Dehydrative C-H/N-OH functionalizations in H2O by ruthenium(II) catalysis: Subtle effect of carboxylate ligands and mechanistic insight

Article abstract of DOI:10.1021/jo501884v

(Chemical Equation Presented) A ruthenium(II) complex derived from the electron-deficient aromatic carboxylic acid 3-(F₃C)C₆H₄CO₂H proved to be a highly efficient catalyst for dehydrative alkyne annulation by NH-free hydroxamic acids in water. The C-H/N-OH functionalization occurred with excellent positional selectivity as well as ample substrate scope, setting the stage for effective intermolecular alkenylations of hydroxamic acids. Detailed mechanistic studies were suggestive of a kinetically relevant C-H metalation by carboxylate assistance along with subsequent migratory alkyne insertion, reductive elimination, and intramolecular oxidative addition.

Full text of DOI:10.1021/jo501884v

Article
pubs.acs.org/joc
Dehydrative C−H/N−OH Functionalizations in H2O by Ruthenium(II)
Catalysis: Subtle Effect of Carboxylate Ligands and Mechanistic
Insight
Fanzhi Yang and Lutz Ackermann*
Institut fur Organische und Biomolekulare Chemie, Georg-August-Universitat, Tammannstrasse 2, 37077 Gottingen, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: A ruthenium(II) complex derived from the electron-deficient aromatic carboxylic acid 3-(F3C)C6H4CO2H proved
to be a highly efficient catalyst for dehydrative alkyne annulation by NH-free hydroxamic acids in water. The C−H/N−OH
functionalization occurred with excellent positional selectivity as well as ample substrate scope, setting the stage for effective
intermolecular alkenylations of hydroxamic acids. Detailed mechanistic studies were suggestive of a kinetically relevant C−H
metalation by carboxylate assistance along with subsequent migratory alkyne insertion, reductive elimination, and intramolecular
oxidative addition.
of this strategy, we performed detailed studies of dehydrative
alkyne annulations with free hydroxamic acids, which led to a
significantly more powerful catalyst derived from electron-
deficient m-(trifluoromethyl)benzoic acid. Herein we present a
full account of the development of our second-generation
catalyst for C−H/N−OH functionalizations with alkynes or
alkenes as well as detailed mechanistic insight into these
dehydrative transformations.
INTRODUCTION
■
Methods for the activation and functionalization of otherwise
unreactive C−H bonds represent powerful tools for the
development of step-economical syntheses of bioactive hetero-
cycles.1,2 Particularly, the oxidative annulation of alkynes by C−
H/N−H cleavages has recently emerged as a useful strategy for
the sustainable preparation of N-heterocycles.3−5 These
approaches largely required the use of stoichiometric or
catalytic amounts of terminal oxidants.3−6 However, catalyzed
C−H/N−O functionalizations with N-substituted benzamides
featuring internal oxidants provided the means to avoid the use
of external oxidants with notable advances through independ-
ent studies.7,8
In recent years, ruthenium(II)-catalyzed C−H functionaliza-
tions have been recognized as increasingly viable methods for
oxidative heterocycle synthesis.9,10 In 2011 we devised reaction
conditions for ruthenium(II)-catalyzed alkyne annulations by
C−H/N−O cleavages11 for a green isoquinolone synthesis in
H2O12−14 (Scheme 1),15 while Li and Wang independently
disclosed effective annulations in methanol.16,17
RESULTS AND DISCUSSION
■
Optimization Studies. At the outset of our studies, we
tested various solvents for the C−H/N−O functionalization
with free hydroxamic acid 1a (Table 1). Among a set of
representative reaction media, H2O proved to be optimal for
the dehydrative transformation (entries 1−5). While [RuCl2(p-
cymene)]2 was found to be the ruthenium precatalyst of choice
(entries 6 and 7), cocatalytic additives furnished improved
yields of the desired product 3a (entries 8−27), with the
optimal results being accomplished with the potassium salt of
the electron-deficient carboxylic acid 3-(F3C)C6H4CO2H
(entry 22).
Our previous optimization of alkyne annulation by N-
methoxybenzamides highlighted MesCO2K as the cocatalytic
additive of choice.15 While the byproduct of these C−H
functionalizations was MeOH, a more atom-economical and
sustainable approach to isoquinolones was established with the
use of NH-free hydroxamic acids, thereby generating H2O as
the sole byproduct.15 Given the environmentally benign nature
Substrate Scope. With an optimized ruthenium(II)
catalyst in hand, we next explored its substrate scope in the
Special Issue: Mechanisms in Metal-Based Organic Chemistry
Received: August 15, 2014
© XXXX American Chemical Society
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Scheme 1. Evolution of Dehydrative C−H/N−OH Alkyne Annulation in H2O
a
Table 1. Optimization of Oxidative Alkyne Annulation by C−H/N−O Cleavage
entry
additive
MesCO2K
solvent
H2O
yield (%)
1
2
62
7
MesCO2K
1,4-dioxane
t-AmOH
DMF
PhMe
H2O
3
MesCO2K
11
12
6
4
MesCO2K
5
MesCO2K
b
6
MesCO2K
trace
c
7
MesCO2K
H2O
trace
8
−
K2CO3
H2O
25
13
23
38
27
55
66
59
61
68
71
66
70
66
76
74
74
9
H2O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
KPF6
H2O
AgSbF6
H2O
TBAB
H2O
KOAc
H2O
PhCO2K
H2O
2-(MeO)C6H4CO2K
4-(MeO)C6H4CO2K
4-FC6H4CO2K
4-(O2N)C6H4CO2K
2,6-(F3C)2C6H4CO2K
3,5-(F3C)2C6H4CO2K
3,4,5-F3C6H4CO2K
3-(F3C)C6H4CO2K
3-(F3C)C6H4CO2Na
3-(F3C)C6H4CO2Cs
3-(F3C)C6H4CO2K
3-(F3C)C6H4CO2K
3-(F3C)C6H4CO2K
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
d
H2O
60
e
H2O
34
f
H2O
69
a
Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), [RuCl2(p-cymene)]2 (5.0 mol %), additive (30.0 mol %), solvent (2.0 mL), 100 °C, 18 h.
b
c
d
Average isolated yields of two independent catalytic reactions are shown. [RuCl2(cod)]n (5.0 mol %). RuCl2(PPh3)3 (5.0 mol %). Additive (20.0
mol %). [RuCl2(p-cymene)]2 (2.5 mol %). Reaction at 80 °C.
e
f
dehydrative alkyne annulation by C−H/N−OH cleavages
(Scheme 2). The annulation of aryl-substituted alkynes
proceeded efficiently, thereby delivering NH-isoquinolones 3
in high yields. The robust ruthenium(II) catalyst displayed
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Scheme 2. Substrate Scope with Aromatic Alkynes 2
Scheme 3. Annulations of Aliphatic Alkynes 4
remarkable chemoselectivity in that valuable functional groups
such as fluoro, chloro, bromo, iodo, and nitro substituents were
well-tolerated. Different aryl-substituted alkynes 2 were
efficiently converted by the ruthenium(II) catalyst as well.
Intramolecular competition experiments with meta-substituted
arenes indicated the excellent positional selectivity of the C−
H/N−OH functionalization. While the site selectivity was
largely controlled by steric interactions (3ia−3ka), the
C
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Scheme 4. Regioselectivity with Unsymmetrically Substituted Alkynes 6
Scheme 5. Dehydrative Alkenylation
inductive effect of a fluoro substituent led to exclusive C−C
bond formation at C2 of hydroxamic acid 1l.
the corresponding styrene derivatives 9 in a step-economical
manner (Scheme 5).
The ruthenium(II) catalyst was not restricted to aromatic
alkynes 2. Indeed, alkyl-substituted analogues 4 were also
converted with high catalytic efficacy (Scheme 3). Again, the
considerable tolerance of electrophilic functional groups
became apparent by the preparation of isoquinolones 5 bearing
useful functionalities.
Mechanistic Studies. Given the unique chemoselectivity of
the robust ruthenium(II) catalyst, we became interested in
unraveling its mode of action. To this end, we performed
intermolecular competition experiments between differently
substituted alkynes 2, which illustrated the improved reactivity
of electron-deficient alkyne 2c (Scheme 6).
The regioselectivity of the C−H/N−OH functionalization
with unsymmetrically substituted alkynes was found to be
synthetically useful, generally placing the aliphatic substituent
distal to nitrogen (Scheme 4).10k Notably, the robust
ruthenium(II) catalyst proved to be tolerant of an unprotected
hydroxyl group and a thiophene moiety, among others.
It is noteworthy that the dehydrative C−H/N−OH
functionalization strategy was not restricted to transformations
of alkynes. Hence, this strategy also enabled the efficient
intermolecular alkenylation with hydroxamic acids 1 to furnish
The intermolecular competition between electronically
different hydroxamic acids 1 revealed the inherently higher
reactivity of more weakly coordinating, electron-deficient
arenes (Scheme 7). This observation is not in agreement
with an electrophilic activation mode but can be rationalized in
terms of a carboxylate-assisted18,19 deprotonative C−H
ruthenation.20
As to the elementary step of N−O cleavage, a set of
competition experiments highlighted that hydroxamic acids 1
were more reactive than the N-methoxybenzamides 10
D
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(II)cycloheptene 14, which upon reductive elimination
furnishes ruthenium(0) intermediate 15. Thereafter, we
propose that oxidative addition of the N−OH bond onto the
ruthenium(0) species takes place, likely in an intramolecular
fashion, to yield ruthenium(II) amide 16. Finally, proto-
deamidation releases the desired product 3 while at the same
time regenerating the catalytically active ruthenium(II)
biscarboxylate catalyst 11.
Scheme 6. Intermolecular Competition Experiments
between Alkynes 2
CONCLUSIONS
■
In summary, we have reported on a novel ruthenium(II)
biscarboxylate catalyst for dehydrative alkyne annulations by
C−H/N−OH functionalizations in water. Thus, an in situ-
generated ruthenium(II) catalyst derived from the electron-
deficient carboxylic acid 3-(F3C)C6H4CO2H enabled efficient
annulations of various alkynes by NH-free hydroxamic acids.
The catalyst displayed a remarkable broad substrate scope and
set the stage for highly regio- and site-selective C−H
functionalizations. The ruthenium(II) biscarboxylate complex
was not limited to functionalizations with alkynes, but likewise
allowed for effective intermolecular alkenylations of hydroxamic
acids with water as the reaction medium. Detailed mechanistic
studies provided strong support for an initial kinetically relevant
C−H ruthenation along with a subsequent migratory alkyne
insertion. The proposed catalytic cycle furthermore features a
reductive elimination and an intramolecular N−OH oxidative
addition.
