Pd-Catalyzed Tandem Isomerization/Cyclization for the Synthesis of Aromatic Oxazaheterocycles and Pyrido[3,4- b]indoles

Article abstract of DOI:10.1021/acs.joc.1c00770

An effient tandem process consisting of palladium-catalyzed double-bond isomerization of long-chain olefins and subsequent intramolecular cyclization promoted by B2(OH)2 for the synthesis of aromatic oxazaheterocycles is disclosed. This strategy can also provide rapid access to pyrido[3,4-b]indoles, trans-2-olefins, and eneamides bearing various functional groups with high regio- and stereoselectivity.

Full text of DOI:10.1021/acs.joc.1c00770

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Article
Pd-Catalyzed Tandem Isomerization/Cyclization for the Synthesis of
Aromatic Oxazaheterocycles and Pyrido[3,4‑b]indoles
Linglong Ding, Yan-Ning Niu, and Xiao-Feng Xia*
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ABSTRACT: An effient tandem process consisting of palladium-
catalyzed double-bond isomerization of long-chain olefins and
subsequent intramolecular cyclization promoted by B2(OH)2 for
the synthesis of aromatic oxazaheterocycles is disclosed. This
strategy can also provide rapid access to pyrido[3,4-b]indoles,
trans-2-olefins, and eneamides bearing various functional groups
with high regio- and stereoselectivity.
palladium-boronate/borane-system-catalyzed isomerization of
olefins (Scheme 2a).10 Very recently, a similar strategy
involving a palladium/borane-catalyzed selective synthesis of
prenylated indoles was reported by Chen.11 In these
transformations, a B−Pd−H active species was involved as
the key catalyst. To continue our interest in Pd−H catalysis,12
we report, herein, an expedient pathway for alkene isomer-
ization/cyclization by harnessing the versatility of B2X4
reagents, which can serve as both a transition metal oxidant
and as a Lewis acid for cyclization (Scheme 2b).
INTRODUCTION
■
Metal-catalyzed alkene isomerization has emerged as a
powerful strategy with wide application for the synthesis of
high-value chemicals in industry and academia. During the past
few decades, a great number of C−C double-bond isomer-
ization protocols have been developed using catalysts derived
from noble metals1 as well as base metals.2 Despite the
remarkable developments and applications in organic synthesis
with these strategies, its use for C−C or C−X bond formation
in the synthesis of heterocyclic compounds has not been well
investigated.3 As early as 2012, Kochi and co-workers
developed a complex Pd-catalyzed alkene isomerization
strategy for catalytic cycloisomerization of 1,n-dienes.4 Later
on, Nielsen, Scheidt, and other groups reported a variety of
metal-catalyzed alkene isomerization of N- and O-allylic
systems to access structurally complex and diverse heterocycles
(Scheme 1).5 In 2016, a tandem long-distance chain-walking/
cyclization reaction via RuH2(CO)(PPh3)3/Brønsted acid
RESULTS AND DISCUSSION
■
We commenced our investigation using 1a as a model
substrate in the presence of previously reported conditions;13
cycloisomerization product 2a was obtained in a 43% yield
(Table 1, entry 1). However, glycerol and ethanol in place of
glucose as a hydrogen source failed miserably to give the
desired products (entries 2 and 3). Then, D-mannitol in place
of glucose as the hydrogen source improved the yield of
benzoxazine 2a to 67% (entry 4). Compared with B2Pin2,
B2(OH)4 is more environmentally benign and much atom
economic; therefore, we decided to replace B2Pin2 with
B2(OH)4.14 To our delight, when 3 equiv of B2(OH)4 was
used, the yield of 2a was increased to 79% (entry 5).
Subsequent fine tuning the reaction by reducing the amount of
B2(OH)4 to 2 equiv indicated that the yield of 2a was
improved further to 81% (entry 6). Moreover, when the
amount of B2(OH)4 was kept at 1.2 equiv, the yield of 2a was
cocatalysis leading to aromatic oxazaheterocycles was realized
6
́
by the Saa group. Recently, a complex nickel hydride/
Brønsted acid-cocatalyzed tandem isomerization/cyclization
reaction of allyl ethers and amines was disclosed by Fleischer
and co-workers.7 Although a series of catalysts have been
reported for the alkene isomerization/cyclization, developing
an efficient and simple catalytic system capable of expanding
the boundaries of long-distance alkene isomerization/cycliza-
tion is imperative in modern organic synthesis.
Recently, boranes or boronates have been reported as
efficient ancillary ligands with metal catalysts for activation of
olefins due to their potential to engage in Lewis acid coligand−
metal−substrate bridging interaction.8 In light of this strategy,
in 2016, Stokes, Song, and Prabhu groups developed a series of
diboron-assisted palladium-catalyzed transfer hydrogenations
of olefins and N-heteroaromatics, respectively (Scheme 2a).9
Later on, this was further explored by the Prabhu group in
Received: April 1, 2021
Published: July 19, 2021
https://doi.org/10.1021/acs.joc.1c00770
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© 2021 American Chemical Society
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Scheme 1. Previous Works on Tandem Alkene Isomerization/Cyclization
Scheme 2. Pd-Catalyzed Transfer Hydrogenations or Isomerization of Olefins
a
Table 1. Optimization of Reaction Conditions
b
yield (%)
entry
H source
additive (equiv)
solvent (mL)
2a
2a′
1
2
3
4
5
6
7
8
9
10
11
glucose
glycerol
EtOH
B2Pin2 (3.0)
B2Pin2 (3.0)
B2Pin2 (3.0)
B2Pin2 (3.0)
DCE (1.0)
DCE (1.0)
DCE (1.0)
DCE (1.0)
DCE (1.0)
DCE (1.0)
DCE (1.0)
DCE (1.0)
DCE (1.0)
DCE (1.0)
DCE (2.0)
DCE (2.0)
DMF (2.0)
toluene (2.0)
toluene (1.0)
toluene (1.0)
toluene (1.0)
toluene (1.0)
43
<5
D-mannitol
D-mannitol
D-mannitol
D-mannitol
D-mannitol
Fructose
Sucrose
67
79
81
19
58
73
79
82
55
0
B2(OH)4 (3.0)
B2(OH)4 (2.0)
B2(OH)4 (1.2)
B2(OH)4 (2.0)
B2(OH)4 (2.0)
B2(OH)4 (2.0)
B2(OH)4 (2.0)
B2(OH)4 (2.0)
B2(OH)4 (2.0)
B2(OH)4 (2.0)
B2(OH)4 (1.2)
B2(OH)4 (60%)
B2Pin2 (30%)
B2Pin2 (30%)
48
c
d
e
12
13
14
15
16
17
18
0
0
25
22
51
30
0
EtOH
EtOH
EtOH
H2O
52
43
<5
55
a
Conditions: 1a (0.05 mmol), H source (0.15 mmol), Pd(tBu3P)2 (10 mol %), NaOAc (0.15 mmol), and solvent (1 mL) at 130 °C for 24 h.
b
c
d
e
Isolated yields. 115 °C. 1a (0.1 mmol). Pd(tBu3P)2 (5 mol %).
dramatically reduced to 19% and enamine 2a′ was obtained in
a 48% yield concomitantly (entry 7). By decreasing the
temperature to 115 °C, a slightly reduced yield was observed
(entry 8). In addition, fructose and sucrose in place of D-
mannitol as the hydrogen source also gave the desired product
2a in 73 and 79% yields, respectively (entries 9 and 10).
