Electron-Transfer-Induced Intramolecular Heck Carbonylation Reactions Leading to Benzolactones and Benzolactams

Article abstract of DOI:10.1055/s-0037-1609964

A metal-catalyst-free intramolecular Heck carbonylation reaction of benzyl alcohols and benzyl amines with carbon monoxide under heating at 250 °C affords the corresponding benzolactones and benzolactams in good to excellent yields. A hybrid radical/ionic chain mechanism, involving electron transfer from radical anions generated by nucleophilic attack of alcohols or amines on intermediate acyl radicals, is proposed.

Full text of DOI:10.1055/s-0037-1609964

SYNTHESIS
0
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3
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–G
special topic
A
en
T. Fukuyama et al.
Special Topic
Synthesis
Electron-Transfer-Induced Intramolecular Heck Carbonylation Re-
actions Leading to Benzolactones and Benzolactams
Takahide Fukuyamaa
Takanobu Bandoa
Ilhyong Ryu*a,b
O
I
R
O
R
OH
Δ or hν
+
CO
a Department of Chemistry, Graduate School of Science,
Osaka Prefecture University, 1-1 Gakuen-cho, Sakai,
Osaka, 599-8531, Japan
ryu@c.s.osakafu-u.ac.jp
b Department of Applied Chemistry, National Chiao Tung
University, 1001 University Road, Hsinchu, Taiwan
transition-metal-free
O
I
R
N
R'
R
NHR'
up to 95% yield, 20 examples
Published as part of the Special Topic Modern Radical
Methods and their Strategic Applications in Synthesis
Received: 07.03.2018
Accepted after revision: 18.04.2018
Published online: 29.05.2018
ly, with the delivery of one electron to the substrates from
radical anion intermediates. Lei and co-workers reported
that aryl iodides react with CO and t-BuOK as a radical me-
diator in the presence of 1,10-phenanthroline to give t-Bu
esters in good yields.11 Fukuoka reported that aryl iodides
react with CO and alkali metal aryloxides under heating
(250 °C, 2 h) to give high yields of esters (Scheme 1, eq 1).12
The groups of Xiao13 and von Wangelin14 concurrently re-
ported that arene diazonium salts also participate in
alkoxycarbonylation with CO and alcohols under photo-
redox-catalyzed conditions using eosin Y. More recently,
von Wangelin and Koziakov reported that alkoxycarbonyla-
tion of aryl diazonium salts was affected by the use of mild
bases such as HCO2Na.15 All these efforts represent the de-
velopment of transition-metal-catalyst-free Heck carbon-
ylations. We previously reported the aminocarbonylation of
aryl iodides with CO and amines by employing photoirradi-
ation with a Xe lamp (Scheme 1, eq 2).16 In this paper, we
report the intramolecular variation of a metal-catalyst-free
carbonylation reaction to synthesize benzolactones and
benzolactams using aryl iodides that possess nucleophilic
hydroxy and amino substituents.
DOI: 10.1055/s-0037-1609964; Art ID: ss-2018-c0146-st
Abstract A metal-catalyst-free intramolecular Heck carbonylation re-
action of benzyl alcohols and benzyl amines with carbon monoxide un-
der heating at 250 °C affords the corresponding benzolactones and
benzolactams in good to excellent yields. A hybrid radical/ionic chain
mechanism, involving electron transfer from radical anions generated
by nucleophilic attack of alcohols or amines on intermediate acyl radi-
cals, is proposed.
Key words carbonylation, electron transfer, radical reactions, metal-
free, lactones, lactams
Carbonylation using CO is a fundamental synthetic
method for the construction of carbonyl compounds.1 Since
the pioneering work by Heck and co-workers in the 1970s,2
both Pd-catalyzed alkoxy- and amino-carbonylation of aryl
halides with CO have been used in numerous applications
for the synthesis of aromatic esters and amides. Carbonyla-
tive cyclization of haloarenes containing either an amino or
hydroxy moiety, an intramolecular variant, affords benzo-
lactones and benzolactams.3
Fukuoka's work: Thermally Induced Alkoxycarbonylation of Aryl Iodides (ref. 12)
Our group has been fascinated by radical carbonylation
methods4,5 that employ the addition of a variety of carbon-
centered alkyl, vinyl, and aryl radicals to CO. Recent topics
have involved metal-free carbonylation reactions of aryl ha-
lides and related substrates based on the novel concept of
using an ‘electron’ as a catalyst.6,7 In the general scheme of
these reactions, one electron transfer to aryl halides trig-
gers the generation of aryl radicals and a radical carbonyla-
tion of aryl radicals8 then follows to generate acyl radicals,5
the carbonyl function of which is then attacked by alkoxide
anions and amines to give esters and amides,9,10 respective-
O
I
Δ
+
+
CO
O
(1)
NaO
Our previous work: Photo-Induced Aminocarbonylation of Aryl Iodides (ref. 16)
O
I
hν
HN
N
(2)
+ CO
+
O
O
Scheme 1 Thermally induced alkoxycarbonylation (ref. 12) and photo-
induced aminocarbonylation of aryl iodides (ref. 16)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