(Scheme 8). These findings indicated the cleavage of the N−
OH bond to be more facile than that of the N−OMe bond.
Moreover, our studies unraveled remarkably different reac-
tivities of methyl- versus ethyl-substituted arenes.
Subsequently, we conducted experiments with isotopically
labeled solvents and substrates (Scheme 9). These studies
uncovered a minor H/D exchange in the absence of an alkyne
(Scheme 9a) as well as a minor D/H scrambling in the product
[Dn]-3aa (Scheme 9b).
In accordance with these observations, a kinetic isotope effect
(KIE) of kH/kD ≈ 2.6 was suggestive of a kinetically relevant
C−H ruthenation step (Scheme 10).
A crossover experiment demonstrated that the N−O bond
cleavage likely occurred in an intramolecular fashion (Scheme
11).
On the basis of our mechanistic studies, we propose that the
ruthenium(II)-catalyzed C−H/N−OH functionalization is
initiated by a kinetically relevant C−H ruthenation step with
the in situ-generated complex 11 by carboxylate assistance
(Scheme 12). Subsequent migratory insertion of alkyne 2 with
cyclometalated complex 13 delivers benzannulated azaruthena-
EXPERIMENTAL SECTION
■
General Remarks. Catalytic reactions were carried out under an
atmosphere of N2 in predried Schlenk tubes. H2O was degassed. The
following starting materials were synthesized according to previously
described methods: N-Hydroxybenzamides 1,21 N-Methoxybenza-
mides 10,8k and alkynes 2b,22 2c,22 and 4a−c.23 Other chemicals
were obtained from commercial sources and were used without further
purification. Yields refer to isolated compounds, estimated to be >95%
1
pure as determined by H NMR spectroscopy. NMR spectra were
recorded in the indicated solvents; chemical shifts (δ) are given in
parts per million. High-resolution mass spectrometry (HRMS) was
performed by FTICR.
Representative Procedure for Ruthenium-Catalyzed C−H/
N−OH Alkyne Annulations: Synthesis of 3,4-Diphenylisoqui-
nolin-1(2H)-one (3aa). A mixture of N-hydroxybenzamide (1a) (69
mg, 0.50 mmol), diphenylacetylene (2a) (134 mg, 0.75 mmol),
[RuCl2(p-cymene)]2 (15.3 mg, 5.0 mol %), and potassium 3-
Scheme 7. Intermolecular Competition Experiments between Arenes 1
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Scheme 8. Relative Reactivities of N-Methoxybenzamides 10 and Hydroxamic Acids 1
Scheme 9. C−H/N−OH Functionalizations with Isotopically Labeled Solvent and Substrate [D5]-1a
1
(trifluoromethyl)benzoate (34 mg, 30.0 mol %) in H2O (2 mL) was
stirred at 100 °C under an atmosphere of N2 for 16 h. At ambient
temperature, the reaction mixture was diluted with H2O (25 mL) and
extracted with EtOAc (3 × 25 mL). The combined organic phase was
washed with brine (50 mL) and dried over sodium sulfate. After
filtration and evaporation of the solvent in vacuo, the crude product
was purified by column chromatography on silica gel (n-pentane/
EtOAc 2/1) to yield 3aa (113 mg, 76%) as a colorless solid (mp =
253−255 °C). H NMR (300 MHz, DMSO-d6): δ = 11.48 (s, 1H),
8.33 (dd, J = 8.0, 1.5 Hz, 1H), 7.63 (ddd, J = 8.4, 7.1, 1.6 Hz, 1H), 7.51
(ddd, J = 8.1, 7.2, 1.3 Hz, 1H), 7.36−7.11 (m, 11H). 13C NMR (75
MHz, DMSO-d6): δ = 161.6 (Cq), 138.5 (Cq), 138.0 (Cq), 135.8 (Cq),
134.5 (Cq), 132.3 (CH), 131.6 (CH), 129.7 (CH), 128.1 (CH), 128.0
(CH), 127.5 (CH), 126.9 (CH), 126.7 (CH), 126.1 (CH), 124.9 (Cq),
124.8 (CH), 115.3 (Cq). IR (neat): 3161, 3017, 2885, 1641, 1606,
1446, 1343, 693 cm−1. MS (EI) m/z (relative intensity): 297 ([M+],
F
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Scheme 10. Kinetic Isotope Effect of the C−H/N−OH Functionalizations
Scheme 11. Crossover Experiment Indicating Intramolecular N−O Cleavage
100), 296 (55), 278 (21), 190 (5), 165 (15), 139 (7), 77 (8). HRMS
(EI) m/z: calcd for C21H15NO+ [M+] 297.1154, found 297.1156. The
analytical data are in accordance with those reported in the literature.8k
6-Methyl-3,4-diphenylisoquinolin-1(2H)-one (3ba). The represen-
tative procedure was followed using N-hydroxy-4-methylbenzamide
(1b) (76 mg, 0.50 mmol). Purification by column chromatography (n-
pentane/EtOAc 2/1) yielded 3ba (103 mg, 66%) as a colorless solid
(mp = 277−279 °C). 1H NMR (300 MHz, CDCl3): δ = 9.17 (s, 1H),
8.37 (d, J = 8.2 Hz, 1H), 7.35−7.12 (m, 12H), 2.38 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ = 162.6 (Cq), 143.3 (Cq), 138.7 (Cq), 137.1
(Cq), 135.8 (Cq), 135.2 (Cq), 131.8 (CH), 129.2 (CH), 128.5 (CH),
128.3 (CH), 128.3 (CH), 128.2 (CH), 127.5 (CH), 127.2 (CH),
125.3 (CH), 122.9 (Cq), 117.0 (Cq), 22.1 (CH3). IR (neat): 3171,
3021, 2898, 1648, 1614, 1488, 1161, 698 cm−1. MS (EI) m/z (relative
intensity): 311 ([M+], 100), 310 (54), 292 (12), 178 (11), 104 (7), 77
(16). HRMS (EI) m/z: calcd for C22H17NO+ [M+] 311.1310, found
311.1297. The analytical data are in accordance with those reported in
the literature.16
6-Fluoro-3,4-diphenylisoquinolin-1(2H)-one (3da). The represen-
tative procedure was followed using 4-fluoro-N-hydroxybenzamide
(1d) (78 mg, 0.50 mmol). Purification by column chromatography (n-
pentane/EtOAc 2/1) yielded 3da (128 mg, 81%) as a colorless solid
1
(mp = 251−253 °C). H NMR (300 MHz, DMSO-d6): δ = 11.58 (s,
1H), 8.37 (dd, J = 8.9, 6.1 Hz, 1H), 7.38−7.13 (m, 11H), 6.73 (dd, J =
10.9, 2.5 Hz, 1H). 13C NMR (125 MHz, DMSO-d6): δ = 164.3 (d,
JC−F = 249.2 Hz, Cq), 160.7 (Cq), 140.5 (d, JC−F = 9.7 Hz, Cq), 140.0
(Cq), 135.1 (Cq), 134.0 (Cq), 131.3 (CH), 130.3 (CH), 130.2 (CH),
129.5 (CH), 128.2 (CH), 127.5 (CH), 127.1 (CH), 121.7 (d, JC−F
=
1.6 Hz, Cq), 114.7 (d, JC−F = 3.4 Hz, Cq), 114.5 (d, JC−F = 23.6 Hz,
CH), 109.4 (d, JC−F = 23.2 Hz, CH). 19F NMR (283 MHz, DMSO-
d6): δ = −106.4 (ddd, J = 10.9, 8.4, 6.3 Hz). IR (neat): 3116, 3030,
2917, 1644, 1610, 1450, 1178, 695 cm−1. MS (EI) m/z (relative
intensity): 315 ([M+], 60), 314 (36), 296 (12), 183 (9), 98 (22), 57
(32), 43 (100). HRMS (EI) m/z: calcd for C21H14FNO+ [M+]
315.1059, found 315.1064. The analytical data are in accordance with
those reported in the literature.15
6-Chloro-3,4-diphenylisoquinolin-1(2H)-one (3ea). The represen-
tative procedure was followed using 4-chloro-N-hydroxybenzamide
(1e) (86 mg, 0.50 mmol). Purification by column chromatography (n-
pentane/EtOAc 2/1) yielded 3ea (103 mg, 62%) as a colorless solid
6-Methoxy-3,4-diphenylisoquinolin-1(2H)-one (3ca). The repre-
sentative procedure was followed using N-hydroxy-4-methoxybenza-
mide (1c) (84 mg, 0.50 mmol). Purification by column chromatog-
raphy (n-pentane/EtOAc 2/1 → 1/1 → 1/2) yielded 3ca (96 mg,
59%) as an off-white solid (mp = 292−294 °C). 1H NMR (300 MHz,
DMSO-d6): δ = 11.38 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 7.37−7.05 (m,
11H), 6.49 (d, J = 2.5 Hz, 1H), 3.65 (s, 3H). 13C NMR (75 MHz,
DMSO-d6): δ = 162.2 (Cq), 161.2 (Cq), 140.0 (Cq), 139.1 (Cq), 135.8
(Cq), 134.6 (Cq), 131.6 (CH), 129.7 (CH), 129.0 (CH), 128.1 (CH),
128.0 (CH), 127.5 (CH), 126.9 (CH), 118.8 (Cq), 115.0 (Cq), 114.4
(CH), 107.1 (CH), 55.1 (CH3). IR (neat): 3020, 2979, 2884, 1639,
1608, 1275, 1027, 694 cm−1. MS (EI) m/z (relative intensity): 327
([M+], 100), 326 (50), 283 (7), 254 (7), 152 (12), 104 (6), 77 (8).