Interestingly, in the absence of extra hydrogen sources and
bases, the cycloisomerization also smoothly occurred to give
the desired product 2a in 82% yields (entry 11). Further,
decreasing the catalyst loading to 5 mol % reduced the reaction
yield (55%, entry 12). Solvent screening revealed that
dichloroethane (DCE) was the best solvent, whereas
dimethylformamide (DMF) and toluene failed to give the
desired product (entries 13 and 14). Notably, when the
reaction was carried out under an ethanol/toluene system,
corresponding product 2a and enamine 2a′ were both
obtained (entries 15 and 16). When B2Pin2 (30 mol %) was
used, only enamine 2a′ was detected (entry 17). In addition,
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a
Table 2. Variations in an Alkene-Bearing Chain
a
b
c
Conditions: 1 (0.20 mmol), Pd(tBu3P)2 (10 mol %), and B2(OH)4 (0.40 mmol) in 3 mL of DCE at 130 °C for 24 h. Isolated yields. 1.0 mmol
d
e
1a was used. 48 h. 12 h.
using H2O in place of ethanol as the hydrogen source, the yield
of 2a was increased to 55% and enamine 2a′ was obtained in a
30% yield (entry 18). Therefore, the optimized reaction
conditions for this cycloisomerization were defined as
Pd(tBu3P)2 (10 mol %), and B2(OH)4 (2 equiv) in DCE at
130 °C under an argon atmosphere for 24 h (entry 11).
Under the optimized reaction conditions (Table 1, entry
11), the substrate scope of this reaction was examined (Table
2). Substrates with various long-distance olefins were subjected
to the cycloisomerization reactions and smoothly converted
into benzoxazines in moderate to good yields. Short-distance-
chain olefin derivatives were well tolerated, leading to the
corresponding products 2a and 2b in 82 and 76% yields,
respectively (entries 1 and 3). Long-distance-chain olefin
derivatives 1c,d cycloisomerized to benzoxazines 2c,d; lower
yields were obtained (44 and 38%, respectively, entries 4 and
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a
Table 3. Variations in Aryls and Oxygenated Nucleophiles
a
b
c
Conditions: 1 (0.20 mmol), Pd(tBu3P)2 (10 mol %), and B2(OH)4 (0.40 mmol) in 3 mL of DCE at 130 °C for 24 h. Isolated yields. 36 h.
5) even though the reaction was prolonged to 48 h. An internal
olefin derivative could also afford the desired product 2a in a
good yield (81%, entry 2). Substrate 1e with a sulfonamide
protecting group was compatible with this transformation to
give benzoxazine 2e in an 87% yield (entry 6). Notably, 1,1-
disubstituted alkene 1f can be also tolerated in this
transformation, affording 2f below average yield (45%, entry
7). A scale-up experiment (1.0 mmol) was carried out and
cycloisomerization product 2a was obtained in an 85% yield
(entry 1).
the corresponding cycloisomerization products 2g and 2h were
obtained in 60 and 73% yields, respectively (Table 3, entries 1
and 2). Secondary alcohol 1i had no effect on the reaction,
giving an excellent yield of product 2i (82%, entry 3).
However, due to the steric hindrance, substrates 1j and 1k
cycloisomerized to give benzoxazine 2j and 2k in fairly lower
yields (60 and 30%, respectively, entries 4 and 5). Finally, the
substrate having a long hydroxyl chain was also suitable for the
cycloisomerization reaction to give the seven-membered
benzoxazepines 2l in a good yield (70%, entry 6).
An electron-withdrawing group such as −Cl and an electron-
donating group such as −Me slightly influenced the yields, and
To further investigate the scope of this novel cyclo-
isomerization system, the reaction of N-tosyl tryptamine
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derivatives was carried out under the slightly modified reaction
conditions (Scheme 3). It is worth noting that the conversion
(entry 6). As expected, long-distance olefin substrates 5g and
5h can go through the chain-walking process over two
positions to give the corresponding E-isomer 6g and 6h in
60 and 64% yields at high temperatures, respectively (entries 7
and 8). Similarly, the 1,2-disubstituted alkenes 5i can also give
the isomerized product 6h in a lower yield (entry 9).
Substrates 5j and 5k had no effect on the reaction and the
corresponding isomerized products 6i and 6j were obtained in
42 and 80% yields, respectively (entries 10 and 11). However,
simple terminal alkenes such as 1-dodecene and 5-hexen-1-ol
were not tolerated in these isomerization conditions (not
shown in Table 4).
Scheme 3. Scope for the Synthesis of Pyrido[3,4-b]indoles
To better understand the mechanism of this cycloisomeriza-
tion, deuterium-labeled experiments were carried out with 1a
under different reaction conditions. As expected, the cyclo-
isomerization went smoothly when D2O was added in the
standard condition. NMR analysis of purified 2a-d2 indicated
that deuterium had been embedded at two different positions
(Scheme 4(1)). Deuteration on the β-position of a N atom in
2a-d2 meant that there was a process of tautomerization
between enamine and imine before the cyclization. The
reaction of 1a with ethanol-d6 gave product 2a-d1, whose NMR
spectra revealed that a deuterium atom had been incorporated
mainly at the terminal carbon position (Scheme 4(2)). These
phenomena were in accordance with previous reports.9,10
Control experiments were performed to gain insight into the
mechanism of this transformation (Scheme 5). Treatment of
1a with 3 equiv of ethanol and 1.2 equiv of B2Pin2 in toluene
under otherwise standard conditions gave rise to enamine 2a′
in a 79% yield (Scheme 5(1)), which can go through
intramolecular cyclization to afford 2a in the presence of
B2(OH)2 at 80 °C (Scheme 5(2)). The reaction of 1a with
ethanol and B2Pin2 systems could also give 2-olefin 2a″ in an
85% yield after 30 min, which could further go through
isomerization/cyclization to afford 2a in an 81% yield under
standard conditions (Scheme 5(3),(4)). These phenomena
meant that chain-walking of a double bond and cyclization
were involved as the key steps in this transformation.6
efficiency was improved significantly when the reaction
temperature decreased to 90 °C, as the reaction could be
completed within 8 h. The unprotected indole could undergo
cyclization to give a high yield of product 4a (82%). Methyl- or
benzyl-protected indoles gave the corresponding products 4b
and 4c in 70 and 68% yields, respectively. In addition, the C-5
substituted unprotected indoles with a methyl or a methoxyl
group smoothly underwent cyclization to give products 4d and
4e in 67 and 70% yields, respectively.
The isomerization process was further investigated on the
simple olefins with functionalized chains.15 As shown in Table
4, a series of trans-2-olefins bearing various functional groups
were obtained in good yields. 1-Phenylbut-3-en-1-ol, which
contains a −OH group, showed good compatibility with the
metal catalyst and furnished the isomerized products (E)-1-
phenylbut-2-en-1-ol (6a) instead of thermodynamically more
favored butyrophenone at a mild reaction condition (40 °C).11
In addition, substrate 5b containing a phenolic −OH group
can also give the isomerized product 6b in a 71% yield (entry
2). The corresponding isoeugenol derivative (E)-1,2-dime-
thoxy-4-(prop-1-en-1-yl)benzene (6c) was obtained in an
excellent yield (96%, entry 3). Further, substrates with allyl
ether can be also tolerated in this transformation, affording the
isomerized products 6d and 6e in good yields with moderate
selectivities (entries 4 and 5). Similarly, the isomerization of
the substrate with N-allyl 5f was also facile and afforded the
corresponding enamine E-isomer 6f in a 67% yield at 40 °C
According to deuterium experiments and mechanistic
investigations, a possible transformation pathway has been
proposed in Scheme 6. First, a Pd catalyst goes through
oxidative addition with B2(OH)4 to give active Pd species A;
water then coordinates to one boron atom to give adduct B,
which goes through H atom transfer to afford Pd−hydride C.
