methacrylamide (1v): colorless liquid (0.77 g, 40% yield). Rf
= 0.20 (PE: EA, 20:1). 1H NMR (400 MHz, CDCl3) δ 9.66 (s, 1H), 8.59 (dd, J = 12.5,
5.2 Hz, 1H), 7.72 (tt, J = 9.0, 4.5 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.24 (t, J = 7.1
Hz, 1H), 5.68 (s, 1H), 5.31 (d, J = 21.2 Hz, 1H), 5.10 (s, 2H), 1.94 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 156.3, 149.2, 137.0, 123.2, 122.7, 120.4, 77.7, 18.3.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C10H13N2O2 193.0972; Found 193.0971.
Characterizations of products.
3,4-dipropylisoquinolin-1(2H)-one (3ab): white solid (39.8 mg, 87%). Rf = 0.45
o
(DCM:EA, 3:1). mp 181–182 C. 1H NMR (400 MHz, CDCl3) δ 11.50 (s, 1H), 8.46
(d, J = 8.0 Hz, 1H), 7.74–7.59 (m, 2H), 7.48–7.36 (m, 1H), 2.70 (td, J = 8.0, 1.6 Hz,
13
4H), 1.83–1.68 (m, 2H), 1.68–1.50 (m, 2H), 1.05 (dt, J = 9.2, 7.3 Hz, 6H). C{1H}
NMR (101 MHz, CDCl3) δ 163.8, 138.5, 138.2, 132.3, 127.7, 125.3, 123.1, 113.1,
32.9, 28.6, 23.6, 22.8, 14.3, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C15H20NO 230.1539; Found 230.1537.
6-methyl-3,4-dipropylisoquinolin-1(2H)-one (3bb): white solid (39.9 mg, 82%). Rf =
o
0.44 (DCM:EA, 3:1). mp 191–192 C. 1H NMR (400 MHz, CDCl3) δ 10.87 (s, 1H),
8.33 (d, J = 8.1 Hz, 1H), 7.43 (s, 1H), 7.25 (dd, J = 6.4, 1.3 Hz, 1H), 2.66 (dd, J =
15.8, 7.9 Hz, 4H), 2.51 (s, 3H), 1.79–1.67 (m, 2H), 1.65–1.53 (m, 2H), 1.04 (t, J = 7.3
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Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 163.6, 142.7, 138.6, 138.2, 127.7,
126.9, 122.9, 122.8, 112.7, 33.0, 28.5, 23.6, 22.7, 22.3, 14.3, 14.0. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C16H22NO 244.1696; Found 244.1694.
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6-ethyl-3,4-dipropylisoquinolin-1(2H)-one (3cb): white solid (42.6 mg, 83%). Rf =
o
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0.40 (DCM:EA, 3:1). mp 145–147 C. H NMR (400 MHz, CDCl3) δ 10.50 (s, 1H),
8.36 (d, J = 8.2 Hz, 1H), 7.45 (s, 1H), 7.29 (t, J = 6.8 Hz, 1H), 2.80 (q, J = 7.6 Hz,
2H), 2.74–2.59 (m, 4H), 1.80–1.67 (m, 2H), 1.67–1.53 (m, 2H), 1.32 (t, J = 7.6 Hz,
3H), 1.04 (td, J = 7.3, 1.6 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 163.4, 149.1,
138.7, 137.7, 128.1, 127.8, 127.6, 127.5, 126.0, 121.7, 121.5, 115.9, 113.2, 33.0, 29.6,
28.5, 23.6, 22.6, 15.5, 14.3, 13.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C17H24NO 258.1852; Found 258.1851.
6-(tert-butyl)-3,4-dipropylisoquinolin-1(2H)-one (3db): white solid (44.5 mg, 78%).
o
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Rf = 0.40 (DCM:EA, 3:1). mp 175–176 C. H NMR (400 MHz, CDCl3) δ 11.07 (s,
1H), 8.38 (d, J = 8.5 Hz, 1H), 7.66 (dd, J = 8.2, 2.6 Hz, 1H), 7.51 (dd, J = 8.5, 1.7 Hz,
1H), 2.79–2.61 (m, 4H), 1.80–1.68 (m, 2H), 1.68–1.55 (m, 2H), 1.41 (s, 9H), 1.05 (td,
J = 7.3, 1.8 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 163.6, 155.5, 138.3, 138.1,
127.4, 123.4, 122.8, 119.0, 113.1, 35.3, 33.0, 31.2, 28.6, 23.5, 22.8, 14.3, 14.0. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C19H28NO 286.2165; Found 286.2166.