1
(mp = 270−272 °C). H NMR (300 MHz, DMSO-d6): δ = 11.65 (s,
1H), 8.31 (d, J = 8.5 Hz, 1H), 7.54 (dd, J = 8.6, 2.0 Hz, 1H), 7.36−
7.13 (m, 10H), 7.05 (d, J = 2.0 Hz, 1H). 13C NMR (125 MHz,
DMSO-d6): δ = 160.8 (Cq), 140.1 (Cq), 139.5 (Cq), 137.4 (Cq), 134.9
(Cq), 134.0 (Cq), 131.4 (CH), 129.5 (CH), 129.1 (CH), 128.2 (CH),
128.2 (CH), 127.5 (CH), 127.1 (CH), 126.1 (CH), 123.6 (CH),
123.4 (Cq), 114.3 (Cq). IR (neat): 3155, 3022, 2882, 1644, 1594,
1442, 1080, 696 cm−1. MS (EI) m/z (relative intensity): 331 ([M+],
100), 330 (50), 295 (15), 267 (12), 163 (15), 77 (15). HRMS (EI)
m/z: calcd for C21H14ClNO+ [M+] 331.0764, found 331.0762. The
analytical data are in accordance with those reported in the literature.15
6-Bromo-3,4-diphenylisoquinolin-1(2H)-one (3fa). The represen-
tative procedure was followed using 4-bromo-N-hydroxybenzamide
+
HRMS (EI) m/z: calcd for C22H17NO2 [M+] 327.1259, found
327.1266. The analytical data are in accordance with those reported in
the literature.8k
G
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Scheme 12. Plausible Catalytic Cycle for the C−H/N−OH Functionalizations (Ar = 3-(F3C)C6H4)
(1f) (108 mg, 0.50 mmol). Purification by column chromatography
(n-pentane/EtOAc 2/1) yielded 3fa (138 mg, 73%) as a colorless solid
(mp = 285−286 °C). H NMR (300 MHz, DMSO-d6): δ = 11.69 (s,
HRMS (EI) m/z: calcd for C21H14INO+ [M+] 423.0120, found
423.0123. The analytical data are in accordance with those reported in
the literature.16
1
1H), 8.21 (d, J = 8.6 Hz, 1H), 7.66 (dd, J = 8.6, 1.9 Hz, 1H), 7.39−
7.09 (m, 11H). 13C NMR (75 MHz, DMSO-d6): δ = 161.1 (Cq), 140.2
(Cq), 139.8 (Cq), 135.1 (Cq), 134.1 (Cq), 131.5 (CH), 129.6 (CH),
129.2 (CH), 129.0 (CH), 128.3 (CH), 127.6 (CH), 127.3 (CH),
126.8 (CH), 126.7 (Cq), 123.8 (Cq), 114.3 (Cq). IR (neat): 3164,
3020, 2902, 1645, 1588, 1438, 1066, 696 cm−1. MS (EI) m/z (relative
intensity): 376 ([M+], 95), 375 (100), 295 (28), 267 (16), 239 (13),
163 (25), 77 (20). HRMS (EI) m/z: calcd for C21H1479BrNO+ [M+]
375.0259, found 375.0272. The analytical data are in accordance with
those reported in the literature.8k
6-Iodo-3,4-diphenylisoquinolin-1(2H)-one (3ga). The representa-
tive procedure was followed using N-hydroxy-4-iodobenzamide (1g)
(132 mg, 0.50 mmol). Purification by column chromatography (n-
pentane/CH2Cl2/EtOAc 2/1/1) yielded 3ga (81 mg, 38%) as a
colorless solid (mp = 311−312 °C). 1H NMR (300 MHz, DMSO-d6):
δ = 11.67 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.83 (dd, J = 8.4, 1.6 Hz,
1H), 7.43 (d, J = 1.6 Hz, 1H), 7.36−7.09 (m, 10H). 13C NMR (125
MHz, DMSO-d6): δ = 161.3 (Cq), 139.9 (Cq), 139.7 (Cq), 135.1 (Cq),
134.7 (CH), 134.2 (Cq), 133.1 (CH), 131.6 (CH), 129.7 (CH), 128.7
(CH), 128.3 (CH), 128.3 (CH), 127.6 (CH), 127.2 (CH), 124.1 (Cq),
114.1 (Cq), 101.1 (Cq). IR (neat): 3160, 3020, 2934, 1648, 1597,
1437, 1154, 697 cm−1. MS (EI) m/z (relative intensity): 423 ([M+],
100), 422 (28), 295 (14), 267 (11), 239 (9), 163 (15), 77 (10).
6-Nitro-3,4-diphenylisoquinolin-1(2H)-one (3ha). The representa-
tive procedure was followed using N-hydroxy-4-nitrobenzamide (1h)
(91 mg, 0.50 mmol). Purification by column chromatography (n-
pentane/EtOAc 2/1) yielded 3ha (114 mg, 67%) as a yellow solid
(mp = 260−262 °C). 1H NMR (300 MHz, CDCl3): δ = 10.12 (s, 1H),
8.65−8.50 (m, 1H), 8.31−8.15 (m, 2H), 7.42−7.23 (m, 8H), 7.22−
7.14 (m, 2H). 13C NMR (75 MHz, CDCl3): δ = 161.7 (Cq), 150.6
(Cq), 139.7 (Cq), 139.5 (Cq), 134.3 (Cq), 134.1 (Cq), 131.6 (CH),
129.6 (CH), 129.2 (CH), 129.2 (CH), 128.9 (CH), 128.6 (Cq), 128.5
(CH), 128.1 (CH), 121.2 (CH), 120.1 (CH), 117.1 (Cq). IR (neat):
3332, 3022, 1664, 1611, 1525, 1340, 701 cm−1. MS (EI) m/z (relative
intensity): 342 ([M+], 100), 341 (18), 295 (16), 268 (14), 190 (12),
+
165 (12), 121 (15). HRMS (EI) m/z: calcd for C21H14N2O3 [M+]
342.1004, found 342.1001. The analytical data are in accordance with
those reported in the literature.8k
7-Methyl-3,4-diphenylisoquinolin-1(2H)-one (3ia). The represen-
tative procedure was followed using N-hydroxy-3-methylbenzamide
(1i) (76 mg, 0.50 mmol) at 120 °C. Purification by column
chromatography (CH2Cl2/Et2O 5/1) yielded 3ia (94 mg, 60%) as a
colorless solid (mp = 292−293 °C). 1H NMR (300 MHz, DMSO-d6):
δ = 11.38 (s, 1H), 8.12 (dd, J = 1.9, 0.9 Hz, 1H), 7.47 (dd, J = 8.3, 2.0
Hz, 1H), 7.33−7.19 (m, 8H), 7.17−7.10 (m, 2H), 7.06 (d, J = 8.3 Hz,
1H), 2.45 (s, 3H). 13C NMR (75 MHz, DMSO-d6): δ = 161.0 (Cq),
H
dx.doi.org/10.1021/jo501884v | J. Org. Chem. XXXX, XXX, XXX−XXX

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138.0 (Cq), 136.5 (Cq), 136.3 (Cq), 136.3 (Cq), 135.1 (Cq), 134.2
(CH), 132.1 (CH), 130.3 (CH), 128.6 (CH), 128.5 (CH), 128.1
(CH), 127.4 (CH), 126.8 (CH), 125.5 (Cq), 125.4 (CH), 115.8 (Cq),
21.3 (CH3). IR (neat): 3138, 3026, 2911, 1642, 1616, 1444, 1342, 696
cm−1. MS (EI) m/z (relative intensity): 311 ([M+], 100), 310 (48),
292 (9), 178 (7), 104 (5), 77 (12). HRMS (EI) m/z: calcd for
C22H17NO+ [M+] 311.1310, found 311.1313. The analytical data are in
accordance with those reported in the literature.8j
125.8 (CH), 124.8 (CH), 124.8 (Cq), 114.7 (Cq), 113.7 (CH), 113.0
(CH), 55.0 (CH3), 54.9 (CH3). IR (neat): 3156, 3003, 2834, 1645,
1603, 1509, 1243, 1031 cm−1. MS (EI) m/z (relative intensity): 357
([M+], 100), 356 (14), 342 (11), 282 (7), 152 (7), 77 (3). HRMS
(EI) m/z: calcd for C23H19NO3+ [M+] 357.1365, found 357.1366. The
analytical data are in accordance with those reported in the literature.16
3,4-Bis(4-fluorophenyl)isoquinolin-1(2H)-one (3ac). The repre-
sentative procedure was followed using 1,2-bis(4-fluorophenyl)ethyne
(2c) (161 mg, 0.75 mmol). Purification by column chromatography
(n-pentane/EtOAc 2/1) yielded 3ac (105 mg, 63%) as a colorless
7-(Trifluoromethyl)-3,4-diphenylisoquinolin-1(2H)-one (3ja). The
representative procedure was followed using N-hydroxy-3-
(trifluoromethyl)benzamide (1j) (103 mg, 0.50 mmol). Purification
by column chromatography (CH2Cl2/Et2O 10/1) yielded 3ja (76 mg,
1
solid (mp = 296−298 °C). H NMR (300 MHz, DMSO-d6): δ =
11.58 (s, 1H), 8.30 (dd, J = 8.0, 1.5 Hz, 1H), 7.64 (ddd, J = 8.4, 7.2,
1.6 Hz, 1H), 7.51 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.31−7.03 (m, 9H).
13C NMR (125 MHz, DMSO-d6): δ = 161.5 (d, JC−F = 245.4 Hz, Cq),
161.4 (Cq), 160.9 (d, JC−F = 243.8 Hz, Cq), 137.8 (Cq), 137.7 (Cq),
133.4 (d, JC−F = 8.1 Hz, CH), 132.4 (CH), 131.9 (d, JC−F = 8.5 Hz,
CH), 131.8 (d, JC−F = 3.3 Hz, Cq), 130.7 (d, JC−F = 3.3 Hz, Cq), 126.6
(CH), 126.1 (CH), 124.9 (Cq), 124.6 (CH), 114.8 (d, JC−F = 21.3 Hz,
CH), 114.5 (d, JC−F = 21.7 Hz, CH), 114.4 (Cq). 19F NMR (283 MHz,
DMSO-d6): δ = −113.1 (tt, J = 9.0, 5.5 Hz), −115.1 (tt, J = 8.9, 5.7
Hz). IR (neat): 3160, 3066, 2916, 1648, 1613, 1506, 1223, 773 cm−1.
