Site-Selective Carbonylative Synthesis of Structurally Diverse Lactams from Heterocyclic Amines with TFBen as the CO Source

Article abstract of DOI:10.1021/acs.joc.9b02114

A palladium-catalyzed site-selective C-H carbonylation of heterocyclic amines for the synthesis of lactam motifs has been developed. The reaction of 3-thiophene methylamines, 2-thiophene methylamines, and tryptamines with benzene-1,3,5-triyl triformate (TFBen) as the CO source provides a series of structurally diverse lactams in moderate to high yields with excellent regioselectivities.

Full text of DOI:10.1021/acs.joc.9b02114

Note
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Site-Selective Carbonylative Synthesis of Structurally Diverse
Lactams from Heterocyclic Amines with TFBen as the CO Source
Jun Ying,† Qian Gao,† and Xiao-Feng Wu*,†,‡
†Department of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou 310018, People’s Republic of China
‡Leibniz-Institut fu
̈
r Katalyse e. V. an der Universitat Rostock, Albert-Einstein-Straβe 29a, Rostock 18059, Germany
̈
S
* Supporting Information
ABSTRACT: A palladium-catalyzed site-selective C−H carbonylation of heterocyclic amines for the synthesis of lactam motifs
has been developed. The reaction of 3-thiophene methylamines, 2-thiophene methylamines, and tryptamines with benzene-
1,3,5-triyl triformate (TFBen) as the CO source provides a series of structurally diverse lactams in moderate to high yields with
excellent regioselectivities.
ransition-metal-catalyzed C−H carbonylation with car-
producing a variety of structurally diverse lactams in moderate
Tbon monoxide or its surrogates has become one of the to good yields with excellent regioselectivities (Scheme 1).
At the outset, 3-thiophene methylamine 1a was selected as
the model substrate for the C−H carbonylation (Table 1). We
used 1a to react with TFBen (2.0 equiv) in the presence of
Pd(TFA)2 (10 mol %) as the catalyst and Cu(OAc)2 (1.5
equiv) as the oxidant at 110 °C for 20 h. Fortunately, the
reaction occurred at the 2-position of the thiophene ring with
an excellent regioselectivity to give the desired product 2a in
49% yield (Table 1, entry 1). Replacing the catalyst with
Pd(OAc)2 slightly improved the yield to 52% (Table 1, entry
2). Increasing the amount of TFBen did not affect the yield of
2a (Table 1, entry 3). Finally, it was found that the reaction
yield was enhanced remarkably to 73% when 2.0 equiv of
Cu(OAc)2 was employed (Table 1, entry 4). Further
increasing the amount of Cu(OAc)2 added could not continue
to promote the reaction outcome (Table 1, entry 5). It is
important to mention that other oxidants such as BQ,
tBuOOH, K2S2O8, and TEMPO were also tested but failed.
Then, the optimal reaction conditions (Table 1, entry 4)
were applied to a series of 3-thiophene methylamines 1, and
the results are summarized in Scheme 2. It was shown that 3-
thiophene methylamines bearing electron-donating groups
could undergo the reaction smoothly to give the corresponding
products 2b−d in 55−75% yields. The reaction of compounds
with electron-withdrawing substituents led to the expected
products 2e−f in moderate yields. The substrate with ortho-
methyl substituted on the phenyl ring can be transformed as
most powerful methods for the construction of various
carbonyl compounds and has received more attention over
the past decades.1,2 Recently, the direct C−H carbonylation of
amine derivatives has been well developed to access key lactam
motifs that are ubiquitous in drug molecules and natural
products.3−9 For instance, Orito and co-workers developed a
useful synthetic protocol toward isoindolinone ring systems via
C−H carbonylation of benzylamines using Pd(OAc)2 and
Cu(OAc)2 as the catalyst system under an atmosphere of CO
gas containing air.3 In 2018, Li and co-workers realized an
efficient method for the synthesis of N-unprotected benzo-
lactams via palladium-catalyzed ortho-C−H carbonylation of
free benzylamines using NH2 as the directing group.4 Wang
and Li developed an interesting palladium-catalyzed carbon-
ylation of α,α-disubstituted benzylamines to synthesize the
corresponding sterically hindered benzolactams under atmos-
pheric pressure of CO.5 Zhao and Shi disclosed a Ru(II)-
catalyzed C−H carbonylation of benzylamines with isocyanate
as the CO source.6 Very recently, our group developed a facile
approach for the synthesis of isoindolinone skeleton via
palladium-catalyzed C−H carbonylation of benzylamines.7
TFBen, used in this reaction, is a solid, safe, and convenient
CO surrogate.2a,7,10 However, these synthetic protocols are
only suitable for simple benzylamine derivatives. It may
encounter selectivity issues when complicated heterocyclic
amines containing more than one possible carbonylation sites
are employed. Herein, we report a palladium-catalyzed C−H
carbonylation of 3-thiophene methylamines, 2-thiophene
methylamines, and tryptamines with TFBen as the CO source,
Received: August 1, 2019
Published: October 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b02114
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 1. C−H Carbonylative Synthesis of Lactam Motifs
a
well and give the corresponding product in 43% yield, 2g.
Additionally, compounds with alkyl substituents were tolerated
as well to access the products 2h−j in high yields.
Next, we screened the reaction conditions of C−H
carbonylation with 2-thiophene methylamine 3a (Table 2).
Table 1. Screening of the Reaction Conditions with 1a
entry
[Pd]
oxidant
[CO]
yield (%)
a
Table 2. Screening of the Reaction Conditions with 3a
1
2
3
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
TFBen
TFBen
TFBen
TFBen
TFBen
49
52
48
73
72
b
c
4
d
5
a
Reaction condition: 1a (0.5 mmol), Pd catalyst (10 mol %),
entry
[Pd]
PdCl2
oxidant
[CO]
yield (%)
Cu(OAc)2 (1.5 equiv), TFBen (2.0 equiv), Et3N (2.0 equiv),
1
2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
TFBen
TFBen
TFBen
TFBen
TFBen
TFBen
TFBen
30
43
35
34
50
60
55
toluene/DMSO = 10:1 (2.2 mL), 110 °C, 20 h, isolated yield.
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
b
c
d
TFBen (4.0 equiv). Cu(OAc)2 (2.0 equiv). Cu(OAc)2 (3.0 equiv).
b
3
c
4
5
a
Scheme 2. Scope of 3-Thiophene Methylamines 1
d
de
,
6
7
df
,
a
Reaction condition: 3a (0.5 mmol), Pd catalyst (10 mol %),
Cu(OAc)2 (3.0 equiv), TFBen (2.0 equiv), Et3N (2.0 equiv),
toluene/DMSO = 10:1 (2.2 mL), 110 °C, 20 h, isolated yield.
b
c
d
e
f
TFBen (1.0 equiv). TFBen (3.0 equiv). 135 °C. 16 h. 12 h.
When 3a was treated with TFBen (2.0 equiv) and Cu(OAc)2
(3.0 equiv) in the presence of PdCl2 (10 mol %) as the catalyst
at 110 °C for 20 h, the carbonylation selectively occurred at
the ortho-position of the benzene ring to give the desired
product 4a as a single regiomer in 30% yield (Table 2, entry 1).
Using Pd(OAc)2 instead of PdCl2 as the catalyst enhanced the
yield to 43% (Table 2, entry 2). Moreover, increasing or
reducing the amount of TFBen hampered the reaction (Table
2, entries 3 and 4). Gratifyingly, the reaction yield was
improved to 50% when the temperature was raised (Table 2,
entry 5). Finally, shortening the reaction time to 16 h increased
the yield to 60% (Table 2, entry 6). Further reduction of the
reaction time slightly decreased the yield of 4a (Table 2, entry
7).
Subsequently, the scope of 2-thiophene methylamines 3 was
investigated under optimal reaction conditions (Table 2, entry
6) as shown in Scheme 3. The reaction of substrates bearing
electron-donating groups gave the expected products 4b−e in
45−68% yields. It should be noted that the strong electron-
donating group such as −OMe facilitates the carbonylation
reaction. Furthermore, the chloro-substituted compound 3f
was successfully converted to product 4f in a 54% yield as well.
As we expected, ortho-methyl substituted substrate can be
transformed into the desired product in 48% yield 4g.
a
Reaction condition: 1 (0.5 mmol), Pd(OAc)2 (10 mol %),
Cu(OAc)2 (2.0 equiv), TFBen (2.0 equiv), Et3N (2.0 equiv),
toluene/DMSO = 10:1 (2.2 mL), 110 °C, 20 h, isolated yield. 1g
(0.25 mmol).
b
B
DOI: 10.1021/acs.joc.9b02114
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Scheme 3. Scope of 2-Thiophene Methylamines 3
a
Reaction condition: 3 (0.5 mmol), Pd(OAc)2 (10 mol %), Cu(OAc)2 (3.0 equiv), TFBen (2.0 equiv), Et3N (2.0 equiv), toluene/DMSO = 10:1
(2.2 mL), 135 °C, 16 h, isolated yield.
a
Scheme 4. Scope of Tryptamines 5
a
Reaction condition: 5 (0.5 mmol), Pd(TFA)2 (10 mol %), Cu(OAc)2 (1.5 equiv), TFBen (2.0 equiv), Et3N (2.0 equiv), toluene/DMSO = 10:1
b
(2.2 mL), 110 °C, 20 h, isolated yield. 5e (0.25 mmol).
