Blue Light-Promoted Formal [4+1]-Annulation of Diazoacetates with o-Aminoacetophenones: Synthesis of Polysubstituted Indolines and Computational Study

Article abstract of DOI:10.1021/acs.joc.0c01974

A blue light-promoted formal [4+1]-annulation of diazoacetates with o-aminoacetophenones has been reported, which provides an environmentally friendly method for the synthesis of polysubstituted indoline derivatives in moderate to good yields with excellent diastereoselectivities. Detailed mechanistic studies through density functional theory calculations reveal that the (E)-enol species is the key intermediate in this transformation, and the excellent diastereoselectivity is enabled via H-bonding in the intramolecular Aldol-type addition.

Full text of DOI:10.1021/acs.joc.0c01974

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Article
Blue Light-Promoted Formal [4+1]-Annulation of Diazoacetates with
o‑Aminoacetophenones: Synthesis of Polysubstituted Indolines and
Computational Study
Jinzhou Chen,† Shuhao Liu,† Xinxin Lv, Kemiao Hong, Jinping Lei, Xinfang Xu,* and Wenhao Hu*
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ABSTRACT: A blue light-promoted formal [4+1]-annulation of diazoace-
tates with o-aminoacetophenones has been reported, which provides an
environmentally friendly method for the synthesis of polysubstituted indoline
derivatives in moderate to good yields with excellent diastereoselectivities.
Detailed mechanistic studies through density functional theory calculations
reveal that the (E)-enol species is the key intermediate in this transformation,
and the excellent diastereoselectivity is enabled via H-bonding in the
intramolecular Aldol-type addition.
Scheme 1. Ylide Intermediate Formation and Interception
INTRODUCTION
■
The diazo compounds are versatile and useful reagents in
organic chemistry,1 which are generally used as carbene
precursors under transition metal catalysis in a variety of
transformations.2 On the other hand, as an eco-friendly and
sustainable approach, the light-induced free carbene reaction
has caught much attention,3 including X−H insertion,4
cyclopropenation,5 cyclopropanation,6 cross-coupling,7 and
others.8 Enlightened by these works and as our continuing
interest in the multicomponent reactions (MCRs) through the
interception of reactive ylide intermediate that generated in
situ from metal carbene and corresponding nucleophile
(Scheme 1a, path a),9,10 we envisioned that if the demetalation
of ylide A might occur to form the free ylide intermediate B,
and both A and B could be trapped by electrophile (E) to
deliver the three-component products, then a light-induced
multicomponent reaction, which would give the same products
that were obtained in the metal-catalyzed version, could be
realized through intermediate B (Scheme 1a, path b). Herein,
we wish to report our recent progress in this direction, a blue
light-promoted formal [4+1]-annulation of diazoacetates with
o-aminoacetophenones (Scheme 1b).11 This method provides
an environmentally friendly access to polysubstituted indoline
derivatives in moderate to good yields with excellent
diastereoselectivity. These generated multisubstituted indoles
are core structural motifs in many biologically active nature
products and drugs.12 Moreover, the detailed mechanistic
studies through density functional theory (DFT) calculations
reveal that the (E)-enol species D is the key intermediate,
which is formed through free ylide C via a H-shift process. The
excellent diastereoselectivity in the following intramolecular
Received: August 15, 2020
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© XXXX American Chemical Society
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a
Table 1. Condition Optimization
b
c
entry
1
solvent
DCM
DCM
DCM
DCM
yield (%) of 3a/4/5
dr
51/9/-
56/9/-
64/7/-
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
d
2
e
3
f
4
g
63/<5/-
42/13/18
32/17/19
37/22/32
37/18/23
40/17/18
<5/34/-
<5/14/9
NR
5
DCM
DCE
6
7
8
9
toluene
chlorobenzene
acetonitrile
chloroform
THF
10
11
12
h
DCM
a
Unless otherwise noted, the reaction was carried out on a 0.1 mmol scale, phenyl diazoacetate 1a (0.2 mmol), ketone 2a (0.1 mmol), and 4 Å MS
b
(100 mg) in 1.0 mL of solvent. The reaction mixture was stirred under the irradiation of blue LEDs at room temperature for 48 h. The yields were
determined by 1H NMR of the crude reaction mixture using 2,4,5-trichloropyrimidine as an internal standard; 5 was formed as a mixture of Z- and
c
d
E-isomers. The dr values were determined by 1H NMR of the crude reaction mixture. The aryl diazoacetates 1a in DCM (1.5 mL) was added via
e
f
a syringe pump for 1 h. The phenyl diazoacetate 1a (0.1 mmol) and ketone 2a (0.2 mmol) were used. The reaction was conducted under an
argon atmosphere. The reaction was carried out without 4 Å MS. The reaction was carried out in the dark. NR = no reaction.
g
h
Aldol-type addition is enabled through H-bonding between the
enol species and the tethered carbonyl group.
reactivity under these conditions, either using methods A or B
with longer reaction times (96 h with ∼20% conversion, 3l and
3m). Substrates 1 with electron-donating and electron-neutral
groups gave better results in term of yields. N-Benzyl or N-
ethyl substituted o-aminoacetophenones reacted smoothly,
giving the corresponding products in good yields with >95:5
dr. The N-acyl protected one did not react with diazo
compound under current conditions. The reaction of bromo-
substituted o-aminoacetophenone generated the product 3r in
78% yields. In addition, 81% yield could be obtained when the
reaction was conducted on a gram scale, which shows the
synthetic potential of this method (note c). The structure of
these generated compounds was assigned by the comparison of
the NMR data with these reported results.11a Moreover, we
have conducted the NOE analysis for product 3p (see the
Supporting Information for details), which is consistent with
the assigned structure, and other compounds were assigned by
analogy.
