Blue LED-Mediated N-H Insertion of Indoles into Aryldiazoesters at Room Temperature in Batch and Flow: Reaction Kinetics, Density Functional Theory, and Mechanistic Study

Article abstract of DOI:10.1021/acs.joc.0c02649

Mild blue light-mediated N-H insertion of indole and its derivatives into aryldiazoesters has been reported in a batch and flow strategy to afford the corresponding N-alkylated product in moderate-to-excellent yield. Detailed high-performance liquid chromatography-based reaction kinetics measurements, control experiments, and kinetic isotope effect reveal that 3-substituted indoles with electron-withdrawing groups such as -CN and -CHO facilitated the product formation, whereas the electron-donating group retarded the process. The neutral indole performed in between them. Furthermore, Hammett plot and density functional theory-based transition-state optimization studies showed substantial correlation of the electronic nature of the substituents at the C3 position of indoles with the rate of the N-H insertion reaction. The strategy was utilized to synthesize a key intermediate for the natural product (-)-psychotrimine.

Full text of DOI:10.1021/acs.joc.0c02649

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Blue LED-Mediated N−H Insertion of Indoles into Aryldiazoesters at
Room Temperature in Batch and Flow: Reaction Kinetics, Density
Functional Theory, and Mechanistic Study
Debajit Maiti,† Ranajit Das,† and Subhabrata Sen*
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ABSTRACT: Mild blue light-mediated N−H insertion of indole and its derivatives into aryldiazoesters has been reported in a batch
and flow strategy to afford the corresponding N-alkylated product in moderate-to-excellent yield. Detailed high-performance liquid
chromatography-based reaction kinetics measurements, control experiments, and kinetic isotope effect reveal that 3-substituted
indoles with electron-withdrawing groups such as −CN and −CHO facilitated the product formation, whereas the electron-donating
group retarded the process. The neutral indole performed in between them. Furthermore, Hammett plot and density functional
theory-based transition-state optimization studies showed substantial correlation of the electronic nature of the substituents at the
C3 position of indoles with the rate of the N−H insertion reaction. The strategy was utilized to synthesize a key intermediate for the
natural product (−)-psychotrimine.
In another example, blue LED-mediated photolysis of
tosylhydrazone in the presence of cesium carbonate as a base
led to the formation of N−H-inserted indole products with a
phenyl diazoester (Scheme 1d).8a,b Interestingly, one of the
severe shortcomings of photochemical reactions in batch
synthesis is diminishing light intensity due to the absorbing
media as governed by Lambert−Beers’ law.9 This limitation
magnifies manifold during scale up of batch reactions due to
the increase in reactor volume. However, this can be addressed
by applying a continuous flow strategy wherein the reactors
allow homogeneous irradiation of the reaction mixture under a
laminar flow which in turn leads to the reduced reaction time
and better yield of the desired products.10
Herein, we report a mild blue LED-mediated batch and flow
synthetic strategy for the N−H insertion of indole derivatives
into aryldiazoesters. We developed a photo-microreactor
assembly consisting of a glass holder containing 6.3 mL of
perfluoroalkoxy alkane (PFA) in a capillary reactor with an
internal diameter (ID) 2 mm [see Supporting Information,
1. INTRODUCTION
By their ubiquitous presence in several natural products and
drug molecules, indoles hold a niche position in the field of
organic chemistry and pharmaceutical sciences.1,2 Hence,
functionalizing indole moieties are interesting reactions
which provide motifs efficiency to diverse biological targets.3,4
In the recent past, our research group has published a report
about the blue LED-mediated intramolecular C2−H activation
of indoles via installation of a diazo moiety to afford a variety
of azepino[4,5-b] indoles.5 During this reaction, we observed
the formation of a byproduct (∼5%) which was later
characterized as the N−H-inserted intermolecular adduct 3A
(Scheme 1a). Since this was a one-pot reaction from
tryptamine with phenyl methyl acetate, we anticipated that
unreacted tryptamine and phenyl diazoester (formed in situ)
could have afforded 3A during the reaction (Scheme 1a). This
prompted us to develop a blue LED-mediated, metal- and
base-free N−H insertion of indoles with aryldiazoesters. Apart
from the blue LED-mediated N−H insertion reaction of
carbazoles, pyrazoles, and benzotriazole (Scheme 1b), careful
curation of the literature provided few strategies until date for
the N−H insertion of indoles with aryldiazoesters.6−8 The
palladium-catalyzed enantioselective strategy in the presence of
a Ph-spiro box, sodium bromide, and chloroform afforded
eight examples with yields ranging from 11 to 89% and
enantiomeric excess (ee) between 53 and 80% (Scheme 1c).7
Received: November 6, 2020
Published: January 8, 2021
https://dx.doi.org/10.1021/acs.joc.0c02649
© 2021 American Chemical Society
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Scheme 1. Literature Reports and Preliminary Observation
Figure 1. UV absorption study of phenyl diazoacetate in different solvents irradiated in the presence of blue LED (with spectral range of 435−445
nm); (A) at 0 h; (B) at 1 h; and (C) at 2 h.
Figure S1] to investigate the N−H reaction via flow. The
reaction kinetics was determined through high-performance
liquid chromatography (HPLC). From the generic reactions, it
was observed that electron-withdrawing groups at the C3
position of indoles facilitated the reaction.
2. RESULTS AND DISCUSSION
For the reaction optimization, we investigated the appropriate
solvent for the reaction. To optimize the solvent that could
maximize the absorption by aryldiazoesters, phenyl methyl
diazoacetate 2a was deployed as a model substrate (Figure 1).
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Accordingly, three different classes of solvents were screened,
where 2a was dissolved in dichloromethane (DCM) (non-
polar), methanol (polar protic), and acetonitrile (ACN) (polar
aprotic). They were subsequently irradiated by blue LED and
their UV absorption spectra were measured as 2a generated
the corresponding carbene (Figure 1). From the UV spectra, it
was evident that 2a in methanol exhibited the least absorption
energy. Additionally, the resulting carbene could get quenched
by methanol or by the water present in the methanol (Figure
1a). The carbene formation is the fastest in DCM as observed
by the rapidly diminished absorption peak of 2a in DCM over
time (Figure 1A−C). The carbene formation in ACN happens
to occur steadily as observed from gradual diminishing of its
absorption peak over time (Figure 1A−C). We had the option
of utilizing both DCM and ACN for our purpose.
compared to the other two products, that is, 3a and b. Figure
2C−E depicts the initial rate of the formation of individual
products 3a → c, over the whole period of 8 h. Generation of
3a was faster than that of 3b. Eventually, from the plot and the
bar graph depicted in Figure 2F,G, the rate for the formation of
3c was calculated to be 9.76 0.07 10−3 M h−1, whereas the
same for 3a/b is 3.96 0.05 10−3 and 2.53 0.06 10−3 M h−1,
respectively (for details, see Experimental Procedures and
Figures S2−S8).
To optimize the flow synthesis, a photo-microreactor
assembly was developed in our laboratory containing a glass
holder with 6.3 mL of perfluoroalkoxy alkane in a capillary
reactor (PFA ID 1−2.5 mm). Keeping the optimal conditions
for the batch reaction the same (Figure S1 of the Supporting
Information), we explored various concentrations (of the
reactants) and flow rate/internal diameter of the reactor for the
reaction between 1c and 2a (Table 2, entry 1−9). The
condition with 0.1 and 0.2 M of 1c and 2a, respectively, with 2
mL/h flow rate and a microreactor with 2 mm ID provided the
best yield of 71% of 3c (Table 2, entry 6). Any increment or
reduction of the ID did not improve the yield further (Table 2,
entry 7−9). 3.15 h is the optimal residence time for the best
output of compound 3c (Table 2, entry 6).