Migratory insertion of a double bond of 1a with Pd−hydride C
could afford Pd−alkyl intermediate D, which give intermediate
E through β-H elimination. Enamine intermediate F could be
Scheme 4. Deuterium Experiments
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a
Table 4. Scope for Isomerization of Alkenes
a
b
c
d
Conditions: 5 (0.20 mmol), Pd(tBu3P)2 (10 mol %), and B2(OH)4 (0.40 mmol) in 3 mL of DCE. Isolated yields. Determined by 1H NMR. 5g
e
(0.20 mmol), Pd(tBu3P)2 (10 mol %), B2Pin2 (1.2 equiv), and C2H5OH (3.0 equiv) in 3 mL of toluene. Anhydrous DCE is used.
obtained after isomerization from E. In the presence of
B2(OH)4, enamine intermediate can easily transform into
imine intermediate G, which could go through intramolecular
cyclization to afford product 2a.
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further characterized by HRMS (high-resolution mass spectra); high-
resolution mass spectrometry (HRMS) spectra were obtained on a
micrOTOF-Q instrument equipped with an ESI source. Copies of
their 1H NMR and 13C NMR spectra are provided. Pd(tBu3P)2,
B2(OH)4, and the substrate 5f were purchased from Sigma-Aldrich.
All reagents or catalysts were directly used as purchased without
further purification. The substrates 1a−1l, 3a−3e, 5a, 5b were
synthesized according to a previous report.5a,6 The solvent for
recrystallization of all solid compounds was CH2Cl2.
Scheme 5. Mechanistic Investigations
General Procedure for the Synthesis of Products 2, 4, and
6. A mixture of N-(but-3-en-1-yl)-N-(2-(hydroxymethyl)-phenyl)-4-
methyl-benzene-sulfonamide 1a (0.20 mmol), B2(OH)4 (0.40 mmol),
and Pd(tBu3P)2 (0.02 mmol) was combined in DCE (3.0 mL) at 130
°C in an oil bath for 24 h under an argon atmosphere. After the
reaction, 10 mL of water was added to quench the reaction, and the
resulting mixture was extracted twice with CH2Cl2 (2 × 10 mL). The
combined organic extracts were washed with brine (10 mL), dried
over Na2SO4, and concentrated. Purification of the crude product by
flash column chromatography afforded the product 2a (petroleum
ether/ethyl acetate = 6:1).
A mixture of N-(2-(1H-indol-3-yl)ethyl)-N-allyl-4-methylbenzene-
sulfonamide 3a (0.20 mmol), B2(OH)4 (0.40 mmol), and Pd(tBu3P)2
(0.02 mmol) was combined in DCE (3.0 mL) at 90 °C in an oil bath
for 8 h under an argon atmosphere. After the reaction, 10 mL of water
was added to quench the reaction, and the resulting mixture was
extracted twice with CH2Cl2 (2 × 10 mL). The combined organic
extracts were washed with brine (10 mL), dried over Na2SO4, and
concentrated. Purification of the crude product by flash column
chromatography afforded the product 4a (petroleum ether/ethyl
acetate = 3:1).
A mixture of 1-phenylbut-3-en-1-ol 5a (0.20 mmol), B2(OH)4
(0.40 mmol), and Pd(tBu3P)2 (0.02 mmol) was combined in DCE
(3.0 mL) at 40 °C in an oil bath for 6 h under an argon atmosphere.
After the reaction, 10 mL of water was added to quench the reaction,
and the resulting mixture was extracted twice with CH2Cl2 (2 × 10
mL). The combined organic extracts were washed with brine (10
mL), dried over Na2SO4, and concentrated. Purification of the crude
product by flash column chromatography afforded the product 6a
(petroleum ether/ethyl acetate = 10:1).
Scale-Up Experiment for the Synthesis of 2a. A mixture of N-
(but-3-en-1-yl)-N-(2-(hydroxymethyl)-phenyl)-4-methyl-benzene-sul-
fonamide 1a (1.0 mmol), B2(OH)4 (2.0 mmol), and Pd(tBu3P)2 (0.1
mmol) was combined in DCE (10 mL) at 130 °C in an oil bath for 24
h under an argon atmosphere. After the reaction, 20 mL of water was
added to quench the reaction, and the resulting mixture was extracted
twice with CH2Cl2 (2 × 20 mL). The combined organic extracts were
washed with brine (20 mL), dried over Na2SO4, and concentrated.
Purification by column chromatography on a silica gel (petroleum
ether/ethyl acetate = 6:1) provided the product 2a (281 mg, 85%) as
a yellow solid.
CONCLUSIONS
■
In summary, we have developed an efficient double-bond
isomerization/intramolecular cyclization process for the syn-
thesis of six- or seven-membered 1,3-oxazaheterocycles and
pyrido[3,4-b]indoles. A series of trans-2-olefins and eneamides
bearing various functional groups can be also obtained with
high regio- and stereoselectivity. B2X4 reagents were crucial for
this Pd−H catalytic procedure and intramolecular cyclization
as a Lewis acid. This protocol serves as a platform to open new
approaches in palladium hydride-catalyzed tandem trans-
formations.
EXPERIMENTAL SECTION
General Remarks. Column chromatography was carried out on a
■
1
silica gel. Unless noted, H NMR spectra were recorded at 400 MHz
in CDCl3, 13C NMR spectra were recorded at 100 MHz in CDCl3,
and IR spectra were recorded on an FTIR spectrometer and only
major peaks are reported in cm−1. Melting points were determined on
a microscopic apparatus and were uncorrected. All new products were
Scheme 6. Proposed Mechanism
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2-Propyl-1-tosyl-1,4-dihydro-2H-benzo[d][1,3]oxazine (2a). Mp
= 100−102 °C, 82%, yellow solid, 54 mg, 24 h, Rf = 0.6 (petroleum
ether/EtOAc = 6:1); CAS: 1863980-22-6;6 1H NMR (400 MHz,
CDCl3): 7.78 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 8.2 Hz, 2H), 7.30−7.25
(m, 1H), 7.14 (dd, J = 23.0, 7.8 Hz, 3H), 6.83 (d, J = 7.6 Hz, 1H),
5.79 (t, J = 7.0 Hz, 1H), 4.59 (d, J = 15.6 Hz, 1H), 4.11 (d, J = 15.6
Hz, 1H), 2.34 (s, 3H), 1.66−1.60 (m, 2H), 1.44 (dt, J = 14.7, 7.3 Hz,
2H), 0.92 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3):
143.5, 135.5, 132.5, 129.0, 128.3, 127.7, 127.2, 127.1, 126.1, 124.2,
83.7, 60.7, 33.2, 21.5, 18.2, 13.5; IR (cm−1): 2959, 2871, 1598, 1492,
1457, 1378, 1348, 1306, 1239, 1202, 1168, 1107, 1088, 1059, 1020,
917, 804, 760, 704, 681, 649.
2-Ethyl-1-tosyl-1,4-dihydro-2H-benzo[d][1,3]oxazine (2b). Mp =
69−71 °C, 76%, yellow solid, 48 mg, 24 h, Rf = 0.6 (petroleum ether/
EtOAc = 6:1); CAS: 1863980-26-0;6 1H NMR (400 MHz, CDCl3):
7.79 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.30−7.25 (m,
1H), 7.18−7.10 (m, 3H), 6.83 (d, J = 7.6 Hz, 1H), 5.69 (t, J = 7.1 Hz,
1H), 4.59 (d, J = 15.6 Hz, 1H), 4.11 (d, J = 15.6 Hz, 1H), 2.34 (s,
3H), 1.72−1.64 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): 143.5, 135.5, 132.5, 129.0, 128.3, 127.7, 127.2,
127.1, 126.0, 124.2, 85.2, 60.7, 24.6, 21.5, 9.3; IR (cm−1): 3065, 2969,
2935, 2876, 1598, 1492, 1457, 1378, 1347, 1272, 1208, 1170, 1114,
1087, 1050, 1019, 949, 935, 877, 809, 762, 704, 682, 649.