We also employed the modified reaction conditions in the
carbonylation of various tryptamines 5, and the results are
illustrated in Scheme 4. The carbonylation of substrates with
either electron-donating or electron-withdrawing groups
occurred at the 2-position of the indole ring to give the
corresponding products 6a−f with excellent regioselectivities
and yields (62−92%). Additionally, the alkyl-substituted
tryptamine 5g could be transformed into product 6g in a
94% yield.
thiophene ring afforded the lactam 8 in 57% yield (Scheme 5,
eq 1). Moreover, it was found that the treatment of the amine
9 bearing indole and 2-thiophene units with the Pd(TFA)2
catalytic system promoted the selective carbonylation at the 2-
position of the indole ring, accessing to the lactam 10 in 81%
yield (Scheme 5, eq 2). Finally, the amine 11 having indole
and 3-thiophene units selectively carbonylated at the 2-
position of the indole ring to give the lactam 12 in 78%
yield (Scheme 5, eq 3). Furan and pyridine related substrates
were prepared and tested; however, a mixture of isomers was
obtained and not separable (Scheme 5, eqs 4 and 5). In the
Interestingly, when the amine 7 containing 2-thiophene and
3-thiophene units was subjected to the Pd(OAc)2 catalytic
system, the selective carbonylation at the 2-position of the 3-
C
DOI: 10.1021/acs.joc.9b02114
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 5. Selective Carbonylation of Heterocyclic Amines
Preparation of TFBen. Formic acid (8.4 mL, 222.8 mmol, 5.0
equiv) was added to acetic anhydride (16.8 mL, 178.2 mmol, 4.0
equiv) at rt. The mixture was stirred at 60 °C in an oil bath for 1 h
and cooled to rt. The resulting solution was poured into a flask
containing 1,3,5-trihydroxybenzene (5.62 g, 44.6 mmol, 1.0 equiv)
and AcONa (1.83 g, 22.3 mmol, 0.5 equiv). The mixture was stirred
for 4 h in a water bath and then diluted with toluene (100 mL) and
washed with H2O (50 mL) two times. The organic phase was kept in
a fridge (2−8 °C) overnight and then filtered and dried in vacuo to
afford the desired product benzene-1,3,5-triyl triformate (TFBen)
(5.1 g, 55%) as a white solid.
General Procedure for the Syntheses of the Secondary
Amines. In a round-bottomed flask fitted with a magnetic stirring
bar, primary amine (3 mmol, 1.0 equiv) and aldehyde (3.3 mmol, 1.1
equiv) were dissolved in MeOH (8 mL). The reaction mixture was
added with molecular sieves (4 Å) and stirred at rt. The reaction was
monitored by TLC, and upon full conversion of benzaldehyde (24 h),
solid NaBH4 (147.5 mg, 3.9 mmol, 1.3 equiv) was added. After a
further 16 h of stirring, the reaction mixture was filtered through a pad
of Celite, which was washed with MeOH. The filtrate was evaporated
in vacuo. The residue was taken up in sat. NaHCO3 (10 mL), H2O
case of pyrrole related substrate, no desired product could be
detected (Scheme 5, eq 6).
In conclusion, we have developed an efficient approach for
the synthesis of lactam motifs via palladium-catalyzed site-
selective C−H carbonylation of heterocyclic amines using
TFBen as the CO source. The reaction proceeds smoothly
with 3-thiophene methylamines, 2-thiophene methylamines,
and tryptamines, affording structurally diverse lactams in
moderate to high yields and with excellent regioselectivities.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise noted, all reactions were
carried out under a nitrogen atmosphere. All reagents were obtained
from commercial sources and used as received without further
purification. Column chromatography was performed on silica gel
(200−300 mesh) using petroleum ether (bp 60−90 °C) and ethyl
1
acetate as an eluent. H and 13C NMR spectra were taken on 400
MHz instruments, and spectral data were reported in ppm relative to
tetramethylsilane (TMS) as an internal standard and CDCl3 or
DMSO-d6 as a solvent.
D
DOI: 10.1021/acs.joc.9b02114
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(10 mL), and EtOAc (30 mL) and transferred to a separatory funnel.
The organic layer was separated and washed with H2O (20 mL) and
brine (20 mL). The organic layer was dried over Na2SO4. The crude
mixture was purified by flash column chromatography on silica gel
eluted with petroleum ether/ethyl acetate (3:1) or pure DCM to give
the secondary amine products.
2,2-Dimethyl-N-(thiophen-3-ylmethyl)propan-1-amine (1i):
222.5 mg, 40% yield, pale yellow oil; H NMR (400 MHz, CDCl3)
1
δ 7.29−7.26 (m, 1H), 7.13 (d, J = 1.8 Hz, 1H), 7.05 (d, J = 4.9 Hz,
1H), 3.82 (s, 2H), 2.37 (s, 2H), 0.92 (s, 9H); 13C NMR {1H} (101
MHz, CDCl3) δ 142.1, 127.6, 125.5, 121.1, 61.7, 49.8, 31.5, 27.8;
HRMS (ESI-TOF) [M + H]+ calcd for C10H18NS+ 184.1154, found
184.1165.
Characterization of TFBen and the Secondary Amines.
Benzene-1,3,5-triyltriformate (TFBen):10 5.1 g, 55% yield, white
solid, mp 53.2−55.6 °C; 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 3H),
6.95 (s, 3H); 13C NMR {1H} (101 MHz, CDCl3) δ 158.0, 150.5,
112.8.
2-Phenyl-N-(thiophen-3-ylmethyl)ethan-1-amine (1j): 261.1 mg,
40% yield, pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.31−7.24
(m, 3H), 7.20 (t, J = 5.6 Hz, 3H), 7.08 (dd, J = 1.8, 0.9 Hz, 1H), 7.00
(d, J = 4.9 Hz, 1H), 3.81 (s, 2H), 2.91 (t, J = 6.9 Hz, 2H), 2.82 (t, J =
7.0 Hz, 2H); 13C NMR {1H} (101 MHz, CDCl3) δ 140.8, 139.8,
128.7, 128.5, 127.6, 126.2, 125.8, 121.8, 50.4, 48.6, 36.1; HRMS (ESI-
TOF) [M + H]+ calcd for C13H16NS+ 218.0998, found 218.1008.
N-Benzyl-1-(thiophen-2-yl)methanamine (3a):12 330.2 mg, 54%
N-Benzyl-1-(thiophen-3-yl)methanamine (1a):11 339.8 mg, 55%
yield, pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 4.4
Hz, 4H), 7.27−7.21 (m, 2H), 7.11 (d, J = 1.8 Hz, 1H), 7.04 (dd, J =
4.9, 1.1 Hz, 1H), 3.79 (d, J = 2.8 Hz, 4H); 13C NMR {1H} (101 MHz,
CDCl3) δ 141.4, 140.2, 128.5, 128.2, 127.7, 127.0, 125.8, 121.6, 53.2,
48.2.
1
yield, pale yellow oil; H NMR (400 MHz, CDCl3) δ 7.34−7.27 (m,
4H), 7.26−7.20 (m, 1H), 7.19−7.15 (m, 1H), 6.91 (ddd, J = 7.0, 3.5,
2.3 Hz, 2H), 3.95 (s, 2H), 3.79 (s, 2H); 13C NMR {1H} (101 MHz,
CDCl3) δ 144.3, 140.1, 128.5, 128.3, 127.1, 126.7, 125.0, 124.5, 52.8,
47.6.
N-(4-Methylbenzyl)-1-(thiophen-3-yl)methanamine (1b): 361.8
mg, 55% yield, pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.22−
7.18 (m, 1H), 7.17−7.12 (m, 2H), 7.06 (d, J = 5.0 Hz, 3H), 6.98 (t, J
= 3.9 Hz, 1H), 3.73 (d, J = 3.4 Hz, 2H), 3.70 (d, J = 3.4 Hz, 2H), 2.26
(d, J = 3.4 Hz, 3H); 13C NMR {1H} (101 MHz, CDCl3) δ 141.5,
137.2, 136.6, 129.1, 128.2, 127.7, 125.7, 121.5, 53.0, 48.1, 21.1;
HRMS (ESI-TOF) [M + H]+ calcd for C13H16NS+ 218.0998, found
218.1004.
N-(4-Methylbenzyl)-1-(thiophen-2-yl)methanamine (3b): 342.6
1
mg, 52% yield, pale yellow oil; H NMR (400 MHz, CDCl3) δ 7.21
(d, J = 5.4 Hz, 3H), 7.13 (d, J = 7.2 Hz, 2H), 6.96−6.89 (m, 2H),
3.97 (s, 2H), 3.78 (s, 2H), 2.33 (s, 3H); 13C NMR {1H} (101 MHz,
CDCl3) δ 144.3, 137.0, 136.6, 129.1, 128.2, 126.6, 124.9, 124.4, 52.5,
47.5, 21.1; HRMS (ESI-TOF) [M + H]+ calcd for C13H16NS+
218.0998, found 218.1013.