Reactions of 1a and 2a in ACN at 78 °C provided the
desired 3a in 21% (Table 1, entry 1). Room temperature (25
Table 1. Optimization of Batch Synthesis for the N−H
a
Insertion Reaction
With the optimized reaction condition in hand, we assessed
the robustness of the reaction by reacting various 3-substituted
indoles 1a−e with phenyl diazoacetate 2a and aryldiazoesters
with diverse substitutions on the phenyl ring 2b−h (Figure 3,
Scheme S1). In general, the N−H insertion reaction was well-
tolerated and was decent yielding, generating a library of N-
alkylated indoles 3a → r. Overall, the flow strategy provided
better yields over batch. The electron-withdrawing substituents
at the C3 position of indole, that is, cyano 1c and carbaldehyde
1d, facilitated the N−H insertion with much better yields of
the desired products 3c−e and 3k−q over the compounds 3a/
r from the reactions of unsubstituted indole 1a. Compounds
3b and 3f−j obtained from the electron-donating C3-
substituted indoles, that is, 1b/e, were also generated in
poor yield. The 3-methyl indole 1b was least yielding under
flow synthesis, where the desired product 3b was obtained in
45% yield. The electron-donating and electron-withdrawing
group-encrusted aryldiazoesters were equally amenable toward
the N−H insertion. However, we have not observed any other
distinct pathways that can contribute to form other products
during these N−H insertion reactions. N−H insertion was
always the preferred pathway in N−H-free indoles. Addition-
ally, we have not observed competing cyclopropanation or
formal C−H insertion products even when the indole-C3 was
unsubstituted. It could be possible that they were forming but
in extremely negligible quantity. During our effort to isolate the
products of the blue LED-induced N−H insertion reaction of
indole (1a) with phenyl diazoacetate (2a), we could obtain the
N−H-inserted compound (3a) as the major product along
with the dimerized diazo compound (4a) as the byproduct. To
demonstrate the practical utility of our strategy, we executed
the synthesis of 3c in gram scale in the flow setup and we were
able to generate 1.39 g of the desired compound (69% yield).
As an application of our strategy, we synthesized 3-(1H-
indolyl-1-yl)indolin-2-ones, 5 (Scheme 2). It is a key
intermediate for the synthesis of (−)-psychotrimine.11 In the
synthesis, indole 1a was treated with 2k under the batch-
optimized condition in blue LED in DCM to afford the N−H-
inserted product 3s (Scheme 2). Subsequent reduction of the
azide in zinc dust and ammonium formate led to in situ
b
entry
solvent
2a (equiv)
T (°C)
yield (%)
1
2
3
4
ACN
ACN
DCM
DCM
DCM
DCM
DCM
1.0
1.0
1.0
1.0
1.5
2.0
2.5
78
25
40
25
25
25
25
21
42
39
45
51
55
51
c
5
c
6
c
7
a
1a (0.3 mmol, 35 mg) and 2a (as specified equivalence in each
entry) in ACN or DCM (3 mL) were reacted under blue light
irradiation for 22 h. Isolated yield (reaction scale 50 mg).
b
c
Compound 2a was added in portions to the reaction mixture.
°C) proved more conducive toward the reaction to provide the
desired compound 3a in 42% yield (Table 1, entry 2). Next,
the reaction in DCM at 40 °C could not improve the yield
further however the same reaction at rt afforded 3a in 45%
yield (Table 1, entry 3 and 4). Varying the relative amount of
2a to 1.5 → 2.5 equiv (Table 1, entry 5 → 7) indicated that the
optimal ratio for 1a:2a is 1:2. Hence, for a batch-scale
synthesis, the optimum procedure involved reaction of 1a and
2a, in 1:2 equiv at rt in DCM.
Next, to understand the kinetics of the N−H insertion
reaction, three differently substituted indoles, that is, indole 1a,
3-methyl indole 1b, and 3-cyano indole 1c, were reacted with
phenyl diazoacetate 2a in DCM for 8 h in blue LED under the
batch-optimized condition (Figure 2). The reactions were
monitored closely by HPLC, where initially the samples were
injected at an interval of 10 min for 2 h. After which, the
samples were injected at an interval of 1 h for next 6 h. The
desired N−H-inserted products 3a → c were obtained at the
end of the reaction (Figure 2A) along with the dimeric phenyl
diazoacetate 4a as a minor byproduct.
Figure 2B compares the initial rate of the formation of
products 3a → c and the depletion of the corresponding
starting material 1a → c at the first 3 h. It indicates that right
from the initiation of the reaction, the rate of 3c is faster
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Figure 2. Reaction kinetics of various 1a−c with 2a: (A) blue LED-mediated N−H insertion reaction of 1a−c with 2a under standardized reaction
condition. (B) HPLC chromatogram of 1a−c with 2a depicting the relative formation of 3a−c under standard reaction condition after 3 h; (C)
percentage degradation of starting materials 1a and 2a and percentage formation of desired product 3a over time; (D) percentage degradation of
starting materials 1c and 2a and percentage formation of desired product 3c over time; (E) percentage degradation of starting materials 1b and 2a
and percentage formation of desired product 3b over time; and (F) comparison of percentage formation of N−H-inserted desired products (3a−c)
over time. (G) Bar diagram showing the calculated initial rate of formation of N−H-inserted products (3a−c).
a
Table 2. Optimization of Flow Synthesis for the N−H Insertion Reaction
sl no.
concn 1c (M)
concn 2a (M)
flow rate (mL h−1
)
internal diameter (mm)
residence time (h)
% isolated yield of 3c
1
2
3
4
5
6
7
8
9
10
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.2
0.2
0.2
0.2
0.2
6
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.5
1.5
1.0
1.0
1.4
1.8
2.0
2.2
3.15
4.2
4.9
1.8
0.8
12
23
39
56
64
71
69
62
51
43
4.5
3.5
3.0
3.0
2.0
1.5
2.0
2.0
2.0
a
1c (1 equiv, 0.5 mmol, 71 mg) and 2a (1 or 2 equiv as specified) were dissolved in DCM (5 mL) to prepare a single stock solution, injected to the
microreactor through a syringe pump with varying flow rates as specified in each entry; stock solution was kept protected from light throughout the
reaction time.
lactamization to afford 5 (Scheme 2). In a bid to introduce
chiral selectivity in 5, we have tried to synthesize chiral diazo
reagent 2j (Supporting Information, Scheme S1) in our
laboratory to observe any stereo-controlled product formation;
however, we were unable to synthesize 2j. We also tried the
blue LED-induced N−H insertion reaction between 1a and 2i
in the presence of Co−Salen complexes [(R,R)-(−)-N,N′-
b i s ( 3 , 5 - d i - t e r t - b u t y l s a l i c y l i d e n e ) - 1 , 2 -
cyclohexanediaminocobalt(II) and (S,S)-(+)-N,N′-bis(3,5-di-
tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II)] to
introduce chiral induction in 3s, but unfortunately, we could
not see any chiral induction in the desired compound 3s.
In a bid to understand the mechanism of the reaction, few
control experiments were performed (Scheme 3A). When 1a
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Figure 3. Generic synthesis of various N-alkylated indoles under batch and flow synthesis.