B
T. Fukuyama et al.
Special Topic
Synthesis
Initially, we examined the cyclative carbonylation using
2-iodobenzyl alcohol (1a) as a model substrate, and Fukuo-
ka’s heating conditions were tested. When 1a was treated
with pressurized CO (65 atm) in the presence of five equiv-
alents of Et3N in MeCN (10 mL) at 230 °C for 16 hours, to
our delight, the anticipated reaction proceeded to give ben-
zolactone 2a in 58% yield (Table 1, entry 1). Since a signifi-
cant amount of 1a remained intact, we instead used an ele-
vated temperature of 250 °C, which resulted in full conver-
sion of 1a to give 2a in 91% yield (entry 2). Lowering the CO
pressure to 40 atm led to a decreased yield of 2a (entry 3).
The use of 2-bromobenzyl alcohol (1a′) was unsuccessful
(entry 4). We also examined photoirradiation conditions
using a 500 W Xe lamp and a quartz tube, which worked
well, but required a longer reaction time (entries 5 and 6).
seven-membered benzolactone 2l was obtained in a low
yield (entry 12). Benzolactone 2k was also obtained under
photoirradiation conditions, albeit in an inferior yield (en-
try 11). We also tested 2-iodoacetoamide 1m, which was
converted into 2-methyl-4-oxo-3,1-benzoxazine (2m) in a
36% yield. The result of the reaction of 5-bromo-2-iodoben-
zyl alcohol (1n) was intriguing since the less reactive bromo-
arene portion also underwent aminocarbonylation (entry
14). The formation of 2n′ would have been caused by intra-
molecular electron transfer, and, indeed, a similar result
was observed in a photo-induced aminocarbonylation reac-
tion.16
We propose an electron-transfer-based pathway for the
present carbonylation leading to lactones (Scheme 2). A sin-
gle-electron transfer (SET) between Et3N and the aryl iodide
1a generates radical anion A, which is followed by the elim-
ination of an iodide anion to generate aryl radical B. The
aryl radical B would then react with CO to give acyl radical
C. Nucleophilic addition of the hydroxy group to the acyl
radical moiety would give a zwitterionic radical intermedi-
ate D.10 Deprotonation followed by a single-electron trans-
fer (SET) from radical anion E to another molecule of start-
ing substrate 1a would then give 2a and regenerate radical
anion A.
Table 1 Optimization of the Reaction Conditions for the Synthesis of
Benzolactone 2a
O
X
Δ or hν
CO
O
OH
Et3N (5 equiv)
MeCN (10 mL)
1a X = I
1a' X = Br
2a
(0.5 mmol)
CO (atm)a
Conditions
Time (h)
Yield (%)b
CO
Entry
Substrate
I
1
1a
1a
1a
1a′
1a
1a
65
65
40
65
75
70
230 °C
250 °C
250 °C
250 °C
Xe
16
16
16
16
22
48
58 (40)
91 (0)
OH
OH
I–
2
O
1a
B
3
79c (3)
0 (100)
60c (22)
85 (7)
Δ or hν
SET
Et3N
OH
4
5d
6e
C
Xe
I
Et3N
a Initial CO pressure.
OH
b Yield of isolated product after silica gel chromatography. NMR yield of un-
reacted substrate is shown in parentheses.
c NMR yield.
A
O–
O+
d Xe lamp (500 W, quartz), Et3N (2.5 equiv).
e Xe lamp (500 W, quartz), Et3N (2 equiv).