N-(4-(tert-Butyl)benzyl)-1-(thiophen-3-yl)methanamine (1c):
1
467.0 mg, 60% yield, pale yellow oil; H NMR (400 MHz, CDCl3)
δ 7.35 (d, J = 8.2 Hz, 2H), 7.25 (dd, J = 9.9, 6.1 Hz, 3H), 7.14 (dd, J
= 1.7, 0.8 Hz, 1H), 7.06 (d, J = 5.0 Hz, 1H), 3.82 (s, 2H), 3.78 (s,
2H), 2.14 (s, 1H), 1.31 (s, 9H); 13C NMR {1H} (101 MHz, CDCl3)
δ 149.9, 137.0, 129.2, 127.9, 127.7, 125.7, 125.3, 121.6, 52.8, 48.1,
34.5, 31.4; HRMS (ESI-TOF) [M + H]+ calcd for C16H22NS+
260.1467, found 260.1483.
N-(4-Ethylbenzyl)-1-(thiophen-2-yl)methanamine (3c): 352.2 mg,
50% yield, pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J =
7.6 Hz, 2H), 7.20 (d, J = 5.0 Hz, 1H), 7.15 (d, J = 7.5 Hz, 2H), 6.93
(d, J = 5.3 Hz, 2H), 3.98 (s, 2H), 3.79 (s, 2H), 2.63 (q, J = 7.6 Hz,
2H), 2.10 (s, 1H), 1.22 (t, J = 7.6 Hz, 3H); 13C NMR {1H} (101
MHz, CDCl3) δ 144.0, 143.1, 137.0, 128.3, 128.0, 126.7, 125.0, 124.4,
52.5, 47.5, 28.6, 15.7; HRMS (ESI-TOF) [M + H]+ calcd for
C14H18NS+ 232.1154, found 232.1169.
N-(4-Methoxybenzyl)-1-(thiophen-3-yl)methanamine (1d): 427.1
1
mg, 61% yield, pale yellow oil; H NMR (400 MHz, CDCl3) δ 7.28
(dd, J = 4.9, 3.0 Hz, 2H), 7.24 (s, 1H), 7.14 (s, 1H), 7.06 (d, J = 4.9
Hz, 1H), 6.87 (d, J = 8.5 Hz, 2H), 3.81 (d, J = 3.4 Hz, 5H), 3.75 (s,
2H); 13C NMR {1H} (101 MHz, CDCl3) δ 158.7, 141.5, 132.3,
129.3, 127.6, 125.7, 121.5, 113.8, 55.3, 52.6, 48.0; HRMS (ESI-TOF)
[M + H]+ calcd for C13H16NOS+ 234.0947, found 234.0958.
N-(4-Chlorobenzyl)-1-(thiophen-3-yl)methanamine (1e): 369.8
mg,52% yield, pale yellow oil; 1H NMR (400 MHz, CDCl3) δ
7.30−7.23 (m, 5H), 7.12 (s, 1H), 7.04 (d, J = 4.9 Hz, 1H), 3.78 (s,
2H), 3.75 (s, 2H); 13C NMR {1H} (101 MHz, CDCl3) δ 141.2,
138.7, 132.7, 129.5, 128.5, 127.6, 125.9, 121.7, 52.4, 48.1; HRMS
(ESI-TOF) [M + H]+ calcd for C12H13ClNS+ 238.0452, found
238.0464.
N-(4-Bromobenzyl)-1-(thiophen-3-yl)methanamine (1f): 379.3
mg, 45% yield, pale yellow oil; 1H NMR (400 MHz, CDCl3) δ
7.48−7.43 (m, 2H), 7.30 (dd, J = 4.9, 3.0 Hz, 1H), 7.22 (d, J = 8.4
Hz, 2H), 7.15−7.13 (m, 1H), 7.06 (dd, J = 5.0, 1.1 Hz, 1H), 3.81 (s,
2H), 3.77 (s, 2H); 13C NMR {1H} (101 MHz, CDCl3) δ 141.1,
139.1, 131.5, 129.9, 127.6, 125.8, 121.7, 120.8, 52.4, 48.0; HRMS
(ESI-TOF) [M + H]+ calcd for C12H13BrNS+ 281.9947, found
281.9959.
N-(4-(tert-Butyl)benzyl)-1-(thiophen-2-yl)methanamine (3d):
415.1 mg, 53% yield, pale yellow oil; H NMR (400 MHz, CDCl3)
1
δ 7.35 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 7.22−7.18 (m,
1H), 6.93 (dd, J = 8.5, 3.6 Hz, 2H), 3.99 (s, 2H), 3.80 (s, 2H), 1.31
(s, 9H); 13C NMR {1H} (101 MHz, CDCl3) δ 149.9, 144.4, 137.0,
127.9, 126.6, 125.3, 124.8, 124.3, 52.5, 47.7, 34.5, 31.4; HRMS (ESI-
TOF) [M + H]+ calcd for C16H22NS+ 260.1467, found 260.1482.
N-(4-Methoxybenzyl)-1-(thiophen-2-yl)methanamine (3e): 327.3
1
mg, 47% yield, pale yellow oil; H NMR (400 MHz, CDCl3) δ 7.25
(s, 1H), 7.23 (s, 1H), 7.20 (dd, J = 5.0, 1.2 Hz, 1H), 6.94 (dd, J = 5.0,
3.5 Hz, 1H), 6.92−6.89 (m, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.85 (d, J
= 1.9 Hz, 1H), 3.96 (d, J = 0.5 Hz, 2H), 3.78 (s, 3H), 3.76 (s, 2H);
13C NMR {1H} (101 MHz, CDCl3) δ 158.7, 144.3, 132.2, 129.4,
126.6, 124.9, 124.3, 113.9, 55.3, 52.2, 47.5; HRMS (ESI-TOF) [M +
H]+ calcd for C13H16NOS+ 234.0947, found 234.0957.
N-(4-Chlorobenzyl)-1-(thiophen-2-yl)methanamine (3f): 346.3
mg, 49% yield, pale yellow oil; 1H NMR (400 MHz, CDCl3) δ
7.28 (s, 3H), 7.27−7.20 (m, 2H), 6.97−6.89 (m, 2H), 3.97 (s, 2H),
3.79 (s, 2H); 13C NMR {1H} (101 MHz, CDCl3) δ 144.0, 138.5,
132.7, 129.5, 128.5, 126.7, 125.0, 124.5, 52.0, 47.5; HRMS (ESI-
TOF) [M + H]+ calcd for C12H13ClNS+ 238.0452, found 238.0465.
N-(2-Methylbenzyl)-1-(thiophen-2-yl)methanamine (3g): 456.3
mg, 70.1% yield, yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.22 (t, J
= 3.2 Hz, 1H), 7.15−7.12 (m, 1H), 7.10−7.05 (m, 3H), 6.89−6.85
(m, 2H), 3.95 (s, 2H), 3.73 (s, 2H), 2.25 (s, 3H); 13C NMR {1H}
(101 MHz, CDCl3) δ 144.4, 138.0, 136.5, 130.3, 128.6, 127.1, 126.6,
125.9, 124.8, 124.4, 50.7, 48.1, 19.0; HRMS (ESI-TOF) [M + H]+
calcd for C13H16NS+ 218.0998, found 218.0996.
N-(2-Methylbenzyl)-1-(thiophen-3-yl)methanamine (1g): 434.4
1
mg, 66.7% yield, yellow oil; H NMR (400 MHz, CDCl3) δ 7.32−
7.25 (m, 2H), 7.18−7.12 (m, 4H), 7.07 (dd, J = 4.9, 1.0 Hz, 1H), 3.86
(s, 2H), 3.78 (s, 2H), 2.32 (s, 3H); 13C NMR {1H} (101 MHz,
CDCl3) δ 141.5, 138.1, 136.4, 130.3, 128.5, 127.7, 127.0, 125.9, 125.7,
121.6, 51.0, 48.6, 18.9; HRMS (ESI-TOF) [M + H]+ calcd for
C13H16NS+ 218.0998, found 218.0996.
2-Methyl-N-(thiophen-3-ylmethyl)propan-1-amine (1h): 169.4
mg, 33% yield, pale yellow oil; 1H NMR (400 MHz, CDCl3) δ
7.30−7.27 (m, 1H), 7.14 (s, 1H), 7.06 (d, J = 4.7 Hz, 1H), 3.81 (s,
2H), 2.46 (d, J = 6.3 Hz, 2H), 1.79 (dt, J = 13.3, 6.6 Hz, 1H), 0.92
(dd, J = 6.6, 1.5 Hz, 6H); 13C NMR {1H} (101 MHz, CDCl3) δ
141.5, 127.6, 125.6, 121.5, 57.4, 49.0, 28.2, 20.7; HRMS (ESI-TOF)
[M + H]+ calcd for C9H16NS+ 170.0998, found 170.1007.
N-Benzyl-2-(1H-indol-3-yl)ethan-1-amine (5a):13 526.1 mg, 70%
1
yield, white solid; H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.59
(d, J = 7.6 Hz, 1H), 7.39−7.06 (m, 8H), 6.94 (s, 1H), 3.80 (s, 2H),
2.99 (s, 4H), 2.04 (s, 1H); 13C NMR {1H} (101 MHz, CDCl3) δ
140.1, 136.5, 128.4, 128.2, 127.5, 127.0, 122.1, 122.0, 119.2, 118.9,
113.8, 111.2, 53.8, 49.3, 25.7.