2-Butyl-1-tosyl-1,4-dihydro-2H-benzo[d][1,3]oxazine (2c). Mp =
83−85 °C, 44%, yellow solid, 31 mg, 48 h, Rf = 0.6 (petroleum ether/
EtOAc = 6:1); CAS: 1863980-27-1;6 1H NMR (400 MHz, CDCl3):
7.79 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 8.3 Hz, 2H), 7.27 (t, J = 7.0 Hz,
1H), 7.19−7.09 (m, 3H), 6.83 (d, J = 7.6 Hz, 1H), 5.77 (t, J = 7.0 Hz,
1H), 4.59 (d, J = 15.6 Hz, 1H), 4.11 (d, J = 15.6 Hz, 1H), 2.34 (s,
3H), 1.65 (dt, J = 8.6, 6.2 Hz, 2H), 1.44−1.28 (m, 4H), 0.87 (t, J =
7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): 143.5, 135.5, 132.5,
129.0, 128.3, 127.7, 127.2, 127.1, 126.1, 124.2, 84.0, 60.7, 30.9, 27.0,
22.1, 21.5, 13.9; IR (cm−1): 2955, 2859, 1598, 1492, 1457, 1379,
1348, 1230, 1168, 1089, 1052, 1019, 808, 760, 704, 681, 649.
2-Pentyl-1-tosyl-1,4-dihydro-2H-benzo[d][1,3]oxazine (2d). Mp
= 76−78 °C, 38%, yellow solid, 27 mg, 48 h, Rf = 0.6 (petroleum
ether/EtOAc = 6:1); CAS: 1863980-28-2;6 1H NMR (400 MHz,
CDCl3): 7.78 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.27 (t, J
= 7.8 Hz, 1H), 7.18−7.10 (m, 3H), 6.83 (d, J = 6.2 Hz, 1H), 5.77 (t, J
= 7.0 Hz, 1H), 4.59 (d, J = 15.6 Hz, 1H), 4.11 (d, J = 15.6 Hz, 1H),
2.34 (s, 3H), 1.64 (qd, J = 7.1, 2.1 Hz, 2H), 1.46−1.38 (m, 2H),
1.30−1.23 (m, 4H), 0.89−0.83 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3): 143.5, 135.5, 132.5, 129.0, 128.3, 127.7, 127.2, 127.1, 126.1,
124.2, 84.0, 60.7, 31.2, 31.1, 24.6, 22.4, 21.5, 13.9; IR (cm−1): 2928,
2858, 1598, 1492, 1457, 1378, 1349, 1212, 1168, 1090, 1053, 1019,
969, 917, 805, 761, 704, 681, 649.
1457, 1346, 1306, 1224, 1209, 1168, 1110, 1078, 1051, 1022, 952,
905, 808, 759, 704, 683, 650.
6-Chloro-2-propyl-1-tosyl-1,4-dihydro-2H-benzo[d][1,3]oxazine
(2g). Mp = 87−89 °C, 60%, yellow solid, 44 mg, 24 h, Rf = 0.6
(petroleum ether/EtOAc = 6:1); 1H NMR (400 MHz, CDCl3): 7.74
(d, J = 8.7 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.8 Hz, 1H),
7.15 (d, J = 8.1 Hz, 2H), 6.85 (s, 1H), 5.77 (t, J = 7.0 Hz, 1H), 4.55
(d, J = 15.9 Hz, 1H), 4.10 (d, J = 15.9 Hz, 1H), 2.36 (s, 3H), 1.64−
1.59 (m, 2H), 1.44 (dq, J = 15.3, 7.6 Hz, 2H), 0.93 (t, J = 7.4 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): 143.8, 135.3, 131.7, 131.2,
129.8, 129.2, 128.4, 127.7, 127.6, 124.2, 83.7, 60.4, 33.1, 21.5, 18.2,
13.5; IR (cm−1): 2959, 2871, 1598, 1480, 1417, 1351, 1240, 1197,
1168, 1119, 1088, 1032, 983, 921, 837, 812, 769, 705, 684, 662;
HRMS (ESI) m/z calcd for C18H20ClNO3S+ (M + Na)+ 388.0750,
found 388.0745.
8-Methyl-2-propyl-1-tosyl-1,4-dihydro-2H-benzo[d][1,3]oxazine
(2h). Mp = 113−115 °C, 73%, white solid, 50 mg, 24 h, Rf = 0.6
(petroleum ether/EtOAc = 6:1); 1H NMR (400 MHz, CDCl3): 7.38
(d, J = 8.4 Hz, 2H), 7.23 (d, J = 7.8 Hz, 1H), 7.15 (dt, J = 7.6, 3.5 Hz,
3H), 6.66 (d, J = 7.5 Hz, 1H), 5.68 (t, J = 6.4 Hz, 1H), 4.30 (d, J =
15.2 Hz, 1H), 3.51 (d, J = 15.1 Hz, 1H), 2.54 (s, 3H), 2.38 (s, 3H),
1.40 (td, J = 12.5, 12.0, 7.4 Hz, 4H), 0.88 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): 143.6, 138.9, 135.7, 132.5, 131.6,
130.1, 128.9, 128.4, 127.0, 121.8, 84.5, 61.9, 34.9, 21.5, 18.9, 18.2,
13.5; IR (cm−1): 2920, 2850, 1594, 1458, 1349, 1240, 1197, 1181,
1162, 1142, 1132, 1076, 1047, 1017, 924, 911, 880, 809, 776, 727,
703, 675, 635; HRMS (ESI) m/z calcd for C19H23NO3S+ (M + Na)+
368.1296, found 368.1291.
4-Methyl-2-propyl-1-tosyl-1,4-dihydro-2H-benzo[d][1,3]oxazine
(2i). Mp = 84−86 °C, 82%, white solid, 56 mg, 24 h, Rf = 0.6
(petroleum ether/EtOAc = 6:1), dr = 3.4:1; CAS: 1863980-34-0;6 1H
NMR (400 MHz, CDCl3): 7.79 (dd, J = 8.0, 1.2 Hz, 1Hdiast1), 7.71
(dd, J = 8.0, 1.2 Hz, 1Hdiast2), 7.42 (d, J = 8.3 Hz, 1Hdiast1), 7.34
(d, J = 8.4 Hz, 3Hdiast2), 7.29 (d, J = 18.8 Hz, 1Hdiast2), 7.21 (qd, J
= 7.5, 1.3 Hz, 1Hdiast1), 7.11 (d, J = 8.1 Hz, 2Hdiast1, 2Hdiast2),
6.98 (d, J = 7.6 Hz, 1Hdiast2), 6.89 (d, J = 8.0 Hz, 1Hdiast1), 5.79 (t,
J = 7.0 Hz, 1Hdiast1), 5.59 (t, J = 6.2 Hz, 1Hdiast2), 4.74 (q, J = 6.4
Hz, 1Hdiast1), 3.61 (q, J = 6.6 Hz, 1Hdiast2), 2.35 (s, 3Hdiast2),
2.33 (s, 3Hdiast1), 1.72−1.38 (m, 4Hdiast1, 4Hdiast2), 1.30 (d, J =
6.6 Hz, 3Hdiast2), 0.92 (t, J = 7.3 Hz, 3Hdiast1), 0.89 (d, J = 7.2 Hz,
3Hdiast2), 0.72 (d, J = 6.5 Hz, 3Hdiast1); 13C{1H} NMR (100 MHz,
CDCl3): 143.5, 143.4, 136.3, 135.6, 133.1, 132.9, 131.9, 129.2, 128.9,
128.1, 127.7, 127.7, 127.5, 127.3, 127.1, 126.5, 126.2, 124.6, 123.6,
85.2, 83.8, 68.2, 66.1, 38.0, 33.0, 21.5, 21.4, 20.9, 20.6, 18.3, 18.1,
13.6, 13.5; IR (cm−1): 2959, 2872, 1598, 1486, 1456, 1351, 1306,
1245, 1202, 1168, 1090, 1021, 813, 758, 705, 684, 664.