O
O
SET
H
O–
O
D
2a
With the optimized thermal conditions in hand (Table 1,
entry 2), we next examined the substrate scope of the pres-
ent intramolecular Heck carbonylation leading to benzo-
lactones (Table 2). The reaction proceeded regardless of the
class of alcohol, and secondary (1b and 1c) and tertiary (1d)
alcohols gave the corresponding benzolactones 2b–d in
good yields (entries 2–4). Substituted iodoarenes 1e–i par-
ticipated in the present benzolactone synthesis: the reac-
tions of 2-iodo-3-methylbenzyl alcohol (1e), 2-iodo-4-
methylbenzyl alcohol (1f), 4-chloro-2-iodobenzyl alcohol
(1g), 2-iodo-5-methylbenzyl alcohol (1h), and 5-chloro-2-
iodobenzyl alcohol (1i) gave good yields of products 2e–i
(entries 5–9). The reaction of 3-hydroxymethyl-2-io-
donaphthalene (1j) gave naphtholactone 2j in a 95% yield.
The protocol was successfully extended to the synthesis of
six-membered benzolactone 2k as well (entry 11), whereas
I
Et3N
OH
E
+
Et3NH
1a
Scheme 2 Proposed mechanism for the cyclative carbonylation of iodo-
arenes with an electron as the catalyst
We next investigated the reaction of 2-iodobenzyl
amines (Scheme 3). The reaction of 2-iodobenzyl amine
(3a) with CO at 250 °C gave the corresponding benzolactam
4a in a 60% yield along with a 10% yield of ethyl-substituted
benzolactam (4a′). The by-product 4a′ would be formed by
the reaction of 4a with EtI, which would be generated by
the reaction of Et3N with HI·Et3N at 250 °C.17 We found that
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

C
T. Fukuyama et al.
Special Topic
Synthesis
the formation of 4a′ was suppressed by the use of DABCO
(1,4-diazabicyclo[2.2.2]octane) as the base, and benzolactam
4a was obtained as the sole product in a 78% yield.
in good yield (entry 2). Halogen-substituted benzolactams
4c and 4d were also obtained in good yields (entries 3 and
4). The reaction of benzyl amine 3e having a CF3 substituent
proceeded well to give CF3-substituted benzolactam 4e in
an 85% yield (entry 5). In a similar manner, the reaction of
2-iodobenzamide 3f gave phthalimide 4f in a 73% yield (en-
try 6).
In summary, we have found that a transition-metal-free
synthesis of benzolactones and benzolactams by carbonyla-
tion can be achieved using an electron as the catalyst. Fur-
ther applications of metal-free carbonylation reactions
based on the same concept are currently being investigated
in our laboratory.
O
O
I
amine (5 equiv)
NH
N Et
CO
NH2
MeCN (10 mL)
65 atm, 16 h, 250 °C
3a
(0.5 mmol)
4a
4a'
Et3N
DABCO
60%
78%
10%
0%
Scheme 3 Synthesis of benzolactam 4a from benzyl amine 3a and CO
Next, we examined the substrate scope of the intramo-
lecular aminocarbonylation (Table 3). The reaction of sec-
ondary amine 3b gave the corresponding benzolactam 4b
Table 2 Synthesis of Benzolactones 2 from Substrates 1 and CO
O
R
R
I
Et3N (5 equiv)
+
CO
O
OH
MeCN (10 mL)
n
n
65 atm, 250 °C, 16 h
1
2
(0.5 mmol)
Entry
1
Substrate
Product
Yield (%)a
91 (85)b
O
I
I
1a
2a
O
OH
OH
O
2
3
1b, R = Me
1c, R = Pr
2b
2c
59
73
O
R
I
R
O
4
1d
1e
2d
2e
79
75
OH
O
O
I
5c
O
OH
I
O
R
6c
7
1f, R = Me
1g, R = Cl
2f
2g
75
81
R
O
OH
O
I
8c
9
1h, R = Me
1i, R = Cl
2h
2i
71
87
O
OH
I
R
R
O
10
1j
2j
95
O
OH
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

D
T. Fukuyama et al.
Special Topic
Synthesis
Table 2 (continued)
Entry
Substrate
Product
Yield (%)a
93 (51)b
O
I
11c
1k
2k
O
O
OH
O
I
12
13
1l
2l
25
36
OH
O
I
O
1m
2m
O
N
H
N
O
O
Br
I
2n
2n′
3d
34
14
1n
O
OH
Br
O
Et2N
O
a Yield of isolated product after silica gel column chromatography.
b Xe lamp irradiation, quartz tube, Et3N (2 equiv), CO (70 atm), 48 h.
c Reaction time: 24 h.
d NMR yield.