E
DOI: 10.1021/acs.joc.9b02114
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
2-(1H-Indol-3-yl)-N-(4-methylbenzyl)ethan-1-amine (5b): 545.3
mg, 69% yield, white solid, mp 260.3−265.5 °C; 1H NMR (400 MHz,
CDCl3) δ 8.23 (s, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.31 (d, J = 8.0 Hz,
1H), 7.15 (ddd, J = 24.8, 17.4, 10.4 Hz, 6H), 6.95 (s, 1H), 3.76 (s,
2H), 2.98 (s, 4H), 2.31 (s, 3H), 2.15 (s, 1H); 13C NMR {1H} (101
MHz, CDCl3) δ 137.0, 136.5, 136.4, 129.1, 128.2, 127.5, 122.1, 122.0,
119.2, 118.9, 113.8, 111.2, 53.5, 49.2, 25.7, 21.1; HRMS (ESI-TOF)
113.3, 111.6, 49.5, 48.8, 25.8; HRMS (ESI-TOF) [M + H]+ calcd for
C15H17N2S+ 257.1107, found 257.1122.
General Procedure for C−H Carbonylation of 3-Thiophene
Methylamines. To the ex-tube (15 mL) of an oven-dried in−ex tube
were added amine 1 (0.5 mmol, 1.0 equiv), Pd(OAc)2 (11.2 mg, 0.05
mmol, 10 mol %), Cu(OAc)2 (181 mg, 1.0 mmol, 2.0 equiv), and a
stirring bar. In the in-tube (2.5 mL), TFBen (210 mg, 1.0 mmol, 2.0
equiv) was added. Then the in−ex tube was placed under a vacuum
and refilled with nitrogen three times. Et3N (102 mg, 1.0 mmol, 2.0
equiv), toluene (2.0 mL), and DMSO (0.2 mL) were added into the
ex-tube via syringe. The in−ex tube was sealed and stirred at 110 °C
in an oil bath for 20 h. Upon reaction completion, the mixture was
diluted with CH2Cl2 and washed with water three times. The crude
mixture was purified by silica gel column chromatography (PE/
EtOAc = 5:1 to 3:1) to obtain the desired products 2.
General Procedure for C−H Carbonylation of 2-Thiophene
Methylamines. To the ex-tube (15 mL) of an oven-dried in−ex tube
were added amine 3 (0.5 mmol, 1.0 equiv), Pd(OAc)2 (11.2 mg, 0.05
mmol, 10 mol %), Cu(OAc)2 (279 mg, 1.5 mmol, 3.0 equiv), and a
stirring bar. In the in-tube (2.5 mL), TFBen (210 mg, 1.0 mmol, 2.0
equiv) was added. Then the in−ex tube was placed under a vacuum
and refilled with nitrogen three times. Et3N (102 mg, 1.0 mmol, 2.0
equiv), toluene (2.0 mL), and DMSO (0.2 mL) were added into the
ex-tube via syringe. The in−ex tube was sealed and stirred at 135 °C
in an oil bath for 16 h. Upon reaction completion, the mixture was
diluted with CH2Cl2 and washed with water three times. The crude
mixture was purified by silica gel column chromatography (PE/
EtOAc = 5:1 to 3:1) to obtain the desired products 4.
General Procedure for C−H Carbonylation of Tryptamines. To
the ex-tube (15 mL) of an oven-dried in−ex tube were added amine 5
(0.5 mmol, 1.0 equiv), Pd(TFA)2 (15.0 mg, 0.05 mmol, 10 mol %),
Cu(OAc)2 (136 mg, 0.75 mmol, 1.5 equiv), and a stirring bar. To the
in-tube (2.5 mL) was added TFBen (210 mg, 1.0 mmol, 2.0 equiv).
Then the in−ex tube was placed under a vacuum and refilled with
nitrogen three times. Et3N (102 mg, 1.0 mmol, 2.0 equiv), toluene
(2.0 mL), and DMSO (0.2 mL) were added into the ex-tube via
syringe. The in−ex tube was sealed and stirred at 110 °C in an oil
bath for 20 h. Upon reaction completion, the mixture was diluted with
CH2Cl2 and washed with water three times. The crude mixture was
purified by alumina column chromatography (EtOAc) to obtain the
desired products 6.
+
[M + H]+ calcd for C18H21N2 265.1699, found 265.1714.
2-(1H-Indol-3-yl)-N-(4-methoxybenzyl)ethan-1-amine (5c):14
1
550.5 mg, 66% yield, white solid; H NMR (400 MHz, CDCl3) δ
8.17 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.20−
7.16 (m, 3H), 7.12−7.08 (m, 1H), 6.98 (d, J = 1.7 Hz, 1H), 6.84−
6.80 (m, 2H), 3.77 (s, 3H), 3.75 (s, 2H), 2.98 (s, 4H), 2.00 (s, 1H);
13C NMR {1H} (101 MHz, CDCl3) δ 158.6, 136.4, 132.3, 129.3,
127.5, 122.0, 119.2, 118.9, 113.9, 113.8, 111.1, 55.3, 53.2, 49.2, 25.7.
N-(4-Chlorobenzyl)-2-(1H-indol-3-yl)ethan-1-amine (5d): 475.6
mg, 56% yield, white solid, mp 254.2−259.3 °C; 1H NMR (400 MHz,
CDCl3) δ 8.22 (s, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 8.0 Hz,
1H), 7.22 (d, J = 8.3 Hz, 2H), 7.17 (t, J = 8.0 Hz, 3H), 7.10 (t, J = 7.3
Hz, 1H), 6.93 (s, 1H), 3.74 (s, 2H), 3.01−2.90 (m, 4H); 13C NMR
{1H} (101 MHz, CDCl3) δ 138.8, 136.5, 132.6, 129.5, 128.5, 127.5,
122.1, 119.3, 118.9, 113.8, 111.2, 53.1, 49.3, 25.8; HRMS (ESI-TOF)
+
[M + H]+ calcd for C17H18ClN2 285.1153, found 285.1171.
2-(1H-Indol-3-yl)-N-(2-methylbenzyl)ethan-1-amine (5e): 590.1
mg, 74.5% yield, pale yellow solid, mp 88.1−91.3 °C; 1H NMR (400
MHz, CDCl3) δ 8.43 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.22−7.16 (m,
2H), 7.09 (tt, J = 14.0, 7.2 Hz, 5H), 6.80 (s, 1H), 3.74 (s, 2H), 2.98
(t, J = 5.0 Hz, 4H), 2.19 (s, 3H), 1.80 (s, 1H); 13C NMR {1H} (101
MHz, CDCl3) δ 138.2, 136.6, 136.3 130.4, 128.4, 127.5, 127.1, 126.0,
122.2, 122.0, 119.2, 118.9, 113.7, 111.3, 51.4, 49.8, 25.8, 19.0; HRMS
(ESI-TOF) [M + H]+ calcd for C18H21N2+ 265,1699, found 265,1702.
N-Benzyl-2-(5-methyl-1H-indol-3-yl)ethan-1-amine (5f): 317.0
1
mg, 40.1% yield, pale yellow oil; H NMR (400 MHz, CDCl3) δ
8.15 (s, 1H), 7.37 (s, 1H), 7.30−7.25 (m, 4H), 7.22 (dd, J = 6.4, 2.1
Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.88 (d, J
= 1.3 Hz, 1H), 3.80 (s, 2H), 2.97 (s, 4H), 2.44 (s, 3H), 1.64 (s, 1H);
13C NMR {1H} (101 MHz, CDCl3) δ 140.4, 134.8, 128.4, 128.2,
127.8, 126.9, 123.6, 122.2, 118.6, 113.4, 110.9, 53.9, 49.4, 25.8, 21.5;
+
HRMS (ESI-TOF) [M + H]+ calcd for C18H21N2 265.1699, found
265.1702.
N-(2-(1H-Indol-3-yl)ethyl)-2,2-dimethylpropan-1-amine (5g):
314.4 mg, 46% yield, white solid, mp 98.3−103.5 °C; 1H NMR
(400 MHz, CDCl3) δ 8.24 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.30 (d, J
= 8.1 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), 6.97
(d, J = 1.6 Hz, 1H), 2.94 (s, 4H), 2.38 (s, 2H), 0.85 (s, 9H); 13C
NMR {1H} (101 MHz, CDCl3) δ 136.4, 127.6, 121.9, 121.9, 119.2,
119.0, 114.2, 111.1, 62.3, 51.1, 31.5, 27.9, 25.6; HRMS (ESI-TOF)
Procedure for C−H Carbonylation of the Amine. To the ex-tube
(15 mL) of an oven-dried in−ex tube were added amine 7 (0.5 mmol,
1.0 equiv), Pd(OAc)2 (11.2 mg, 0.05 mmol, 10 mol %), Cu(OAc)2
(181 mg, 1.0 mmol, 2.0 equiv), and a stirring bar. In the in-tube (2.5
mL), TFBen (210 mg, 1.0 mmol, 2.0 equiv) was added. Then the in−
ex tube was placed under a vacuum and refilled with nitrogen three
times. Et3N (102 mg, 1.0 mmol, 2.0 equiv), toluene (2.0 mL), and
DMSO (0.2 mL) were added into the ex-tube via syringe. The in−ex
tube was sealed and stirred at 110 °C in an oil bath for 20 h. Upon
reaction completion, the mixture was diluted with CH2Cl2 and
washed with water three times. The crude mixture was purified by
silica gel column chromatography (PE/EtOAc = 5:1 to 3:1) to obtain
the desired product 8.