4-Phenyl-2-propyl-1-tosyl-1,4-dihydro-2H-benzo[d][1,3]oxazine
(2j). Mp = 85−87 °C, 60%, yellow solid, 48 mg, 36 h, Rf = 0.6
(petroleum ether/EtOAc = 6:1), dr = 3.7:1; CAS: 1863980-35-1;6 1H
NMR (400 MHz, CDCl3): 7.98 (d, J = 8.2 Hz, 1Hdiast1), 7.74 (d, J =
6.8 Hz, 1Hdiast2), 7.56 (d, J = 8.3 Hz, 2Hdiast1), 7.42 (d, J = 8.3 Hz,
2Hdiast2), 7.38−7.19 (m, 6Hdiast1, 6Hdiast2), 7.08 (t, J = 7.6 Hz,
2Hdiast1, 2Hdiast2), 6.94 (dd, J = 6.7, 2.8 Hz, 1Hdiast1, 1Hdiast2),
6.61 (d, J = 7.6 Hz, 1Hdiast1), 6.35 (dd, J = 15.1, 7.2 Hz, 1Hdiast1,
2Hdiast2), 6.01 (t, J = 7.0 Hz, 1Hdiast1), 5.72 (t, J = 5.9 Hz,
1Hdiast2), 5.65 (s, 1Hdiast1), 4.03 (s, 1Hdiast2), 2.45 (s, 3Hdiast1),
2.44 (s, 3Hdiast2), 1.90−1.81 (m, 2Hdiast1), 1.79−1.72 (m,
2Hdiast2), 1.63−1.52 (m, 2Hdiast1), 1.47−1.39 (m, 2Hdiast2),
0.99 (t, J = 7.4 Hz, 3Hdiast1), 0.90 (t, J = 7.4 Hz, 3Hdiast2); 13C{1H}
NMR (100 MHz, CDCl3): 143.9, 143.6, 139.9, 138.1, 137.2, 135.9,
135.7, 133.9, 132.5, 130.3, 129.6, 129.4, 128.5, 128.4, 128.3, 128.2,
128.0, 127.9, 127.6, 127.4, 126.7, 126.3, 125.8, 125.2, 85.8, 84.9, 75.3,
73.7, 38.9, 33.2, 21.5, 18.3, 17.8, 13.7, 13.6; IR (cm−1): 3064, 3030,
2959, 2930, 2871, 1598, 1481, 1455, 1355, 1305, 1289, 1242, 1168,
1108, 1088, 1019, 867, 814, 757, 700, 664.
1-(Phenylsulfonyl)-2-propyl-1,4-dihydro-2H-benzo[d][1,3]-
oxazine (2e). Mp = 99−101 °C, 87%, white solid, 55 mg, 24 h, Rf =
1
0.6 (petroleum ether/EtOAc = 6:1); H NMR (400 MHz, CDCl3):
7.79 (d, J = 9.4 Hz, 1H), 7.57−7.50 (m, 2H), 7.47 (t, J = 7.5 Hz, 1H),
7.34−7.25 (m, 3H), 7.17 (t, J = 6.9 Hz, 1H), 6.82 (d, J = 7.7 Hz, 1H),
5.80 (t, J = 7.0 Hz, 1H), 4.58 (d, J = 15.6 Hz, 1H), 4.07 (d, J = 15.6
Hz, 1H), 1.63 (dt, J = 8.9, 6.4 Hz, 2H), 1.46 (p, J = 7.4 Hz, 2H), 0.92
(t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): 138.3, 132.7,
132.4, 128.4, 128.3, 127.7, 127.2, 127.1, 126.2, 124.2, 83.8, 60.7, 33.2,
18.2, 13.5; IR (cm−1): 3060, 2961, 2925, 2863, 1607, 1584, 1491,
1456, 1377, 1337, 1240, 1204, 1169, 1104, 1087, 1061, 1025, 981,
960, 941, 917, 875, 803, 755, 725, 709, 690, 662, 600; HRMS (ESI)
m/z calcd for C17H19NO3S+ (M + Na)+ 340.0983, found 340.0978.
2-Isopropyl-1-tosyl-1,4-dihydro-2H-benzo[d][1,3]oxazine (2f).
Mp = 106−108 °C, 45%, yellow solid, 30 mg, 12 h, Rf = 0.6
(petroleum ether/EtOAc = 6:1); CAS: 1863980-33-9;6 1H NMR
(400 MHz, CDCl3): 7.78 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 8.3 Hz,
2H), 7.30−7.25 (m, 1H), 7.19−7.10 (m, 3H), 6.83 (d, J = 7.8 Hz,
1H), 5.30 (d, J = 10.0 Hz, 1H), 4.58 (d, J = 15.6 Hz, 1H), 4.08 (d, J =
15.6 Hz, 1H), 2.34 (s, 3H), 1.85 (dp, J = 9.9, 6.6 Hz, 1H), 0.99 (dd, J
= 6.6, 4.4 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3): 143.5, 135.6,
132.5, 129.1, 128.7, 127.7, 127.2, 127.1, 126.1, 124.2, 89.0, 60.8, 28.6,
21.5, 18.6, 18.1; IR (cm−1): 3065, 2961, 2925, 2871, 1598, 1492,
4-Ethyl-4-methyl-2-propyl-1-tosyl-1,4-dihydro-2H-benzo[d][1,3]-
oxazine (2k). Mp = 73−75 °C, 30%, yellow solid, 20 mg, 36 h, Rf =
1
0.6 (petroleum ether/EtOAc = 6:1); H NMR (400 MHz, CDCl3):
7.80 (dd, J = 8.1, 3.6 Hz, 1H), 7.47 (dd, J = 14.6, 8.3 Hz, 2H), 7.27 (t,
J = 7.8 Hz, 1H), 7.22−7.17 (m, 1H), 7.14 (dd, J = 8.2, 4.1 Hz, 2H),
10039
https://doi.org/10.1021/acs.joc.1c00770
J. Org. Chem. 2021, 86, 10032−10042

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
6.97−6.92 (m, 1H), 5.77−5.68 (m, 1H), 2.33 (d, J = 3.9 Hz, 3H),
1.78−1.50 (m, 4H), 1.45 (dd, J = 15.5, 6.9 Hz, 2H), 1.33 (s, 1H),
0.95−0.84 (m, 5H), 0.51−0.45 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3): 143.5, 143.5, 138.0, 137.6, 136.4, 136.4, 131.4, 131.3, 129.2,
129.1, 128.5, 128.3, 128.1, 127.9, 127.2, 126.9, 126.8, 126.4, 126.2,
125.2, 125.1, 83.8, 83.7, 75.3, 75.0, 37.6, 36.7, 36.4, 35.0, 27.2, 27.1,
21.4, 21.4, 19.0, 18.9, 13.5, 7.9, 7.5; IR (cm−1): 3064, 3029, 2961,
2935, 2874, 1598, 1485, 1447, 1350, 1305, 1288, 1249, 1212, 1168,
1100, 1057, 1019, 953, 874, 812, 761, 679, 648; HRMS (ESI) m/z
calcd for C21H27NO3S+ (M + Na)+ 396.1609, found 396.1604.
2-Propyl-1-tosyl-1,2,4,5-tetrahydrobenzo[d][1,3]oxazepine (2l).
Mp = 148−150 °C, 70%, white solid, 48 mg, 24 h, Rf = 0.6
(petroleum ether/EtOAc = 6:1); CAS: 1863980-38-4;6 1H NMR
(400 MHz, CDCl3): 7.55 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 6.8 Hz,
1H), 7.25−7.18 (m, 4H), 7.02−6.98 (m, 1H), 5.94 (t, J = 6.8 Hz,
1H), 3.60−3.50 (m, 2H), 2.40 (s, 3H), 2.19 (d, J = 16.1 Hz, 1H),
2.02 (ddd, J = 15.2, 9.8, 5.2 Hz, 1H), 1.40 (dq, J = 32.4, 7.0 Hz, 4H),
0.86 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): 143.3,
139.8, 138.0, 135.2, 132.4, 129.9, 129.2, 128.5, 127.7, 127.2, 84.9,
59.1, 36.3, 32.5, 21.5, 18.2, 13.5; IR (cm−1): 3071, 2958, 2879, 1595,
1488, 1451, 1388, 1340, 1247, 1166, 1110, 1089, 1070, 1027, 996,
934, 864, 820, 773, 750, 709, 670, 636.
