Organo Photoinduced Decarboxylative Alkylation of Coumarins with N-(Acyloxy)phthalimide

Article abstract of DOI:10.1021/acs.joc.9b00977

A metal-free and mild, photoinduced decarboxylative 4-position alkylation of coumarins has been reported. Photoinduced single electron transfer has been initiated by utilizing the visible-light absorptivity of Eosin Y for a reductive generation of alkyl r

Full text of DOI:10.1021/acs.joc.9b00977

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Note
Organo Photoinduced Decarboxylative Alkylation
of Coumarins with N-(Acyloxy)phthalimide
KRISHNA N. TRIPATHI, Md. Belal, and Ravi P. Singh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00977 • Publication Date (Web): 26 Nov 2019
Downloaded from pubs.acs.org on November 27, 2019
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Organo Photoinduced Decarboxylative Alkylation of Coumarins with N-
(Acyloxy)phthalimide
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Krishna N. Tripathi,‡, Md. Belal,‡, and Ravi P. Singh*
*Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi
E-mail: ravips@chemistry.iitd.ac.in
O
O
R3
R3
N
O
R2
O
R2
O
O
R1
R1
Eosin Y, DIPEA
DCM, room temp
24 h
O
O
 metal-free
 mild conditions
 broad substrate scope
R1 = H, Me, OMe
R2 = CN, Cl, CO2Et; R3 = 1°, 2°, and 3° alkyl groups
Abstract: A metal free and mild, photo-induced decarboxylative 4-position alkylation of coumarins has
been reported. Photo-induced single electron transfer has been initiated by utilizing the visible-light
absorptivity of Eosin Y for a reductive generation of alkyl radicals from N-(acyloxy)phthalimide esters.
Depending on the nature of N-(acyloxy)phthalimide esters (primary, secondary, and tertiary carboxylic
acid derived) several saturated and unsaturated C-4 alkylated coumarins were synthesized. Both control
experiments and photophysical studies supported a radical based mechanism for the selective alkylation.
Visible light catalyzed selective construction of carbon-carbon bond has started to garner attention from
chemists recently.1 The attractiveness of such selective photoreactions are attributed to the synthetic utility
of a photo active catalyst, which on excitation by appropriate wavelength functions as single electron or
energy transfer source to yield free radical intermediates.2 Many metals based homogeneous photo redox
catalysts such as ruthenium and iridium complexes, and heterogeneous semiconductor catalyst have been
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extensively explored for various synthetic transformations.3 On the contrary, while many organic dyes
have demonstrated photocatalytic activities, their use as catalyst for reactions that enables previously
inaccessible synthetic transformations are scarce in selective organic synthesis.4 For example, it has been
reported that aliphatic carboxylic acids and their derivatives can generate a corresponding alkyl radical
by photo-redox mediated single electron transfer and CO2 extrusion mechanism. Typically, the alkyl
radical can be generated either by esterification of the acid followed by reductive cleavage of the esters5a-c
or by direct oxidative cleavage of the acid.5d-f Similar reactions that uses the low energy visible light has
been utilized to achieve photocatalytic decarboxylative reactions such as arylations,6a fluorinations,6b
vinylations,6c allylations6d and alkynylations.6e It has been demonstrated that in situ generated radicals can
then react with the activated alkene to yield corresponding analogues7. Recently, Eosin Y has been
extensively used as a catalyst to achieve various photochemical transformations.
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R"
Zimmerman et al.
EWG
R''I, Et3B/O2
R1
(i)
room temp
(R' = H; R2 = EWG)
O
O
EWG
O
Patel et al.
H
O
OtBu
O
(ii)
, AcOH
EWG
O
TBHP, 110 °C
O
this work
R3
O
O
O
O
Eosin Y, DIPEA
DCM, rt, 24 h
R2
O
R2
R3
R1
R1
+
N
O
O
O
R1 = Me, OMe; R2 = CN, Cl, CO2Et; R3 = 1°, 2°, and 3° alkyl groups
Fig. 1. Previous Contributions and Current Approach for Alkylation of Coumarins.
König and coworkers have demonstrated, Eosin Y catalyzed decarboxylative alkylation of acrylates from
N-(acyloxy)phtalimide esters.5a Interestingly, while one can find many examples of alkylation of
monosubstituted and disubstituted alkene, the trisubstituted alkene alkylations are limited. Addressing the
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lacuna, in our present protocol, we have attempted to explore the reactivity of the radical intermediates
generated by photocatalytic decarboxylation of N-(acyloxy)pthalimide esters with 3-substituted
coumarins and its analogues. Coumarins are naturally occurring compounds and have utility in organic
materials for optical property8a-c and in pharmaceuticals for anti-inflammatory, anti-oxidant, antimicrobial
and anti-cancer bio-activities.8d-g Various approaches such as nucleophilic addition to Michael acceptor,
direct C-H functionalization through oxidative cross coupling reaction with metal or without metal have
been explored for the synthesis of coumarin derivatives.9 However, the alkylation of coumarins yielding
chain alkylated derivatives and other highly functionalized scaffold installation through alkylation via
oxidative coupling reaction is still an arduous task. To the best of our knowledge, thus far there is no
report on such alkylation of coumarin at C-4 position except Zimmerman’s report,10a which could provide
the alkylation of coumarins by a metal free approach (Fig. 1, eq. i). Recently, Patel10b demonstrated a
similar alkylation method of coumarin using TBHP as an oxidant ended in di-functionalization (an
alkylation at C-4 and peroxidation at C-3) (Fig. 1, eq. ii). In all the reports while it’s commendable that
the reactions were direct and without any side products the limited substrate scopes and high temperature
reactions limits them for post synthesis functional group manipulations. While preparing our manuscript,
Sun11 reported visible–light induced Ir catalyzed regioselective, decarboxylative C-3 alkylation of
coumarin, although with limited substrate scope. In the present work we are reporting a photocatalyzed
approach to access a library of alkylated coumarins where several phthalimide esters have been used as
source of alkyl radicals. Interestingly, we could isolate the saturated and unsaturated products depending
on the nature of the phthalimide esters used.