Reaction of 2-Iodobenzyl Alcohol (1a) with CO under Thermal
Conditions; Typical Procedure
Photoirradiation reactions were carried out using a stainless auto-
clave with quartz windows lined with a 30 mmϕ quartz glass liner
and employing a 500 W Xenon short arc lamp (Using Co. Ltd., lamp
house: SX-UI500XQ, Xenon short arc lamp: UXL-500SX, power sup-
ply: BA-X500). Thin-layer chromatography (TLC) was performed on
Merck precoated plates (silica gel 60 F254, Art 5715, 0.25 nm). The
products were purified by flash chromatography on silica gel [Kanto
Chem. Co. Silica Gel 60N (spherical, neutral, 40–50 μm)] and, if neces-
sary, were further purified by recycling preparative HPLC (Japan Ana-
lytical Industry Co. Ltd., LC-918) equipped with GPC columns (JAIGEL-
1H + JAIGEL-2H columns) using CHCl3 as the eluent. Melting points
were measured in capillary tubes using a BÜCHI Melting Point B-540
instrument. Infrared spectra were recorded on a JASCO FT/IR-4100
A magnetic stir bar, 2-iodobenzyl alcohol (1a) (116.0 mg, 0.5 mmol),
Et3N (251.6 mg, 2.5 mmol), and MeCN (10 mL) were placed in a stain-
less steel autoclave equipped with an inserted Pyrex glass liner. The
autoclave was closed, purged three times with CO, pressurized with
65 atm of CO and then heated at 250 °C in a salt bath with stirring for
16 h. After the reaction was complete, excess CO was discharged at
room temperature. The solvent was removed under reduced pressure
and the residue was purified by flash chromatography on silica gel
(hexane/EtOAc, 3:1) to give 2a (60.4 mg, 91%) as a white solid.
Reaction of 2-Iodobenzyl Alcohol (1a) with CO under Photoirradi-
ation Conditions; Typical Procedure
spectrometer and are reported as wavenumbers (cm–1). 1H, 13C and 19
F
A magnetic stir bar, 2-iodobenzyl alcohol (1a) (117.7 mg, 0.5 mmol),
Et3N (101.2 mg, 1.0 mmol), and MeCN (10 mL) were placed in a stain-
less steel autoclave for photoreactions equipped with an inserted
quartz glass liner. The autoclave was closed, purged three times with
carbon monoxide, pressurized with 70 atm of CO and then irradiated
with a Xenon arc lamp (500 W) with stirring for 48 h. After the reac-
tion was complete, excess CO was discharged at room temperature.
The solvent was removed under reduced pressure and the residue was
purified by flash chromatography on silica gel (hexane/EtOAc, 5:1) to
give 2a (57 mg, 85%) as a white solid.
NMR spectra were recorded with JEOL JNM-ECS400 and Varian
MR400 spectrometers. 1H NMR spectra were recorded at 400 MHz
and referenced to the residual solvent peak at 7.26 ppm. 13C NMR
spectra were recorded at 100 MHz and referenced to the solvent peak
at 77.00 ppm. 19F NMR spectra were recorded at 378 MHz. Splitting
patterns are indicated as follows: br, broad; s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet. Low-resolution El mass spectra
(EIMS) were recorded with a JEOL MS700 spectrometer. High-resolu-
tion mass spectra (HRMS) were recorded with a JEOL MS700 spec-
trometer and ESI-QTOF (compact-NPC, Bruker).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

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T. Fukuyama et al.
Special Topic
Synthesis
Table 3 Synthesis of Benzolactams 4 via Carbonylation of Substrates 3
O
I
DABCO (5 equiv)
NR
+
CO
NHR
MeCN (10 mL)
65 atm, 250 °C, 16 h
3
4
(0.5 mmol)
Entry
1
Substrate
Product
Yield (%)a
78
O
I
3a
4a
NH
NH2
O
I
2
3
4
5
3b
3c
3d
3e
4b
4c
4d
4e
66
72
66
85
H
N
N
Me
Me
O
N
I
H
Me
N
Cl
Me
Cl
O
I
H
N
Me
N
F
Me
F
O
F3C
I
F3C
H
N
N
Me
Me
O
I
H
6
3f
4f
73
N
Me
N
Me
O
O
a Yield of isolated product after silica gel column chromatography.
Phthalide (2a)18a
1H NMR (400 MHz, CDCl3): δ = 7.90 (d, J = 7.6 Hz, 1 H), 7.67 (t, J = 7.6
Hz, 1 H), 7.53 (t, J = 7.2 Hz, 1 H), 7.44 (d, J = 6.8 Hz, 1 H), 5.49 (dd, J =
8.0 Hz, 4.0 Hz, 1 H), 2.06–1.98 (m, 1 H), 1.80–1.71 (m, 1 H), 1.62–1.45
(m, 2 H), 0.99 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.6, 150.1, 133.8, 129.0, 126.1,
125.6, 121.7, 82.2, 36.8, 18.2, 13.8.