MS (EI) m/z (relative intensity): 333 ([M+], 100), 332 (52), 314
(22), 183 (16), 122 (7), 95 (7). HRMS (EI) m/z: calcd for
C21H13F2NO+ [M+] 333.0965, found 333.0961. The analytical data are
in accordance with those reported in the literature.15
1
42%) as a colorless solid (mp = 234−235 °C). H NMR (300 MHz,
CDCl3): δ = 9.90 (s, 1H), 8.77−8.67 (m, 1H), 7.76 (dd, J = 8.6, 2.0
Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.38−7.23 (m, 8H), 7.21−7.14 (m,
2H). 13C NMR (125 MHz, CDCl3): δ = 162.1 (Cq), 141.0 (Cq), 139.5
(Cq), 134.9 (Cq), 134.3 (Cq), 131.6 (CH), 129.1 (CH), 129.0 (CH),
128.6 (CH), 128.5 (CH), 128.4 (CH), 128.3 (d, JC−F = 33.3 Hz, Cq),
127.6 (CH), 126.5 (CH), 125.1 (dd, JC−F = 8.2, 4.0 Hz, CH), 124.8
(Cq), 123.8 (d, JC−F = 271.7 Hz, Cq), 116.7 (Cq). 19F NMR (283 MHz,
CDCl3): δ = −62.4 (s). IR (neat): 3153, 3034, 2929, 1653, 1618, 1320,
1121, 697 cm−1. MS (EI) m/z (relative intensity): 365 ([M+], 100),
364 (55), 346 (19), 267 (8), 239 (5), 163 (5), 77 (13). HRMS (EI)
m/z: calcd for C22H14F3NO+ [M+] 365.1027, found 365.1024. The
analytical data are in accordance with those reported in the literature.8k
3,4-Diphenylbenzo[g]isoquinolin-1(2H)-one (3ka). The represen-
tative procedure was followed using N-hydroxy-2-naphthamide (1k)
(94 mg, 0.50 mmol). Purification by column chromatography (n-
pentane/EtOAc 2/1) yielded 3ka (126 mg, 73%) as a pale-green solid
3,4-Di-n-propylisoquinolin-1(2H)-one (5aa). The representative
procedure was followed using oct-4-yne (4a) (83 mg, 0.75 mmol).
Purification by column chromatography (n-pentane/EtOAc 2/1)
yielded 5aa (86 mg, 75%) as a colorless solid (mp = 188−190 °C).
1H NMR (300 MHz, CDCl3): δ = 10.99 (s, 1H), 8.44 (dt, J = 8.0, 1.1
Hz, 1H), 7.68−7.63 (m, 2H), 7.42 (dt, J = 8.1, 4.1 Hz, 1H), 2.73−2.61
(m, 4H), 1.81−1.66 (m, 2H), 1.66−1.51 (m, 2H), 1.04 (t, J = 7.3 Hz,
3H), 1.03 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ = 163.8
(Cq), 138.6 (Cq), 138.2 (Cq), 132.4 (CH), 127.8 (CH), 125.4 (CH),
125.3 (Cq), 123.2 (CH), 113.1 (Cq), 33.1 (CH2), 28.8 (CH2), 23.7
(CH2), 22.9 (CH2), 14.5 (CH3), 14.1 (CH3). IR (neat): 3164, 3025,
2869, 1653, 1628, 1470, 1167, 774 cm−1. MS (EI) m/z (relative
intensity): 229 ([M+], 30), 201 (20), 200 (100), 172 (12), 115 (10),
77 (6). HRMS (EI) m/z: calcd for C15H19NO+ [M+] 229.1467, found
229.1462. The analytical data are in accordance with those reported in
the literature.8j
1
(mp = 287−289 °C). H NMR (300 MHz, DMSO-d6): δ = 11.29 (s,
1H), 9.02 (s, 1H), 8.28−8.13 (m, 1H), 7.88−7.80 (m, 1H), 7.63 (s,
1H), 7.61−7.50 (m, 2H), 7.41−7.16 (m, 10H). 13C NMR (75 MHz,
DMSO-d6): δ = 162.1 (Cq), 137.3 (Cq), 136.0 (Cq), 134.8 (Cq), 134.7
(Cq), 134.6 (Cq), 131.7 (CH), 130.7 (Cq), 129.7 (CH), 129.0 (CH),
128.2 (CH), 128.1 (CH), 128.0 (CH), 128.0 (CH), 127.7 (CH),
127.6 (CH), 127.0 (CH), 126.0 (CH), 123.8 (Cq), 123.3 (CH), 115.2
(Cq). IR (neat): 3051, 3024, 2884, 1649, 1616, 1596, 1357, 697 cm−1.
MS (EI) m/z (relative intensity): 347 ([M+], 100), 346 (22), 328
(12), 251 (12), 158 (6), 77 (5). HRMS (EI) m/z: calcd for
C25H17NO+ [M+] 347.1310, found 347.1301. The analytical data are in
accordance with those reported in the literature.16
5-Fluoro-3,4-diphenylisoquinolin-1(2H)-one (3la). The represen-
tative procedure was followed using 3-fluoro-N-hydroxybenzamide
(1l) (78 mg, 0.50 mmol). Purification by column chromatography
(CH2Cl2/Et2O 5/1) yielded 3la (91 mg, 58%) as a colorless solid (mp
= 250−252 °C). 1H NMR (300 MHz, CDCl3): δ = 9.50 (s, 1H), 8.29
(dd, J = 7.9, 1.3 Hz, 1H), 7.44 (td, J = 8.0, 4.5 Hz, 1H), 7.34−7.12 (m,
11H). 13C NMR (125 MHz, CDCl3): δ = 161.6 (d, JC−F = 3.1 Hz, Cq),
158.6 (d, JC−F = 255.5 Hz, Cq), 138.5 (Cq), 137.4 (d, JC−F = 3.9 Hz,
Cq), 134.8 (Cq), 131.0 (d, JC−F = 3.7 Hz, CH), 129.3 (CH), 128.7
(CH), 128.2 (CH), 127.5 (CH), 127.4 (d, JC−F = 2.5 Hz, Cq), 127.3
(d, JC−F = 8.4 Hz, CH), 127.3 (d, JC−F = 8.8 Hz, Cq), 126.9 (CH),
123.7 (d, JC−F = 4.0 Hz, CH), 119.8 (d, JC−F = 22.6 Hz, CH), 113.3 (d,
JC−F = 2.1 Hz, Cq). 19F NMR (283 MHz, CDCl3): δ = −107.3 (dd, J =
12.4, 4.5 Hz). IR (neat): 3165, 3016, 2888, 1652, 1613, 1444, 1253,
697 cm−1. MS (EI) m/z (relative intensity): 315 ([M+], 100), 314
(20), 296 (7), 183 (12), 104 (4), 77 (8). HRMS (EI) m/z: calcd for
C21H14FNO+ [M+] 315.1059, found 315.1071. The analytical data are
in accordance with those reported in the literature.15
6-Methoxy-3,4-di-n-propylisoquinolin-1(2H)-one (5ca). The rep-
resentative procedure was followed using N-hydroxy-4-methoxybenza-
mide (1c) (84 mg, 0.50 mmol) and oct-4-yne (4a) (83 mg, 0.75
mmol). Purification by column chromatography (n-pentane/EtOAc 1/
1) yielded 5ca (91 mg, 70%) as an off-white solid (mp = 158−160
°C). 1H NMR (300 MHz, CDCl3): δ = 10.97 (s, 1H), 8.38 (d, J = 9.6
Hz, 1H), 7.07−6.96 (m, 2H), 3.93 (s, 3H), 2.68−2.57 (m, 4H), 1.80−
1.54 (m, 4H), 1.05 (t, J = 7.3 Hz, 3H), 1.04 (t, J = 7.3 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ = 163.3 (Cq), 163.0 (Cq), 140.7 (Cq),
139.0 (Cq), 129.9 (CH), 119.2 (Cq), 114.0 (CH), 112.6 (Cq), 105.4
(CH), 55.5 (CH3), 33.2 (CH2), 28.9 (CH2), 23.4 (CH2), 22.9 (CH2),
14.5 (CH3), 14.1 (CH3). IR (neat): 3156, 2966, 2864, 1632, 1601,
1467, 1232, 833 cm−1. MS (EI) m/z (relative intensity): 259 ([M+],
40), 231 (32), 230 (100), 202 (14), 189 (8), 115 (6), 77 (3). HRMS
+
(EI) m/z: calcd for C16H21NO2 [M+] 259.1572, found 259.1574.
6-Fluoro-3,4-di-n-propylisoquinolin-1(2H)-one (5da). The repre-
sentative procedure was followed using 4-fluoro-N-hydroxybenzamide
(1d) (78 mg, 0.50 mmol) and oct-4-yne (4a) (83 mg, 0.75 mmol).
Purification by column chromatography (n-pentane/EtOAc 2/1)
yielded 5da (94 mg, 76%) as a colorless solid (mp = 170−172 °C).
1H NMR (300 MHz CDCl3): δ = 11.24 (s, 1H), 8.45 (ddd, J = 8.9,
6.2, 2.9 Hz, 1H), 7.27 (dd, J = 10.9, 2.7 Hz, 1H), 7.13 (td, J = 8.5, 2.5
Hz, 1H), 2.72−2.58 (m, 4H), 1.82−1.68 (m, 2H), 1.66−1.51 (m, 2H),
1.06 (t, J = 7.3 Hz, 3H), 1.04 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz,
CDCl3): δ = 165.6 (d, JC−F = 251.3 Hz, Cq), 163.1 (Cq), 141.1 (d, JC−F
= 9.7 Hz, Cq), 139.8 (Cq), 130.8 (d, JC−F = 10.2 Hz, CH), 121.8 (d,
JC−F = 1.5 Hz, Cq), 114.0 (d, JC−F = 23.6 Hz, CH), 112.7 (d, JC−F = 3.5
Hz, Cq), 108.4 (d, JC−F = 22.6 Hz, CH), 33.2 (CH2), 28.9 (CH2), 23.6
(CH2), 23.0 (CH2), 14.5 (CH3), 14.2 (CH3). 19F NMR (283 MHz,
3,4-Bis(4-methoxyphenyl)isoquinolin-1(2H)-one (3ab). The rep-
resentative procedure was followed using 1,2-bis(4-methoxyphenyl)-
ethyne (2b) (179 mg, 0.75 mmol). Purification by column
chromatography (n-pentane/EtOAc 2/1 → 1/1 → 1/3) yielded 3ab
1
(103 mg, 58%) as an off-white solid (mp = 265−267 °C). H NMR
(300 MHz, DMSO-d6): δ = 11.42 (s, 1H), 8.27 (dd, J = 8.0, 1.5 Hz,
1H), 7.65−7.56 (m, 1H), 7.46−7.51 (m, 1H), 7.15−7.12 (m, 3H),
7.04 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 6.77 (d, J = 8.6 Hz,
2H), 3.72 (s, 3H), 3.69 (s, 3H). 13C NMR (75 MHz, DMSO-d6): δ =
161.7 (Cq), 158.8 (Cq), 157.9 (Cq), 138.5 (Cq), 138.3 (Cq), 132.7
(CH), 132.2 (CH), 131.0 (CH), 127.9 (Cq), 126.9 (Cq), 126.6 (CH),
I
dx.doi.org/10.1021/jo501884v | J. Org. Chem. XXXX, XXX, XXX−XXX

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1
CDCl3): δ = −106.2 (ddd, J = 11.1, 8.1, 6.2 Hz). IR (neat): 3027,
2954, 2871, 1666, 1614, 1461, 1188, 863 cm−1. MS (EI) m/z (relative
intensity): 247 ([M+], 21), 219 (15), 218 (100), 202 (7), 190 (12),
133 (7), 43 (13). HRMS (EI) m/z: calcd for C15H18FNO+ [M+]
247.1372, found 247.1364. The analytical data are in accordance with
those reported in the literature.15
6-Iodo-3,4-di-n-propylisoquinolin-1(2H)-one (5ga). The represen-
tative procedure was followed using N-hydroxy-4-iodobenzamide (1g)
(132 mg, 0.50 mmol) and oct-4-yne (4a) (83 mg, 0.75 mmol).