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Table 1.a Selected Optimization Reaction Condition Results.
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O
O
CN
O
CN
O
Eosin Y (10 mol %)
+
N
O
DIPEA (2.0 equiv)
CH2Cl2, room temp,
24 h
O
O
O
3e
1a
2e
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yield (%)b
deviation from above
entry
1
2
none
60
ND
ND
ND
42
in the absence of Eosin Y
in the absence of DIPEA
in the absence of light
5 mol % Eosin Y
3
4
5
6
30
5 mol % of Ru(bpy)2PF6 instead of Eosin Y
10 mol % of Mes-Acr+ instead of Eosin Y
10 mol % of Rose Bengal instead of Eosin Y
CH3CN instead of CH2Cl2
7
ND
20
8
9
35
10
11
12
13
ND
22
DMF instead of CH2Cl2
CHCl3 instead of CH2Cl2
C2H4Cl2 instead of CH2Cl2
Et3N instead of DIPEA
45
ND
b
aReaction Conditions 1a:2e = 1.2:1, for 0.2 mmol scale, solvent 3mL. Isolated yield. DIPEA = N,N-
Diisopropylethylamine, ND
tetrafluoroborate.
=
not detected, Mes-Acr+
=
9-Mesityl-10-methylacridinium
Our study was initiated by an investigation of the proposed alkylation of 3-cyanocoumarins (1) and N-
(acyloxy) phthalimide of cyclohexyl carboxylic acid (2e) as model substrates for the decarboxylative
alkylation in the presence of photoredox catalyst under a green LED irradiation. After extensive screening
we were delighted to established that a combination of Eosin Y (10 mol %), DIPEA (2.0 equiv.) in
dichloromethane (0.08 M) under photo-irradiation at room temperature was optimum, affording the
desired product 3e in 60% isolated yield (Table 1, entry 1). Control experiments indicated that deviation
from the optimal condition led to either no product or significant drop in the yield of 3e. Notably, in the
absence of any reaction component such as Eosin Y or DIPEA or visible-light irradiation, no alkylated
product was observed (Table 1, entry 2-4). Lowering of catalyst loading from 10 mol % to 5 mol %
yielded lower conversion (Table 1, entry 5). Eosin Y was the only effective photocatalyst and with other
photocatalyst no improvement in yield of the product was observed. The common Ru metallic
photocatalyst (Table 1, entry 6) or other organo-photocatalysts such as Mes-Acr+ and Rose Bengal were
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least effective (Table 1, entry 7, 8). The choices of solvents played critical role in optimizing the reaction
outcome. Switching reaction solvent from DCM to acetonitrile or CHCl3 or DMF or DCE produced
alkylated product in much lower yield (Table 1, entry 9-12). A survey of organic bases revealed that the
DIPEA was the best choice. Replacing DIPEA with Et3N yielded no product (Table 1, entry 13). The
substrate scope, which ensued from the above optimized reaction conditions is summarized in Table 2
and Table 3. Unexpectedly, secondary carboxylic acids derived NHPI esters when coupled with 3-
substituted coumarins under optimized reaction conditions provided 3,4-substituted 2-chromanone
instead of 3,4-substituted 2-chromenones. NHPI esters of isobutyric and 2,2-dimethylbutanoic acids
provided 4-(2-propyl) and 4-(2-pentyl) substituted 3-cyano-2-chromanones 3a and 3b in 50% and 72%
of isolated yields, respectively (Table 2). Structure of 3a was unambiguously confirmed by single crystal
XRD (CCDC no. 1906778). Secondary carboxylic acids appended to acyclic chains (cyclobutyl,
cyclopentyl and cyclohexyl) were converted into corresponding 4-alkylated 2-chromanones products with
57%-86% of isolated yields (Table 2, entries 3c-3e). In lieu of above results, we tried pivalic, 2,2-
dimethylbutanoic and 1-methyl-1-cyclohexane tertiary aliphatic carboxylic acids derived NHPI esters.
Coherently, we obtained 52%-82% of isolated yield of 4-alkylated products when pivalic acid derived
NHPI ester has been used with various coumarins {Table 2, R2 = CN (3f), Cl (3i) and CO2Et (3j)}. NHPI
esters of 2,2-dimethylbutanoic and 1-methyl-1-cyclohexane tertiary aliphatic carboxylic acids gave 72%
and 59% of isolated yield of 4-alkylated 3-cyano-2-chromanones (Table 2, entry 3g, 3h). NHPI ester
derived from 9,10-dihydro-9,10-ethanoanthracene-11-carboxylic acid gave anomalous result in which we
observed unsaturation with elimination of nitrile group (Table 2, entry 3l, yield 55%).
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Table 2.a Scope of decarboxylative 4-position alkylation of coumarins with various secondary and
tertiary carboxylic acid derived NHPI esters.