1596, 1495, 1463, 1335, 1156, 1091, 1034, 968, 914, 853, 815, 735,
662; HRMS (ESI) m/z calcd for C21H24N2O2S+ (M + H)+ 369.1637,
found 369.1631.
1-Ethyl-6-methoxy-2-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]-
indole (4e). Oil, 70%, 53 mg, 24 h, Rf = 0.6 (petroleum ether/EtOAc
1
= 3:1); H NMR (400 MHz, CDCl3): 8.00 (s, 1H), 7.62 (d, J = 8.3
Hz, 2H), 7.15 (d, J = 8.6 Hz, 1H), 7.07 (d, J = 6.3 Hz, 2H), 6.79−
6.74 (m, 2H), 5.05 (dd, J = 8.7, 5.0 Hz, 1H), 4.14−4.08 (m, 1H), 3.79
(s, 3H), 3.43−3.34 (m, 1H), 2.44 (dd, J = 16.2, 4.2 Hz, 1H), 2.37−
2.29 (m, 1H), 2.26 (s, 3H), 1.93−1.75 (m, 2H), 1.07 (t, J = 7.4 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): 153.8, 143.1, 138.1, 134.0,
130.9, 129.4, 126.9, 126.7, 111.5, 111.4, 107.2, 100.3, 55.8, 54.5, 39.6,
28.8, 21.3, 19.8, 10.8; IR (cm−1): 3331, 2967, 2935, 1695, 1596, 1492,
1331, 1287, 1216, 1156, 1090, 1029, 972, 912, 851, 815, 734, 662;
HRMS (ESI) m/z calcd for C21H24N2O3S+ (M + H)+ 385.1586,
found 385.1580.
(E)-1-Phenylbut-2-en-1-ol (6a). Oil, 74%, 22 mg, 40 °C, 6 h, Rf =
0.5 (petroleum ether/EtOAc = 10:1); CAS: 52755-39-2;15d 1H NMR
(400 MHz, CDCl3): 7.39−7.32 (m, 4H), 7.29−7.25 (m, 1H), 5.80−
5.65 (m, 2H), 5.16 (d, J = 3.5 Hz, 1H), 1.90 (d, J = 3.2 Hz, 1H), 1.72
(d, J = 6.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): 143.3, 133.6,
128.5, 127.5, 126.1, 75.2, 17.7; IR (cm−1): 3349, 3061, 3027, 2963,
2914, 2854, 1672, 1601, 1491, 1450, 1377, 1194, 1115, 1068, 1004,
964, 912, 845, 754, 698, 630.
(E)-2-(Prop-1-en-1-yl)phenol (6b). Oil, 71%, 19 mg, 40 °C, 12 h,
Rf = 0.5 (petroleum ether/EtOAc = 10:1); CAS: 23619-59-2;7 1H
NMR (400 MHz, CDCl3): 7.29 (d, J = 6.0 Hz, 1H), 7.12−7.07 (m,
1H), 6.91−6.86 (m, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 15.9
Hz, 1H), 6.25−6.16 (m, 1H), 4.95 (s, 1H), 1.92 (dd, J = 6.6, 1.8 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): 152.4, 128.2, 127.9, 127.3,
125.3, 125.0, 120.8, 115.7, 18.9; IR (cm−1): 3397, 2960, 2921, 1643,
1615, 1576, 1495, 1454, 1343, 1285, 1257, 1195, 1180, 1132, 1105,
1076, 1028, 972, 877, 841, 796, 750, 698, 635.
1-Ethyl-2-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (4a).
Oil, 82%, 58 mg, 24 h, Rf = 0.6 (petroleum ether/EtOAc = 3:1);
CAS: 864953-98-0;16b 1H NMR (400 MHz, CDCl3): 8.09 (s, 1H),
7.62 (d, J = 8.2 Hz, 2H), 7.31−7.25 (m, 2H), 7.13−7.00 (m, 4H),
5.09 (dd, J = 8.8, 4.9 Hz, 1H), 4.12 (dd, J = 15.1, 5.2 Hz, 1H), 3.43−
3.34 (m, 1H), 2.48 (dd, J = 15.1, 4.2 Hz, 1H), 2.38−2.29 (m, 1H),
2.25 (s, 3H), 1.97−1.79 (m, 2H), 1.09 (t, J = 7.4 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3): 143.2, 138.1, 135.8, 133.1, 129.4, 126.7,
126.5, 121.8, 119.2, 117.9, 110.9, 107.4, 54.5, 39.6, 28.8, 21.3, 19.7,
10.8; IR (cm−1): 3387, 3054, 2966, 2930, 1596, 1492, 1451, 1377,
1332, 1303, 1158, 1091, 1034, 974, 929, 813, 727, 710, 696, 652.
1-Ethyl-9-methyl-2-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]-
indole (4b). Mp = 146−148 °C, 70%, white solid, 50 mg, 24 h, Rf =
(E)-1,2-Dimethoxy-4-(prop-1-en-1-yl)benzene (6c). Oil, 96%, 34
mg, 80 °C, 1 h, Rf = 0.5 (petroleum ether/EtOAc = 10:1); CAS:
6379-72-2;10 1H NMR (400 MHz, CDCl3): 6.90−6.78 (m, 3H), 6.34
(d, J = 15.7 Hz, 1H), 6.15−6.06 (m, 1H), 3.88 (d, J = 9.1 Hz, 6H),
1.86 (dd, J = 6.6, 1.7 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3):
149.0, 148.1, 131.1, 130.6, 123.7, 118.6, 111.2, 108.5, 55.9, 55.7, 18.3;
IR (cm−1): 2998, 2954, 2932, 2833, 1602, 1582, 1513, 1464, 1415,
1376, 1333, 1263, 1231, 1156, 1138, 1026, 962, 921, 855, 816, 783,
764, 614.
1
0.6 (petroleum ether/EtOAc = 3:1); H NMR (400 MHz, CDCl3):
7.57 (d, J = 8.2 Hz, 2H), 7.29−7.23 (m, 2H), 7.20−7.14 (m, 1H),
7.03 (t, J = 7.9 Hz, 3H), 5.04 (dd, J = 10.3, 3.7 Hz, 1H), 4.09 (dd, J =
14.9, 6.2 Hz, 1H), 3.65 (s, 3H), 3.46−3.38 (m, 1H), 2.48 (dd, J =
16.0, 5.4 Hz, 1H), 2.42−2.32 (m, 1H), 2.21 (s, 3H), 1.88−1.73 (m,
2H), 1.17 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3):
143.1, 137.9, 137.0, 134.8, 129.2, 126.7, 126.3, 121.4, 119.0, 118.1,
108.7, 106.2, 53.7, 38.5, 29.8, 27.9, 21.3, 19.5, 11.2; IR (cm−1): 2953,
2921, 2849, 1466, 1377, 1334, 1196, 1180, 1161, 1141, 1132, 1076,
972, 814, 742, 714, 635; HRMS (ESI) m/z calcd for C21H24N2O2S+
(M + H)+ 369.1637, found 369.1631.