Procedure for C−H Carbonylation of the Amine 9. To the ex-
tube (15 mL) of an oven-dried in−ex tube were added amine 9 (0.5
mmol, 1.0 equiv), Pd(TFA)2 (15.0 mg, 0.05 mmol, 10 mol %),
Cu(OAc)2 (136 mg, 0.75 mmol, 1.5 equiv), and a stirring bar. In the
in-tube (2.5 mL), TFBen (210 mg, 1.0 mmol, 2.0 equiv) was added.
Then the in−ex tube was placed under a vacuum and refilled with
nitrogen three times. Et3N (102 mg, 1.0 mmol, 2.0 equiv), toluene
(2.0 mL), and DMSO (0.2 mL) were added into the ex-tube via
syringe. The in−ex tube was sealed and stirred at 110 °C in an oil
bath for 20 h. Upon reaction completion, the mixture was diluted with
CH2Cl2 and washed with water three times. The crude mixture was
purified by alumina column chromatography (EtOAc) to obtain the
desired product 10.
+
[M + H]+ calcd for C15H23N2 231.1856, found 231.1869.
1-(Thiophen-2-yl)-N-(thiophen-3-ylmethyl)methanamine (7):
1
383.1 mg, 61% yield, pale yellow oil; H NMR (400 MHz, CDCl3)
δ 7.27 (dd, J = 4.9, 3.0 Hz, 1H), 7.20 (dd, J = 5.0, 1.1 Hz, 1H), 7.13
(dd, J = 1.8, 0.8 Hz, 1H), 7.05 (d, J = 4.9 Hz, 1H), 6.96−6.93 (m,
1H), 6.91 (d, J = 3.3 Hz, 1H), 3.99 (s, 2H), 3.84 (s, 2H); 13C NMR
{1H} (101 MHz, CDCl3) δ 144.1, 141.1, 127.7, 126.7, 125.8, 125.0,
124.4, 121.7, 47.8, 47.6; HRMS (ESI-TOF) [M + H]+ calcd for
+
C10H12NS2 210.0406, found 210.0412.
2-(1H-Indol-3-yl)-N-(thiophen-2-ylmethyl)ethan-1-amine (9):15
1
500.93 mg, 65% yield, yellow oil; H NMR (400 MHz, CDCl3) δ
8.29 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 7.13
(ddd, J = 28.4, 12.5, 7.8 Hz, 3H), 6.89 (dd, J = 12.5, 7.6 Hz, 3H), 3.97
(s, 2H), 2.99 (s, 4H); 13C NMR {1H} (101 MHz, CDCl3) δ 144.0,
136.5, 127.5, 126.7, 125.0, 124.4, 122.2, 122.0, 119.3, 118.9, 113.7,
111.3, 49.2, 48.3, 25.7.
2-(1H-Indol-3-yl)-N-(thiophen-3-ylmethyl)ethan-1-amine (11):
1
459.4 mg, 60% yield, yellow oil; H NMR (400 MHz, CDCl3) δ
8.93 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.20−7.03 (m, 4H), 6.94 (d, J
= 1.8 Hz, 1H), 6.89 (d, J = 4.9 Hz, 1H), 6.74 (s, 1H), 3.72 (s, 2H),
2.93 (s, 4H), 2.07 (s, 1H); 13C NMR {1H} (101 MHz, CDCl3) δ
141.1, 136.7, 127.9, 127.6, 126.0, 122.6, 122.0, 122.0, 119.3, 119.0,
Procedure for C−H Carbonylation of the Amine 11. To the ex-
tube (15 mL) of an oven-dried in−ex tube were added amine 11 (0.5
mmol, 1.0 equiv), Pd(TFA)2 (15.0 mg, 0.05 mmol, 10 mol %),
F
DOI: 10.1021/acs.joc.9b02114
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Cu(OAc)2 (136 mg, 0.75 mmol, 1.5 equiv), and a stirring bar. In the
in-tube (2.5 mL), TFBen (210 mg, 1.0 mmol, 2.0 equiv) was added.
Then the in−ex tube was placed under a vacuum and refilled with
nitrogen three times. Et3N (102 mg, 1.0 mmol, 2.0 equiv), toluene
(2.0 mL), and DMSO (0.2 mL) were added into the ex-tube via
syringe. The in−ex tube was sealed and stirred at 110 °C in an oil
bath for 20 h. Upon reaction completion, the mixture was diluted with
CH2Cl2 and washed with water three times. The crude mixture was
purified by alumina column chromatography (EtOAc) to obtain the
desired product 12.
Characterization of Products. 5-Benzyl-4,5-dihydro-6H-
thieno[2,3-c]pyrrol-6-one (2a):16 83.6 mg, 73% yield, colorless oil;
1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 4.6 Hz, 1H), 7.35−7.26
(m, 5H), 6.99 (d, J = 4.5 Hz, 1H), 4.75 (s, 2H), 4.19 (d, J = 3.0 Hz,
2H); 13C NMR {1H} (101 MHz, CDCl3) δ 164.6, 150.9, 137.3,
135.7, 134.6, 128.8, 128.1, 127.7, 120.9, 48.2, 47.0.
136.0, 134.3, 120.6, 55.8, 52.0, 33.9, 28.2; HRMS (ESI-TOF) [M +
H]+ calcd for C11H16NOS+ 210.0947, found 210.0964.
5-Phenethyl-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-one (2j): 92.3
mg, 76% yield, colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J
= 4.8 Hz, 1H), 7.31−7.27 (m, 2H), 7.25−7.19 (m, 3H), 6.97 (d, J =
4.7 Hz, 1H), 4.10 (s, 2H), 3.82 (t, J = 7.3 Hz, 2H), 2.98 (t, J = 7.3 Hz,
2H); 13C NMR {1H} (101 MHz, CDCl3) δ 164.6, 150.7, 138.9,
136.0, 134.2, 128.7, 128.6, 126.5, 120.7, 49.4, 44.8, 35.2; HRMS (ESI-
TOF) [M + H]+ calcd for C14H14NOS+, 244.0791, found 244.0804.
2-(Thiophen-2-ylmethyl)isoindolin-1-one (4a):17 68.7 mg, 60%
1
yield, colorless oil; H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.5
Hz, 1H), 7.51 (dt, J = 7.4, 3.7 Hz, 1H), 7.45 (t, J = 7.3 Hz, 1H), 7.40
(d, J = 7.4 Hz, 1H), 7.25−7.22 (m, 1H), 7.04 (d, J = 3.2 Hz, 1H),
6.96 (dd, J = 5.0, 3.5 Hz, 1H), 4.97 (s, 2H), 4.35 (s, 2H); 13C NMR
{1H} (101 MHz, CDCl3) δ 168.1, 141.2, 139.4, 132.5, 131.5, 128.1,
127.0, 126.8, 125.7, 123.9, 122.8, 49.3, 40.8.
6-Methyl-2-(thiophen-2-ylmethyl)isoindolin-1-one (4b): 55.9 mg,
46% yield, colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H),
7.32 (d, J = 7.7 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 7.22 (dd, J = 5.1,
1.2 Hz, 1H), 7.04−7.01 (m, 1H), 6.95 (dd, J = 5.1, 3.5 Hz, 1H), 4.95
(s, 2H), 4.30 (s, 2H), 2.43 (s, 3H); 13C NMR {1H} (101 MHz,
CDCl3) δ 168.2, 139.5, 138.4, 138.0, 132.6, 132.4, 126.9, 126.6, 125.5,
124.1, 122.4, 49.1, 40.8, 21.3; HRMS (ESI-TOF) [M + Na]+ calcd for
C14H13NNaOS+ 266.0610, found 266.0627.
6-Ethyl-2-(thiophen-2-ylmethyl)isoindolin-1-one (4c): 59.1 mg,
46% yield, colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H),
7.36−7.32 (m, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.22 (dd, J = 5.1, 1.1
Hz, 1H), 7.03 (d, J = 3.0 Hz, 1H), 6.95 (dd, J = 5.0, 3.5 Hz, 1H), 4.96
(s, 2H), 4.30 (s, 2H), 2.73 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz,
3H); 13C NMR {1H} (101 MHz, CDCl3) δ 168.3, 144.5, 139.5,
138.7, 132.6, 131.5, 127.0, 126.7, 125.6, 122.9, 122.6, 49.1, 40.8, 28.8,
15.7; HRMS (ESI-TOF) [M + Na]+ calcd for C15H15NNaOS+
280.0767, found 280.0780.