RESULTS AND DISCUSSION
■
Initially, diazoacetate 1a and o-aminoacetophenone 2a were
used as the mode substrates under the irradiation of blue light
(460 nm) at room temperature, and all these reactions were
conducted for 48 h to ensure the full consumption of
diazoacetate 1a (Table 1). To our delight, the reaction
proceeded well in dichloromethane (DCM), delivering 3a as a
single diastereomer in 51% yield contaminated with 4 as a
byproduct in 9% yield (entry 1). Only a slight change has been
observed by a slow addition protocol (entry 2), whereas the
yields increased more than 10% by using an excess of o-
aminoacetophenone (entry 3) or conducting the reaction
under an argon atmosphere (entry 4). Then, a variety of
solvents was trialed in this reaction. High reactivity was
observed when the reaction was conducted in 1,2-dichloro-
ethane (DCE), toluene, chlorobenzene, or acetonitrile,
affording indoline 3a in moderate yield with excellent
diastereoselectivity (entries 5−9). The byproducts 4 and 5
were observed in these cases in minor amounts, which were
generated from 1a via oxidation and dimerization reactions,
respectively. No cyclization product 3a was detected when
chloroform or tetrahydrofuran (THF) was used as the solvent
(entries 10 and 11). Control experiment in the dark turned out
to have no reaction at all, which confirmed that the reaction
should be initiated by the blue light (entry 12).
Two possible reaction pathways are proposed in Scheme 2
for this blue light-promoted reaction. Initially, the photo-
excitation of diazo compound 1a will generate two kinds of
1
carbene species, the higher energy singlet state Int1 and the
lower energy triplet state 3Int1.13 These two species are
interconvertible via intersystem crossing (ISC).14 The
3
following addition of triplet carbene Int1 with 2a could go
through a diradical process to generate the cyclized product 3a
(Scheme 2, path a), whereas the singlet state 1Int1 forms ylide
and enol species in sequence with 2a to deliver the same
product (Scheme 2, path b). To distinguish these two
pathways and elucidate the exceptionally high diastereoselec-
tivity in this reaction, detailed density functional theory (DFT)
calculations were conducted.
Considering the cost and conveniences, method A (Table 1,
entry 1) and method B (Table 1, entry 3) were used as the
optimal conditions for the investigation of the substrate scope
(Table 2). A variety of substations on the aryl ring of the diazo
compounds could be well tolerated under these two
conditions, generating the indolines 3a−3n in synthetically
useful to high yields with >95:5 dr. The diazo compounds with
strong electron-withdrawing groups, which showed very low
Singlet Rather than Triplet Carbene. We set the free
1
energy of the singlet carbene Int1 as the benchmark. The
3
structure of triplet carbene Int1 was also optimized and the
corresponding free energy was calculated. As shown in Figure
B
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a
Table 2. Blue Light-Induced Formal [4+1]-Annulation
Scheme 2. Possible Reaction Pathways
Figure 1. Triplet carbene vs singlet carbene.
about 26.5 kcal/mol. Meanwhile, the energy barrier is only
1
about 9.4 kcal/mol in the addition of singlet carbene Int1
1
with 2a to form the ylide intermediate Int2. Moreover, the
1
ylide intermediate Int2 is much stable as its energy is 38.2
kcal/mol lower than the diradical intermediate 3Int2. The free
energy barrier for the overall reaction pathway starting from
the triplet carbene is quite high (see Figure S1 for details).
Formation of (E)-Enol Intermediate. After the gener-
ation of ylide 1Int2, it could smoothly form the corresponding
1
enol intermediate Int3-1 by proton transfer from nitrogen
a
atom to the carbonyl oxygen (Figure 2).16 The free energy
barrier for the enol formation is only about 1.3 kcal/mol, and
the energy of (E)-1Int3-1 is about 8.6 kcal/mol lower than the
Method A: Reactions were carried out on a 0.3 mmol scale, aryl
diazoacetates 1 (0.6 mmol, 2.0 equiv), phenyl ketones 2 (0.3 mmol,
1.0 equiv), and 4 Å MS (200 mg) in 3.0 mL of DCM, and the reaction
mixture was stirred under the irradiation of 460 nm blue LEDs at
room temperature for 36−72 h. The yields are given in isolated yields
and only one diastereoisomer (dr > 95:5) was isolated in all these
1
ylide Int2. The product 3a might be directly generated from
1Int2 through a concerted ring closing and hydrogen
b
transferring from nitrogen to the carbonyl oxygen of ketone
cases. Method B: Reactions were carried out on a 0.3 mmol scale,
1
aryl diazoacetates 1 (0.3 mmol, 1.0 equiv), phenyl ketones 2 (0.6
mmol, 2.0 equiv), and 4 Å MS (200 mg) in 3.0 mL of DCM, and the
reaction mixture was stirred under the irradiation of 460 nm blue
LEDs at room temperature for 18−72 h. The yields are given in
isolated yields and only one diastereoisomer (dr > 95:5) was isolated
in all these cases. The reaction was conducted on a 4.0 mmol scale
with method B.