Scheme 2. Synthesis of 5, a Key Intermediate for the
Synthesis of Natural Product (−)-Psychotrimine
Scheme 3. (A) Control Experiments: Reaction of 2a with 1a
in the Absence of Blue LED and in the Presence of BHT;
(B) KIE: Schematic Diagram Showing the Reaction between
Indole(N−H) 1a or Indole(N−D) 1a−D with 2a (kH/kD =
1.32); and (C) Initial Rate of Formation of 3a [Indole(N−
H)] and 3a−D [Indole(N−D)], under Standard Batch
Reaction Condition
was reacted with 2a in the absence of blue LED in other batch-
optimized conditions, only traces of the N−H-inserted product
were obtained. Next, the addition of radical scavenger
butylated hydroxytoluene (BHT) to the reaction mixture did
not suppress the reaction, and the desired product 3a was
obtained in 55% yield (Scheme 3A). Next, the kinetic isotope
effect (KIE) study of 1a and its deuterated analogue 1a−D was
performed under batch-optimized condition by reacting with
1.32) [Scheme 3A,B]. Additionally, we also observed 35%
deuteration at the quaternary carbon center in 1H NMR
phenyl diazoacetate (2a) to provide apparent KIE (kH/kD
=
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Scheme 4. (A) Putative Mechanism of the N−H Insertion of Indole Derivatives into Aryldiazoesters; (B) Total Energy Profile
a
of the Reactions between Various C3-Substituted Indoles (1a−c) and Phenyl Diazoacetate (2a)
a
All energies are in kcal mol−1, relative to the free molecules. TS = transition states.
spectra of the desired product, 3a−D (see Supporting
Information, page S58). These observations affirm the
involvement of the N−H bond of indole in the rate-limiting
step of the reaction.
(28.62 kcal mol−1) which suggest that the reaction with 1c and
2a was the less energy-required process than the reaction of 1a
and 1b with 2a. Furthermore, highest occupied molecular
orbital/lowest unoccupied molecular orbital (HOMO/
LUMO) analysis of the optimized geometry of the reactants
shows that the LUMO of 1c (−1.27 eV) is located lower in
energy than the LUMO of 1a (−0.72 eV) or 1b (−0.69 eV)
(Figure S9) and, thus, the energy gap between the HOMO of
the carbene generated from the phenyl diazoacetate (2a) and
the LUMO of 3CN-indole (1a) is the lowest relative to that for
other C3-substituted indoles, that is, 1a and 1b. Thus,
combination of all these calculated parameters possibly
accounts for the high reactivity of 1c among other C3-
substituted indoles toward phenyl diazoacetate (2a). On the
other hand, we noticed that the LUMO of 1b is located at
−0.69 eV; thus, the energy gap between the LUMO of 1b and
HOMO of the carbene is the highest compared to the other
C3-substituted indoles 1a and 1c, and the relatively high
activation energy required for the N−H insertion reaction of
1b with 2a explains why the reactions between 1b and 2a
proceed slowly. Hence, from the aforementioned DFT studies
and control reactions, it can be surmised that the reaction
sequence begins with the sharing of the N−H σ bond of 1a
with the carbene generated by blue LED from 2a via a side-on
approach (Scheme 4A). In this, the HOMO of the N−H bond
interacts with the LUMO of singlet carbene (empty p-orbital)
and the LUMO of the N−H bond interacts with the HOMO
of singlet carbene (filled sp2 orbital). The electron-deficient
carbene carbon atom attracts the electron density of the
partially formed C−N bond toward itself, thereby developing a
partial negative charge (Scheme 4A). It subsequently abstracts
the heteroproton from indole N through a concerted N−H
bond breaking and C−H bond formation. Hence, an electron-
withdrawing group at the C3 position of the indole facilitates
the reaction (as observed during the formation of 3c in Figure
2).
In order to gain further insight into the mechanism of the
N−H insertion reaction of C3-substituted indoles (1a−c) with
phenyl diazoacatate 2a, we have performed quantum chemical
calculations [density functional theory (DFT)] using the
B3LYP(PCM)/6-311++G(2d,p) level of theory in the solvent
phase (DCM, as a solvent). The initial state of the reaction
proceeds with the generation of carbene from 2a which
involves in blue LED-mediated photochemical energy transfer
from the blue light to 2a. It resulted in the generation of
carbene species at the sp2 carbon center of the phenyl acetate
via the transition state [1a → cTS1]‡, as shown in Scheme 4B
and Figures S10−S12. This transformation was also accom-
panied by the elimination of nitrogen gas (N2). As the carbene
generation proceeds via photochemical pathway in the
presence of blue LED, thus to understand the process in a
deeper aspect, time-dependent DFT (TDDFT) calculation has
been performed in DCM to optimize the first-singlet exited
state (S1) for the transition states [1a → cTS1]‡ and compared
with the ground state (S0) of the same. Surprisingly, it has been
found that in the first-exited transition states [1a → cTS1]‡
were further stabilized (2.9−4.15 kcal mol−1) by the N−H···O
hydrogen-bonding (1.96−2.18 Å) interaction between C3-
substituted indoles (1a−c) with the 2a carbenes via the
interaction of sp oxygen of the 2a with the N−H proton of the
C3-substituted indoles (1a−c) which may further facilitate the
carbene formation reaction Figure S13 and Tables S2−S5 in
the Supporting Information.
Finally, the carbene generated from the 2a reacts with the
C3-substituted indoles via the transition state [1a → c-TS2]‡
which is ultimately culminating in the desired N−H-inserted
C3-substituted indoles (3a−c). Fascinatingly, the activation
energy required for the N−H insertion reactions of 1c (21.38
kcal mol−1) via the transition state [1c-TS2]‡ was the lowest
compared to [1a-TS2]‡ (24.65 kcal mol−1) and [1b-TS2]‡
To further demonstrate the effect of the substituent at the
C3 position of indole, we investigated through the Hammett
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1
Figure 4. C3 substitution effect of indoles on the N−H insertion reaction: A correlation study with Hammett’s substitution constants. (A) H
NMR (400 MHz, CDCl3) stack spectra showing the chemical shift (δ) values of N−H protons of various C3-substituted indoles (1a−1d); (B)
Correlation between the substituent effect at the C3 position of indoles with the initial rate of formation of products using calculated σΔδ (ρ =
0.53); and (C) Hammett’s correlation between the substituents at the C3 position of indoles with the rate of formation of products using σm (ρ =
0.79).
plot whether there is any linear relationship between chemical
shift changes of N−H protons, varied C3-substituents, and the
corresponding rate of the reactions (Figure 4). In general,
Hammett’s substituent constant determines the relative
electronic effects of any given substituents on the electron
density of the reaction center under consideration.12
Numerous studies suggested that Hammett parameters can
be correlated with the NMR chemical shift values.12−15
Accordingly, the chemical shift values of N−H protons of
indole (1a), 3-Me-indole (1b), indole 3-carboxaldehyde (1d),
3. CONCLUSIONS
In conclusion, a mild blue LED-mediated N−H insertion
protocol for indoles has been developed. The reaction was
performed both in batch and flow and is amenable to a wide
variety of functionalities. The continuous flow protocol proved
efficient by reducing the reaction time by one-seventh (3 h vs
22 h). Control experiments, HPLC-based kinetics study, DFT
calculations, and KIE investigation suggested a concerted
mechanism with indole N−H abstraction as the rate-limiting
step. The Hammett plot further revealed strong influence of
the substitution at the C3 position of the indoles on the N−H
insertion reaction. The strategy is also applied toward the
synthesis of 5, a key intermediate for the formal synthesis of
natural product (−)-psychotrimine.