Yield: 60 mg (91%); white solid; mp 72.2–73.0 °C.
1H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 6.2 Hz, 1 H), 7.70 (t, J = 7.6
Hz, 1 H), 7.57–7.50 (m, 2H), 5.32 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 171.2, 146.6, 134.1, 129.1, 125.7,
122.2, 69.8.
3,3-Dimethyl-3H-isobenzofuran-1-one (2d)18d
3-Methylphthalide (2b)18b
Yield: 62 mg; colorless oil.
Yield: 60 mg (59%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.0 Hz, 1 H), 7.67 (dd, J = 7.6
Hz, 7.2 Hz, 1 H), 7.51 (dd, J = 7.6 Hz, 7.0 Hz, 1 H), 7.40 (d, J = 7.2 Hz, 1
H), 1.67 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 169.7, 154.9, 134.1, 128.8, 125.6,
125.2, 120.6, 85.3, 27.2.
1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 7.6 Hz, 1 H), 7.70–7.66 (m,
J = 7.6 Hz, 1 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.45 (d, J = 7.6 Hz, 1 H), 5.58 (q,
J = 6.8 Hz, 1 H), 1.64 (d, J = 4.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.4, 151.1, 134.0, 129.0, 125.6,
121.5, 77.7, 20.3.
7-Methylphthalide (2e)18e
3-n-Propylphthalide (2c)18c
Yield: 60 mg (75%); white solid; mp 87.1–87.5 °C.
Yield: 68 mg (73%); colorless oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

F
T. Fukuyama et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.54 (t, J = 7.6 Hz, 1 H), 7.30–7.26 (m, 2
13C NMR (100 MHz, CDCl3): δ = 172.4, 137.5, 132.6, 131.6, 130.1,
H), 5.26 (s, 2 H), 2.69 (s, 3 H).
128.6, 127.3, 66.5, 29.4, 27.7.
13C NMR (100 MHz, CDCl3): δ = 171.2, 147.0, 139.7, 133.7, 130.5,
123.1, 119.3, 68.8, 17.2.
2-Methyl-3,1-benzoxazin-4-one (2m)18j
Yield: 29 mg (36%); white solid; mp 73.6–76.2 °C.
1H NMR (400 MHz, CDCl3): δ = 8.20 (dd, J = 8.0 Hz, 1.6 Hz, 1 H), 7.82–
6-Methylphthalide (2f)18d
Yield: 56 mg (75%); yellow solid; mp 118.0–118.7 °C.
7.78 (m, 1 H), 7.56–7.49 (m, 2 H), 2.48 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.72 (s, 1 H), 7.50 (d, J = 8.0 Hz, 1 H),
7.36 (d, J = 7.6 Hz, 1 H), 5.29 (s, 2 H), 2.47 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 160.2, 159.7, 146.4, 135.5, 128.4,
128.2, 126.4, 116.6, 21.4.
13C NMR (100 MHz, CDCl3): δ = 171.2, 143.8, 139.2, 135.1, 125.8,
125.6, 121.7, 69.5, 21.2.
N,N-Diethyl-1,3-dihydro-1-oxo-5-isobenzofurancarboxamide
(2n′)
6-Chlorophthalide (2g)18f
Yield: 39 mg (34%); yellow solid; mp 105.0–109.0 °C.
Yield: 69 mg (81%); white solid; mp 108.3–109.2 °C.
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 2.0 Hz, 1 H), 7.66 (d, J = 8.4
Hz, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 5.32 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 169.5, 144.6, 135.3, 134.3, 127.5,
125.6, 123.3, 69.4.
IR (neat): 3486, 3225, 2979, 2877, 2520, 2370, 2130, 1752, 1637,
1449, 1278, 1159, 1065, 1005, 867, 784, 706, 579 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.98–7.93 (m, 1 H), 7.52–7.51 (m, 2 H),
5.36 (s, 2 H), 3.59–3.48 (m, 2 H), 3.32–3.23 (m, 2 H), 1.29–1.26 (m, 3
H), 1.20–1.11 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.2, 169.5, 146.8, 143.0, 127.0,
5-Methylphthalide (2h)18f
126.1, 126.0, 120.1, 69.5, 43.2, 39.4, 14.1, 12.8.
EIMS: m/z (%) = 233 (18) [M]+, 232 (47), 161 (100), 133 (19), 103 (10),
Yield: 52 mg (71%); white solid; mp 117.7–119.1 °C.