9-Benzyl-1-ethyl-2-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]-
indole (4c). Oil, 68%, 60 mg, 24 h, Rf = 0.6 (petroleum ether/EtOAc
= 3:1); 1H NMR (400 MHz, CDCl3): 7.39 (d, J = 8.3 Hz, 2H), 7.33−
7.27 (m, 4H), 7.17 (d, J = 8.2 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.04
(t, J = 6.7 Hz, 1H), 6.97 (t, J = 7.9 Hz, 4H), 5.38 (d, J = 16.9 Hz, 1H),
5.17 (d, J = 16.9 Hz, 1H), 4.93 (dd, J = 9.0, 4.8 Hz, 1H), 4.16 (dd, J =
15.0, 6.2 Hz, 1H), 3.49−3.40 (m, 1H), 2.52 (dd, J = 16.2, 4.5 Hz,
1H), 2.38 (s, 1H), 2.25 (s, 3H), 1.78−1.70 (m, 2H), 1.09 (t, J = 7.3
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): 142.9, 138.1, 137.3,
136.9, 134.9, 129.3, 128.9, 127.7, 126.7, 126.2, 121.8, 119.3, 118.2,
109.6, 107.2, 53.8, 46.9, 38.5, 28.2, 21.4, 19.6, 11.2; IR (cm−1): 3029,
2966, 2931, 1597, 1495, 1464, 1335, 1305, 1180, 1161, 1091, 1032,
971, 932, 910, 813, 736, 714, 648; HRMS (ESI) m/z calcd for
C27H28N2O2S+ (M + H)+ 445.1950, found 445.1944.
1-Methoxy-3-(2-(prop-1-en-1-yloxy)ethyl)benzene (6d).5f E/Z =
55:45, oil, 68%, 26 mg, 40 °C, 30 h, Rf = 0.5 (petroleum ether/EtOAc
1
= 10:1); H NMR (400 MHz, CDCl3): 7.22 (dd, J = 15.4, 7.9 Hz,
1H), 6.83−6.75 (m, 3H), 5.95 (dd, J = 6.2, 1.7 Hz, 1H), 4.44−4.37
(m, 1H), 3.92 (t, J = 7.1 Hz, 1H), 3.84 (t, J = 7.1 Hz, 1H), 3.79 (s,
3H), 2.91 (t, J = 7.1 Hz, 2H), 1.56 (ddd, J = 14.5, 6.8, 1.6 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): 159.6, 159.6, 146.3, 145.3, 139.9,
139.9, 129.4, 129.3, 121.3, 121.2, 114.7, 114.7, 111.7, 111.7, 101.3,
98.7, 72.6, 69.6, 55.1, 36.4, 35.8, 12.6, 9.3; IR (cm−1): 3038, 2936,
2867, 2834, 1667, 1601, 1489, 1454, 1436, 1378, 1356, 1259, 1152,
1093, 1044, 931, 874, 778, 696.
2-(Prop-1-en-1-yloxy)naphthalene (6e). E/Z = 68:32, oil, 74%, 27
mg, 80 °C, 1 h, Rf = 0.5 (petroleum ether/EtOAc = 10:1); CAS: 831-
27-6;7 1H NMR (400 MHz, CDCl3): 7.75 (dd, J = 18.7, 8.5 Hz, 3H),
7.44 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 6.9 Hz, 1H), 7.29−7.17 (m, 2H),
6.58−6.47 (m, 1H), 5.04−4.89 (m, 1H), 1.74 (ddd, J = 18.8, 6.9, 1.7
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): 155.4, 155.3, 141.8,
140.8, 134.3, 129.7, 129.6, 127.7, 126.9, 126.5, 124.2, 118.6, 118.6,
110.2, 110.0, 108.9, 108.1, 12.3, 9.5; IR (cm−1): 3055, 2918, 2858,
1670, 1628, 1599, 1509, 1465, 1392, 1357, 1255, 1214, 1173, 1123,
1084, 1016, 959, 927, 844, 810, 745, 614.
1-Ethyl-6-methyl-2-tosyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]-
indole (4d). Oil, 67%, 49 mg, 24 h, Rf = 0.6 (petroleum ether/EtOAc
1
= 3:1); H NMR (400 MHz, CDCl3): 7.84 (s, 1H), 7.63 (d, J = 8.3
Hz, 2H), 7.16 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 7.9 Hz, 3H), 6.95 (d, J
= 8.2 Hz, 1H), 5.05 (dd, J = 8.6, 5.0 Hz, 1H), 4.11 (dd, J = 14.8, 5.6
Hz, 1H), 3.42−3.33 (m, 1H), 2.44 (dd, J = 15.1, 4.1 Hz, 1H), 2.39 (s,
3H), 2.37−2.29 (m, 1H), 2.27 (s, 3H), 1.96−1.79 (m, 2H), 1.09 (t, J
= 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): 143.1, 138.2,
134.1, 133.2, 129.4, 128.6, 126.9, 126.7, 123.3, 117.8, 110.5, 107.2,
54.5, 39.7, 28.9, 21.3, 19.7, 10.8; IR (cm−1): 3328, 2962, 2925, 1696,
(E)-2-(Prop-1-en-1-yl)isoindoline-1,3-dione (6f). Mp = 147−149
°C, 67%, yellow solid, 25 mg, 40 °C, 8 h, Rf = 0.5 (petroleum ether/
EtOAc = 10:1); CAS: 93250-83-0;10 1H NMR (400 MHz, CDCl3):
7.85 (dd, J = 5.5, 3.0 Hz, 2H), 7.72 (dd, J = 5.5, 3.0 Hz, 2H), 6.61−
6.53 (m, 2H), 1.84 (d, J = 5.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): 166.7, 134.2, 131.7, 123.4, 118.3, 118.1, 16.3; IR (cm−1):
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Article
2936, 1771, 1712, 1609, 1466, 1396, 1381, 1323, 1196, 1141, 1063,
1016, 948, 876, 783, 712, 626.
over Na2SO4, and concentrated. Purification of the crude product by
flash column chromatography afforded the product 2a−d1 (petroleum
ether/ethyl acetate = 6:1) in a 73% yield. 1H NMR (400 MHz,
CDCl3): 7.78−7.79 (m, 1 H), 7.40−7.42 (m, 2 H), 7.28−7.29 (m, 1
H), 7.10−7.18 (m, 3 H), 6.82−6.84 (m, 1 H), 5.79 (m, 1 H), 4.59 (d,
J = 16.0 Hz, 1 H), 4.11 (d, J = 16.0 Hz, 1 H), 2.34 (s, 3 H), 1.50−1.66
(m, 2 H), 1.40−1.48 (m, 2 H), 0.92 (t, J = 4.0 Hz, 2.67 H).
(E)-2-(But-1-en-1-yl)isoindoline-1,3-dione (6g). Mp = 53−55 °C,
60%, yellow solid, 24 mg, 12 h, Rf = 0.5 (petroleum ether/EtOAc =
10:1); CAS: 184947-06-6;15d 1H NMR (400 MHz, CDCl3): 7.85 (dd,
J = 5.5, 3.0 Hz, 2H), 7.72 (dd, J = 5.5, 3.0 Hz, 2H), 6.66−6.58 (m,
2H), 2.27−2.15 (m, 2H), 1.10 (t, J = 7.4 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): 168.4, 166.7, 134.2, 133.8, 132.2, 131.7, 124.5,
123.4, 123.1, 116.9, 24.3, 13.7; IR (cm−1): 2963, 2926, 1771, 1718,
1610, 1465, 1387, 1309, 1197, 1151, 1128, 1077, 962, 911, 875, 713,
622.
(E)-N-(But-1-en-1-yl)-4-methyl-N-phenylbenzenesulfonamide
(6h). Mp = 126−128 °C, 64%, white solid, 38 mg, 24 h, Rf = 0.5
(petroleum ether/EtOAc = 10:1); CAS: 1863980-42-0;6 1H NMR
(400 MHz, CDCl3): 7.55 (d, J = 8.3 Hz, 2H), 7.36−7.31 (m, 3H),
7.27 (d, J = 8.2 Hz, 2H), 7.00−6.95 (m, 2H), 6.91 (d, J = 14.0 Hz,
1H), 4.43 (dt, J = 13.8, 6.8 Hz, 1H), 2.43 (s, 3H), 2.00−1.92 (m,
2H), 0.90 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3):
143.6, 137.1, 136.1, 130.2, 129.5, 129.3, 128.7, 128.1, 127.5, 114.8,
23.0, 21.5, 14.3; IR (cm−1): 2957, 2910, 2841, 1651, 1595, 1486,
1449, 1380, 1352, 1320, 1247, 1169, 1117, 1100, 1089, 1019, 970,
948, 912, 872, 812, 741, 696, 662, 619.