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R3
O
Eosin Y
(10 mol %),
R2
R2
O
R1
+
N
O
O
R1
DIPEA
(2.0 equiv)
DCM, rt,
R3
O
O
O
O
2
3
1
NHPI Esters
when R3 = secondary

CN
O
CN
CN
O
O
O
O
O
CCDC 190677824
(72%)
(57%)
3a
3b
3c
(50%)
NHPI Esters
when R3 = tertiary

CN
O
CN
CN
O
CN
O
O
O
O
O
O
3d
(86%)
3e
(60%)
3f
3g
(52%)
(72%)
R2
Me
CN
O
CN
O
O
O
O
O
3i
R2 = Cl; (68%)
3j
R2 = CO2Et; (61%)
3k
(82%)
O
(55%)
O
3h
(59%)
3l
aReaction conditions: All the reactions were carried out with 0.24 mmol of 1 and 0.2 mmol of 2 in the
presence of 10 mol % of Eosin Y in 3 mL of DCM at room temperature under green light irradiation.
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Table 3.a Scope of decarboxylative 4-position alkylation of coumarins with various primary
carboxylic acid derived NHPI esters.
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R3
O
Eosin Y ( 10 mol %)
DIPEA (2.0 equiv)
R2
O
R2
O
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R1
+
N
O
O
R1
R3
, DCM, rt
24 h
O
O
O
2
4
1
A. NHPI Esters; when R3 = primary
Cl
CN
O
CN
O
CN
O
CN
O
CN
O
CN
CN
O
O
O
O
O
O
O
O
O
4a
CCDC 190681324
4b
4c
4d
4e
4f
(75%)
(99%)
(62%)
(67%)
(57%)
(65%)
4g (58%)
S
Br
NHBoc
NHBoc
NH
NH
CN
2
3
(
)
3
CN
O
CN
CN
O
CN
CN
O
CN
O
O
O
O
O
O
O
O
O
(75%)
O
O
4h
4i
4j
4k
4l
4m
(56%)
(48%)
(56%)
(43%)
(49%)
4n
(71%)
HO
(
)
13
C. Natural Products
& Drugs
B
Coumarins
.
Cl
CN
when R1 = H, Me, OMe
Me
CN
O
Ph
H
OH
O
H
O
O
H
O
O
N
Palmitic acid. 4s
(79%)
4o
H
(95%)
HO
CN
6
7
OMe
CN
CO2Et
CN
CN
O
CN
O
O
O
O
MeO
O
O
O
O
O
Cholic acid, 4v
O
O
Fenbufen, 4r
(44%)
4p
(84%)
4q
(72%)
Oleic acid, 4t
(70%)
Indomethacin, 4u
(46%)
(55%)
aReaction conditions: All the reactions were carried out with 0.24 mmol of 1 and 0.2 mmol of 2 in presence
of 10 mol% of Eosin Y in 3 mL of DCM at room temperature under green light irradiation.
Primary carboxylic acid derived NHPI esters produced surprising results when used with 3-substituted
coumarins under this visible-light mediated decarboxylative alkylation strategy (Table 3). In this process,
primary carboxylic acids of alkyl, branched alkyl, -positioned alkene, -positioned alkyne, benzylic
substrates, substrates bearing extended aromatics, heterocycles (thiophene, indole) and amino acids (-
alanine and -alanine) were converted into the corresponding 4-alkylated-3-cyanocoumarins in good to
high yields via their phthalimide esters (Table 3, Part A, entry 4a-4n). Functional variations on coumarins
itself with electron donating 6-Me and 7-OMe groups supported this alkylation well with yields up to 95%
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(Table 3, Part B, entry 4o, 4p). In case when we made an attempt to alkylate ethyl 3-coumarincarboxylate,
we observed saturated instead of unsaturated coumarin 4q in 72% yield (Table 3, Part B).
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Scheme 1. Plausible mechanism of alkylation.
9
CO2
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O
R2
O
R3
O
R3
O
O
iPr2NHEt
O
1
N
R3
NH
R2
O
R3
O
iPr2NEt
O
O
O
O
R2
O
R3
O
3
EY
N
O
A
CH3
O
O
1,2-H
(iPr)2N
migration
t
E
EY*
R3
N
2
r
i
P
iPr2NEt
O
O
R2
O
R3
if R3 = 2° and 3°
R3
N
EY
O
A'
R3
O
2
O
R2
O
iPr2NEt
iPr2NEt iPr2NHEt
if R3 = 1°
R2
O
O
4
B
Scheme 2. Control Experiment.
O
CN
O
CN
optimized conditions
N
O
O
+
TEMPO (1.0 equiv.)
O
O
O
O
3e
(0%)
To showcase the utility of the transformation for diversifying natural-products and drugs caboxylic acids,
we prepared a diverse collection of N-(aceloxy)phthalimide esters and subjected them to the optimized
reaction conditions (Table 3, Part C, entry 4r-4v, 44%-79% yield). The proposed mechanism illustrated
in Scheme 1 can be rationalized by spectroscopic and electrochemical studies performed on control
reactions (Supporting Information) and based on similar observations in the literature.4b,5a Photo-
irradiation via the green LED, excites Eosin Y leading to single electron transfer (SET) from DIPEA (0.72
V vs SCE in CH3CN) to excited Eosin Y* (Eosin Y*/Eosin Y˙ˉ = 0.83 V vs SCE in CH3CN-H2O, 1:1)
(Scheme 1). Following this, regeneration of Eosin Y take place by single electron reduction of NHPI ester
(-1.20 V vs SCE in CH3CN-H2O, 1:1). The reduced ester produces ˙R3 after breaking of the N–O bond
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and subsequent elimination of CO2. To confirm the formation of radical ˙R3, we performed radical
trapping experiment with 1.0 equiv. of TEMPO. Presence of radical trapper inhibited the reaction and no
product formation was observed (Scheme 2), thus, confirming the radical pathway. The˙R3 is then added
on coumarin and generates an open radical A. Further, intramolecular 1,2-hydrogen migration took place
which facilitated the generation of 4-positioned benzylic radical A’. We hypothesized two possible
pathways of terminations. First, if ˙R3 is secondary or tertiary then oxidized DIPEA will transfer H˙ to A’
and consequently formation of 3 will be observed. Secondly, if ˙R3 is primary then A’ will get oxidized
by Eosin Y* and B will be formed, which will produce 4 after abstraction of H+ by DIPEA. Since Eosin
Y has a fluorescence emission (λem = 550nm, λex = 520nm) it can be used to study the structural changes
in Eosin Y by observing the changes in the fluorescence emission. When the Fluorescence spectra of
Eosin Y and NHPI were recorded no significant difference in the fluorescence peak (Supporting
Information, Figure S1) was observed suggesting very poor quenching due to any electron transfer.