1
and 3-cyano indole (1c) (from their H NMR spectra) were
compared with their initial rate of N−H insertion to the phenyl
diazoester. It was observed that the more electron-donating the
C3 substituent (of the indole) is, the more upfield the N−H
protons are and consequently the slower is the rate of the
reaction [Figure 4A]. Next, the logarithmic ratio, log(k/k0) of
the initial rates of the reaction between 1b−d and 2a versus 1a
and 2a, was plotted against σΔδ (ppm), which is the deviation
in the chemical shift of N−H protons of 1b−d wrt 1a (Figure
4B). A linear relationship was obtained with a positive slope
(ρΔδ = +0.53) (Figure 4B). We compared this with the plot of
log(k/k0) against σm (the reported Hammett’s substitution
constant with substituents at the meta position [which is
comparable to C3 position of indole]) [Figure 4C].15 We were
delighted to find a similar linear relationship as mentioned
above with a positive slope (ρ = +0.79). This strongly suggests
that the calculated σΔδ parameter of C3-substituted indoles is
analogous to Hammett’s substitution constant, σm. Addition-
ally, the experiment further proved that the variation in the rate
of the reaction depends on the electronic effect (electron-
withdrawing nature) of the C3 substitutions of indoles, which
in turn depends on the acidity of the N−H proton.
4. EXPERIMENTAL PROCEDURE
4.1. General Experimental Procedure. All blue light batch
reactions were carried out under air as specified in Photochemical
ReactorAldrich Micro Photochemical Reactor, blue LED lights
(ALDKIT001-1EA). LED light is an IP68 double density 12 V DC
waterproof blue light with a spectral range of 435−445 nm with a wall
plug power supply of 500 mA with 5−6 W. The irradiation vessel
material is borosilicate glass. The distance of the irradiation vessel
from the light source is 2 cm. For flow synthesis, a photo-microreactor
assembly was developed in our laboratory containing a glass holder
with 6.3 mL of perfluoroalkoxy alkane in a capillary reactor (PFA ID
1−2.5 mm) with a 3−4 W blue LED light strip (with a spectral range
of 435−445 nm) (Figure S1). In both batch and flow setup, reactions
were cooled using an external DC portable cooling fan. Reactions
were monitored through thin layer chromatography by visualizing in a
UV detector. All purifications were carried out in silica gel (100−200
mesh size) column chromatography. All H and 13C NMR spectra
1
were recorded taking tetramethylsilane as an internal standard at
ambient temperature unless otherwise indicated with Bruker 400
MHz instruments at 400 MHz for H and 100 MHz for 13C NMR
1
spectroscopy. Splitting patterns are designated as singlet (s), broad
singlet (br s), doublet (d), triplet (t), quartet (q), quintet (quin),
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1
doublet of doublets (dd), and triplet of doublets (td). Splitting
patterns that could not be interpreted or easily visualized are
designated as multiplet (m). MS analyses were carried out using an
Agilent 6540 accurate-mass Q-TOF LC/MS (Agilent Technologies,
U.S.A.). MS analyses were performed under the following operation
parameters: dry gas temperature 350 °C, dry gas (N2) flow rate 10 L/
min, nebulizer pressure 30 psi, Vcap 4000, and fragmentor voltage 110
V. Mass spectra were acquired in the positive ion mode by scanning
from 100 to 1500 in the mass-to-charge ratio (m/z). The mobile-
phase composition used for UHPLC-QTOF MS comprises H2O (A)
and ACN (B), with optimized linear gradient elution. The injection
volume was 5 μL. The flow rate was set at 0.3 mL/min. Accurate mass
analysis calibration was carried out by ESI-low concentration tuning
mix solution provided by Agilent Technologies, U.S.A. The accuracy
error threshold was set at 5 ppm. HPLC experiments were carried out
on the Agilent 1290 infinity series of the LC system (Agilent
Technologies, U.S.A.) with a photodiode array/ELSD detector to
monitor the progress of the blue LED-mediated N−H insertion
reaction of indoles. HPLC experiments were carried out on a Waters
Alliance System (Milford, MA) consisting of an e2695 separation
module and a 2998 photodiode-array detector. The HPLC system
was controlled with EMPOWER software (Waters Corporation,
Milford, MA). Due to COVID 19 restrictions, it is difficult to obtain
higher-quality solvents from overseas suppliers; therefore, numerous
grease/impurity peaks are present in the NMR spectra from the
lower-quality solvents.
4.1.1. Synthesis of Aryldiazoesters (2a−i). All aryldiazoacetates
were prepared by following the reported procedure. Aryl acetates (1
equiv, 5 mmol) were dissolved in ACN (10 mL) in a clean oven-dried
round-bottom flask, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (1.2
equiv, 6 mmol) was added, stirred for 10 min, p-ABSA (4-
acetamidobenzenesulfonyl azide) (1.2 equiv, 6 mmol) was added,
and stirred for 4 h in the dark and rt; after completion, ACN was
removed under vacuum, diluted with ethyl acetate (25 mL), and
washed with water, and the organic layer was dried with brine and
sodium sulphate and purified with flash column chromatography in
silica gel (100−200 mesh size) with 5% ethyl acetate in hexane to
yield 98%.16
in hexane. H NMR (CDCl3, 400 MHz): δH 7.42−7.40 (m, 4H),
7.39−7.35 (m, 6H), 3.54 (s, 6H); 13C{1H} NMR (CDCl3, 100
MHz): δC 168.8, 137.9, 135.7, 129.2, 128.8, 128.3, 52.6; HRMS (ESI-
TOF) m/z: calcd for [M + H]+ C18H17N2O4, 325.1183; found,
325.1199.
4.2.2.3. Methyl 2-(3-Methyl-1H-indol-1-yl)-2-phenylacetate, 3b.
3b was synthesized using general procedure by reacting 1b and 2a,
and purification was performed by column chromatography in silica
gel (100−200 mesh size) in 5% ethyl acetate in hexane to yield a
yellow, amorphous solid (36.46 mg, 42% in batch and 65.10 mg, 45%
in flow); 1H NMR (400 MHz, CDCl3): δH 7.57 (d, J = 7.6 Hz, 1H),
7.41−7.38 (m, 3H), 7.34−7.29 (m, 3H), 7.22 (t, J = 7.2 Hz, 1H),
7.14 (t, J = 7.4 Hz, 1H), 6.89 (s, 1H), 6.22 (s, 1H), 3.80 (s, 3H), 2.28
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δC 170.4, 136.9, 135.0,
129.3, 129.1, 129.0, 128.2, 124.2, 122.0, 119.6, 119.4, 111.8, 108.9,
61.9, 52.9, 9.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C18H18NO2, 280.1332; found, 280.1321.
4.2.2.4. Methyl 2-(3-Cyano-1H-indol-1-yl)-2-phenylacetate, 3c.
3c was synthesized using general procedure by reacting 1c and 2a, and
purification was performed by column chromatography in silica gel
(100−200 mesh size) in 10% ethyl acetate in hexane to yield an off
white, amorphous solid (60.97 mg, 70% in batch and 108.87 mg, 75%
in flow); 1H NMR (400 MHz, CDCl3): δH 7.77 (dd, J = 6.8 Hz, 1H),
7.59 (s, 1H), 7.47−7.46 (m, 3H), 7.42−7.40 (m, 1H), 7.39−7.31 (m,
4H), 6.25 (s, 1H), 3.84 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3):
δC 185.1, 169.2, 137.7, 137.6, 133.0, 129.9, 129.7, 128.5, 125.5, 124.5,
123.6, 122.6, 119.1, 109.5, 62.4, 53.4, 29.8; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C18H15N2O2, 291.1128; found, 291.1115.