Purification by column chromatography (n-pentane/EtOAc 2/1)
yielded 5ga (122 mg, 69%) as an off-white solid (mp = 184−186
°C). 1H NMR (300 MHz, DMSO-d6): δ = 11.19 (s, 1H), 7.98 (s, 1H),
7.89 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 2.61−2.42 (m, 4H),
1.64−1.34 (m, 4H), 1.00−0.83 (m, 6H). 13C NMR (125 MHz,
DMSO-d6): δ = 161.3 (Cq), 140.3 (Cq), 139.4 (Cq), 133.7 (CH),
131.4 (CH), 128.8 (CH), 124.1 (Cq), 109.7 (Cq), 101.0 (Cq), 31.7
(CH2), 27.4 (CH2), 23.0 (CH2), 22.4 (CH2), 13.9 (CH3), 13.5 (CH3).
IR (neat): 3169, 2953, 2867, 1666, 1625, 1589, 1455, 775 cm−1. MS
(EI) m/z (relative intensity): 355 ([M+], 40), 327 (15), 326 (100),
298 (7), 199 (20), 184 (6), 102 (5). HRMS (EI) m/z: calcd for
C15H18INO+ [M+] 355.0433, found 355.0433.
7-Methyl-3,4-di-n-propylisoquinolin-1(2H)-one (5ia). The repre-
sentative procedure was followed using N-hydroxy-3-methylbenzamide
(1i) (76 mg, 0.50 mmol) and oct-4-yne (4a) (83 mg, 0.75 mmol).
Purification by column chromatography (n-pentane/EtOAc 2/1)
yielded 5ia (85 mg, 70%) as a colorless solid (mp = 176−178 °C).
1H NMR (300 MHz, CDCl3): δ = 10.44 (s, 1H), 8.24 (s, 1H), 7.58
(dd, J = 8.4, 1.7 Hz, 1H), 7.49 (dt, J = 8.4, 1.9 Hz, 1H), 2.72−2.60 (m,
4H), 2.48 (s, 3H), 1.82−1.51 (m, 4H), 1.08−1.00 (m, 6H). 13C NMR
(125 MHz, CDCl3): δ = 163.2 (Cq), 136.6 (Cq), 136.0 (Cq), 135.1
(Cq), 133.7 (CH), 127.1 (CH), 125.0 (Cq), 123.0 (CH), 112.9 (Cq),
32.9 (CH2), 28.7 (CH2), 23.7 (CH2), 22.7 (CH2), 21.2 (CH3), 14.4
(CH3), 14.0 (CH3). IR (neat): 2956, 2930, 2870, 1659, 1629, 1352,
900, 815 cm−1. MS (EI) m/z (relative intensity): 243 ([M+], 32), 215
(15), 214 (100), 186 (13), 115 (12), 77 (3). HRMS (EI) m/z: calcd
for C16H21NO+ [M+] 243.1623, found 243.1629.
3,4-Diethylisoquinolin-1(2H)-one (5ab). The representative pro-
cedure was followed using hex-3-yne (4b) (62 mg, 0.75 mmol) at 80
°C. Purification by column chromatography (n-pentane/EtOAc 2/1)
yielded 5ab (87 mg, 86%) as a colorless solid (mp = 178−180 °C). 1H
NMR (300 MHz, CDCl3): δ = 11.31 (s, 1H), 8.48 (dt, J = 7.8, 1.1 Hz,
1H), 7.77−7.62 (m, 2H), 7.44 (ddd, J = 8.1, 5.8, 2.3 Hz, 1H), 2.68−
2.81 (m, 4H), 1.34 (t, J = 7.6 Hz, 3H), 1.22 (t, J = 7.5 Hz, 3H). 13C
NMR (125 MHz, CDCl3): δ = 164.0 (Cq), 139.3 (Cq), 138.3 (Cq),
132.4 (CH), 127.8 (CH), 125.3 (CH), 125.2 (Cq), 122.9 (CH), 114.0
(Cq), 24.5 (CH2), 19.7 (CH2), 15.2 (CH3), 14.3 (CH3). IR (neat):
3163, 2966, 2872, 1648, 1631, 1474, 1163, 769 cm−1. MS (EI) m/z
(relative intensity): 201 ([M+], 43), 187 (15), 186 (100), 168 (10),
128 (10), 115 (20), 77 (6). HRMS (EI) m/z: calcd for C13H15NO+
[M+] 201.1154, found 201.1152. The analytical data are in accordance
with those reported in the literature.16
154−155 °C). H NMR (300 MHz, CDCl3): δ = 8.86 (s, 1H), 8.43
(dt, J = 8.0, 1.1 Hz, 1H), 7.77−7.66 (m, 2H), 7.53−7.37 (m, 6H),
2.68−2.56 (m, 2H), 1.61−1.47 (m, 2H), 1.27 (tt, J = 7.3, 7.3 Hz, 2H),
0.81 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ = 162.3 (Cq),
138.1 (Cq), 136.9 (Cq), 135.7 (Cq), 132.8 (CH), 129.3 (CH), 129.1
(CH), 128.9 (CH), 128.1 (CH), 126.4 (CH), 126.0 (Cq), 123.9 (CH),
114.5 (Cq), 32.9 (CH2), 27.1 (CH2), 22.9 (CH2), 13.9 (CH3). IR
(neat): 3160, 2950, 2869, 1646, 1615, 1469, 1157, 761 cm−1. MS (EI)
m/z (relative intensity): 277 ([M+], 35), 235 (15), 234 (100), 216
(19), 178 (6), 77 (11), 43 (24). HRMS (EI) m/z: calcd for
C19H19NO+ [M+] 277.1467, found 277.1461.
4-n-Butyl-3-(4-methoxyphenyl)isoquinolin-1(2H)-one (7ab). The
representative procedure was followed using 1-(hex-1-yn-1-yl)-4-
methoxybenzene (6b) (141 mg, 0.75 mmol). Purification by column
chromatography (n-pentane/EtOAc 2/1 → 1/1) yielded 7ab (100 mg,
65%) as an off-white solid (mp = 167−169 °C). 1H NMR (300 MHz,
DMSO-d6): δ = 11.09 (s, 1H), 8.28 (dd, J = 7.9, 1.0 Hz, 1H), 7.83−
7.71 (m, 2H), 7.50 (dt, J = 8.1, 4.1 Hz, 1H), 7.39−7.32 (m, 2H),
7.08−7.01 (m, 2H), 3.83 (s, 3H), 2.56−2.49 (m, 2H), 1.53−1.39 (m,
2H), 1.23 (tt, J = 7.3, 7.3 Hz, 2H), 0.77 (t, J = 7.3 Hz, 3H). 13C NMR
(125 MHz, DMSO-d6): δ = 161.0 (Cq), 159.1 (Cq), 137.8 (Cq), 137.2
(Cq), 132.2 (CH), 130.4 (CH), 127.1 (Cq), 126.9 (CH), 125.5 (CH),
125.5 (Cq), 123.4 (CH), 113.4 (CH), 112.0 (Cq), 55.1 (CH3), 32.2
(CH2), 26.2 (CH2), 22.0 (CH2), 13.5 (CH3). IR (neat): 2955, 2932,
2869, 1634, 1604, 1245, 1023, 532 cm−1. MS (EI) m/z (relative
intensity): 307 ([M+], 50), 265 (20), 264 (100), 249 (12), 233 (18),
+
165 (6), 102 (6), 43 (15). HRMS (EI) m/z: calcd for C20H21NO2
[M+] 307.1572, found 307.1580. The analytical data are in accordance
with those reported in the literature.15
4-n-Butyl-3-(4-fluorophenyl)isoquinolin-1(2H)-one (7ac). The
representative procedure was followed using 1-fluoro-4-(hex-1-yn-1-
yl)benzene (6c) (132 mg, 0.75 mmol). Purification by column
chromatography (n-pentane/EtOAc 3/1) yielded 7ac (102 mg, 69%)
as a colorless solid (mp = 182−184 °C). 1H NMR (300 MHz,
CDCl3): δ = 9.44 (s, 1H), 8.39 (dt, J = 7.8, 1.0 Hz, 1H), 7.77−7.66
(m, 2H), 7.54−7.37 (m, 3H), 7.22−7.13 (m, 2H), 2.65−2.54 (m, 2H),
1.52 (tt, J = 8.0, 6.3 Hz, 2H), 1.28 (tt, J = 7.3, 7.3 Hz, 2H), 0.82 (t, J =
7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ = 163.2 (d, JC−F = 249.2
Hz, Cq), 162.5 (Cq), 138.0 (Cq), 136.1 (Cq), 132.8 (CH), 131.6 (d,
JC−F = 3.5 Hz, Cq), 131.2 (d, JC−F = 8.4 Hz, CH), 128.1 (CH), 126.5
(CH), 126.0 (Cq), 123.9 (CH), 116.0 (d, JC−F = 21.6 Hz, CH), 114.8
(Cq), 32.9 (CH2), 27.1 (CH2), 22.9 (CH2), 13.9 (CH3). 19F NMR
(283 MHz, CDCl3): δ = −111.6 (tt, J = 8.6, 5.3 Hz). IR (neat): 3163,
2929, 2860, 1644, 1602, 1221, 840 cm−1. MS (EI) m/z (relative
intensity): 295 ([M+], 18), 253 (20), 252 (100), 234 (29), 196 (6), 77
(5). HRMS (EI) m/z: calcd for C19H18FNO+ [M+] 295.1372, found
295.1368.