6-methoxy-3,4-dipropylisoquinolin-1(2H)-one (3eb): white solid (18.7 mg, 36%). Rf
= 0.48 (DCM:EA, 3:1). mp 184–185 oC. 1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1H),
8.40–8.34 (m, 1H), 7.03 (dd, J = 7.4, 2.3 Hz, 2H), 3.93 (s, 3H), 2.64 (dd, J = 16.0, 8.3
Hz, 4H), 1.71 (dt, J = 7.2, 6.0 Hz, 2H), 1.66–1.54 (m, 2H), 1.04 (td, J = 7.3, 1.5 Hz,
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6H). C{1H} NMR (101 MHz, CDCl3) δ 163.1, 162.9, 140.5, 138.5, 129.8, 119.1,
113.8, 112.6, 105.3, 55.4, 33.1, 28.7, 23.3, 22.6, 14.3, 14.0. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C16H22NO2 260.1645; Found 260.1644.
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6-fluoro-3,4-dipropylisoquinolin-1(2H)-one (3fb): white solid (35.1 mg, 71%). Rf =
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0.45 (DCM:EA, 3:1). mp 173–174 C. H NMR (400 MHz, CDCl3) δ 11.61 (s, 1H),
8.56–8.35 (m, 1H), 7.28 (dd, J = 10.5, 1.5 Hz, 1H), 7.14 (td, J = 8.4, 2.0 Hz, 1H),
2.77–2.58 (m, 4H), 1.83–1.70 (m, 2H), 1.66–1.51 (m, 2H), 1.06 (dd, J = 15.9, 7.4 Hz,
6H). 13C{1H} NMR (101 MHz, CDCl3) δ 165.6 (JC-F = 249.1 Hz), 163.3, 141.1 (JC-F
=
9.2 Hz), 141.0 (JC-F = 8.6 Hz), 130.8 (JC-F = 10.2 Hz), 121.7, 113.9 (JC-F = 25.4 Hz),
112.7 (JC-F = 3.0 Hz), 108.4 (JC-F = 23.4 Hz), 33.0, 28.7, 23.4, 22.8 (JC-F = 2.54 Hz),
14.3, 14.0. 19F{1H} NMR (376 MHz, CDCl3) δ -106.13. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C15H19FNO 248.1445; Found 248.1446.
6-chloro-3,4-dipropylisoquinolin-1(2H)-one (3gb): white solid (39.5 mg, 75%). Rf =
o
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0.43 (DCM:EA, 3:1). mp 192–193 C. H NMR (400 MHz, DMSO-d6) δ 11.23 (s,
1H), 8.18 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.45 (dd, J = 8.5, 1.9 Hz, 1H),
2.66–2.57 (m, 2H), 2.53 (dd, J = 6.7, 4.8 Hz, 2H), 1.66–1.53 (m, 2H), 1.53–1.41 (m,
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2H), 0.96 (dt, J = 21.7, 7.3 Hz, 6H). C{1H} NMR (151 MHz, DMSO-d6) δ 161.6,
141.2, 139.9, 138.1, 129.8, 125.8, 124.1, 122.8, 110.7, 32.3, 28.0, 23.7, 22.9, 14.4,
14.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H19ClNO 264.1150; Found
264.1149.
6-bromo-3,4-dipropylisoquinolin-1(2H)-one (3hb): white solid (43.6 mg, 71%). Rf =
o
1
0.43 (DCM:EA, 3:1). mp 183–185 C. H NMR (400 MHz, DMSO-d6) δ 11.15 (s,
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1H), 8.13 (t, J = 19.1 Hz, 1H), 7.83 (d, J = 1.5 Hz, 1H), 7.58 (dd, J = 8.5, 1.6 Hz, 1H),
2.60 (dd, J = 16.4, 8.3 Hz, 2H), 2.57–2.51 (m, 2H), 1.59 (dq, J = 14.8, 7.3 Hz, 2H),
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1.48 (dq, J = 14.7, 7.2 Hz, 2H), 0.96 (dt, J = 21.1, 7.3 Hz, 6H). C{1H} NMR (151
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MHz, DMSO-d6) δ 161.5, 141.2, 140.1, 129.8, 128.6, 127.3, 125.8, 124.4, 110.6,
32.3, 27.9, 23.6, 22.9, 14.4, 14.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C15H19BrNO 308.0645; Found 308.0647.