A mixture of N-(but-3-en-1-yl)-N-(2-(hydroxymethyl)phenyl)-4-
methyl-benzenesulfonamide 1a (0.10 mmol), D2O (0.20 mmol),
B2(OH)4 (0.20 mmol), and Pd(tBu3P)2 (0.01 mmol) was combined
in anhydrous DCE (2.0 mL) at 130 °C in an oil bath for 24 h under
an argon atmosphere. After the reaction, 10 mL of water was added to
quench the reaction, and the resulting mixture was extracted twice
with CH2Cl2 (2 × 10 mL). The combined organic extracts were
washed with brine (10 mL), dried over Na2SO4, and concentrated.
Purification of the crude product by flash column chromatography
afforded the product 2a−d2 (petroleum ether/ethyl acetate =6:1) in
1
an 80% yield. H NMR (400 MHz, CDCl3): 7.78−7.79 (m, 1 H),
7.40−7.42 (m, 2 H), 7.27−7.29 (m, 1 H), 7.10−7.18 (m, 3 H), 6.82−
6.84 (m, 1 H), 5.79 (m, 1 H), 4.59 (d, J = 16.0 Hz, 1 H), 4.11 (d, J =
16.0 Hz, 1 H), 2.34 (s, 3 H), 1.50−1.66 (m, 1.65 H), 1.40−1.50 (m, 2
H), 0.92 (t, J = 4.0 Hz, 2.85 H).
(E)-Ethyl-2-benzoylpent-2-enoate (6i). Oil, 42%, 19 mg, 130 °C,
36 h, Rf = 0.5 (petroleum ether/EtOAc = 20:1); CAS: 39626-68-1;16a
1H NMR (400 MHz, CDCl3): 7.90 (d, J = 7.0 Hz, 2H), 7.59 (t, J =
7.4 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.16 (t, J = 7.9 Hz, 1H), 4.16
(q, J = 7.1 Hz, 2H), 2.13 (p, J = 7.6 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H),
1.04 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): 194.4,
164.6, 149.5, 136.8, 133.6, 133.2, 129.0, 128.7, 61.1, 23.0, 13.9, 12.8;
IR (cm−1): 2975, 2935, 1723, 1674, 1640, 1596, 1580, 1448, 1367,
1233, 1178, 1143, 1076, 1031, 944, 909, 716, 689, 671.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00770.
■
sı
1H NMR and 13C NMR spectra of all compounds
(PDF)
2-(2-Methylprop-1-en-1-yl)isoindoline-1,3-dione (6j). Mp = 86−
88 °C, 80%, white solid, 32 mg, 12 h, Rf = 0.5 (petroleum ether/
EtOAc = 10:1); CAS: 73286-68-7;16c 1H NMR (400 MHz, CDCl3):
7.88 (dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.0 Hz, 2H), 5.90 (s,
1H), 1.93 (d, J = 1.6 Hz, 3H), 1.67 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): 167.4, 139.1, 134.1, 132.0, 123.4, 112.1, 22.7, 18.9; IR
(cm−1): 3065, 2973, 2934, 2914, 1766, 1715, 1609, 1464, 1393, 1340,
1286, 1224, 1110, 1085, 1066, 981, 890, 798, 784, 730, 712, 531.
(E)-N-(But-1-en-1-yl)-N-(2-(hydroxymethyl)phenyl)-4-methylben-
zenesulfonamide (2a′). Oil, 51%, 17 mg, Rf = 0.5 (petroleum ether/
EtOAc = 6:1); CAS: 1863980-66-8; 6 1H NMR (400 MHz, CDCl3):
7.65 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.44−7.39 (m,
1H), 7.31 (d, J = 8.0 Hz, 2H), 7.18−7.13 (m, 1H), 6.96 (d, J = 13.9
Hz, 1H), 6.38 (d, J = 7.9 Hz, 1H), 4.76 (d, J = 11.1 Hz, 1H), 4.53−
4.43 (m, 1H), 4.27 (dt, J = 13.8, 6.8 Hz, 1H), 2.77−2.64 (m, 1H),
2.46 (s, 3H), 1.96 (p, J = 7.4 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): 144.2, 141.8, 135.5, 134.5, 131.0,
AUTHOR INFORMATION
Corresponding Author
■
Xiao-Feng Xia − Key Laboratory of Synthetic and Biological
Colloids, Ministry of Education, School of Chemical and
Material Engineering, Jiangnan University, Wuxi, Jiangsu
214122, China; Guangxi Key Laboratory of Agricultural
Resources Chemistry and Biotechnology, College of Chemistry
and Food Science, Yulin Normal University, Yulin, Guangxi
537000, China; orcid.org/0000-0002-1837-0638;
Email: xiaxf@jiangnan.edu.cn
Authors
Linglong Ding − Key Laboratory of Synthetic and Biological
Colloids, Ministry of Education, School of Chemical and
Material Engineering, Jiangnan University, Wuxi, Jiangsu
214122, China
Yan-Ning Niu − Department of Teaching and Research,
Nanjing Forestry University, Huaian, Jiangsu 223003, China
129.8, 129.7, 129.4, 128.5, 127.9, 127.6, 114.9, 61.0, 22.9, 21.6, 14.4;
IR (cm−1): 3438, 2960, 2927, 2871, 1653, 1596, 1488, 1452, 1356,
1165, 1129, 1088, 1039, 972, 941, 894, 813, 767, 747, 711, 662, 579.
(E)-N-(But-2-en-1-yl)-N-(2-(hydroxymethyl)phenyl)-4-methylben-
zenesulfonamide (2a″).6 Oil, 73%, 24 mg, Rf = 0.5 (petroleum
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00770
1
ether/EtOAc = 6:1); H NMR (400 MHz, CDCl3): 7.56 (dd, J =
15.9, 8.0 Hz, 4H), 7.33−7.27 (m, 3H), 7.16−7.11 (m, 1H), 6.43 (d, J
= 6.7 Hz, 1H), 5.39−5.35 (m, 1H), 4.96 (d, J = 9.0 Hz, 1H), 4.53−
4.40 (m, 2H), 3.68 (dd, J = 13.5, 7.1 Hz, 1H), 3.10−3.06 (m, 1H),
2.46 (s, 3H), 1.53 (d, J = 4.8 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): 143.8, 142.4, 137.2, 134.9, 131.5, 130.9, 129.5, 128.9, 128.2,
128.0, 127.7, 124.4, 61.2, 54.4, 21.5, 17.5; IR (cm−1): 3515, 2921,
1597, 1491, 1451, 1340, 1160, 1090, 1038, 966, 920, 861, 814, 764,
747, 710, 655, 575.
Deuterium Labeling Experiments. A mixture of N-(but-3-en-1-
yl)-N-(2-(hydroxymethyl)phenyl)-4-methyl-benzenesulfonamide 1a
(0.20 mmol), C2D5OD (0.60 mmol), B2(OH)4 (0.24 mmol), and
Pd(tBu3P)2 (0.02 mmol) was combined in toluene (3.0 mL) at 130
°C in an oil bath for 24 h under an argon atmosphere. After the
reaction, 10 mL of water was added to quench the reaction, and the
resulting mixture was extracted twice with CH2Cl2 (2 × 10 mL). The
combined organic extracts were washed with brine (10 mL), dried
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge financial support from the
Guangxi Key Laboratory of Agricultural Resources Chemistry
and Biotechnology (2020KF01). They also thank the Central
Laboratory, School of Chemical and Material Engineering,
Jiangnan University for characterization analysis.
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