4-(Methoxymethyl)-3-phenylisoquinolin-1(2H)-one (7ad). The
representative procedure was followed using (3-methoxyprop-1-yn-1-
yl)benzene (6d) (110 mg, 0.75 mmol). Purification by column
chromatography (n-pentane/EtOAc 1/1 → 1/2) yielded 7ad (97 mg,
73%) as an off-white solid (mp = 236−238 °C). 1H NMR (300 MHz,
CDCl3): δ = 9.33 (s, 1H), 8.40 (dd, J = 8.1, 1.4 Hz, 1H), 7.91−7.82
(m, 1H), 7.75 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H), 7.61−7.45 (m, 6H), 4.42
(s, 2H), 3.40 (d, J = 1.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ =
162.9 (Cq), 140.6 (Cq), 138.2 (Cq), 134.5 (Cq), 133.2 (CH), 129.9
(CH), 129.1 (CH), 129.0 (CH), 127.8 (CH), 126.8 (CH), 125.6 (Cq),
124.2 (CH), 110.4 (Cq), 68.4 (CH2), 58.1 (CH3). IR (neat): 3171,
2971, 2886, 2807, 1653, 1608, 1090, 697 cm−1. MS (EI) m/z (relative
intensity): 265 ([M+], 40), 235 (18), 234 (100), 216 (30), 178 (8),
3,4-Di-n-butylisoquinolin-1(2H)-one (5ac). The representative
procedure was followed using dec-5-yne (4c) (104 mg, 0.75 mmol).
Purification by column chromatography (CH2Cl2/Et2O 4/1) yielded
1
5ac (101 mg, 78%) as a colorless solid (mp = 85−87 °C). H NMR
(300 MHz, CDCl3): δ = 11.24 (s, 1H), 8.43 (d, J = 8.0 Hz, 1H), 7.66
(m, 2H), 7.41 (dt, J = 8.1, 4.0 Hz, 1H), 2.76−2.61 (m, 4H), 1.68 (tt, J
= 7.9, 6.3 Hz, 2H), 1.60−1.38 (m, 6H), 0.96 (t, J = 7.2 Hz, 6H). 13C
NMR (75 MHz, CDCl3): δ = 163.7 (Cq), 138.5 (Cq), 138.3 (Cq),
132.2 (CH), 127.6 (CH), 125.2 (CH), 125.1 (Cq), 122.9 (CH), 112.9
(Cq), 32.6 (CH2), 31.6 (CH2), 30.8 (CH2), 26.2 (CH2), 23.0 (CH2),
22.7 (CH2), 14.0 (CH3), 13.8 (CH3). IR (neat): 3164, 2961, 2926,
2861, 1649, 1627, 1471, 769 cm−1. MS (EI) m/z (relative intensity):
257 ([M+], 58), 215 (23), 214 (100), 173 (22), 172 (83), 144 (10),
115 (12), 77 (5). HRMS (EI) m/z: calcd for C17H23NO+ [M+]
257.1780, found 257.1788.
+
102 (15), 77 (22). HRMS (EI) m/z: calcd for C17H15NO2 [M+]
265.1103, found 265.1102.
4-(4-Hydroxybutyl)-3-phenylisoquinolin-1(2H)-one (7ae). The
representative procedure was followed using 6-phenylhex-5-yn-1-ol
(6e) (131 mg, 0.75 mmol). Purification by column chromatography
(n-pentane/EtOAc 1/3) yielded 7ae (103 mg, 70%) as a colorless
solid (mp = 113−115 °C). 1H NMR (300 MHz, CDCl3): δ = 8.95 (s,
1H), 8.41 (d, J = 7.7 Hz, 1H), 7.77−7.65 (m, 2H), 7.52−7.34 (m,
6H), 3.51 (t, J = 6.4 Hz, 2H), 2.70−2.57 (m, 2H), 1.77 (s, 1H), 1.70−
1.41 (m, 4H). 13C NMR (125 MHz, CDCl3): δ = 162.2 (Cq), 137.9
4-n-Butyl-3-phenylisoquinolin-1(2H)-one (7aa). The representa-
tive procedure was followed using hex-1-yn-1-ylbenzene (6a) (119 mg,
0.75 mmol). Purification by column chromatography (n-pentane/
EtOAc 2/1) yielded 7aa (110 mg, 79%) as a colorless solid (mp =
J
dx.doi.org/10.1021/jo501884v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(Cq), 137.0 (Cq), 135.5 (Cq), 132.8 (CH), 129.3 (CH), 129.0 (CH),
128.9 (CH), 128.1 (CH), 126.4 (CH), 125.9 (Cq), 123.8 (CH), 114.1
(Cq), 62.5 (CH2), 32.6 (CH2), 27.1 (CH2), 26.9 (CH2). IR (neat):
3167, 2931, 2860, 1647, 1606, 1359, 1053, 764 cm−1. MS (EI) m/z
(relative intensity): 293 ([M+], 35), 235 (17), 234 (100), 216 (25),
Ethyl (E)-3-(2-Carbamoyl-5-fluorophenyl)acrylate (9da). The
representative procedure was followed using 4-fluoro-N-hydroxyben-
zamide (1d) (78 mg, 0.5 mmol) and ethyl acrylate (8a) (75 mg, 0.75
mmol) at 60 °C. Purification by column chromatography (CH2Cl2/
EtOAc 2/1) yielded 9da (80 mg, 67%) as an off-white solid (mp =
+
1
204 (10), 178 (8), 77 (10). HRMS (EI) m/z: calcd for C19H19NO2
162−164 °C). H NMR (300 MHz, acetone-d6): δ = 8.17 (dd, J =
[M+] 293.1416, found 293.1423.
16.0, 1.7 Hz, 1H), 7.70−7.59 (m, 2H), 7.38 (br s, 1H), 7.23 (td, J =
8.4, 2.6 Hz, 1H), 6.93 (br s, 1H), 6.56 (d, J = 16.0 Hz, 1H), 4.22 (q, J
= 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, acetone-
d6): δ = 169.9 (Cq), 166.6 (Cq), 164.1 (d, JC−F = 247.4 Hz), 141.9 (d,
JC−F = 2.2 Hz), 136.5 (d, JC−F = 8.2 Hz), 134.9 (d, JC−F = 3.3 Hz),
131.0 (d, JC−F = 8.8 Hz), 122.0 (CH), 117.1 (d, JC−F = 22.0 Hz), 114.2
(d, JC−F = 22.9 Hz), 60.9 (CH2), 14.6 (CH3). 19F NMR (283 MHz,
acetone-d6): δ = −107.1 (dddd, J = 9.7, 7.7, 5.7, 1.7 Hz). IR (neat):
3389, 3203, 3004, 1688, 1650, 1388, 1215, 978 cm−1. MS (EI) m/z
(relative intensity): 237 ([M+], 1), 208 (5), 192 (6), 164 (100), 149
(15), 135 (9), 120 (9). HRMS (EI) m/z: calcd for C12H13FNO3+ [M
+ H+] 238.0879, found 238.0876.
4-n-Butyl-3-(thiophen-2-yl)isoquinolin-1(2H)-one (7af). The rep-
resentative procedure was followed using 2-(hex-1-yn-1-yl)thiophene
(6f) (123 mg, 0.75 mmol). Purification by column chromatography
(n-pentane/EtOAc 2/1) yielded 7af (63 mg, 44%) as an off-white
1
solid (mp = 164−166 °C). H NMR (300 MHz, DMSO-d6): δ =
11.18 (s, 1H), 8.28 (dd, J = 7.8, 1.1 Hz, 1H), 7.83−7.77 (m, 2H), 7.75
(dd, J = 5.1, 1.2 Hz, 1H), 7.54 (ddd, J = 8.1, 5.1, 3.1 Hz, 1H), 7.31 (dd,
J = 3.6, 1.2 Hz, 1H), 7.19 (dd, J = 5.1, 3.6 Hz, 1H), 2.72−2.60 (m,
2H), 1.52 (tt, J = 7.9, 6.2 Hz, 2H), 1.32 (tt, J = 7.3, 7.3 Hz, 2H), 0.84
(t, J = 7.3 Hz, 3H). 13C NMR (125 MHz, DMSO-d6): δ = 160.9 (Cq),
136.7 (Cq), 134.6 (Cq), 132.4 (CH), 130.6 (Cq), 129.0 (CH), 127.6
(CH), 126.9 (CH), 126.9 (CH), 126.2 (CH), 125.8 (Cq), 123.7 (CH),
114.4 (Cq), 32.5 (CH2), 26.7 (CH2), 22.1 (CH2), 13.5 (CH3). IR
(neat): 3067, 2952, 2849, 1641, 1600, 1156, 764 cm−1. MS (EI) m/z
(relative intensity): 283 ([M+], 35), 241 (18), 240 (100), 222 (13),
184 (6), 128 (5), 77 (3). HRMS (EI) m/z: calcd for C17H17NOS+
[M+] 283.1031, found 283.1027.
n-Butyl (E)-3-(2-Carbamoylphenyl)acrylate (9ab). The represen-
tative procedure was followed using butyl acrylate (8b) (96 mg, 0.75
mmol) at 60 °C. Purification by column chromatography (CH2Cl2/
EtOAc 2/1) yielded 9ab (90 mg, 73%) as a colorless solid (mp =
140−141 °C). 1H NMR (300 MHz, CDCl3): δ = 8.10 (d, J = 16.0 Hz,
1H), 7.68−7.54 (m, 2H), 7.52−7.37 (m, 2H), 6.40 (d, J = 16.0 Hz,
1H), 6.03 (br s, 1H), 5.87 (br s, 1H), 4.19 (t, J = 6.7 Hz, 2H), 1.73−
1.63 (m, 2H), 1.50−1.35 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ = 170.4 (Cq), 166.5 (Cq), 141.8 (CH), 135.7
(Cq), 133.1 (Cq), 130.8 (CH), 129.7 (CH), 127.8 (CH), 127.3 (CH),
121.2 (CH), 64.6 (CH2), 30.7 (CH2), 19.2 (CH2), 13.7 (CH3). IR
(neat): 3356, 3167, 2952, 1707, 1626, 1276, 974, 766 cm−1. MS (EI)
m/z (relative intensity): 247 ([M+], 6), 190 (15), 174 (12), 146 (100),
4-n-Butyl-3-(cyclohex-1-en-1-yl)isoquinolin-1(2H)-one (7ag). The
representative procedure was followed using 1-(hex-1-yn-1-yl)-
cyclohex-1-ene (6g) (122 mg, 0.75 mmol). Purification by column
chromatography (CH2Cl2/Et2O 5/1) yielded 7ag (69 mg, 49%) as a
colorless solid (mp = 152−154 °C). 1H NMR (300 MHz, CDCl3): δ =
9.05 (s, 1H), 8.43 (d, J = 8.0 Hz, 1H), 7.74−7.62 (m, 2H), 7.45 (dt, J
= 8.2, 4.1 Hz, 1H), 5.91 (dd, J = 3.8, 2.1 Hz, 1H), 2.66 (dd, J = 9.9, 6.0
Hz, 2H), 2.31−2.14 (m, 4H), 1.87−1.65 (m, 4H), 1.63−1.35 (m, 4H),
0.96 (t, J = 7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ = 162.6
(Cq), 139.2 (Cq), 138.3 (Cq), 133.3 (Cq), 132.3 (CH), 130.9 (CH),
127.8 (CH), 125.7 (CH), 125.5 (Cq), 123.6 (CH), 112.9 (Cq), 33.0
(CH2), 28.9 (CH2), 27.1 (CH2), 25.2 (CH2), 23.0 (CH2), 22.7 (CH2),
21.8 (CH2), 13.9 (CH3). IR (neat): 2958, 2922, 2856, 1650, 1622,
1460, 764 cm−1. MS (EI) m/z (relative intensity): 281 ([M+], 40), 239
(20), 238 (100), 196 (23), 178 (11), 115 (9), 77 (6). HRMS (EI) m/
z: calcd for C19H23NO+ [M+] 281.1780, found 281.1770.