4.2.2.5. Ethyl 2-(3-Formyl-1H-indol-1-yl)-2-(p-tolyl)acetate, 3d.
3d was synthesized using general procedure by reacting 1d and 2b,
and purification was performed by column chromatography in silica
gel (100−200 mesh size) in 10% ethyl acetate in hexane to yield a
pale yellow, amorphous solid (66.52 mg, 69% in batch and 123.73 mg,
1
77% in flow); H NMR (400 MHz, CDCl3): δH 9.84 (s, 1H), 8.25−
8.23 (m, 1H), 7.60 (s, 1H), 7.32−7.29 (m, 1H), 7.28−7.27 (m, 1H),
7.25−7.24 (m, 1H), 7.21−7.17 (m, 4H), 6.11 (s, 1H), 4.26−4.16 (m,
2H), 2.32 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3): δC 185.1, 168.9, 140.1, 137.8, 137.7, 130.4, 130.0,
128.5, 124.4, 123.5, 122.5, 109.6, 62.6, 62.3, 21.4, 14.2; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C20H20NO3, 322.1438; found,
322.1431.
4.2. General Procedure for Synthesis of 3a−r. 4.2.1. Batch
Synthesis of 3a−g, 3i, 3k, 3o, 3p, and 3r. Various substituted
indoles (1a−e) (1 equiv, 0.3 mmol) were taken in 20 mL vials
dissolved in DCM (3 mL), various substituted diazoesters (2a−h) (2
equiv) were added, and stirred in rt under the irradiation of blue light
for 22 h. Purifications were performed by column chromatography in
silica gel (100−200 mesh size) in 5−10% ethyl acetate in hexane.
4.2.2. Flow Synthesis of 3a−r. Various substituted indoles (1a−e)
(1 equiv, 0.5 mmol) and aryldiazoesters (2a−h) (1 or 2 equiv as
specified) were dissolved in DCM (5 mL) to prepare the stock
solution and taken in a syringe pump to push into the microreactor
(Figure S1). Flow rates were monitored through programming the
rates in the syringe pump. The eluted reaction mixture was collected
in a vial attached with the outlet of the microreactor. Purification was
performed with the same procedure as in batch synthesis.
4.2.2.6. Ethyl 2-(3-Cyano-1H-indol-1-yl)-2-(p-tolyl)acetate, 3e. 3e
was synthesized using general procedure by reacting 1c and 2b, and
purification was performed by column chromatography in silica gel
(100−200 mesh size) in 10% ethyl acetate in hexane to yield an off
white, amorphous solid (57.31 mg, 60% in batch and 113.02 mg, 71%
in flow); 1H NMR (400 MHz, CDCl3): δH 7.77−7.76 (m, 1H), 7.56
(s, 1H), 7.43−7.41 (m, 1H), 7.38−7.29 (m, 2H), 7.27−7.26 (m, 4H),
6.18 (s, 1H), 4.34−4.24 (m, 2H), 2.40 (s, 3H), 1.27 (d, J = 7.2 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): δC 168.7, 140.1, 135.8,
134.4, 130.4, 129.8, 128.4, 127.9, 124.3, 122.8, 120.3, 115.8, 110.2,
87.0, 62.6, 62.4, 21.3, 14.2; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C20H19N2O2, 319.1441; found, 319.1437.
4.2.2.1. Methyl 2-(1H-Indol-1-yl)-2-phenylacetate, 3a. 3a was
synthesized using general procedure by reacting 1a and 2a, and
purification was performed by column chromatography in silica gel
(100−200 mesh size) in 5% ethyl acetate in hexane to yield an off
white, amorphous solid (43.78 mg, 55% in batch, and 76.94 mg, 58%
in flow); 1H NMR (400 MHz, CDCl3): δH 7.64 (d, J = 7.6 Hz, 1H),
7.40−7.38 (m, 3H), 7.36−7.33 (m, 3H), 7.25−7.21 (m, 1H), 7.17−
7.14 (m, 1H), 7.13 (d, J = 3.2 Hz, 1H), 6.54 (d, J = 3.2 Hz, 1H), 6.27
(s, 1H), 3.81 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δC 170.2,
136.6, 134.7, 129.2, 129.1, 128.9, 128.2, 126.8, 122.1, 121.3, 120.3,
109.1, 102.6, 62.1, 52.9; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C17H16NO2, 266.1176; found, 266.1185.
4.2.2.2. Dimethyl 2,2′-(Hydrazine-1,2-diylidene) (2,2′)-bis(2-
phenylacetate), 4a. 4a (yellow, amorphous solid, 20.55 mg, 11% in
batch) was obtained as a byproduct in the reaction of 1a and 2a along
with the formation of 3a. Purification was performed by column
chromatography in silica gel (100−200 mesh size) in 5% ethyl acetate
4.2.2.7. Methyl 2-(4-Chlorophenyl)-2-(3-((1,3-dioxoisoindolin-2-
yl)methyl)-1H-indol-1-yl)acetate, 3f. 3f was synthesized using
general procedure by reacting 1e and 2c, and purification was
performed by column chromatography in silica gel (100−200 mesh
size) in 5% ethyl acetate in hexane to yield a yellow, amorphous solid
(70.21 mg, 51% in batch and 144.15 mg, 63% in flow); 1H NMR (400
MHz, CDCl3): δH 7.96−7.94 (m, 1H), 7.81−7.77 (m, 2H), 7.67−
7.63 (m, 2H), 7.37−7.35 (m, 3H), 7.27 (s, 1H), 7.24−7.16 (m, 4H),
6.16 (s, 1H), 4.97 (s, 2H), 3.79 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δC 169.6, 168.2, 136.6, 135.2, 133.9, 133.1, 132.4, 129.5,
127.8, 127.6, 123.3, 122.6, 120.7, 120.2, 111.6, 109.3, 61.6, 53.1, 32.7;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H20ClN2O4,
459.1106; found, 459.1112.
4.2.2.8. Methyl 2-(3-Bromophenyl)-2-(3-((1,3-dioxoisoindolin-2-
yl)methyl)-1H-indol-1-yl)acetate, 3g. 3g was synthesized using
general procedure by reacting 1e and 2d, and purification was
performed by column chromatography in silica gel (100−200 mesh
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size) in 5% ethyl acetate in hexane to yield a yellow, amorphous solid
(61.91 mg, 41% in batch and 130.87 mg, 52% in flow); 1H NMR (400
MHz, CDCl3): δH 7.99−7.97 (m, 1H), 7.84−7.81 (m, 2H), 7.69−
6.67 (m, 2H), 7.54−7.52 (m, 1H), 7.55−7.48 (m, 2H), 7.42 (s, 1H),
7.26−7.20 (m, 4H), 6.18 (s, 1H), 5.01 (s, 2H), 3.83 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δC 169.2, 168.1, 139.3, 136.7, 133.8, 132.3,
132.2, 130.9, 130.6, 127.7, 127.4, 126.4, 123.2, 122.5, 120.6, 120.0,
114.1, 111.5, 109.1, 61.4, 53.0, 31.9; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C26H20BrN2O4, 503.0601; found, 503.0619.
Hz), 115.5, 110.1, 87.7, 61.7, 51.5; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C18H14FN2O2, 309.1034; found, 309.1041.