via TS3-2 (Figure 2, blue line). However, the energy barrier
for this reaction pathway is much higher (12.2 kcal/mol) than
the formation of the enol intermediate (E)-1Int3-1 (Figure 2,
black line). The concerted pathway involves the transition state
1TS3-2 that has a larger ring strain and distortion when
c
1
compared with the five-membered ring structure of TS3-1
(see Figure S2 for details). The enol intermediate could
smoothly produce the cyclized product 3a by an Aldol-type
addition with a synchronous proton transfer via TS4-1. The
energy barrier for this reaction pathway is 10.2 kcal/mol.
The selective formation of (E)-1Int3-1 is then studied
(Figure 3). According to the computational data, the free
3
1
1, the triplet carbene Int1 is a little more stable than singlet
carbene 1Int1, which is consistent with a previous study.15 The
free energy barrier for the formation of the diradical
intermediate 3Int2 from 3Int1 through 3TS2 is too high,
C
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1
Figure 2. Calculated reaction pathway via ylide intermediate Int2.
results in a distortion of the planar enol structure and is
difficult for the subsequent proton transfer process (Figure 5).
Therefore, the main product 3a is favored to be generated via
Si-face addition, and the formation of diastereomer 3a* is
difficult to occur.
Moreover, control experiment in the presence of TEMPO
(2.0 equiv) has been conducted, generating the product with
comparable yield of the model reaction (eq 1). These results
ruled the mechanism involving radicals. Based on DFT
calculation and control experimental results, a feasible reaction
pathway is proposed for this blue light-promoted formal
[4+1]-annulation (Scheme 3). Initially, under the irradiation of
the blue light, the diazo compound 1a will generate an
Figure 3. Comparison of the formation of E- and Z-enol
intermediates.
1
energy barrier for the formation of (Z)-1Int3-1 via 1TS3-3 with
the assistance of two molecules of water is about 9.3 kcal/mol,
which is much higher (8.0 kcal/mol) than the formation of the
enol intermediate (E)-1Int3-1 (Figure 3, blue line vs black
line). Moreover, the (E)-enol intermediate is more stable (2.0
kcal/mol) compared with the Z isomer.
electrophilic singlet carbene Int1 that would react with the
amino group of 2a to form the ylide intermediate 1Int2. Then,
the ylide intermediate could convert to the enol form
(E)-1Int3-1 via proton shift. Finally, the Si-face Aldol-type
addition of the enol intermediate (E)-1Int3-1 with tethered
carbonyl group generates the cyclized product 3a through
1TS4-1.
Diastereoselectivity Control in the Generation of 3a
with the Assistance of the Intramolecular H-Bonding.
The Aldol-type addition of (E)-enol intermediate could go
through Re- or Si-face addition. Corresponding energy barriers
have been calculated and are listed in Figure 4. The energy
CONCLUSIONS
■
In summary, we have presented a blue light-promoted
environmentally friendly method for the synthesis of 2,2,3-
trisubstitued indolines with excellent diastereoselectivities. The
detailed reaction mechanism has been investigated by
performing DFT calculations. The singlet carbene is more
likely to react with 2-(N-alkylamino)phenyl ketone to generate
the free ylide species followed by the formation of the key (E)-
enol intermediate via H-shift. Finally, the highly diastereose-
lective Aldol-type addition is enabled via H-bonding of the
enol species with the carbonyl group.
1
barriers are much higher for Re-addition via TS4-2 to form
the 3a* (47.7 kcal/mol, blue line), whereas the formation of 3a
through Si-addition via 1TS4-1 has a barrier of only 10.2 kcal/
1
mol (black line). In TS4-1, the hydroxyl group of the enol
part and the oxygen atom of the carbonyl group are positioned
to the same side, making it easy to form a hydrogen bond
network for the Aldol addition and proton transfer, whereas in
1TS4-2, these two species are on the opposite side, which
D
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Figure 4. Energy profile for Re- and Si-face addition.
Scheme 3. Proposed Reaction Mechanism
1
1
Figure 5. Structural comparison of TS4-1 with TS4-2.
EXPERIMENTAL SECTION
General Methods. All solvents were commercially purchased and
used as such without further purification. NMR spectra were recorded
■
General Procedure for the Blue Light-Induced Formal
[4+1]-Annulation. Method A. To a 10 mL oven-dried vial
containing a magnetic stirring bar, diazoacetate 1 (0.6 mmol, 2.0
equiv), o-aminoacetophenone 2 (0.3 mmol, 1.0 equiv), 4 Å MS (200
mg), and 3.0 mL of anhydrous DCM were added in sequence. The
reaction mixture was stirred at room temperature under the
irradiation of blue LEDs for 36−96 h. After completion of the
reaction (monitored by TLC), the reaction mixture was purified by
silica gel column chromatography (petroleum ether/EtOAc = 8:1−
1:1, v/v) without additional treatment to afford the pure products 3 in
moderate to high yields.