+
131 (25), 117 (11), 77 (8). HRMS (EI) m/z: calcd for C14H18NO3
[M + H+] 248.1287, found 248.1282. The analytical data are in
accordance with those reported in the literature.8i
Benzyl (E)-3-(2-Carbamoylphenyl)acrylate (9ac). The representa-
tive procedure was followed using benzyl acrylate (8c) (122 mg, 0.75
mmol) at 60 °C. Purification by column chromatography (CH2Cl2/
EtOAc 2/1) yielded 9ac (115 mg, 82%) as a colorless solid (mp =
149−151 °C). 1H NMR (300 MHz, acetone-d6): δ = 8.26 (d, J = 16.1
Hz, 1H), 7.90−7.83 (m, 1H), 7.59 (dd, J = 7.1, 1.9 Hz, 1H), 7.55−
7.28 (m, 8H), 6.91 (br s, 1H), 6.56 (d, J = 16.1 Hz, 1H), 5.25 (s, 2H).
13C NMR (125 MHz, acetone-d6): δ = 170.8 (Cq), 166.8 (Cq), 143.8
(CH), 138.6 (Cq), 137.5 (Cq), 133.5 (Cq), 130.8 (CH), 130.6 (CH),
129.3 (CH), 129.0 (CH), 128.8 (CH), 128.5 (CH), 127.7 (CH),
120.2 (CH), 66.5 (CH2). IR (neat): 3377, 3181, 1709, 1639, 1276,
1162, 765 cm−1. MS (EI) m/z (relative intensity): 281 ([M+], 7), 237
(3), 190 (19), 146 (100), 131 (30), 91 (72), 77 (17). HRMS (EI) m/
Ethyl (E)-3-(2-Carbamoylphenyl)acrylate (9aa). The representa-
tive procedure was followed using ethyl acrylate (8a) (75 mg, 0.75
mmol) at 60 °C. Purification by column chromatography (CH2Cl2/
EtOAc 2/1) yielded 9aa (90 mg, 82%) as a colorless solid (mp = 161−
163 °C). 1H NMR (300 MHz, CDCl3): δ = 8.10 (d, J = 16.0 Hz, 1H),
7.65−7.56 (m, 2H), 7.50−7.39 (m, 2H), 6.39 (d, J = 16.0 Hz, 1H),
6.12 (br s, 1H), 5.91 (br s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 1.32 (t, J =
7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ = 170.5 (Cq), 166.4
(Cq), 141.8 (CH), 135.8 (Cq), 133.1 (Cq), 130.8 (CH), 129.7 (CH),
127.7 (CH), 127.3 (CH), 121.1 (CH), 60.6 (CH2), 14.3 (CH3). IR
(neat): 3378, 3180, 2980, 1716, 1637, 1315, 1182, 634 cm−1. MS (EI)
m/z (relative intensity): 219 ([M+], 5), 190 (14), 174 (15), 146 (100),
131 (25), 117 (12), 103 (14), 77 (11). HRMS (EI) m/z: calcd for
+
z: calcd for C17H15NO3 [M+] 281.1052, found 281.1051. The
analytical data are in accordance with those reported in the literature.17
(E)-2-(3-Oxobut-1-en-1-yl)benzamide (9ad). The representative
procedure was followed using but-3-en-2-one (8d) (105 mg, 1.50
mmol) at 60 °C. Purification by column chromatography (CH2Cl2/
acetone 2/1) yielded 9ad (49 mg, 52%) as an off-white solid (mp =
148−150 °C). 1H NMR (300 MHz, acetone-d6): δ = 8.10 (d, J = 16.3
Hz, 1H), 7.83 (dd, J = 7.4, 1.7 Hz, 1H), 7.62 (dd, J = 7.3, 1.7 Hz, 1H),
7.54−7.43 (m, 2H), 7.36 (br s, 1H), 6.91 (br s, 1H), 6.70 (d, J = 16.3
Hz, 1H), 2.31 (s, 3H). 13C NMR (125 MHz, acetone-d6): δ = 197.9
(Cq), 170.8 (Cq), 141.7 (CH), 138.5 (Cq), 134.0 (Cq), 130.9 (CH),
130.5 (CH), 129.4 (CH), 128.7 (CH), 127.6 (CH), 27.4 (CH3). IR
(neat): 3354, 3173, 1644, 1616, 1247, 971, 625 cm−1. MS (EI) m/z
(relative intensity): 189 ([M+], 5), 174 (3), 146 (100), 132 (24), 118
(12), 103 (16), 77 (15). HRMS (EI) m/z: calcd for C11H11NO2+ [M+]
189.0790, found 189.0796.
+
C12H13NO3 [M+] 219.0895, found 219.0894. The analytical data are
in accordance with those reported in the literature.17
Ethyl (E)-3-(2-Carbamoyl-5-methylphenyl)acrylate (9ba). The
representative procedure was followed using 4-methyl-N-hydroxyben-
zamide (1b) (76 mg, 0.5 mmol) and ethyl acrylate (8a) (75 mg, 0.75
mmol) at 60 °C. Purification by column chromatography (CH2Cl2/
EtOAc 2/1) yielded 9ba (93 mg, 80%) as a colorless solid (mp =
172−174 °C). 1H NMR (300 MHz, acetone-d6): δ = 8.22 (d, J = 16.0
Hz, 1H), 7.67 (s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.32−7.21 (m, 2H),
6.81 (br s, 1H), 6.46 (d, J = 16.0 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H),
2.40 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, acetone-
d6): δ = 170.8 (Cq), 166.9 (Cq), 143.5 (CH), 141.0 (Cq), 135.6 (Cq),
133.7 (Cq), 131.1 (CH), 128.6 (CH), 128.2 (CH), 120.3 (CH), 60.7
(CH2), 21.1 (CH3), 14.6 (CH3). IR (neat): 3375, 3198, 1690, 1656,
1294, 1040, 643 cm−1. MS (EI) m/z (relative intensity): 233 ([M+],
3), 204 (9), 188 (10), 160 (100), 145 (22), 115 (28), 77 (5). HRMS
Intermolecular Competition Experiments between Alkynes
2 (Scheme 6). The representative procedure was followed using 1,2-
bis(4-fluorophenyl)ethyne (2c) (214 mg, 1.0 mmol) and 1,2-bis(4-
methoxyphenyl)ethyne (2b) (238 mg, 1.0 mmol). Purification by
column chromatography (n-pentane/EtOAc 2/1 → 1/1) yielded 3ac
(86 mg, 52%) and 3ab (36 mg, 20%).
+
(EI) m/z: calcd for C13H15NO3 [M+] 233.1052, found 233.1058.
K
dx.doi.org/10.1021/jo501884v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Intermolecular Competition Experiments between Arenes 1
(Scheme 7). The representative procedure was followed using 4-
fluoro-N-hydroxybenzamide (1d) (155 mg, 1.0 mmol), 4-methyl-N-
hydroxybenzamide (1b) (151 mg, 1.0 mmol), and 1,2-diphenylethyne
(2a) (89 mg, 0.5 mmol). Purification by column chromatography
(CH2Cl2/Et2O 3/1) yielded a mixture of 3da and 3ba (42 mg) in
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
which the ratio of 3da to 3ba was determined to be 61/39 by H
NMR spectroscopy.
AUTHOR INFORMATION
Corresponding Author
*E-mail: Lutz.Ackermann@chemie.uni-goettingen.de.
Notes
■
Relative Reactivities of N-Methoxybenzamides 10 and
Hydroxamic Acids 1 (Scheme 8a). The representative procedure
was followed using 4-methyl-N-methoxybenzamide (10b) (165 mg,
1.0 mmol), 4-ethyl-N-hydroxybenzamide (1m) (165 mg, 1.0 mmol),
and 1,2-diphenylethyne (2a) (89 mg, 0.5 mmol). Purification by
column chromatography (CH2Cl2/Et2O 3/1) yielded a mixture of 3ba
and 3ma (19 mg) in which the ratio of 3ba to 3ma was determined to
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
1
■
be 10/90 by H NMR spectroscopy.
Support by the Chinese Scholarship Council (fellowship to
F.Y.), the CaSuS Ph.D. Program, and the European Research
Council under the European Community’s Seventh Framework
Program (FP7 2007−2013)/ERC Grant Agreement 307535 is
gratefully acknowledged.
Relative Reactivities of N-Methoxybenzamides 10 and
Hydroxamic Acids 1 (Scheme 8b). The representative procedure
was followed using 4-methyl-N-hydroxybenzamide (1b) (151 mg, 1.0
mmol), 4-ethyl-N-methoxybenzamide (10m) (179 mg, 1.0 mmol),
and 1,2-diphenylethyne (2a) (89 mg, 0.5 mmol). Purification by
column chromatography (CH2Cl2/Et2O 3/1) yielded a mixture of 3ba
and 3ma (41 mg) in which the ratio of 3ba to 3ma was determined to
REFERENCES
1
■
be 61/39 by H NMR spectroscopy.
(1) For representative recent reviews of C−H activation, see:
(a) Girard, S. A.; Knauber, T.; Li, C.-J. Angew. Chem., Int. Ed. 2014, 53,
74−100. (b) Ackermann, L. J. Org. Chem. 2014, 79, 8948−8954.
(c) Zhang, X.-S.; Chen, K.; Shi, Z.-J. Chem. Sci. 2014, 5, 2146−2159.
(d) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369−375.
(e) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012,
45, 788−802. (f) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc.
Rev. 2011, 40, 1885−1898. (g) Daugulis, O. Top. Curr. Chem. 2010,
292, 57−84. (h) Thansandote, P.; Lautens, M. Chem.Eur. J. 2009,
15, 5874−5883. (i) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc.