5-(4-Methylbenzyl)-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-one
(2b): 91.2 mg, 75% yield, colorless oil; 1H NMR (400 MHz, CDCl3) δ
7.61 (d, J = 4.8 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 7.9 Hz,
2H), 6.97 (d, J = 4.8 Hz, 1H), 4.71 (s, 2H), 4.17 (s, 2H), 2.33 (s,
3H); 13C NMR {1H} (101 MHz, CDCl3) δ 164.6, 150.9, 137.4,
135.8, 134.4, 134.2, 129.4, 128.1, 120.8, 48.1, 46.7, 21.1; HRMS (ESI-
TOF) [M + H]+ calcd for C14H14NOS+ 244.0791, found 244.0809.
5-(4-(tert-Butyl)benzyl)-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-
1
one (2c): 78.4 mg, 55% yield, colorless oil; H NMR (400 MHz,
CDCl3) δ 7.60 (d, J = 4.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.23 (d, J
= 7.9 Hz, 2H), 6.97 (d, J = 4.6 Hz, 1H), 4.72 (s, 2H), 4.18 (s, 2H),
1.30 (s, 9H); 13C NMR {1H} (101 MHz, CDCl3) δ 164.5, 150.9,
150.6, 135.8, 134.4, 134.2, 127.9, 125.7, 120.9, 48.2, 46.6, 34.5, 31.3;
HRMS (ESI-TOF) [M + H]+ calcd for C17H20NOS+ 286.1260, found
286.1276.
5-(4-Methoxybenzyl)-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-one
(2d): 81.6 mg, 63% yield, colorless oil; 1H NMR (400 MHz, CDCl3) δ
7.60 (d, J = 4.7 Hz, 1H), 7.23 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 4.7 Hz,
1H), 6.89−6.82 (m, 2H), 4.68 (s, 2H), 4.16 (s, 2H), 3.79 (s, 3H);
13C NMR {1H} (101 MHz, CDCl3) δ 164.5, 159.1, 150.9, 135.8,
6-(tert-Butyl)-2-(thiophen-2-ylmethyl)isoindolin-1-one (4d): 64.2
mg, 45% yield, colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J
= 1.7 Hz, 1H), 7.57 (dd, J = 8.0, 1.8 Hz, 1H), 7.33 (d, J = 8.0 Hz,
1H), 7.24−7.20 (m, 1H), 7.03 (d, J = 3.0 Hz, 1H), 6.95 (dd, J = 5.0,
3.5 Hz, 1H), 4.97 (s, 2H), 4.31 (s, 2H), 1.36 (s, 9H); 13C NMR {1H}
(101 MHz, CDCl3) δ 168.5, 151.7, 139.5, 138.5, 132.3, 128.9, 126.9,
126.7, 125.5, 122.4, 120.6, 49.0, 40.9, 35.0, 31.4; HRMS (ESI-TOF)
[M + H]+ calcd for C17H20NOS+ 286.1260, found 286.1271.
6-Methoxy-2-(thiophen-2-ylmethyl)isoindolin-1-one (4e): 88.1
134.4, 129.4, 120.9, 114.1, 55.3, 48.1, 46.4; HRMS (ESI-TOF) [M +
H]+ calcd for C14H14NO2S+ 260.0740, found 260.0754.
5-(4-Chlorobenzyl)-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-one
(2e): 76.3 mg, 58% yield, colorless oil; 1H NMR (400 MHz, CDCl3) δ
7.64 (d, J = 4.8 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz,
2H), 7.00 (d, J = 4.8 Hz, 1H), 4.72 (s, 2H), 4.19 (s, 2H); 13C NMR
{1H} (101 MHz, CDCl3) δ 164.6, 150.9, 135.8, 135.5, 134.8, 133.5,
129.4, 129.0, 120.9, 48.2, 46.3; HRMS (ESI-TOF) [M + H]+ calcd for
C13H11ClNOS+ 264.0244, found 264.0257.
5-(4-Bromobenzyl)-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-one
(2f): 78.3 mg, 51% yield, colorless oil; 1H NMR (400 MHz, CDCl3) δ
7.64 (d, J = 4.8 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.1 Hz,
2H), 7.00 (d, J = 4.7 Hz, 1H), 4.70 (s, 2H), 4.19 (s, 2H); 13C NMR
{1H} (101 MHz, CDCl3) δ 164.6, 150.9, 136.4, 134.8, 131.9, 129.7,
121.6, 120.9, 48.2, 46.4; HRMS (ESI-TOF) [M + Na]+ calcd for
C13H10BrNNaOS+ 329.9559, found 329.9565.
5-(2-Methylbenzyl)-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-one
(2g): 52.3 mg, 43.2% yield, colorless oil; 1H NMR (400 MHz, CDCl3)
δ 7.61 (d, J = 4.8 Hz, 1H), 7.18 (t, J = 6.0 Hz, 4H), 6.97 (d, J = 4.8
Hz, 1H), 4.77 (s, 2H), 4.11 (s, 2H), 2.35 (s, 3H); 13C NMR {1H}
(101 MHz, CDCl3) δ 164.3, 150.9, 136.7, 134.9, 134.5, 130.7, 128.9,
127.9, 126.2, 120.8, 48.2, 45.1, 19.1; HRMS (ESI-TOF) [M + Na]+
calcd for C14H13NNaOS+, 266.0610, found 266.0611.
1
mg, 68% yield, colorless oil; H NMR (400 MHz, CDCl3) δ 7.36
(d, J = 2.4 Hz, 1H), 7.28 (s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 7.08 (dd, J
= 8.3, 2.4 Hz, 1H), 7.03 (d, J = 3.3 Hz, 1H), 6.96 (dd, J = 4.9, 3.6 Hz,
1H), 4.96 (s, 2H), 4.28 (s, 2H), 3.86 (s, 3H); 13C NMR {1H} (101
MHz, CDCl3) δ 168.1, 160.0, 139.4, 133.8, 133.4, 127.0, 126.7, 125.6,
123.6, 119.9, 106.7, 55.7, 48.9, 40.9; HRMS (ESI-TOF) [M + Na]+
calcd for C14H13NNaO2S+ 282.0559, found 282.0577.
6-Chloro-2-(thiophen-2-ylmethyl)isoindolin-1-one (4f): 71.1 mg,
1
54% yield, colorless oil; H NMR (400 MHz, CDCl3) δ 7.84 (d, J =
1.8 Hz, 1H), 7.48 (dd, J = 8.1, 1.9 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H),
7.24 (dd, J = 5.0, 1.1 Hz, 1H), 7.04 (d, J = 2.8 Hz, 1H), 6.97 (dd, J =
5.0, 3.4 Hz, 1H), 4.96 (s, 2H), 4.32 (s, 2H); 13C NMR {1H} (101
MHz, CDCl3) δ 166.8, 139.3, 138.9, 134.4, 134.3, 131.6, 128.9, 127.0,
126.9, 125.8, 124.0, 49.0, 40.9; HRMS (ESI-TOF) [M + Na]+ calcd
for C13H10ClNNaOS+ 286.0064, found 286.0077.
4-Methyl-2-(thiophen-2-ylmethyl)isoindolin-1-one (4g): 58.3 mg,
48.1% yield, colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J =
7.4 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 7.4 Hz, 1H), 7.23
(dd, J = 5.1, 1.1 Hz, 1H), 7.04 (d, J = 2.7 Hz, 1H), 6.96 (dd, J = 5.1,
3.5 Hz, 1H), 4.97 (s, 2H), 4.25 (s, 2H), 2.29 (s, 3H); 13C NMR {1H}
(101 MHz, CDCl3) δ 168.5, 140.1, 139.5, 132.5, 132.3, 132.2, 128.3,
127.0, 126.7, 125.6, 121.4, 48.5, 40.8, 17.5; HRMS (ESI-TOF) [M +
Na]+ calcd for C14H13NNaOS+ 266.0610, found 266.0610.
5-Isobutyl-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-one (2h): 30.8
1
mg, 63% yield, colorless oil; H NMR (400 MHz, CDCl3) δ 7.62
(d, J = 4.7 Hz, 1H), 7.03 (d, J = 4.7 Hz, 1H), 4.30 (s, 2H), 3.38 (d, J =
7.6 Hz, 2H), 2.09−1.96 (m, 1H), 0.96 (d, J = 6.6 Hz, 6H); 13C NMR
{1H} (101 MHz, CDCl3) δ 164.8, 150.5, 136.2, 134.2, 120.7, 50.7,
49.3, 28.1, 20.1; HRMS (ESI-TOF) [M + H]+ calcd for C10H13NOS+
196.0791, found 196.0806.
5-Neopentyl-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-one (2i): 81.5
mg, 78% yield, colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J
= 4.7 Hz, 1H), 7.02 (d, J = 4.8 Hz, 1H), 4.43 (s, 2H), 3.34 (s, 2H),
1.02 (s, 9H); 13C NMR {1H} (101 MHz, CDCl3) δ 165.5, 150.8,
2-Benzyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (6a):18
1
119.3 mg, 86% yield, white solid; H NMR (400 MHz, CDCl3) δ
10.46 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H),
7.41−7.38 (m, 2H), 7.37−7.33 (m, 2H), 7.32−7.28 (m, 1H), 7.25−
7.23 (m, 1H), 7.14−7.09 (m, 1H), 4.86 (s, 2H), 3.66 (t, J = 7.1 Hz,
G
DOI: 10.1021/acs.joc.9b02114
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
2H), 3.03 (t, J = 7.1 Hz, 2H); 13C NMR {1H} (101 MHz, CDCl3) δ
161.8, 137.8, 137.6, 128.7, 128.0, 127.5, 126.9, 125.2, 124.8, 120.0,
118.2, 112.7, 49.6, 47.5, 20.7.