1
on a Bruker spectrometer at 400 or 500 MHz for H NMR, 100 or
125 MHz for 13C{1H} NMR, and 470 MHz for 19F NMR. Chemical
shifts (δ value) were reported in parts per million (ppm) downfield
from internal tetramethylsilane (TMS). HRMS (ESI) mass spectra
were recorded on an IonSpec FT-ICR mass spectrometer.
Diazoacetates 117 and o-aminoacetophenones 218 were prepared
according to the reported methods and had physical and spectral
properties identical to those earlier reported. The manufacturer and
model of the photoreactor: Jihui VLT-II; broadband of light source:
460−465 nm; power of light source: 2*50 W; distance from the light
source to the irradiation vessel: 15 cm; and a general glass vessel was
used instead of a borosilicate glass vessel.
Method B. To a 10 mL oven-dried vial containing a magnetic
stirring bar, diazoacetate 1 (0.3 mmol, 1.0 equiv), o-amino-
acetophenone 2 (0.6 mmol, 2.0 equiv), 4 Å MS (200 mg), and 3.0
E
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mL of anhydrous DCM were added in sequence. The reaction
mixture was stirred at room temperature under the irradiation of blue
LEDs for 18−48 h. After completion of the reaction (monitored by
TLC), the reaction mixture was purified by silica gel column
chromatography (petroleum ether/EtOAc = 8:1−1:1, v/v) without
additional treatment to afford the pure products 3 in moderate to high
yields.
Methyl (2S*,3R*)-1-Benzyl-3-hydroxy-3-methyl-2-phenylindo-
line-2-carboxylate (3a). The reaction mixture was purified by silica
gel column chromatography (petroleum ether/EtOAc = 8:1−6:1, v/
v). Method A: 44.6 mg, 50% yield. Method B: 57.1 mg, 64% yield.
The physical and spectral properties identical to those earlier
reported.11a Yellow oil. 1H NMR (500 MHz, CDCl3) δ (ppm)
7.35−7.34 (comp, 5H), 7.24−7.20 (m, 2H), 6.84−6.81 (m, 1H), 6.56
(d, J = 7.8 Hz, 1H), 3.85 (s, 1H), 3.74 (s, 3H), 2.77 (s, 3H), 1.03 (s,
3H). 13C{1H} NMR (126 MHz, CDCl3) δ (ppm) 171.9, 149.5, 135.8,
134.3, 129.4, 128.1, 128.0, 127.2, 121.9, 119.2, 107.3, 86.0, 83.5, 51.8,
32.5, 25.4. HRMS (TOF MS ESI+) m/z: [M + H]+ calculated for
C18H20NO3 298.1438; found 298.1431.
silica gel column chromatography (petroleum ether/EtOAc = 6:1−
4:1, v/v). Method A: 61.1 mg, 62% yield. Method B: 76.6 mg, 78%
1
yield. Yellow oil; H NMR (500 MHz, CDCl3) δ (ppm) 7.28−7.19
(comp, 3H), 6.92−6.86 (comp, 3H), 6.81 (t, J = 6.9 Hz, 1H), 6.55 (d,
J = 7.5 Hz, 1H), 3.86 (s, 1H), 3.77 (s, 3H), 3.73 (s, 3H), 2.77 (s, 3H),
1.07 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ (ppm) 171.8,
159.4, 149.5, 137.4, 134.3, 129.5, 129.1, 121.9, 119.8, 119.2, 113.5,
112.9, 107.3, 86.0, 83.4, 55.2, 51.8, 32.6, 25.3; HRMS (TOF MS
ESI+) m/z: [M + H]+ calculated for C19H22NO4 328.1543; found
328.1543.
Methyl (2S*,3R*)-3-Hydroxy-1,3-dimethyl-2-(3,4,5-
trimethoxyphenyl)indoline-2-carboxylate (3g). The reaction mix-
ture was purified by silica gel column chromatography (petroleum
ether/EtOAc = 4:1−2:1, v/v). Method A: 53.5 mg, 46% yield.
1
Method B: 72.1 mg, 62% yield. Yellow oil; H NMR (500 MHz,
CDCl3) δ (ppm) 7.23−7.20 (m, 2H), 6.82 (t, J = 7.4 Hz, 1H), 6.57
(d, J = 9.7 Hz, 3H), 3.87 (s, 3H), 3.80 (s, 7H), 3.76 (s, 3H), 2.80 (s,
3H), 1.09 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ (ppm)
171.7, 152.9, 149.4, 137.8, 134.2, 131.2, 129.5, 122.0, 119.3, 107.2,
104.7, 86.1, 83.6, 60.9, 56.2, 51.8, 32.7, 25.3. HRMS (TOF MS ESI+)
m/z: [M + H]+ calculated for C21H26NO6 388.1755; found 388.1757.