83 (13).
1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.0 Hz, 1 H), 7.34 (d, J = 8.4
HRMS (EI): m/z [M]+ calcd for C13H15NO3: 233.1052; found: 233.1056.
Hz, 1 H), 7.28 (s, 1 H), 5.27 (s, 2 H), 2.50 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.1, 147.1, 145.2, 130.2, 125.5,
123.2, 122.3, 69.4, 22.0.
Isoindoline-1-one (4a)18k
Yield: 50 mg (78%); white solid; mp 151.3–151.7 °C.
5-Chlorophthalide (2i)18g
1H NMR (400 MHz, CDCl3): δ = 8.09 (br s, 1 H), 7.88 (d, J = 7.6 Hz, 1 H),
7.60–7.56 (m, 1 H), 7.50–7.47 (m, 2 H), 4.49 (s, 2 H).
Yield: 75 mg (87%); white solid; mp 154.7–155.3 °C.
13C NMR (100 MHz, CDCl3): δ = 172.4, 143.8, 132.3, 131.8, 128.1,
1H NMR (400 MHz, CDCl3): δ = 7.86–7.84 (m, 1 H), 7.55–7.51 (m, 2 H),
123.8, 123.3, 45.9.
5.31 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 169.8, 148.1, 140.7, 129.8, 126.8,
124.2, 122.5, 68.9.
2-Methylisoindoline-1-one (4b)18l
Yield: 44 mg (66%); white solid; mp 112.6–113.9 °C.
Naphtho[2,3-c]furan-1(3H)-one (2j)18h
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 7.2 Hz, 1 H), 7.52–7.50 (m, 1
H), 7.46–7.42 (m, 2 H), 4.37 (s, 2 H), 3.20 (s, 3 H).
Yield: 86 mg (95%); white solid; mp 210.2–211.3 °C.
13C NMR (100 MHz, CDCl3): δ = 168.6, 140.9, 132.8, 131.1, 127.9,
123.5, 122.5, 51.9, 29.4.
1H NMR (400 MHz, CDCl3): δ = 8.50 (s, 1 H), 8.04 (d, J = 8.4 Hz, 1 H),
7.94 (d, J = 8.4 Hz, 1 H), 7.90 (s, 1 H), 7.58–7.68 (m, 2 H), 5.50 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 171.0, 139.9, 136.2, 133.1, 129.9,
129.0, 128.1, 127.0, 126.9, 123.4, 120.9, 69.6.
5-Chloro-2-methylisoindoline-1-one (4c)
Yield: 71 mg (72%); yellow solid; mp 113.3–114.0 °C.
Isochroman-1-one (2k)18e
IR (neat): 3337, 3067, 2917, 2867, 2366, 1920, 1673, 1613, 1423,
1396, 1280, 1173, 1063, 940, 877, 842, 766, 674, 636, 547, 527, 418
Yield: 70 mg (93%); colorless oil.
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 7.6 Hz, 1 H), 7.55 (td, J =
12.0 Hz, 1.2 Hz, 1 H), 7.41 (t, J = 7.2 Hz, 1 H), 7.27 (d, J = 6.4 Hz, 1 H),
4.55 (t, J = 5.6 Hz, 2 H), 3.07 (t, J = 6.0 Hz, 2 H).
1H NMR (400 MHz, CDCl3): δ = 7.76–7.74 (m, 1 H), 7.44–7.43 (m, 2 H),
4.36 (s, 2 H), 3.19 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.5, 142.5, 137.4, 131.4, 128.6,
13C NMR (100 MHz, CDCl3): δ = 165.1, 139.5, 133.6, 130.2, 127.6,
124.7, 123.0, 51.5, 29.5.
127.2, 125.1, 67.2, 27.7.
EIMS: m/z (%) = 183 (39) [M]+, 181 (94), 146 (100), 125 (36), 89 (35),
75 (18).
4,5-Dihydro-2-benzoxepin-1(3H)-one (2l)18i
HRMS (EI): m/z [M]+ calcd for C9H8ClNO: 181.0294; found: 181.0302.
Yield: 20 mg (25%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.72 (dd, J = 8.0 Hz, 1.2 Hz, 1 H), 7.49
(td, J = 7.2 Hz, 1.6 Hz, 1 H), 7.37 (td, J = 8.0 Hz, 0.8 Hz, 1 H), 7.22 (d, J =
8.0 Hz, 1 H), 4.16 (t, J = 6.4 Hz, 2 H), 2.91 (t, J = 7.2 Hz, 2 H), 2.13 (quin,
J = 7.6 Hz, 2 H).