(t, J = 7.6 Hz, 1H), 7.11 (d, J = 2.9 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H),
6.99 (dd, J = 5.0, 3.5 Hz, 1H), 4.86 (s, 2H), 3.64 (t, J = 7.0 Hz, 2H),
2.99 (t, J = 7.0 Hz, 2H); 13C NMR {1H} (101 MHz, DMSO-d6) δ
160.9, 140.9, 137.9, 127.2, 127.1, 126.2, 125.2, 124.6, 120.6, 120.0,
119.0, 113.0, 47.6, 44.3, 20.5; HRMS (ESI-TOF) [M + H]+ calcd for
C16H15N2OS+ 283.0900, found 283.0907.
2-(Thiophen-3-ylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]-
indol-1-one (12): 110.0 mg, 78% yield, pale yellow solid, mp 220.1−
225.8 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 7.58 (d, J
= 8.0 Hz, 1H), 7.52 (dd, J = 4.9, 2.9 Hz, 1H), 7.41 (d, J = 8.1 Hz,
2H), 7.22 (t, J = 7.6 Hz, 1H), 7.06 (dd, J = 12.6, 5.9 Hz, 2H), 4.68 (s,
2H), 3.61 (t, J = 7.0 Hz, 2H), 2.98 (t, J = 7.0 Hz, 2H); 13C NMR
{1H} (101 MHz, DMSO-d6) δ 160.9, 139.2, 137.9, 128.0, 127.4,
127.1, 125.2, 124.5, 123.1, 120.6, 119.9, 118.0, 113.0, 47.7, 44.8, 20.5;
HRMS (ESI-TOF) [M + H]+ calcd for C16H15N2OS+ 283.0900,
found 283.0911.
2-(4-Methylbenzyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-
1
one (6b): 133.5 mg, 92% yield, white solid, mp 260.9−265.2 °C; H
NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 7.57 (d, J = 7.9 Hz,
1H), 7.41 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 7.2 Hz, 3H), 7.16 (d, J =
7.4 Hz, 2H), 7.05 (t, J = 7.4 Hz, 1H), 4.66 (s, 2H), 3.57 (s, 2H), 2.96
(t, J = 6.7 Hz, 2H), 2.28 (s, 3H); 13C NMR {1H} (101 MHz, DMSO-
d6) δ 161.0, 137.9, 136.7, 135.4, 129.6, 128.1, 127.4, 125.2, 124.5,
120.6, 119.9, 117.9, 113.0, 48.9, 47.6, 21.2, 20.5; HRMS (ESI-TOF)
[M + Na]+ calcd for C19H18N2NaO+ 313.1311, found 313.1299.
2-(4-Methoxybenzyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-
1-one (6c): 130.6 mg, 85% yield, white solid, mp 230.2−235.1 °C; 1H
NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1H), 7.61 (d, J = 7.9 Hz,
1H), 7.45 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 8.7 Hz, 2H), 7.29−7.23
(m, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.95 (d, J = 8.7 Hz, 2H), 4.67 (s,
2H), 3.77 (s, 3H), 3.59 (d, J = 7.1 Hz, 2H), 2.99 (t, J = 7.0 Hz, 2H);
13C NMR {1H} (101 MHz, DMSO-d6) δ 161.0, 158.9, 137.9, 130.3,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b02114.
■
S
129.5, 127.5, 125.2, 124.5, 120.5, 119.9, 117.8, 114.4, 113.0, 55.5,
+
48.5, 47.5, 20.5; HRMS (ESI-TOF) [M + H]+ calcd for C19H19N2O2
307.1441, found 307.1451.
NMR spectra of substrates and products (PDF)
2-(4-Chlorobenzyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-
1
one (6d): 127.4 mg, 82% yield, white solid, mp 254.5−259.3 °C; H
NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.58 (d, J = 8.0 Hz,
1H), 7.40 (dt, J = 18.2, 5.8 Hz, 5H), 7.22 (dd, J = 11.3, 3.9 Hz, 1H),
7.06 (t, J = 7.4 Hz, 1H), 4.69 (s, 2H), 3.60 (t, J = 7.0 Hz, 2H), 2.98 (t,
J = 7.0 Hz, 2H); 13C NMR {1H} (101 MHz, DMSO-d6) δ 161.1,
137.9, 137.5, 132.2, 130.0, 129.0, 127.2, 125.2, 124.6, 120.6, 120.0,
118.1, 113.0, 48.6, 47.8, 20.5; HRMS (ESI-TOF) [M + H]+ calcd for
C18H16ClN2O+ 311.0946, found 311.0957.
2-(2-Methylbenzyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-
one (6e): 90 mg, 62.2% yield, pale yellow solid, mp 164.5−168.3 °C;
1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.58 (d, J = 8.0 Hz,
1H), 7.43 (d, J = 8.3 Hz, 1H), 7.27−7.16 (m, 5H), 7.06 (t, J = 7.3 Hz,
1H), 4.70 (s, 2H), 3.58 (t, J = 7.0 Hz, 2H), 2.97 (t, J = 7.0 Hz, 2H),
2.30 (s, 3H); 13C NMR {1H} (101 MHz, DMSO-d6) δ 160.9, 137.9,
136.5, 136.0, 130.7, 127.8, 127.5, 127.4, 126.4, 125.2, 124.5, 120.5,
119.9, 117.9, 113.0, 47.5, 47.1, 20.5, 19.2; HRMS (ESI-TOF) [M +
Na]+ calcd for C19H18N2NaO+ 313.1311, found 313.1309.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xiao-feng.wu@catalysis.de.
ORCID
Xiao-Feng Wu: 0000-0001-6622-3328
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
■
We acknowledge financial support from the Zhejiang Natural
Science Fund for Young Scholars (LQ18B020008), Zhejiang
Sci-Tech University (17062078-Y), and National Natural
Science Foundation of China (21772177).
2-Benzyl-6-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-
one (6f): 118.9 mg, 82.3% yield, white solid, mp 170.3−175.6 °C; 1H
NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 7.35−7.32 (m, 5H),
7.30 (s, 1H), 7.29−7.25 (m, 1H), 7.05 (d, J = 8.4 Hz, 1H), 4.69 (s,
2H), 3.56 (t, J = 7.0 Hz, 2H), 2.93 (t, J = 7.0 Hz, 2H), 2.37 (s, 3H);
13C NMR {1H} (101 MHz, DMSO-d6) δ 161.1, 138.5, 136.4, 129.0,
128.6, 128.0, 127.6, 127.4, 126.4, 125.4, 119.8, 117.4, 112.7, 49.2,
47.8, 21.6, 20.5; HRMS (ESI-TOF) [M + Na]+ calcd for
C19H18N2NaO+ 313.1311, found 313.1309.
2-Neopentyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one
(6g): 60.2 mg, 94% yield, white solid, mp 275.4−277.3 °C; 1H NMR
(400 MHz, CDCl3) δ 10.15 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.47 (d,
J = 8.3 Hz, 1H), 7.29 (dd, J = 7.1, 1.0 Hz, 1H), 7.14 (dd, J = 11.1, 3.9
Hz, 1H), 3.76 (t, J = 6.9 Hz, 2H), 3.39 (s, 2H), 3.06 (t, J = 6.9 Hz,
2H), 1.05 (s, 9H); 13C NMR {1H} (101 MHz, CDCl3) δ 162.5,
137.6, 127.6, 125.3, 124.6, 120.0, 118.4, 112.6, 57.8, 50.9, 33.9, 28.2,
21.0; HRMS (ESI-TOF) [M + H]+ calcd for C16H21N2O+ 257.1648,
found 257.1662.
REFERENCES
■
(1) For selected reviews on oxidative carbonylation, see: (a) Wu, X.-
F.; Neumann, H.; Beller, M. Palladium-catalyzed oxidative carbon-
ylation reactions. ChemSusChem 2013, 6, 229−241. (b) Gabriele, B.;
Mancuso, R.; Salerno, G. Oxidative carbonylation as a powerful tool
for the direct synthesis of carbonylated heterocycles. Eur. J. Org.
Chem. 2012, 2012, 6825−6839. (c) Liu, Q.; Zhang, H.; Lei, A.
Oxidative carbonylation reactions: organometallic compounds (R-M)
or hydrocarbons (R-H) as nucleophiles. Angew. Chem., Int. Ed. 2011,
50, 10788−10799.
(2) For selected examples of carbonylative C−H activation, see:
(a) Ying, J.; Fu, L.-Y.; Zhong, G.; Wu, X.-F. Cobalt-catalyzed direct
carbonylative synthesis of free (NH)-benzo[cd]indol-2(1H)-ones
from naphthylamides. Org. Lett. 2019, 21, 5694−5698. (b) Cabrera-
Pardo, J. R.; Trowbridge, A.; Nappi, M.; Ozaki, K.; Gaunt, M. J.