Similarly addition of coumarin to Eosin Y and NHPI mixture did not alter the fluoresce emission
(Supporting Information, Figure S1). However, when the same reaction was monitored with addition of
DIPEA, a significant quenching of the fluorescence emission was observed over time with almost no
emission after 8 h (Supporting Information, Figure S2), thus, suggesting an electron transfer with DIPEA.
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In conclusion, we have developed a mild, metal-free, low energy (visible-light) mediated organo-
photocatalyzed strategy for 4-alkylation of 3-substituted coumarins. Primary carboxylic acids derived
NHPI esters produced 4-alkylated 3-substituted saturated coumarins while those of secondary and tertiary
carboxylic acids produced 4-alkylated 3-substituted unsaturated coumarins. We believe that developed
methodology offers a powerful post-synthetic modification route for generating various new classes of
highly functionalized small molecules.
Experimental Section
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General Information. The N-(acyloxy)phthalimide esters have been prepared from the commercially
available corresponding carboxylic acids and N-hydroxyphthalimides. Nuclear magnetic resonance
(NMR) spectra were recorded in deuterated solvents with residual protonated solvent signal as internal
reference on a BrückerAva-300, BrückerAva-400 and BrückerAva-500. Chemical shifts are reported in
parts per million using the solvent resonance internal standard (chloroform, 7.26 and 77.0 ppm or DMSO,
2.50 and 40.0 ppm). Data is reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, bs = broad singlet), coupling constant, and integration. Electrospray
and electron impact high resolution mass spectrometry was performed by Brücker mass spectrometer.
The data is recorded as the ionization method followed by the calculated and measured masses. Solvents
for starting material preparation and coupling reactions were dried before use. Green LEDs (2.50 W, λ =
530 nm) Rebel LED, mounted on a 25 mm cool base was purchased from commercial supplier Luxeon
Star LEDs Quadica Developments Inc.10-3447 30 Ave N. Lethbridge, Alberta T1H 7B5 Canada. No filter
has been used. Glass material of round-bottom flask is of borosilicate. Distance of RB from LED was
kept fixed at 5cm (see Supporting Information for photoreaction set-up).
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General Method for the Synthesis of Starting Materials Coumarins (1) and N-(Acyloxy)phthalimide
Esters (2)
2.1. Preparation of Coumarins
2.1.1. Preparation of 3-Cyanocoumarins (1a-c)
3-Cyanocoumarins were synthesized using known literature procedure.12 To a solution of salicylaldehyde
(10.0 mmol) and malononitrile (660 mg, 10.0 mmol) in EtOH (10.0 mL) was added NH4OAc (462 mg,
6.0 mmol) slowly. The reaction mixture was stirred at room temperature for 4h to form the precipitations.
Then the precipitate was filtered and washed with EtOH and dried in vacuum. Next, the products were
dissolved in EtOH by gentle heating at 75 oC in oil bath and then 1 mL HCl was added in reaction mixture.
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The resulting reaction mixture was vigorously stirred at 75 oC in oil bath for 30 min. Subsequently, it was
poured in ice water. A solid precipitate was obtained. The resulting solid was filtered, washed with cold
water and recrystallized in EtOH, yielded corresponding 3-cyanocoumarins.
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2.1.2. Synthesis of ethyl coumarin-3-carboxylate (1d)
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Ethyl coumarin-3-carboxylate 1d were synthesized following known literature procedure.13 To a solution
of salicylaldehyde (1.83 g, 15 mmol) in 30 mL of ethanol was added diethyl malonate (2.88 g, 18 mmol),
2 drops of acetic acid and piperidine (0.15 mL). The reaction mixture was stirred under reflux for 8 h, and
dilution was done with ice-cold water (50 mL). After completion of the reaction, the cake was filtered and
washed with cold water. The product was dried under vacuum to give a white solid (3.07 g, 94% yield).
2.1.3. Synthesis of 3-Chlorocoumarin (1e)
3-Chlorocoumarin (1e) was synthesized following known literature procedure.14 To a solution of
coumarin (10 mmol) in 1M HCl-DMF (15 mL) solution was added m-CPBA (15 mmol). The reaction
mixture was stirred at rt for 30 min. After completion, reaction was quenched with 1M NaHCO3 and
extracted with Et2O (3 x 50 mL) after removal of solvent in vacuo, the product was purified by silica gel
chromatography using EtOAc-hexane (1:4) as eluent.