Methyl (2S*,3R*)-2-(4-Fluorophenyl)-3-hydroxy-1,3-dimethylin-
doline-2-carboxylate (3h). The reaction mixture was purified by
silica gel column chromatography (petroleum ether/EtOAc = 8:1−
6:1, v/v). Method A: 58.3 mg, 59% yield. Method B: 48.2 mg, 51%
yield. Yellow oil; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.34 (s, 2H),
7.23−7.22 (m, 2H), 7.05 (t, J = 7.7 Hz, 2H), 6.83 (t, J = 6.4 Hz, 1H),
6.56 (d, J = 7.0 Hz, 1H), 3.74 (s, 3H), 3.72 (s, 1H), 2.75 (s, 3H), 1.01
(s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ (ppm) 171.6, 162.4 (d,
J = 247.1 Hz), 149.3, 134.1131.6 (d, J = 3.4 Hz), 129.5, 129.0 (d, J =
7.7 Hz), 122.0, 119.3, 115.1 (d, J = 21.4 Hz) 107.4, 85.7, 83.5, 51.9,
32.5, 25.6; 19F NMR (376 MHz, CDCl3) δ (ppm) −114.2; HRMS
(TOF MS ESI+) m/z: [M + H]+ calculated for C18H19NO3F
316.1343; found 316.1343.
Ethyl (2S*,3R*)-3-Hydroxy-2-(4-methoxyphenyl)-1,3-dimethylin-
doline-2-carboxylate (3b). The reaction mixture was purified by
silica gel column chromatography (petroleum ether/EtOAc = 6:1−
4:1, v/v). Method A: 78.9 mg, 77% yield. Method B: 95.3 mg, 93%
1
yield. Yellow oil. H NMR (500 MHz, CDCl3) δ (ppm) 7.25−7.19
(comp, 4H), 6.87 (d, J = 7.9 Hz, 2H), 6.80 (t, J = 7.2 Hz, 1H), 6.53
(d, J = 7.7 Hz, 1H), 4.28−4.20 (m, 2H), 3.81−3.80 (m, 3H), 3.77 (s,
1H), 2.76 (s, 3H), 1.22 (t, J = 6.9 Hz, 3H), 1.06 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3) δ (ppm) 171.4, 159.2, 149.7, 134.3, 129.4,
128.5, 127.9, 121.9, 118.9, 113.4, 107.0, 85.6, 83.4, 61.2, 55.2, 32.4,
25.2, 14.3; HRMS (TOF MS ESI+) m/z: [M + H]+ calculated for
C20H24NO4 342.1700; found 342.1699.
Methyl (2S*,3R*)-3-Hydroxy-2-(4-methoxyphenyl)-1,3-dimethy-
lindoline-2-carboxylate (3c). The reaction mixture was purified by
silica gel column chromatography (petroleum ether/EtOAc = 6:1−
4:1, v/v). Method A: 73.7 mg, 75% yield. Method B: 90.4 mg, 92%
Methyl (2S*,3R*)-3-Hydroxy-1,3-dimethyl-2-(p-tolyl)indoline-2-
carboxylate (3i). The reaction mixture was purified by silica gel
column chromatography (petroleum ether/EtOAc = 8:1−4:1, v/v).
Method A: 53.2 mg, 57% yield. Method B: 84.1 mg, 90% yield. Yellow
1
yield. Yellow oil; H NMR (400 MHz, CDCl3) δ (ppm) 7.26−7.18
(comp, 4H), 6.88−6.85 (m, 2H), 6.82−6.78 (m, 1H), 6.54 (d, J = 7.7
Hz, 1H), 3.79 (s, 3H), 3.74 (s, 3H), 3.71 (s, 1H), 2.74 (s, 3H), 1.07
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 170.9, 158.2,
148.6, 133.0, 128.4, 127.4, 126.8, 120.9, 117.9, 112.4, 106.1, 84.7,
82.4, 54.2, 50.8, 31.3, 24.1; HRMS (TOF MS ESI+) m/z: [M + H]+
calculated for C19H22NO4 328.1543; found 328.1537.
1
oil; H NMR (400 MHz, CDCl3) δ (ppm) 7.24−7.14 (comp, 6H),
6.81 (t, J = 7.4, 1H), 6.54 (d, J = 7.7 Hz, 1H), 3.81 (s, 1H), 3.74 (s,
3H), 2.75 (s, 3H), 2.36 (s, 3H), 1.05 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 172.1, 149.5, 137.8, 134.3, 132.8, 129.4,
128.9, 127.1, 121.9, 119.1, 107.2, 85.9, 83.4, 51.8, 32.4, 25.3, 21.1;
HRMS (TOF MS ESI+) m/z: [M + H]+ calculated for C19H22NO3
312.1594; found 312.1592.