6-iodo-3,4-dipropylisoquinolin-1(2H)-one (3ib): white solid (51.1 mg, 72%). Rf =
o
1
0.43 (DCM:EA, 3:1). mp 177–179 C. H NMR (400 MHz, DMSO-d6) δ 11.20 (s,
1H), 8.02 (d, J = 1.3 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.75 (dd, J = 8.4, 1.4 Hz, 1H),
2.65–2.56 (m, 2H), 2.52 (dd, J = 7.3, 5.5 Hz, 2H), 1.66–1.53 (m, 2H), 1.53–1.40 (m,
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2H), 0.96 (dt, J = 21.4, 7.3 Hz, 6H). C{1H} NMR (101 MHz, DMSO-d6) δ 161.4,
140.4, 139.4, 133.8, 131.5, 128.9, 124.1, 109.8, 101.2, 31.8, 27.4, 23.1, 22.4, 13.9,
13.6. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H19INO 356.0506; Found
356.0507.
3,4-dipropyl-6-(trifluoromethyl)isoquinolin-1(2H)-one (3jb): white solid (26.7 mg,
o
1
45%). Rf = 0.43 (DCM:EA, 3:1). mp 152–153 C. H NMR (400 MHz, CDCl3) δ
11.69 (s, 1H), 8.56 (d, J = 8.3 Hz, 1H), 7.93 (s, 1H), 7.64 (dd, J = 8.4, 1.0 Hz, 1H),
2.81–2.64 (m, 4H), 1.84–1.69 (m, 2H), 1.69–1.52 (m, 2H), 1.07 (dt, J = 8.9, 7.4 Hz,
6H). 13C{1H} NMR (101 MHz, CDCl3) δ 163.2, 140.1, 138.6, 134.0 (JC-F = 32.2 Hz),
128.8, 127.1, 124.0 (JC-F = 272.1 Hz), 121.3 (JC-F = 3.16 Hz), 120.4 (JC-F = 4.21 Hz),
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113.0, 33.0, 28.4, 23.6, 22.8, 14.2, 14.0. F{1H} NMR (376 MHz, CDCl3) δ -62.91.
HRMS (positive ESI) Calcd. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H19F3NO
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298.1413; Found 298.1411.
1-oxo-3,4-dipropyl-1,2-dihydroisoquinolin-6-yl acetate (3kb): white solid (34.5 mg,
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9
o
1
60%). Rf = 0.43 (DCM:EA, 3:1). mp 170–172 C. H NMR (400 MHz, DMSO-d6) δ
11.33 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 8.24 (d, J = 1.1 Hz, 1H), 7.92 (dd, J = 8.3, 1.4
Hz, 1H), 3.93 (s, 3H), 2.77–2.62 (m, 2H), 2.60–2.53 (m, 2H), 1.62 (dt, J = 15.2, 7.4
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Hz, 2H), 1.51 (dt, J = 14.8, 7.4 Hz, 2H), 0.98 (dt, J = 22.4, 7.3 Hz, 6H). C{1H}
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NMR (101 MHz, DMSO-d6) δ 166.0, 161.1, 140.2, 137.6, 132.7, 127.9, 127.7, 124.6,
124.3, 110.8, 52.6, 31.8, 27.6, 23.2, 22.5, 14.0, 13.6. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C17H22NO3 288.1594; Found 288.1592.
6-phenyl-3,4-dipropylisoquinolin-1(2H)-one (3lb): white solid (50.6 mg, 83%). Rf =
o
1
0.45 (DCM:EA, 3:1). mp 189–191 C. H NMR (600 MHz, CDCl3) δ 10.75 (s, 1H),
8.51 (d, J = 8.2 Hz, 1H), 7.84 (s, 1H), 7.67 (t, J = 8.2 Hz, 3H), 7.58–7.47 (m, 2H),
7.41 (dd, J = 19.8, 12.4 Hz, 1H), 2.81–2.73 (m, 2H), 2.72–2.66 (m, 2H), 1.82–1.73
(m, 2H), 1.70–1.60 (m, 2H), 1.14–1.01 (m, 6H). 13C{1H} NMR (151 MHz, CDCl3) δ
163.5, 145.2, 141.0, 138.9, 138.4, 129.0, 128.3, 128.0, 127.6, 124.8, 124.08, 121.6,
113.1, 33.1, 28.6, 23.6, 22.7, 14.3, 14.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C21H24NO 306.1852; Found 306.1852.
7-methyl-3,4-dipropylisoquinolin-1(2H)-one (3mb): white solid (41.8 mg, 86%). Rf =
o
1
0.45 (DCM:EA, 3:1). mp 158–160 C. H NMR (400 MHz, CDCl3) δ 9.68 (s, 1H),
8.23 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 2.74–2.66 (m, 2H),
2.66–2.59 (m, 2H), 2.49 (s, 3H), 1.79–1.66 (m, 2H), 1.59 (dq, J = 15.0, 7.4 Hz, 2H),
1.09–0.98 (m, 6H). C{1H} NMR (101 MHz, CDCl3) δ 163.4, 136.6, 136.2, 135.4,
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