2.2. Preparation of N-(acyloxy)phthalimides (2)
All N-(Acyloxy)phthalimides (2a-2o, 2q-2t, 2w-2z, and 2za) were synthesized by following known
literature procedures.5a,15-23 The NHPI esters 2p, 2u, 2v, and 2zb were synthesized by following the known
method of Koenig5a in which we took respective carboxylic acids (4.0 mmol, 1.0 equiv.), N-
hydroxyphthalimide (721 mg, 4.40 mmol, 1.1 equiv.), N,N’-dicyclohexylcarbodiimide (988 mg, 4.8
mmol, 1.2 equiv.) and 4-dimethylaminopyridine (48 mg, 0.80 mmol, 0.1 equiv.) in a round bottom flask.
Dry THF (20 mL) was added and the orange reaction mixture was stirred for 15 h at room temperature.
After completion of reaction the white precipitate was filtered off and the solution was concentrated by
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evaporation of the solvent. Purification by column chromatography on silica gel (EtOAc: hexane = 3:7)
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gave a solid 2. All characterization data for 2p, 2u, 2v, and 2zb are reported.
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3. General Methods of Preparations for the Synthesis of 3 and 4
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0.2 mmol of N-(acyloxy)phthalimides (1.0 equiv.), coumarin (0.24 mmol, 1.2 equiv.) were taken in a long
neck round bottom flask and 10 mol % of Eosin Y was added into it, the RB was capped with septum.
After that 2.0 equiv. of DIPEA and then 3 ml of dry DCM were added into the reaction mixture via
syringe. The mixture was degassed and filled with N2 (three times). The reaction mixture was irradiated
with green LED for 24 h. After completion (monitored through TLC), reaction was quenched with
saturated NaHCO3 solution and extracted with DCM (3 x 10 mL), washed with brine solution. After
removal of solvent in vacuo, the product was purified by silica gel chromatography using EtOAc-hexane
(1:9 to 4:6) as eluent to provide the desired product.
1,3-Dioxoisoindolin-2-yl 2-(2-chlorophenyl)acetate (2p). Physical state: White solid; Yield: 856.8 mg
(68%). 1H NMR (300 MHz, CDCl3) δ 7.89 – 7.87 (m, 2H), 7.80 – 7.77 (dd, J = 5.4, 2.8 Hz, 2H), 7.42 (s,
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2H), 7.30 – 7.25 (m, 2H), 4.15 (d, J = 2.6 Hz, 2H). C{1H} NMR (75 MHz, CDCl3) δ 166.9, 161.8,
134.9, 129.8, 129.5, 129.0, 127.3, 124.1, 35.8. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for
C16H10ClNO4Na, 338.0190; Found: 338.0180.
1,3-Dioxoisoindolin-2-yl 4-(1H-indol-3-yl)butanoate (2t). Physical state: yellow solid; Yield: 1.08 g,
(78%). 1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.90 – 7.87 (m, 2H), 7.79 – 7.77 (m, 2H), 7.63 (d, J
= 7.7 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.26 – 7.07 (m, 3H), 2.94 (t, J = 7.2 Hz, 2H), 2.70 (t, J = 7.1 Hz,
2H), 2.31 – 2.04 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 169.8, 162.1, 136.5, 134.8, 129.0, 127.4,
124.0, 122.1, 119.4, 114.7, 111.3, 30.3, 25.1, 24.0. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for
C20H16N2O4Na, 371.1002; Found: 371.0990.
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1,3-Dioxoisoindolin-2-yl 3-(tert-butoxycarbonylamino)propanoate (2v). Physical state: white solid;
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Yield: 1.01 g (76%). H NMR (300 MHz, CDCl3) δ 7.90- 7.71 (m, 4H), 5.15 (s, 1H), 3.55 (d, J = 5.8
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Hz, 2H), 2.90 (t, J = 5.9 Hz, 2H), 1.44 (s, 9H). 13C{1H} NMR (75 MHz, CDCl3) δ 168.6, 161.8, 155.8,
134.9, 128.8, 124.0, 79.8, 36.1, 32.1, 28.3. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for
C16H18N2O6Na, 357.1057; Found: 357.1045.
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2-Oxo-4-((3S)-3-((3S,5R,7S,8S,10R,12R,13S,14R,17S)-3,7,12-trihydroxy-10,13-
dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butyl)-2H-chromene-3-carbonitrile
(2zb). Physical state: white solid; Yield: 1.15 g (52%). 1H NMR (300 MHz, CDCl3) 7.88 (s, 2H), 7.79
(s, 2H), 4.00 (s, 1H), 3.85 (s, 1H), 3.45 (s, 1H), 2.64 (t, J = 16.4 Hz, 2H), 2.26 – 2.22 (m, 3H), 1.92 - 1.81
(m, 7H), 1.81 – 1.67 (m, 6H), 1.56 (s, 6H), 1.42 -1.31 (m, 3H), 1.24 (d, J = 7.1 Hz, 1H), 1.13 (d, J = 13.3
Hz, 2H), 0.89 (s, 3H), 0.72 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 170.2, 162.0, 134.7, 128.9, 123.9,
73.1, 71.9, 68.4, 60.4, 46.8, 41.5, 39.5, 35.4,35.1, 34.8, 30.7, 28.1, 27.5, 26.3, 22.3, 22.4, 21.0, 17.3, 14.2,
12.5. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for C32H43NO7Na, 576.2931; Found: 576.2916.
4-Isopropyl-2-oxochromane-3-carbonitrile (3a). Physical state: White solid; Yield: 21.50 mg (50%).