4.2.2.14. Methyl 2-(3-Formyl-1H-indol-1-yl)-2-phenylacetate,
3m. 3m was synthesized using general procedure by reacting 1d
and 2a, and purification was performed by column chromatography in
silica gel (100−200 mesh size) in 10% ethyl acetate in hexane to yield
1
a yellow, amorphous solid (104.13 mg, 71% in flow); H NMR (400
MHz, CDCl3): δH 9.94 (s, 1H), 8.34−8.32 (m, 1H), 7.72 (s, 1H),
7.48−7.46 (m, 3H), 7.41−7.34 (m, 5H), 6.26 (s, 1H), 3.85 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δC 185.1, 169.2, 137.7 137.6,
133.0, 129.9, 129.7, 128.5, 125.5, 124.5, 123.6, 122.6, 119.1, 109.5,
62.4, 53.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H16NO3,
294.1125; found, 294.1116.
4.2.2.9. Methyl 2-(3-((1,3-Dioxoisoindolin-2-yl)methyl)-1H-indol-
1-yl)-2-(4-fluorophenyl)acetate, 3h. 3h was synthesized using
general procedure by reacting 1e and 2e, and purification was
performed by column chromatography in silica gel (100−200 mesh
size) in 5% ethyl acetate in hexane to yield a yellow, amorphous solid
4.2.2.15. Methyl 2-(3-Formyl-1H-indol-1-yl)-2-(3-
methoxyphenyl)acetate, 3n. 3n was synthesized using general
procedure by reacting 1d and 2g, and purification was performed
by column chromatography in silica gel (100−200 mesh size) in 10%
ethyl acetate in hexane to yield an orange-red, amorphous solid
(130.95 mg, 81% in flow); 1H NMR (400 MHz, CDCl3): δH 9.95 (s,
1H), 8.34−8.32 (m, 1H), 7.74 (s, 1H), 7.40−7.32 (m, 4H), 7.00−
7.97 (m, 2H), 6.92 (t, J = 2.2 Hz, 1H), 6.22 (s, 1H), 3.84 (s, 3H),
3.81 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δC 185.3, 169.1,
160.5, 137.7, 137.6, 134.3, 130.8, 125.5, 124.5, 123.6, 122.6, 120.6,
119.1, 115.4, 114.6, 109.5, 62.3, 55.5, 53.4; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C19H18NO4, 324.1230; found, 324.1242.
4.2.2.16. Methyl 2-(3-Cyano-1H-indol-1-yl)-2-(3-
methoxyphenyl)acetate, 3o. 3o was synthesized using general
procedure by reacting 1c and 2g, and purification was performed
by column chromatography in silica gel (100−200 mesh size) in 10%
ethyl acetate in hexane to yield a yellow, amorphous solid (68.23 mg,
1
(146.01 mg, 66% in flow); H NMR (400 MHz, CDCl3): δH 7.89−
7.86 (m, 1H), 7.72−7.70 (m, 2H), 7.58−7.56 (m, 2H), 7.24−7.22
(m, 1H), 7.18−7.09 (m, 4H), 7.03−6.98 (m, 3H), 6.09 (s, 1H), 4.89
(s, 2H), 3.71 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δC 169.7,
168.1, 163.0 (d, J = 248 Hz), 136.4, 133.8, 132.2, 129.9 (d, J = 8.0
Hz), 127.6, 127.4, 123.2, 122.4, 120.5, 120.0, 116.2 (d, J = 22 Hz),
111.2, 109.1, 61.4, 52.9, 32.5; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C26H20FN2O4, 443.1402; found, 443.1425.
4.2.2.10. Methyl 2-(4-Bromophenyl)-2-(3-((1,3-dioxoisoindolin-2-
yl)methyl)-1H-indol-1-yl)acetate, 3i. 3i was synthesized using
general procedure by reacting 1e and 2f, and purification was
performed by column chromatography in silica gel (100−200 mesh
size) in 5% ethyl acetate in hexane to yield a yellow, amorphous solid
(77.01 mg, 51% in batch and 138.42 mg, 55% in flow); 1H NMR (400
MHz, CDCl3): δH 7.93−7.94 (s, 1H), 7.80−7.78 (m, 2H), 7.66−7.64
(m, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.35 (s, 1H), 7.22−7.18 (m, 5H),
6.14 (s, 1H), 4.97 (s, 2H), 3.79 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δC 168.3, 133.9, 133.6, 132.4, 133.3, 129.7, 127.8, 127.6,
123.4, 123.3, 122.6, 120.7, 120.2, 109.3, 61.7, 53.1, 32.7; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C26H20BrN2O4, 503.0601; found,
503.0613.
1
71% in batch and 120.13 mg, 75% in flow); H NMR (400 MHz,
CDCl3): δH 7.78−7.76 (m, 1H), 7.62 (s, 1H), 7.41−7.28 (m, 4H),
7.01−6.92 (m, 2H), 6.89−6.88 (m, 1H), 6.19 (s, 1H), 3.83 (s, 3H);
3.81 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δC 168.9, 160.5,
135.8, 134.4, 134.2, 130.8, 127.9, 124.4, 122.8, 120.4, 120.3, 115.1,
114.5, 110.1, 87.4, 62.4, 55.5, 53.4; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C19H17N2O3, 321.1234; found, 321.1250.
4.2.2.17. Methyl 2-(4-Chlorophenyl)-2-(3-formyl-1H-indol-1-yl)-
acetate, 3p. 3p was synthesized using general procedure by reacting
1d and 2c, and purification was performed by column chromatog-
raphy in silica gel (100−200 mesh size) in 10% ethyl acetate in
hexane to yield an orange, amorphous solid (67.85 mg, 69% in batch
and 117.99 mg, 72% in flow); 1H NMR (400 MHz, CDCl3): δH 9.97
(s, 1H), 8.35−8.32 (m, 1H), 7.74 (s, 1H), 7.44 (d, J = 8.4 Hz, 2H),
7.37−7.32 (m, 5H), 6.23 (s, 1H), 3.85 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δC 185.1, 168.8, 137.6, 137.4, 136.1, 131.6, 129.9,
129.7, 125.4, 124.6, 123.7, 122.7, 119.3, 109.5, 61.7, 53.4; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C18H15ClNO3 328.0735; found,
328.0728.
4.2.2.11. Ethyl 2-(3-((1,3-Dioxoisoindolin-2-yl)methyl)-1H-indol-
1-yl)-2-(p-tolyl)acetate, 3j. 3j was synthesized using general
procedure by reacting 1e and 2b, and purification was performed
by column chromatography in silica gel (100−200 mesh size) in 5%
ethyl acetate in hexane to yield an orange, amorphous solid (106.34
1
mg, 47% in flow); H NMR (400 MHz, CDCl3): δH 7.90−7.87 (m,
1H), 7.74−7.71 (m, 2H), 7.59−7.57 (m, 2H), 7.23−7.09 (m, 8H),
6.07 (s, 1H), 4.90 (s, 2H), 4.24−4.13 (m, 2H), 2.31 (s, 3H), 1.18 (t, J
= 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δC 169.7, 168.2,
139.1, 139.7, 133.8, 132.4, 131.4, 129.9, 128.2, 128.0, 127.6, 123.2,
122.3, 120.4, 120.1, 110.9, 109.3, 62.13, 62.1, 32.8, 21.3, 14.2; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for [M + H]+ C28H25N2O4
453.1809; found, 453.1828.