5-Fluoro-2-methylisoindoline-1-one (4d)
Yield: 54 mg (66%); white solid; mp 78.4–79.3 °C.
IR (neat): 3448, 3071, 2864, 1686, 1619, 1473, 1251, 1090, 770, 678,
570 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

G
T. Fukuyama et al.
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.80 (dd, J = 8.2 Hz, 4.8 Hz, 1 H), 7.17–
7.12 (m, 2 H), 4.36 (s, 2 H), 3.19 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.6, 164.9 (d, JC–F = 248.2 Hz), 143.2
(d, JC–F = 9.6 Hz), 128.9, 125.4 (d, JC–F = 9.5 Hz), 115.7 (d, JC–F = 22.9 Hz),
110.0 (d, JC–F = 23.9 Hz), 51.6, 29.4.
19F NMR (378 MHz, CDCl3): δ = –108.2 (s, 1 F).
EIMS: m/z (%) = 165 (100) [M]+, 164 (59), 136 (57), 109 (44), 69 (81).
HRMS (EI): m/z [M]+ calcd for C9H8FNO: 165.0590; found: 165.0590.
(3) (a) Cowell, A.; Stille, J. K. J. Am. Chem. Soc. 1980, 102, 4193.
(b) Mori, M.; Chiba, K.; Ban, Y. J. Org. Chem. 1978, 43, 1684.
(4) For reviews on radical carbonylation, see: (a) Ryu, I.; Sonoda, N.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1050. (b) Ryu, I.; Sonoda,
N.; Curran, D. P. Chem. Rev. 1996, 96, 177. (c) Ryu, I. Chem. Soc.
Rev. 2001, 30, 16. (d) Ryu, I. Chem. Rec. 2002, 2, 249. (e) Ryu, I.;
Uenoyama, Y.; Matsubara, H. Bull. Chem. Soc. Jpn. 2006, 79,
1476. (f) Schiesser, C. H.; Wille, U.; Matsubara, H.; Ryu, I. Acc.
Chem. Res. 2007, 40, 303. (g) Sumino, S.; Fusano, A.; Fukuyama,
T.; Ryu, I. Acc. Chem. Res. 2014, 47, 1563.
(5) For a review of acyl radicals, see: Chatgilialoglu, C.; Crich, D.;
Komatsu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991.
(6) For reviews, see: (a) Studer, A.; Curran, D. P. Nat. Chem. 2014, 6,
765. (b) Studer, A.; Curran, D. P. Angew. Chem. Int. Ed. 2016, 55,
58.
2-Methyl-6-(trifluoromethyl)isoindoline-1-one (4e)
Yield: 90 mg (85%); brown solid; mp 103.5–106.1 °C.
IR (neat): 3354, 2970, 2918, 1819, 1686, 1483, 1328, 1166, 1132,
1050, 960, 912, 846, 768, 635, 607, 509 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.11 (s, 1 H), 7.79 (d, J = 7.6 Hz, 1 H),
7.58 (d, J = 8.0 Hz, 1 H), 4.45 (s, 2 H), 3.23 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.1, 144.3, 133.6, 130.8 (q, JC–F = 32.5
Hz), 127.9 (q, JC–F = 3.8 Hz), 123.8 (q, JC–F = 270.2 Hz), 123.2, 120.7 (q,
JC–F = 3.8 Hz), 51.8, 29.5.
19F NMR (378 MHz, CDCl3): δ = –62.2 (s, 3 F).
EIMS: m/z (%) = 215 (100) [M]+, 214 (53), 196 (21), 186 (37), 159 (32),
(7) Shirakawa, E.; Hayashi, T. Chem. Lett. 2012, 41, 130.
(8) (a) Ryu, I.; Kusano, K.; Masumi, N.; Yamazaki, H.; Ogawa, A.;
Sonoda, N. Tetrahedron Lett. 1990, 31, 6887. (b) Ryu, I.;
Yamazaki, H.; Ogawa, A.; Kambe, N.; Sonoda, N. J. Am. Chem. Soc.
1993, 115, 1187. (c) Kawamoto, T.; Okada, T.; Curran, D. P.; Ryu,
I. Org. Lett. 2013, 15, 2144.
(9) For carbonylative synthesis of amides and lactams including
trapping of acyl radicals by amines, see: (a) Uenoyama, Y.;
Fukuyama, T.; Nobuta, O.; Matsubara, H.; Ryu, I. Angew. Chem.