1H NMR (300 MHz, CDCl3) δ 7.36 – 7.32 (dd, J = 10.4, 4.2 Hz, 1H), 7.23 – 7.11 (m, 3H), 4.08 (d, J =
6.3 Hz, 1H), 3.30 (dd, J = 6.1, 4.0 Hz, 1H), 2.49-2.39 (m, 1H), 1.09 (d, J = 6.9 Hz, 3H), 0.80(d, J = 6.8
Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 161.9, 151.1, 129.8, 129.8, 125.0, 120.2, 117.5, 114.0, 44.6,
38.1, 30.6, 21.5, 16.8. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for C13H13NO2Na, 238.0838; Found:
238.0832.
2-Oxo-4-(pentan-2-yl)chromane-3-carbonitrile (3b). Physical state: White solid; Yield: 35 mg (72%).
1H NMR (400 MHz, CDCl3) δ 7.41 – 7.32 (m, 1H), 7.25 – 7.15 (m, 2H), 7.15 – 7.09 (m, 1H), 4.06 (t, J
= 5.2 Hz, 1H), 4.01 (s, 1H), 3.41 (dd, J = 6.4, 3.2 Hz, 1H), 3.36 – 3.31 (m, 0.21H), 3.13 (d, J = 7.4 Hz,
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0.50H), 2.27 (s, 1H), 1.67 (s, 3H), 1.49 – 1.35 (m, 6H), 1.21 (m, 4H), 1.08 (d, J= 6.9 Hz, 1H), 0.99 – 0.92
(m, 3H), 0.87 (m, 5H), 0.76 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 161.9, 151.2, 150.7,
129.6, 125.1, 120.3, 117.5, 111.3, 46.3, 43.2, 38.2, 37.4, 35.4, 20.4, 14.1, 14.0. HRMS (ESI/QTOF),
m/z: [M+Na]+ Calcd for C15H17NO2Na, 266.1151; Found: 266.1148.
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4-Cyclobutyl-2-oxochromane-3-carbonitrile (3c). Physical state: Brown gum; Yield: 25.88 mg (57%).
1H NMR (300 MHz, CDCl3) δ 7.39 – 7.33 (m, 1H), 7.24-7.19 (m, 2H), 7.16-7.10 (m, 1H), 3.98 (d, J =
5.2 Hz, 1H), , 3.27 (dd, J = 7.9, 5.2 Hz, 1H), , 2.79-2.74 (m, 1H), 2.26 - 2.17 (m, 1H), 1.99-1.82 (m, 3H),
1.71 (bs, 1H), 0.98 – 0.80 (m, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 161.1, 150.5, 129.7, 128.8, 125.3,
122.2, 117.5, 113.9, 43.8, 37.5, 37.4, 27.3, 26.1, 18.7. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for
C14H13NO2Na, 250.0839; Found: 250.0843.
4-Cyclopentyl-2-oxochromane-3-carbonitrile (3d). Physical state: Brown gum; Yield: 41.45 mg (86%).
1H NMR (500 MHz, CDCl3) δ 7.39 – 7.36 (m, 1H), 7.29 – 7.21 (m, 2H), 7.18 - 7.13(m, 1H), 4.09 (d, J
= 5.5 Hz, 1H), 3.43 (t, J = 5.7, Hz, 1H), 2.32-2.30 (m, 1H), 2.06-2.04 (m, 1H), 1.86 – 1.75 (m, 1H), 1.60
– 1.51 (m, 4H), 1.45 – 1.33 (m, 1H), 1.01 – 0.83 (m, 1H). 13C{1H} NMR (CDCl3, 101 MHz) δ 161.7,
159.8, 1508, 129.7, 129.4, 125.5, 117.5, 114.2, 42.1, 42.5, 39.0, 31.1, 29.4, 24.3. HRMS (ESI/QTOF),
m/z: [M+Na]+ Calcd for C15H15NO2Na, 264.0995; Found: 264.0997.
4-Cyclohexyl-2-oxochromane-3-carbonitrile (3e). Physical state: White solid; Yield: 35.70 mg (70%).
1H NMR (300 MHz, CDCl3) δ 7.38 – 7.32 (m, 1H), 7.22 – 7.09 (m, 3H), 4.04 (dd, J = 4.4, 3.7 Hz, 1H),
3.26 (dd, J = 6.0, 3.7 Hz, 1H), 2.08 – 1.99 (m, 1H), 1.78 (t, J = 13.4 Hz, 2H), 1.63 (s, 2H), 1.39 – 1.07
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(m, 4H), 1.04 – 0.82 (m, 1H), 0.79 – 0.65 (m, 1H). C{1H} NMR (CDCl3, 75 MHz) δ 162.0, 151.0,
129.8, 129.7, 125.0, 121.7, 117.4, 114.0, 44.6, 40.4, 37.8, 31.5, 27.2, 26.2, 25.8, 25.7. HRMS
(ESI/QTOF), m/z: [M+Na]+ Calcd For C16H17NO2Na, 278.1151; Found: 278.1160.
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4-(tert-Butyl)-2-oxochromane-3-carbonitrile (3f). Physical state: White solid; Yield: 23.82 mg (52%).
1H NMR (300 MHz, CDCl3) δ 7.43 – 7.33 (m, 1H), 7.26-7.23 (m, 2H), 7.25- 7.16 (m, 1H), 4.12 (s, 1H),
3.05 (s, 1H), 0.98 (s, 9H). 13C{1H} NMR (75 MHz, CDCl3) δ 160.6, 151.8, 131.4, 130.4, 125.9, 119.7,
117.7, 114.2, 51.8, 35.6, 33.4, 27.8. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd For C14H15NO2Na,
252.0995; Found: 252.1004.