4.2.2.12. Methyl 2-(4-Fluorophenyl)-2-(3-formyl-1H-indol-1-yl)-
acetate, 3k. 3k was synthesized using general procedure by reacting
1d and 2c, and purification was performed by column chromatog-
raphy in silica gel (100−200 mesh size) in 10% ethyl acetate in
hexane to yield an orange, amorphous solid (65.38 mg, 70% in batch
and 118.30 mg, 76% in flow); 1H NMR (400 MHz, CDCl3): δH 9.96
(s, 1H), 8.35−8.32 (m, 1H), 7.72 (s, 1H), 7.41−7.34 (m, 5H), 7.18−
7.14 (m, 2H), 6.24 (s, 1H), 3.85 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δC 185.1, 169.1, 163.5 (d, J = 248.9 Hz), 137.5 (d, J = 20.8
Hz) 130.4 (d, J = 8.4 Hz), 129.0, 128.9, 125.5, 124.6, 123.7, 122.6,
119.3, 116.8 (d, J = 21.8 Hz), 109.5, 61.7, 53.5; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C18H15FNO3, 312.103; found, 312.1027.
4.2.2.13. Methyl 2-(3-Cyano-1H-indol-1-yl)-2-(4-fluorophenyl)-
acetate, 3l. 3l was synthesized using general procedure by reacting
1c and 2e, and purification was performed by column chromatog-
raphy in silica gel (100−200 mesh size) in 10% ethyl acetate in
hexane to yield an off white, amorphous solid (109.45 mg, 71% in
flow); 1H NMR (400 MHz, CDCl3): δH 7.78−7.76 (m, 1H), 7.60 (s,
1H), 740−7.31 (m, 5H), 7.18−7.13 (m, 2H), 7.23 (s, 1H), 3.84 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δC 168.9, 163.5 (d, J =
249.0 Hz), 135.7, 134.0, 130.3 (d, J = 8.5 Hz), 128.8 (d, J = 3.8 Hz),
128.5 (d, J = 8.5 Hz), 127.9, 124.5, 122.9, 120.4, 116.8 (d, J = 21.9
4.2.2.18. Methyl 2-(4-Chlorophenyl)-2-(3-cyano-1H-indol-1-yl)-
acetate, 3q. 3q was synthesized using general procedure by reacting
1c and 2c, and purification was performed by column chromatog-
raphy in silica gel (100−200 mesh size) in 10% ethyl acetate in
hexane to yield an orange, amorphous solid (121.79 mg, 75% in flow);
1H NMR (400 MHz, CDCl3): δH 7.78−7.76 (m, 1H), 7.63 (s, 1H),
7.44−7.41 (m, 2H), 7.37−7.32 (m, 3H), 7.29−7.28 (m, 2H), 6.22 (s,
1H), 3.84 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δC 168.6,
136.2, 135.7, 134.0, 131.5, 129.9, 129.6, 128.9, 128.0, 127.8, 124.5,
122.9, 120.4, 115.5, 110.1, 87.8, 61.7, 51.5; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C18H14ClN2O2, 325.0738; found, 325.0725.
4.2.2.19. Methyl 2-(3-Fluorophenyl)-2-(1H-indol-1-yl)acetate, 3r.
3r was synthesized using general procedure by reacting 1a and 2h,
and purification was performed by column chromatography in silica
gel (100−200 mesh size) in 5% ethyl acetate in hexane to yield an
orange, amorphous solid (45.89 mg, 54% in batch and 80.74 mg, 57%
1
in flow); H NMR (400 MHz, CDCl3): δH 7.65 (d, J = 8.0, 1H),
7.36−7.31 (m, 2H), 7.25−7.21 (m, 1H), 7.19−7.13 (m, 2H), 7.10−
7.03 (m, 3H), 6.57 (d, J = 3.2 Hz, 1H), 6.26 (s, 1H), 3.85 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δC 169.7, 163.1 (d, J = 246.1
Hz), 137.3, 136.5, 130.8 (d, J = 8.2 Hz), 128.9, 126.7, 123.7 (d, J =
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3.1 Hz), 122.2, 121.4, 120.4, 116.1 (d, J = 20.9 Hz), 115.2 (d, J = 22.8
Hz), 109.1, 103.1, 61.5, 53.1; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C17H15FNO2, 284.1081; found, 284.1074.
insertion of indoles. Fractions of crude reaction mixtures were
collected every 10 min interval during first 2 h of the reaction. HPLC
analysis was carried out to measure the initial rate of formation of the
product in which initial 0−10% formation of products (3a and 3a−D)
was considered as the initial rate.
4.4. HPLC Study. The initial rate of formation of products of the
blue LED-mediated N−H insertion reaction of C3-substituted indoles
(1a−c) with phenyl diazoesters (2a) has been calculated by the
HPLC-based kinetic study, in which initial 0−10% formation of
products (3a−c) was considered as the initial rate of formation of the
product.
4.2.2.20. Synthesis of Methyl 2-(2-Azidophenyl)-2-(1H-indol-1-
yl)acetate, 3s. The desired compound was synthesized following
general procedure of batch synthesis. Indole (1 equiv, 0.3 mmol) was
taken in a 20 mL vial dissolved in DCM (5 mL), 2-azidophenyl
diazoacetate (2 equiv, 0.6 mmol) was added, and stirred in rt under
the irradiation of blue light for 22 h. Purification was performed by
column chromatography in silica gel (100−200 mesh size) in 5%
ethyl acetate in hexane to yield an off white, amorphous solid (32.16
mg, 35%); 1H NMR (400 MHz, CDCl3): δH 7.63 (d, J = 8.0 Hz, 1H),
7.45−7.39 (m, 2H), 7.32−7.21 (m, 3H), 7.16−7.10 (m, 3H), 7.54 (d,
J = 3.2 Hz, 1H), 6.49 (s, 1H), 3.79 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δC 178.7, 129.1, 126.5, 125.3, 122.2, 121.3, 118.7,
114.2, 109.4, 102.8, 60.6. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C17H15N4O2, 307.1190; found, 307.1186.
4.5. Computational Details. All the calculations are performed
using the B3LYP18 level of theory as implemented in the Gaussian 09
package.19 For geometry optimizations, the 6-311++G(2d,p) basis set
was used for all atoms. Frequency calculations of all the optimized
structures were performed to ensure that the optimized structures
were the local energy minima without any imaginary frequency also to
obtain zero-point corrections and the Gibbs free energies. Transition
states were obtained using Berny optimization algorithm implemented
in Gaussian 09. Transition states in each case were verified by the
presence of a single imaginary vibrational frequency associated with
the desired reaction coordinate, which also confirmed the nature of
transition states, representing the transfer of −NH proton to −C(sp2)
of the carbene generated from the phenyl diazoacetate. Moreover, the
solvent plays a crucial role in the blue LED-mediated N−H insertion
reaction of C3-substituted indoles. Therefore, the solvent effect has
been considered in self-consistent reaction field (SCRF) method.20
The initial geometry of the ground (S0) and first singlet excited state
(S1) of [1a → c-TS2]‡ was optimized using DFT (for S0) and
TDDFT (for S1).21 First, all the compounds have been optimized in
B3LYP/6-311++G(2d,p) using the SCRF model using DCM as a
solvent. All the compounds have been optimized using the 6-311+
+G(2d,p) basis set, whereas natural bond orbital calculations were
performed in 6-311++G(2d,p) too. The NBO Version 3.1 program
implemented in Gaussian 09 was used to perform NPA. Frequency
calculations were performed at the optimization level of the basis set
to confirm the nature of stationary points and to obtain zero-point
corrections and the Gibbs free energies.22 All the HOMO and LUMO
visualization files were generated from the FCHK file by the help of
Chemcraft software.