Methyl (2S*,3R*)-1-Benzyl-3-hydroxy-2-(4-methoxyphenyl)-3-
methylindoline-2-carboxylate (3d). The reaction mixture was
purified by silica gel column chromatography (petroleum ether/
EtOAc = 6:1−4:1, v/v). Method A: 69.0 mg, 57% yield. Method B:
84.7 mg, 70% yield. Light yellow solid, mp = 138−141 °C; 1H NMR
(500 MHz, CDCl3) δ (ppm) 7.43−7.24 (comp, 9H), 7.03 (t, J = 7.8
Hz, 1H), 6.83−6.82 (m, 3H), 6.18 (d, J = 6.7 Hz, 1H), 4.35 (d, J =
16.5 Hz, 1H), 4.16 (d, J = 16.5 Hz, 1H), 3.83 (s, 1H), 3.77 (s, 3H),
3.74 (s, 3H), 1.24 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
(ppm) 172.4, 159.3, 149.0, 138.5, 134.4, 129.3, 128.6, 128.0, 126.7,
126.5, 121.9, 119.3, 113.7, 108.9, 86.2, 83.3, 55.2, 52.0, 51.1, 24.4;
HRMS (TOF MS ESI+) m/z: [M + H]+ calculated for C25H26NO4
404.1856; found 404.1853.
Methyl (2S*,3R*)-3-Hydroxy-2-(2-methoxyphenyl)-1,3-dimethy-
lindoline-2-carboxylate (3e). The reaction mixture was purified by
silica gel column chromatography (petroleum ether/EtOAc = 6:1−
4:1, v/v). Method A: 60.9 mg, 62% yield. Method B: 83.5 mg, 85%
yield. White solid, mp = 131−134 °C; 1H NMR (500 MHz, CDCl3) δ
(ppm) 7.47 (d, J = 7.4 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.24 (s, 1H),
7.17 (t, J = 7.4 Hz, 1H), 7.03−6.98 (m, 2H), 6.83 (t, J = 7.1 Hz, 1H),
6.53 (d, J = 7.6 Hz, 1H), 4.91 (s, 1H), 3.81 (s, 3H), 3.64 (s, 3H), 2.74
(s, 3H), 0.95 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ (ppm)
171.7, 158.3, 148.1, 135.8, 129.1, 128.7, 128.2, 125.3, 121.7, 120.5,
119.6, 112.2, 107.3, 83.6, 82.0, 56.1, 51.3, 32.3, 27.2; HRMS (TOF
MS ESI+) m/z: [M + H]+ calculated for C19H22NO4 328.1543; found
328.1541.
Methyl (2S*,3R*)-3-Hydroxy-1,3-dimethyl-2-(naphthalen-2-yl)-
indoline-2-carboxylate (3j). The reaction mixture was purified by
silica gel column chromatography (petroleum ether/EtOAc = 8:1−
6:1, v/v). Method A: 55.3 mg, 51% yield. Method B: 52.1 mg, 50%
yield. White foam solid; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.88−
7.80 (comp, 4H), 7.51−7.48 (m, 2H), 7.38 (d, J = 8.6, 1H), 7.25−
7.23 (m, 2H), 6.85 (t, J = 7.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 3.87
(s, 1H), 3.77 (s, 3H), 2.83 (s, 3H), 1.05 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 171.9, 149.6, 134.4, 133.6, 133.1, 133.0,
129.6, 128.4, 127.8, 127.6, 126.3, 126.3, 125.3, 125.3, 122.0, 119.3,
107.5, 86.3, 83.6, 52.0, 32.7, 25.8; HRMS (TOF MS ESI+) m/z: [M +
H]+ calculated for C22H22NO3 348.1594; found 348.1591.
Methyl (2S*,3R*)-2-(4-Chlorophenyl)-3-hydroxy-1,3-dimethylin-
doline-2-carboxylate (3k). The reaction mixture was purified by silica
gel column chromatography (petroleum ether/EtOAc = 8:1−6:1, v/
1
v). Method A: 48.8 mg, 49% yield. Yellow oil; H NMR (500 MHz,
CDCl3) δ (ppm) 7.34−7.30 (comp, 4H), 7.23−7.22 (m, 2H), 6.83 (t,
J = 7.1 Hz, 1H), 6.56 (d, J = 7.4 Hz, 1H), 3.73 (s, 4H), 2.74 (s, 3H),
1.01 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ (ppm) 171.4,
149.3, 134.5, 134.1, 133.9, 129.5, 128.7, 128.3, 122.0, 119.4, 107.4,
85.8, 83.5, 51.9, 32.5, 25.7; HRMS (TOF MS ESI+) m/z: [M + H]+
calculated for C18H19NO3Cl 332.1048; found 332.1050.
Methyl (2S*,3R*)-3-Hydroxy-1,3-dimethyl-2-(4-(trifluoromethyl)-
phenyl)indoline-2-carboxylate (3l). The reaction mixture was
purified by silica gel column chromatography (petroleum ether/
Methyl (2S*,3R*)-3-Hydroxy-2-(3-methoxyphenyl)-1,3-dimethy-
lindoline-2-carboxylate (3f). The reaction mixture was purified by
F
https://dx.doi.org/10.1021/acs.joc.0c01974
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
EtOAc = 4:1−2:1, v/v). Method A: 25.2 mg, 23% yield. Colorless oil;
1H NMR (500 MHz, CDCl3) δ (ppm) 7.63 (d, J = 7.9 Hz, 2H), 7.52
mmol, 1.0 equiv), o-aminoacetophenone 2a (1.193 g, 8.0 mmol, 2.0
equiv), 4 Å MS (1.5 g), and 30 mL of anhydrous DCM were added in
sequence. The reaction mixture was stirred at room temperature
under the irradiation of blue LEDs under an argon atmosphere for
120 h. After completion of the reaction (monitored by TLC), the
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column chromatography (petroleum ether/
EtOAc = 6:1−4:1, v/v) to afford 1.106 g of pure product 3b in 81%
yield.