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2-Oxo-4-(tert-pentyl)chromane-3-carbonitrile (3g). Physical state: White solid; Yield: 34.99 mg (72%).
1H NMR (300 MHz, CDCl3) δ 7.42 – 7.37 (m, 1H), 7.25 (d, J = 5.4 Hz, 2H), 7.22 – 7.15 (m, 1H), 4.09
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(s, 1H), 3.15 (s, 1H), 1.37 (dd, J = 15.0, 7.5 Hz, 2H), 0.94-0.87 (m, 9H). C{1H} NMR (CDCl3, 300
MHz) δ 160.7, 151.2, 131.4, 129.9, 125.1, 119.7, 117.6, 114.7, 49.6, 37.7, 33.5, 31.9, 24.2, 23.3, 8.2.
HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for C15H17NO2Na, 266.1151; Found: 266.1148.
4-(1-Methylcyclohexyl)-2-oxochromane-3-carbonitrile (3h). Physical state: White solid; Yield: 34.45
mg (59%). 1H NMR (500 MHz, CDCl3) δ 7.41 – 7.38 (m, 1H), 7.26 – 7.20 (m, 2H), 7.16 (d, J = 8.2 Hz,
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1H), 4.16 (s, 1H), 3.12 (s, 1H), 1.57-1.25 (m, 10H), 0.85 (s, 3H). C{1H} NMR (126 MHz, CDCl3) δ
160.8, 151.2, 131.6, 129.9, 125.0, 119.4, 117.6, 114.9, 37.5, 35.4, 35.0, 33.0, 25.7, 21.7, 21.4, 19.5.
HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for C17H19NO2Na, 292.1308; Found: 292.1316.
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4-(tert-Butyl)-3-chlorochroman-2-one (3i). Physical state: White solid; Yield: 32.37 mg (68%). H
NMR (300 MHz, CDCl3) δ 7.32 (dd, J = 9.0, 8.2, 1H), 7.16-7.08 (m, 3H), 5.03 (d, J = 5.8 Hz, 1H), 3.18
(d, J = 5.7 Hz, 1H), 1.08 (s, 9H). 13C{1H} NMR (126 MHz, CDCl3) δ 165.8, 150.6, 130.6, 129.4, 125.1,
124.3, 117.4, 56.8, 52.7, 35.9, 29.5. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for C13H15ClO2Na,
261.0653; Found: 261.0655.
Ethyl 4-(tert-butyl)-2-oxochromane-3-carboxylate (3j). Physical state: Brown gum; Yield: 36.47 mg
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(61%). H NMR (300 MHz, CDCl3) δ 7.40 – 7.33 (m, 1H), 7.26 – 7.15 (m, 3H), 4.18 - 4.06 (m, 2H),
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4.05 (s, 1H), 3.22 (s, 1H), 1.06 (s, 12H). 13C{1H} NMR (75 MHz, CDCl3) δ 168.0, 165.9, 151.6, 131.2,
129.0, 124.1, 121.4, 117.0, 62.3, 50.7, 48.7, 34.7, 27.4, 13.9. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd
for C16H20O4Na, 299.1254; Found: 299.1259.
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4-(tert-Butyl)-6-methyl-2-oxochromane-3-carbonitrile (3k). Physical state: White solid; Yield: 39.85
mg (82%). 1H NMR (300 MHz, CDCl3) δ 7.17 (d, J = 8.4 Hz, 1H), 7.05- 6.96 (m, 2H), 4.09 (s, 1H), 2.99
(s, 1H), 2.36 (s, 3H), 0.97 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.8, 149.0, 134.8, 131.8, 130.6,
119.4, 117.3, 114.8, 51.5, 35.0, 34.0, 27.30, 20.9. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for
C15H17NO2Na, 266.1151; Found: 266.1151.
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4-((9S,10S)-9,10-Dihydro-9,10-ethanoanthracen-11-yl)-2H-chromen-2-one (3l). Physical state: White
solid; Yield: 41.0 mg (55%). 1H NMR (400 MHz, CDCl3) δ 7.40-7.31 (m, 5H), 7.24 (s, 2H), 7.17 – 7.13
(m, 3H), 6.97 (dd, J = 7.2, 1.8 Hz, 2H), 5.78 (s, 1H), 4.51 (d, J = 2.5 Hz, 1H), 4.31 (d, J = 1.7 Hz, 1H),
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3.63 – 3.59 (m, 1H), 2.94 – 2.89 (m, 1H), 2.07 – 2.01 (m, 1H). C{1H} NMR (126 MHz, CDCl3) δ
160.61, 148.5, 144.5, 144.1, 143.7, 140.2, 138.0, 128.2, 126.3,125.9, 125.8, 125.1, 125.0, 123.9, 123.8,
123.4, 123.1, 121.2, 117.3, 49.6, 44.6, 38.4, 28.7. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for
C25H18O2Na, 373.1199; Found: 373.1223.
4-Ethyl-2-oxo-2H-chromene-3-carbonitrile (4a). Physical state: White solid; Yield: 29.85 mg (75%).
1H NMR (300 MHz, CDCl3) δ 7.88 – 7.68 (m, 2H), 7.43 (t, J = 7.8 Hz, 1H), 3.14 (q, J = 7.7 Hz, 2H),
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1.42 (t, J = 7.7 Hz, 3H). C{1H} NMR (75 MHz, CDCl3) δ 168.1, 157.0, 154.0, 135.2, 125.9, 125.6,
118.1, 117.2, 113.3, 101.5, 25.4, 14.1. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for C12H10NO2,
200.0706; Found: 200.0717.