Selective palladium(II)-catalyzed carbonylation of methylene β-C-H
bonds in aliphatic amines. Angew. Chem., Int. Ed. 2017, 56, 11958−
11962. (c) Wen, J.; Tang, S.; Zhang, F.; Shi, R.; Lei, A. Palladium/
Copper co-catalyzed oxidative C-H/C-H carbonylation of diphenyl-
amines: a way to access acridones. Org. Lett. 2017, 19, 94−97.
(d) Willcox, D.; Chappell, B. G. N.; Hogg, K. F.; Calleja, J.; Smalley,
A. P.; Gaunt, M. J. A general catalytic β-C-H carbonylation of
aliphatic amines to β-lactams. Science 2016, 354, 851−857. (e) Shi, B.
F.; Maugel, N.; Zhang, Y. H.; Yu, J. Q. PdII-catalyzed enantioselective
activation of C(sp2)-H and C(sp3)-H bonds using monoprotected
amino acids as chiral ligands. Angew. Chem., Int. Ed. 2008, 47, 4882−
4886. (f) Chen, M.; Ren, Z.-H.; Guan, Z.-H. Palladium-catalyzed
regioselective carbonylation of C−H bonds of N-alkyl anilines for
synthesis of isatoic anhydrides. J. Am. Chem. Soc. 2012, 134, 17490−
5-(Thiophen-2-ylmethyl)-4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-
one (8): 70.0 mg, 57% yield, colorless oil; 1H NMR (400 MHz,
CDCl3) δ 7.62 (d, J = 4.8 Hz, 1H), 7.24 (dd, J = 5.0, 0.9 Hz, 1H),
7.03 (d, J = 2.9 Hz, 1H), 7.00 (d, J = 4.8 Hz, 1H), 6.96 (dd, J = 5.0,
3.6 Hz, 1H), 4.91 (s, 2H), 4.27 (s, 2H); 13C NMR {1H} (101 MHz,
CDCl3) δ 164.3, 151.0, 139.6, 135.5, 134.7, 127.0, 126.6, 125.6, 120.9,
+
48.1, 41.4; HRMS (ESI-TOF) [M + H]+ calcd for C11H10NOS2
236.0198, found 236.0207.
2-(Thiophen-2-ylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]-
indol-1-one (10): 114.2 mg, 81% yield, white solid, mp 248.3−252.2
°C; 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 7.58 (d, J = 8.0
Hz, 1H), 7.44 (dd, J = 5.0, 0.8 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.22
H
DOI: 10.1021/acs.joc.9b02114
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
17493. (g) Chen, M.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H.
Palladium-catalyzed oxidative carbonylation of the alkenyl C-H
bonds of enamides: synthesis of 1,3-oxazin-6-ones. Angew. Chem.,
Int. Ed. 2013, 52, 14196−14199. (h) Bai, X. F.; Mu, Q.-C.; Xu, Z.;
Yang, K.-F.; Li, L.; Zheng, Z.-J.; Xia, C. G.; Xu, L.-W. Catalytic
Asymmetric Carbonylation of Prochiral Sulfonamides via C-H
Desymmetrization. ACS Catal. 2019, 9, 1431−1436.
(3) (a) Orito, K.; Miyazawa, M.; Nakamura, T.; Horibata, A.;
Ushito, H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Yamazaki, T.;
Tokuda, M. Pd(OAc)2-catalyzed carbonylation of amines. J. Org.
Chem. 2006, 71, 5951−5958. (b) Orito, K.; Horibata, A.; Nakamura,
T.; Ushito, H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Tokuda, M.
Preparation of benzolactams by Pd(OAc)2-catalyzed direct aromatic
carbonylation. J. Am. Chem. Soc. 2004, 126, 14342−14343.
(4) Zhang, C.; Ding, Y.; Gao, Y.; Li, S.; Li, G. Palladium-catalyzed
direct C-H carbonylation of free primary benzylamines: a synthesis of
benzolactams. Org. Lett. 2018, 20, 2595−2598.
(16) Benachenhou, F.; Mesli, M. A.; Borai, M. E.; Hanquet, B.;
Guilard, R. Synthesis and Structure Elucidation of the Condensation
Products between Thiophene Dicarbaldehydes and Aromatic Amines.
Potential Analgesic and Anti-inflammatory Agents. J. Heterocycl. Chem.
1988, 25, 1531−1534.
̀
(17) Aubert, T.; Farnier, M.; Guilard, R. Nouvelle voie de Synthese
́
d’isoindolones et d’isoquinoleines par condensation d’iminophosphor-
́
́
́
́
anes avec l’ortho-phtalaldehyde: reactions, mecanismes et etude
structural. Can. J. Chem. 1990, 68, 842−851.
(18) Chern, M. S.; Shih, Y. K.; Dewang, P. M.; Li, W. R. Traceless
Solid-Phase Synthesis of Carbolinones. J. Comb. Chem. 2004, 6, 855−
858.
(5) Cheng, X.-F.; Wang, T.; Li, Y.; Wu, Y.; Sheng, J.; Wang, R.; Li,
C.; Bian, K.-J.; Wang, X.-S. Palladium(II)-catalyzed C(sp2)-H
carbonylation of sterically hindered amines with carbon monoxide.
Org. Lett. 2018, 20, 6530−6533.
(6) Han, J.; Wang, N.; Huang, Z.-B.; Zhao, Y.; Shi, D.-Q.
Ruthenium-catalyzed carbonylation of oxalyl amide-protected benzyl-
amines with isocyanate as the carbonyl source. J. Org. Chem. 2017, 82,
6831−6839.
(7) Fu, L.-Y.; Ying, J.; Qi, X.; Peng, J.-B.; Wu, X.-F. Palladium-
catalyzed carbonylative synthesis of isoindolinones from benzylamines
with TFBen as the CO source. J. Org. Chem. 2019, 84, 1421−1429.
(8) Wada, Y.; Nagasaki, H.; Tokuda, M.; Orito, K. Synthesis of N-
protected staurosporinones. J. Org. Chem. 2007, 72, 2008−2014.
(9) Ling, F.; Ai, C.; Lv, Y.; Zhong, W. Traceless directing group
assisted cobalt-catalyzed C-H carbonylation of benzylamines. Adv.
Synth. Catal. 2017, 359, 3707−3712.
(10) (a) Jiang, L.-B.; Qi, X.; Wu, X.-F. Benzene-1,3,5-triyl triformate
(TFBen): a convenient, efficient, and non-reacting CO source in
carbonylation reactions. Tetrahedron Lett. 2016, 57, 3368−3370.
(b) Wang, H.; Ying, J.; Lai, M.; Qi, X.; Peng, J.-B.; Wu, X.-F. Base
promoted carbonylative cyclization of propargylic amines with
selenium under CO gas-free conditions. Adv. Synth. Catal. 2018,
360, 1693−1703. (c) Ying, J.; Zhou, C.; Wu, X.-F. DBU-promoted
carbonylative synthesis of 1,3-oxathiolan-2-ones from propargylic
alcohols with TFBen as the CO source. Org. Biomol. Chem. 2018, 16,
1065−1067. (d) Ying, J.; Wang, H.; Qi, X.; Peng, J.-B.; Wu, X.-F.
Base-promoted sulfur-mediated carbonylative cyclization of prop-
argylic amines. Eur. J. Org. Chem. 2018, 2018, 688−692. (e) Zhou, C.;
Liu, Y.; Ying, J.; Qi, X.; Peng, J.-B.; Wu, X.-F. Cobalt catalyzed
carbonylative cyclization of allyl propargyl ethers with benzene-1,3,5-
triyl triformate as the CO source. Asian J. Org. Chem. 2019, 8, 238−
241. (f) Le, Z.; Ying, J.; Wu, X.-F. More than a CO source: palladium-
catalyzed carbonylative synthesis of butenolides from propargyl
alcohols and TFBen. Org. Chem. Front. 2019, 6, 3158.
(11) Brice, H.; Clayden, J. Doubly Dearomatising Intramolecular
Coupling of a Nucleophilic and an Electrophilicheterocycle. Chem.
Commun. 2009, 15, 1964−1966.
(12) Regnier, R.; Lavastre, O. General and Environmentally Friendly
Synthesis of Heterocyclic Multidentate Molecules Based on Micro-
wave-assisted Heating Protocol. Tetrahedron 2006, 62, 155−159.
(13) Fuente, M. C.; Domínguez, D. Normal Electron Demand Diels-
Alder Cycloaddition of Indoles to 2,3-Dimethyl-1,3-butadiene.
Tetrahedron 2011, 67, 3997−4001.
(14) Martin, D. B. C.; Vanderwal, C. D. Efficient Access to the Core
of the Strychnos, Aspidosperma and Iboga Alkaloids. A Short
Synthesis of Norfluorocurarine. J. Am. Chem. Soc. 2009, 131, 3472−
3473.
(15) Hanna-Elias, A.; T. Manallack, D.; Levit, A.; Nguyen, W.; Ayad,
F.; Perera, G.; Shapiro, M.; R. Irving, H.; M. Coupar, I.; N. Iskander,
M. Synthesis, testing and structure-activity studies on a library of 5-
HT 4 ligands. Med. Chem. 2010, 6, 344−354.
I
DOI: 10.1021/acs.joc.9b02114
J. Org. Chem. XXXX, XXX, XXX−XXX