Control Experiment in the Presence of TEMPO. To a 10 mL
oven-dried vial containing a magnetic stirring bar, diazoacetate 1a
(105.6 mg, 0.6 mmol, 2.0 equiv), o-aminoacetophenone 2a (44.7 mg,
0.3 mmol, 1.0 equiv), 4 Å MS (200 mg), TEMPO (93.6 mg, 0.6
mmol, 2.0 equiv), and 3.0 mL of anhydrous DCM were added in
sequence. The reaction mixture was stirred at room temperature
under the irradiation of blue LEDs for 48 h. After completion of the
reaction (monitored by TLC), the reaction mixture was purified by
silica gel column chromatography (petroleum ether/EtOAc = 8:1−
6:1, v/v) without additional treatment to afford 46.3 mg of pure
product 3a in 52% yield.
(d, J = 7.9 Hz, 2H), 7.24−7.23 (m, 2H), 6.85 (t, J = 7.2 Hz, 1H), 6.59
(d, J = 7.7 Hz, 1H), 3.80 (s, 1H), 3.74 (s, 3H), 2.76 (s, 3H), 0.98 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3) δ (ppm) 171.2, 149.1, 140.1,
134.1, 130.2 (q, J = 32.6 Hz) 129.6, 127.7, 125.1 (q, J = 3.7 Hz),
124.1 (q, J = 270.2 Hz) 121.9, 119.6, 107.6, 86.0, 83.6, 52.0, 32.6,
26.0; 19F NMR (471 MHz, CDCl3) δ (ppm) −62.6; HRMS (TOF
MS ESI+) m/z: [M + H]+ calculated for C19H19NO3F3 366.1312;
found 366.1309.
Methyl (2S*,3R*)-3-Hydroxy-1,3-dimethyl-2-(4-nitrophenyl)-
indoline-2-carboxylate (3m). The reaction mixture was purified by
silica gel column chromatography (petroleum ether/EtOAc = 2:1−
1:1, v/v). Method A: 11.3 mg, 11% yield. Yellow solid, mp = 130−
1
131 °C; H NMR (400 MHz, CDCl3) δ (ppm) 8.23 (d, J = 8.3 Hz,
2H), 7.61 (d, J = 8.3 Hz, 2H), 7.26−7.22 (m, 2H), 6.87 (t, J = 7.1 Hz,
1H), 6.61 (d, J = 7.5 Hz, 1H), 3.81 (s, 1H), 3.74 (s, 3H), 2.77 (s,
3H), 0.96 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm)
170.7, 148.9, 147.6, 143.6, 133.9, 129.7, 128.4, 123.2, 121.9, 119.9,
107.8, 86.1, 83.8, 52.2, 32.7, 26.3; HRMS (TOF MS ESI+) m/z: [M +
H]+ calculated for C18H19N2O5 343.1288; found 343.1285.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01974.
Ethyl (2S*,3R*)-3-Hydroxy-1,3-dimethyl-2-phenylindoline-2-car-
boxylate (3n). The reaction mixture was purified by silica gel column
chromatography (petroleum ether/EtOAc = 8:1−6:1, v/v). Method
A: 51.4 mg, 55% yield. Method B: 56.0 mg, 60% yield. Yellow oil; 1H
NMR (500 MHz, CDCl3) δ (ppm) 7.34 (s, 5H), 7.23−7.19 (m, 2H),
6.82 (t, J = 7.2 Hz, 1H), 6.55 (d, J = 7.6 Hz, 1H), 4.30−4.18 (m, 2H),
3.92 (s, 1H), 2.78 (s, 3H), 1.22 (t, J = 6.9 Hz, 3H), 1.03 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ (ppm) 171.3, 149.5, 135.9,
■
sı
Computational results and 1H, 13C, and 19F NMR
spectra (PDF)
134.4, 129.4, 128.1, 127.9, 127.3, 121.8, 119.1, 107.2, 85.9, 83.4, 61.2,
32.5, 25.5, 14.3; HRMS (TOF MS ESI+) m/z: [M + H]+ calculated
for C19H22NO3 312.1594; found 312.1591.