Int. Ed. 2005, 44, 1075. (b) Uenoyama, Y.; Fukuyama, T.; Ryu, I.
Org. Lett. 2007, 9, 935. (c) Ryu, I.; Fukuyama, T.; Tojino, M.;
Uenoyama, Y.; Yonamine, Y.; Terasoma, N.; Matsubara, H. Org.
Biomol. Chem. 2011, 9, 3780. (d) Fukuyama, T.; Nakashima, N.;
Okada, T.; Ryu, I. J. Am. Chem. Soc. 2013, 135, 1006.
146 (57), 83 (22).
HRMS (EI): m/z [M]+ calcd for C10H8F3NO: 215.0558; found: 215.0560.
N-Methylphthalimide (4f)18m
Yield: 73 mg (73%); white solid; mp 134.0–134.6 °C.
1H NMR (400 MHz, CDCl3): δ = 7.88–7.83 (m, 2 H), 7.74–7.69 (m, 2 H),
3.19 (s, 3 H).
(10) For a related lactone synthesis, see: Ryu, I.; Fukuyama, T.;
Nobuta, O.; Uenoyama, Y. Bull. Korean Chem. Soc. 2010, 31, 545.
(11) Zhang, H.; Shi, R.; Ding, A.; Lu, L.; Chen, B.; Lei, A. Angew. Chem.
Int. Ed. 2012, 51, 12542.
13C NMR (100 MHz, CDCl3): δ = 168.4, 133.8, 132.2, 133.1, 23.9.
(12) Fukuoka, S. Ind. Eng. Chem. Res. 2016, 55, 4830.
(13) Guo, W.; Lu, L.-Q.; Wang, Y.-N.; Chen, J.-R.; Xiao, W. J. Angew.
Chem. Int. Ed. 2015, 54, 2265.
Funding Information
(14) Majek, M.; von Wangelin, A. J. Angew. Chem. Int. Ed. 2015, 54,
2270.
(15) Koziakov, D.; von Wangelin, A. J. Org. Biomol. Chem. 2017, 15,
6715.
This work was supported by Grants-in-Aid for Scientific Research (A)
(no. 26248031) from JSPS and Scientific Research on Innovative Areas
2707 Middle molecular strategy (no. 15H05850) from MEXT.
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(16) Kawamoto, T.; Sato, A.; Ryu, I. Chem. Eur. J. 2015, 21, 14764.
(17) In a separate experiment we confirmed that 1-iodooctane was
formed from trioctylamine and NH4I at 250 °C.
Supporting Information
(18) (a) Jiang, X.; Zhang, J.; Ma, S. J. Am. Chem. Soc. 2016, 138, 8344.
(b) Gerbino, D. C.; Augner, D.; Slavov, N.; Schmalz, H.-G. Org.
Lett. 2012, 14, 2338. (c) Ranade, V. S.; Consiglio, G.; Prins, R.
J. Org. Chem. 2000, 62, 1132. (d) Lodi, M.; Gedu, S. J. Org. Chem.
2015, 80, 7089. (e) Hattori, T.; Ueda, S.; Takakura, R.; Sawama,
Y.; Monguchi, Y.; Sajiki, H. Chem. Eur. J. 2017, 23, 8196.
(f) Nguyen, T. Q.; Rodriguez-Santamaria, J. A.; Yoo, W.-J.;
Kobayashi, S. Green Chem. 2017, 19, 2501. (g) Gonzalez-de-
Castro, A.; Robertson, C. M.; Xiao, J. J. Am. Chem. Soc. 2014, 136,
8350. (h) Bhavani, S. C.; Beeraiah, B. Eur. J. Org. Chem. 2017,
3381. (i) Morimoto, T.; Fujioka, M.; Fuji, K.; Tsutsumi, K.;
Kakiuchi, K. J. Organomet. Chem. 2007, 692, 625. (j) Verma, A.;
Kumar, S. Org. Lett. 2016, 18, 4388. (k) Lopez-Valdez, G.; Olguin-
Uribe, S.; Millan-Orriz, A.; Gamez-Montano, R.; Miranda, L. Tet-
rahedron 2011, 67, 2693. (l) Adachi, S.; Onozuka, M.; Yoshida, Y.;
Ide, M.; Saikawa, Y.; Nakata, M. Org. Lett. 2014, 16, 358.
(m) Wang, L.; Fu, H.; Jiang, Y.; Zhao, Y. Chem. Eur. J. 2008, 14,
10722.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609964.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G