4.2.2.21. Synthesis of 3-(1H-Indol-1-yl)indolin-2-one, 5. 3s (1
equiv, 0.1 mmol) was taken in a clean oven-dried round-bottom flask,
dissolved in methanol, zinc dust (1.5 equiv, 0.15 mmol) was added
followed by the addition of ammonium formate (3 equiv, 0.3 mmol)
and stirred at rt for 2 h. The reaction mixture was filtered through
celite pad, washed with methanol, the solvent was removed under
vacuum, dissolved in DCM, washed with brine, and dried over sodium
sulphate. The crude was purified by column chromatography in silica
gel (100−200 mesh size) using 20−40% ethyl acetate in hexane to
1
yield a pure off white semisolid (23.59 mg, 95%); H NMR (400
MHz, CDCl3): δH 8.68 (s, 1H), 7.65−7.63 (m, 1H), 7.32 (t, J = 7.6
Hz, 1H), 7.53−7.12 (m, 4H), 7.05−7.01 (m, 2H), 6.96 (d, J = 8.0 Hz,
1H), 6.59 (d, J = 3.2 Hz, 1H), 5.90 (s, 1H); 13C{1H} NMR (100
MHz, CDCl3): δC 174.9, 140.1, 136.4, 130.3, 129.4, 127.2, 125.5,
125.3, 123.5, 122.4, 121.4, 120.2, 110.68, 109.8, 103.4, 59.0; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C16H13N2O, 249.1022; found,
249.1032.
4.2.2.22. Synthesis of N-Deuterated Indole 1a−D. Synthesis of
1a−D was carried out by following reported procedure.17 Indole (1
mmol) was dissolved in deuterated methanol (3 mL) in an argon-
filled seal tube stirred in rt for 4 h, the solvent was removed under
vacuum, and the same procedure was repeated for one more time to
afford 95% N-deuterated indole (1a−D). White solid (28.8 mg, 64%),
mp 246−248 °C; 1H NMR (400 MHz, CDCl3): δH 8.19 (s, 0.05 H),
7.79 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 8.2, 0.6 Hz, 1H), 7.35−7.33
(m, 1H), 7.30 (d, J = 3.2 Hz, 1H), 7.28−7.24 (m, 1H), 6.69−6.68 (m,
1H); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C8H7DN,
119.0714; found, mixture of 119.0711 and 118.0648.
The reaction free energies (ΔG) (the Gibbs free energies, i.e., the
term of the sum of electronic and thermal free energies) are calculated
using the following equation.
ΔG = Gproduct − Greactant
4.2.2.23. Synthesis of Methyl 2-(1H-Indol-1-yl)-2-phenylacetate-
d, 3a−D. 3a−D were synthesized by following general procedure.
1a−D (1 equiv, 0.3 mmol) were taken in a 20 mL vial dissolved in
DCM (5 mL), phenyl diazoacetate (2 equiv, 0.6 mmol) was added,
and stirred in rt under the irradiation of blue light for 24 h.
Purification was performed by column chromatography in silica gel
(100−200 mesh size) in 5% ethyl acetate in hexane to yield an off-
Similarly, transition-state energy was calculated as follows
ΔG‡ = Gtransition state − Greactant
where Gproduct and Greactant are the total energies of products and
reactants, respectively.
1
white solid (33.56 mg, 42%); H NMR (400 MHz, CDCl3): δH 7.64
(d, J = 8.0 Hz, 1H), 7.42−7.38 (m, 3H), 7.36−7.33 (m, 3H), 7.23 (td,
J = 7.6, 1.2 Hz, 1H), 7.17−7.12 (m, 2H), 6.54 (dd, J = 3.6, 0.6 Hz,
1H), 6.27 (s, 0.65 H), 3.82 (s, 3H); HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C17H15DNO2, 267.1238; found, a mixture of 267.1231
and 266.1166.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02649.
4.2.2.24. Synthesis of 3c in Gram Scale. 1c (1 equiv, 7.04 mmol, 1
g) and 2a (2 equiv, 14.08 mmol, 2.48 g) were dissolved in 70 mL of
DCM to prepare the stock solution and injected into the microreactor
with a flow rate of 2 mL h−1. The eluted reaction mixture was
collected in a vial attached with the outlet of the microreactor.
Purification was performed with the same method as mentioned in
earlier procedure of 3c to yield 1.39 g, 68%, of 3c (off-white
amorphous solid).
4.3. KIE Study. Two simultaneous reactions were carried out
taking 1a (1 equiv) and 2a (2 equiv) in DCM in one vial and 1a−D
(1 equiv) and 2a (1 equiv) in DCM in another vial using the same
general procedure of batch synthesis of blue LED-mediated N−H
Complete experimental details and characterization data
for the synthesized compound (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Subhabrata Sen − Department of Chemistry, School of
Natural Sciences, Shiv Nadar University, Greater Noida,
Uttar Pradesh 201314, India; orcid.org/0000-0002-
4608-5498; Email: subhabrata.sen@snu.edu.in
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Article
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Lett. 2014, 24, 5170−5174. (b) Gali, R.; Banothu, J.; Gondru, R.;
Bavantula, R.; Velivela, Y.; Crooks, P. A. One-pot multicomponent
synthesis of indole incorporated thiazolylcoumarins and their
antibacterial, anticancer and DNA cleavage studies. Bioorg. Med.
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Taoufik, J.; Mabkhot, Y.; Al-Aizari, F.; Ansar, M. h. Synthesis and
pharmacological activities of pyrazole derivatives: a review. Molecules
2018, 23, 134. (d) Patil, P. O.; Bari, S. B. Synthesis, characterization
and screening for antidepressant and anticonvulsant activity of 4, 5-
dihydropyrazole bearing indole derivatives. Arabian J. Chem. 2016, 9,
588−595. (e) Zhen, X.; Peng, Z.; Zhao, S.; Han, Y.; Jin, Q.; Guan, L.
Synthesis, potential anticonvulsant and antidepressant effects of 2-(5-
methyl-2, 3-dioxoindolin-1-yl) acetamide derivatives. Acta Pharm. Sin.
B 2015, 5, 343−349.
(5) Chauhan, J.; Ravva, M. K.; Gremaud, L.; Sen, S. Blue LED
Mediated Intramolecular C−H Functionalization and Cyclopropana-
tion of Tryptamines: Synthesis of Azepino [4, 5-b] indoles and
Natural Product Inspired Polycyclic Indoles. Org. Lett. 2020, 22,
4537−4541.
(6) (a) Stivanin, M. L.; Fernandes, A. A. G.; Silva, A. F.; Okada, C.
Y.; Jurberg, I. D. Blue Light-Promoted N− H Insertion of Carbazoles,
Pyrazoles and 1, 2, 3-Triazoles into Aryldiazoacetates. Adv. Synth.
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Carbazolation. J. Org. Chem. 2019, 84, 11316−11322. (c) Hansen,
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Authors
Debajit Maiti − Department of Chemistry, School of Natural
Sciences, Shiv Nadar University, Greater Noida, Uttar
Pradesh 201314, India
Ranajit Das − Department of Chemistry, School of Natural
Sciences, Shiv Nadar University, Greater Noida, Uttar
Pradesh 201314, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02649
Author Contributions
†D.M. and R.D. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
D.M. is thankful to Shiv Nadar University for Ph.D.
scholarship. R.D. is grateful to SBIRI-BIRAC (Grant# BT/
SBIRI/1655/37/18) for the project assistantship. We acknowl-
edge the financial and the MAGUS supercomputing support
provided by Shiv Nadar University.
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