Chem. Res. 2008, 41, 1013−1025 and references cited therein.
(2) Alvarez-Builla, J.; Vaquero, J. J.; Barluenga, J. Modern Heterocyclic
Chemistry; Wiley-VCH: Weinheim, Germany, 2011.
6-Ethyl-3,4-diphenylisoquinolin-1(2H)-one (3ma). Off-white solid
(mp = 256−258 °C). 1H NMR (300 MHz, CDCl3): δ = 8.94 (s, 1H),
8.41 (d, J = 8.2 Hz, 1H), 7.48−7.06 (m, 12H), 2.66 (q, J = 7.6 Hz,
2H), 1.19 (t, J = 7.6 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ =
162.4 (Cq), 149.4 (Cq), 138.7 (Cq), 136.9 (Cq), 135.7 (Cq), 135.2
(Cq), 131.7 (CH), 129.0 (CH), 128.5 (CH), 128.3 (CH), 128.2 (CH),
127.5 (CH), 127.1 (CH), 127.0 (CH), 124.2 (CH), 123.1 (Cq), 117.1
(Cq), 29.4 (CH2), 15.4 (CH3). IR (neat): 3118, 3022, 2885, 1640,
1611, 1442, 1151, 695 cm−1. MS (EI) m/z (relative intensity): 325
([M+], 100), 324 (45), 295 (12), 178 (10), 104 (8), 77 (13). HRMS
(EI) m/z: calcd for C23H19NO+ [M+] 325.1467, found 325.1465.
C−H/N−OH Functionalizations with Isotopically Labeled
Solvent (Scheme 9a). A mixture of N-hydroxybenzamide (1a) (69
mg, 0.50 mmol), [RuCl2(p-cymene)]2 (15.3 mg, 5.0 mol %), and
potassium 3-(trifluoromethyl)benzoate (34 mg, 30.0 mol %) in D2O
(2 mL) was stirred at 100 °C under an atmosphere of N2 for 18 h.
D2O was removed in vacuo. Purification by column chromatography
on silica gel (CH2Cl2/acetone 2/1) recovered [Dn]-1a (62 mg, 87%)
with approximately 8% H incorporation at the ortho positions as
(3) Ackermann, L. Acc. Chem. Res. 2014, 47, 281−295.
(4) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651−3678.
(5) Satoh, T.; Miura, M. Chem.Eur. J. 2010, 16, 11212−11222.
(6) Ackermann, L.; Wang, L.; Lygin, A. V. Chem. Sci. 2012, 3, 177−
180.
(7) Patureau, F. W.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50,
1977−1979.
1
estimated by H NMR spectroscopy.
(8) For representative examples, see: (a) Huang, X.; Huang, J.; Du,
C.; Zhang, X.; Song, F.; You, J. Angew. Chem., Int. Ed. 2013, 52,
12970−12974. (b) Quinones, N.; Seoane, A.; Garcia-Fandino, R.;
Mascarenas, J. L.; Gulias, M. Chem. Sci. 2013, 4, 2874−2879. (c) Liu,
G.; Shen, Y.; Zhou, Z.; Lu, X. Angew. Chem., Int. Ed. 2013, 52, 6033−
6037. (d) Zeng, R.; Wu, S.; Fu, C.; Ma, S. J. Am. Chem. Soc. 2013, 135,
18284−18287. (e) Zhen, W.; Wang, F.; Zhao, M.; Du, Z.; Li, X.
Angew. Chem., Int. Ed. 2012, 51, 11819−11823. (f) Ye, B.; Cramer, N.
Science 2012, 338, 504−506. (g) Hyster, T. K.; Knoerr, L.; Ward, T.
R.; Rovis, T. Science 2012, 338, 500−503. (h) Zhong, H.; Yang, D.;
Wang, S.; Huang, J. Chem. Commun. 2012, 48, 3236−3238. (i) Wang,
H.; Grohmann, C.; Nimphius, C.; Glorius, F. J. Am. Chem. Soc. 2012,
134, 19592−19595. (j) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius,
F. J. Am. Chem. Soc. 2011, 133, 2350−2353. (k) Guimond, N.;
Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2011, 133, 6449−6457.
(l) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc. 2010,
132, 6908−6909 and references cited therein.
(9) For recent reviews of ruthenium(II)-catalyzed C−H bond
functionalizations, see: (a) De Sarkar, S.; Liu, W.; Kozhushkov, S. I.;
Ackermann, L. Adv. Synth. Catal. 2014, 356, 1461−1479. (b) Arockiam,
P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879−5918.
(c) Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292, 211−229
and references cited therein.
(10) For selected recent examples of ruthenium(II)-catalyzed
oxidative alkyne or alkene annulations by C−H activation, see:
(a) Nakanowatari, S.; Ackermann, L. Chem.Eur. J. 2014, 20, 5409−
C−H/N−OH Functionalizations with Isotopically Labeled
Substrate [D5]-1a (Scheme 9b). The representative procedure was
followed using [D5]-1a (71 mg, 0.50 mmol). Purification by column
chromatography (n-pentane/EtOAc 2/1) yielded [D4]-3aa (101 mg,
67%) with approximately 15% deuterium incorporation at the ortho
1
position as estimated by H NMR spectroscopy.
3,4-Diphenylisoquinolin-1(2H)-one-5,6,7,8-d4 ([D4]-3aa). Color-
less solid (mp = 254−256 °C). 1H NMR (300 MHz, DMSO-d6): δ =
11.53 (s, 1H), 7.35−7.07 (m, 10H). 13C NMR (125 MHz, DMSO-d6):
δ = 161.4 (Cq), 138.3 (Cq), 137.8 (Cq), 135.6 (Cq), 134.4 (Cq), 131.7
(t, J = 22.7 Hz, CD), 131.5 (CH), 129.6 (CH), 128.0 (CH), 127.9
(CH), 127.4 (CH), 126.8 (CH), 126.5 (t, J = 22.7 Hz, CD), 124.8 (t, J
= 22.7 Hz, CD), 124.7 (Cq), 124.3 (t, J = 22.7 Hz, CD), 115.2 (Cq). IR
(neat): 3149, 3017, 2886, 1642, 1327, 902, 697 cm−1. MS (EI) m/z
(relative intensity): 301 ([M+], 100), 300 (80), 282 (14), 271 (9), 169
(12), 104 (5), 77 (11). HRMS (EI) m/z: calcd for C21H11D4NO+
[M+] 301.1405, found 301.1408. The analytical data are in accordance
with those reported in the literature.15
Kinetic Isotope Effect of the C−H/N−OH Functionalizations
(Scheme 10). The representative procedure was followed using N-
hydroxybenzamide (1a) (137 mg, 1.0 mmol), N-hydroxybenzamide-d5
([D5]-1a) (142 mg, 1.0 mmol), and 1,2-diphenylethyne (2a) (89 mg,
0.5 mmol). Purification by column chromatography (n-pentane/
EtOAc 2/1) yielded a mixture of [Dn]-3aa (15 mg). The kinetic
isotope effect of this reaction was determined to be 2.6 as estimated by
1H NMR spectroscopy.
L
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Article
5413. (b) Mehta, V. P.; Garcia-Lopez, J.-A.; Greaney, M. F. Angew.
Chem., Int. Ed. 2014, 53, 1529−1533. (c) Li, J.; John, M.; Ackermann,
L. Chem.Eur. J. 2014, 20, 5403−5408. (d) Kornhaaß, C.; Kuper, C.;
Ackermann, L. Adv. Synth. Catal. 2014, 356, 1619−1624. (e) Nan, J.;
Zuo, Z.; Luo, L.; Bai, L.; Zheng, H.; Yuan, Y.; Liu, J.; Luan, X.; Wang,
Y. J. Am. Chem. Soc. 2013, 135, 17306−17309. (f) Reddy, M. C.;
Manikandan, R.; Jeganmohan, M. Chem. Commun. 2013, 49, 6060−
6062. (g) Dooley, J. D.; Chidipudi, S. R.; Lam, H. W. J. Am. Chem. Soc.
2013, 135, 10829−10836. (h) Zhang, J.; Ugrinov, A.; Zhao, P. Angew.
Chem., Int. Ed. 2013, 52, 6681−6684. (i) Villuendas, P.; Urriolabeitia,
E. P. J. Org. Chem. 2013, 78, 5254−5263. (j) Parthasarathy, K.;
Senthilkumar, N.; Jayakumar, J.; Cheng, C.-H. Org. Lett. 2012, 14,
3478−3481. (k) Chinnagolla, R. K.; Jeganmohan, M. Chem. Commun.
2012, 48, 2030−2032. (l) Ackermann, L.; Lygin, A. V. Org. Lett. 2012,
14, 764−767. (m) Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano, K.;
Satoh, T.; Miura, M. Org. Lett. 2011, 13, 706−708. (n) Ackermann, L.;
Lygin, A. V.; Hofmann, N. Angew. Chem., Int. Ed. 2011, 50, 6379−
6382 and references cited therein.
(11) Kornhaaß, C.; Li, J.; Ackermann, L. J. Org. Chem. 2012, 77,
9190−9198.
(12) For reviews of metal-catalyzed reactions in or on water, see:
(a) Li, C.-J. Acc. Chem. Res. 2010, 43, 581−590. (b) Butler, R. N.;
Coyne, A. G. Chem. Rev. 2010, 110, 6302−6337.
(13) Herrerias, C. I.; Yao, X.; Li, Z.; Li, C.-J. Chem. Rev. 2007, 107,
2546−2562.
(14) Ackermann, L. Org. Lett. 2005, 7, 3123−3126.
(15) Ackermann, L.; Fenner, S. Org. Lett. 2011, 13, 6548−6551.
(16) Li, B.; Feng, H.; Xu, S.; Wang, B. Chem.Eur. J. 2011, 17,
12573−12577.
(17) Li, B.; Ma, J.; Wang, N.; Feng, H.; Xu, S.; Wang, B. Org. Lett.
2012, 14, 736−739.
(18) Ackermann, L. Chem. Rev. 2011, 111, 1315−1345.
(19) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118−1126.
(20) Ackermann, L.; Vicente, R.; Potukuchi, H. K.; Pirovano, V. Org.
Lett. 2010, 12, 5032−5035.
(21) Porcheddu, A.; Giacomelli, G. J. Org. Chem. 2006, 71, 7057−
7059.
(22) Mio, M. J.; Kopel, L. C.; Braun, J. B.; Gadzikwa, T. L.; Hull, K.
L.; Brisbois, R. G.; Markworth, C. J.; Grieco, P. A. Org. Lett. 2002, 4,
3199−3202.
(23) Lu, B.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 14070−
14072.
M
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