AUTHOR INFORMATION
Corresponding Authors
■
Methyl (2S*,3R*)-1-Benzyl-3-hydroxy-3-methyl-2-phenylindo-
line-2-carboxylate (3o). The reaction mixture was purified by silica
gel column chromatography (petroleum ether/EtOAc = 8:1−6:1, v/
v). Method A: 56.0 mg, 50% yield. The physical and spectral
Xinfang Xu − Guangdong Provincial Key Laboratory of Chiral
Molecule and Drug Discovery, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, China;
orcid.org/0000-0002-8706-5151; Email: xuxinfang@
mail.sysu.edu.cn
Wenhao Hu − Guangdong Provincial Key Laboratory of Chiral
Molecule and Drug Discovery, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, China;
orcid.org/0000-0003-0200-8527; Email: huwh9@
mail.sysu.edu.cn
properties identical to those earlier reported.11a White oil; H NMR
1
(400 MHz, CDCl3) δ (ppm) 7.43−7.42 (m, 2H), 7.38−7.26 (comp,
9H), 7.06−7.02 (m, 1H), 6.84−6.80 (m, 1H), 6.19 (d, J = 7.8 Hz,
1H), 4.40 (d, J = 16.9 Hz, 1H), 4.16 (d, J = 16.7 Hz, 1H), 3.95 (s,
1H), 3.75 (s, 3H), 1.21 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
(ppm) 172.3, 148.8, 138.4, 136.0, 129.3, 128.7, 128.4, 128.2, 126.8,
126.5, 121.9, 119.5, 109.1, 86.5, 83.3, 52.1, 51.2, 24.7. HRMS (TOF
MS ESI+) m/z: [M + H]+ calculated for C24H24NO3 374.1751; found
374.1750.
Authors
Methyl (2S*,3R*)-1-Ethyl-3-hydroxy-3-methyl-2-phenylindoline-
2-carboxylate (3p). The reaction mixture was purified by silica gel
column chromatography (petroleum ether/EtOAc = 8:1−6:1, v/v).
Method A: 48.6 mg, 52% yield. Method B: 55.1 mg, 59% yield. White
solid, mp =106−109 °C; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.31
(s, 5H), 7.25−7.19 (m, 2H), 6.80 (t, J = 7.1 Hz, 1H), 6.61 (d, J = 7.5
Hz, 1H), 3.77 (s, 3H), 3.66 (s, 1H), 3.18 (dd, J = 14.1, 7.1 Hz, 1H),
3.00 (dd, J = 14.0, 6.9 Hz, 1H), 1.35 (t, J = 6.8 Hz, 3H), 1.12 (s, 3H).
C{1H} NMR (126 MHz, CDCl3) δ (ppm) 172.2, 149.3, 136.5, 134.1,
129.5, 128.2, 128.0, 127.2, 122.2, 118.7, 107.2, 86.9, 83.2, 52.0, 41.9,
24.4, 13.8; HRMS (TOF MS ESI+) m/z: [M + H]+ calculated for
C19H22NO3 312.1594; found 312.1592.
Jinzhou Chen − Guangdong Provincial Key Laboratory of
Chiral Molecule and Drug Discovery, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, China
Shuhao Liu − Guangdong Provincial Key Laboratory of Chiral
Molecule and Drug Discovery, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, China
Xinxin Lv − Guangdong Provincial Key Laboratory of Chiral
Molecule and Drug Discovery, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, China
Kemiao Hong − Guangdong Provincial Key Laboratory of
Chiral Molecule and Drug Discovery, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, China
Jinping Lei − Guangdong Provincial Key Laboratory of Chiral
Molecule and Drug Discovery, School of Pharmaceutical
Sciences, Sun Yat-sen University, Guangzhou 510006, China
Methyl (2S*,3R*)-5-Bromo-3-hydroxy-1,3-dimethyl-2-phenylin-
doline-2-carboxylate (3r). The reaction mixture was purified by
silica gel column chromatography (petroleum ether/EtOAc = 10:1−
6:1, v/v). Method A: 88.1 mg, 78% yield. Method B: 76.8 mg, 68%
1
yield. Light yellow solid, mp = 145−147 °C; H NMR (500 MHz,
CDCl3) δ (ppm) 7.37−7.36 (comp, 3H), 7.33−7.29 (comp, 4H),
6.43 (d, J = 8.2 Hz, 1H), 3.98 (s, 1H), 3.74 (s, 3H), 2.75 (s, 3H), 0.98
(s, 3H). C{1H} NMR (126 MHz, CDCl3) δ (ppm) 171.73, 148.39,
136.68, 135.21, 131.98, 128.23, 127.14, 125.12, 110.91, 108.84, 86.04,
83.10, 51.99, 32.53, 25.59. HRMS (TOF MS ESI+) m/z: [M + H]+
calculated for C18H19BrNO3 376.0543; found 376.0542.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01974
Author Contributions
†J.C. and S.L. contributed equally in this research.
Notes
Procedure for the Scale-Up. To a 50 mL oven-dried vial
containing a magnetic stirring bar, diazoacetate 1b (0.881 g, 4.0
The authors declare no competing financial interest.
G
https://dx.doi.org/10.1021/acs.joc.0c01974
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
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Koenigs, R. M. Sustainable Carbene Transfer Reactions with Iron and
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ACKNOWLEDGMENTS
■
This work is supported by the National Natural Science
Foundation of China (21971262 and 81973176), Guangdong
Provincial Key Laboratory of Chiral Molecule and Drug
Discovery (2019B030301005), National Mega-project for
Innovative Drugs (2019ZX09721001-006-001), and The
Program for Guangdong Introducing Innovative and En-
trepreneurial Teams (no. 2016ZT06Y337).
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