2-Oxo-4-propyl-2H-chromene-3-carbonitrile (4b). Physical state: White solid; Yield: 42.17 mg (99%).
1H NMR (400 MHz, CDCl3) δ 7.76-7.68 (m, 2H), 7.43 – 7.40 (m, 2H), 3.10 (t, J = 8.0 Hz, 2H), 1.85-
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1.79 (m, 2H), 1.16-1.12 (t, J = 8.0 Hz, 3H). C{1H} NMR (126 MHz, CDCl3) δ 166.5, 157.0, 153.9,
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4-Neopentyl-2-oxo-2H-chromene-3-carbonitrile (4c). Physical state: White solid; Yield: 29.88 mg
(62%). 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J = 7.3 Hz, 1H), 7.71 - 7.66 (m, 1H), 7.41-7.36 (m, 2H),
3.11 (s, 2H), 1.12 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 164.5, 157.0, 153.8, 135.0, 127.7, 124.9,
118.8, 117.9, 114.6, 103.9, 43.65, 35.7, 30.09. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for
C15H15NO2Na, 264.0995; Found: 264.1020.
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4-(But-3-en-1-yl)-2-oxo-2H-chromene-3-carbonitrile (4d). Physical state: White solid; Yield: 33.23 mg
(67%). 1H NMR (500 MHz, CDCl3) δ 7.76 – 7.69 (m, 2H), 7.45 – 7.26 (m, 2H), 5.90 (ddt, J = 17.0, 10.5,
6.8 Hz, 1H), 5.11 – 5.07 (m, 2H), 3.21 (t, J = 7.8 Hz, 2H), 2.52 (dd, J = 15.0, 7.0 Hz, 2H). 13C{1H} NMR
(126 MHz, CDCl3) δ 165.6, 156.9, 153.8, 135.2, 135.1, 126.0, 125.6, 118.1, 117.6, 117.3, 113.4, 102.2,
33.6, 31.4. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for C14H11NO2Na, 248.0681; Found: 248.0682.
2-Oxo-4-(pent-4-yn-1-yl)-2H-chromene-3-carbonitrile (4e). Physical state: White solid; Yield: 29.64
mg (57%). 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz, 1H), 7.75-7.68 (m, 1H), 7.45-7.39 (m, 2
H), 3.25 (dd, J = 9.2, 7.2 Hz, 2H), 2.44 (td, J = 6.6, 2.5 Hz, 2H), 2.14 (dd, J = 3.3, 1.8 Hz, 1H), 1.96 (dt,
J = 16.1, 7.2 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 166.9, 156.5, 153.8, 135.4, 126.0, 125.7, 118.0,
117.3, 113.3, 102.1, 82.5, 70.5, 30.8, 28.3, 18.8. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for
C15H11NO2Na, 260.0681; Found: 260.0667.
4-Benzyl-2-oxo-2H-chromene-3-carbonitrile (4f). Physical state: White solid; Yield: 33.93 mg (65%).
1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 7.8, 1H), 7.40 (t, J = 8.2, 1H), 7.36-
7.24 (m, 6H), 4.48 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 163.9, 156.9, 154.0, 135.2, 135.0 129.4,
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128.3, 127.9, 127.0, 125.5, 118.0, 117.6, 113.7, 103.4, 37.7. HRMS (ESI/QTOF), m/z: [M+H]+ Calcd
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for C17H12NO2, 262.0863; Found: 262.0880.
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4-(2-Chlorobenzyl)-2-oxo-2H-chromene-3-carbonitrile (4g). Physical state: White solid; Yield: 33.93
mg (58%) 1H NMR (500 MHz, CDCl3) δ 7.69 – 7.64 (m, 1H), 7.53 (dd, J = 8.1, 1.3 Hz, 1H), 7.49 (dd, J
= 8.0, 1.0 Hz, 1H), 7.41 (dd, J = 8.3, 0.6 Hz, 1H), 7.30 – 7.27 (m, 1H), 7.24 (dd, J = 7.7, 1.1 Hz, 1H),
7.16 (td, J = 7.6, 1.1 Hz, 1H), 6.93 (d, J = 7.4 Hz, 1H), 4.60 (s, 2H). 13C{1H} NMR (126 MHz, CDCl3)
δ 163.1, 156.7, 153.8, 135.3, 133.6, 132.9, 130.3, 129.2, 128.9, 127.7, 126.9, 125.8, 117.9, 117.5, 113.3,
104.5, 35.0. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for C17H10ClNO2Na, 318.0292; Found:
318.0295.
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4-(4-Bromobenzyl)-2-oxo-2H-chromene-3-carbonitrile (4h). Physical state: White solid; Yield: 38.08
mg (56%). 1H NMR (300 MHz, CDCl3) δ 7.70 – 7.64 (m, 2H), 7.48 – 7.45 (m, 2H), 7.42 (dd, J = 9.0,
1.2 Hz, 1H), 7.36 – 7.31 (m, 1H), 7.16 (d, J = 8.5 Hz, 2H), 4.42 (s, 2H). 13C{1H} NMR (126 MHz, CDCl3)
δ 162.8, 156.6, 154.1, 135.4, 134.0, 132.6, 130.0, 126.7, 125.6, 122.0, 118.1, 117.4, 113.6, 103.6, 37.1.
HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for C17H10BrNO2Na, 361.9787; Found: 361.9802.
4-(Naphthalen-2-ylmethyl)-2-oxo-2H-chromene-3-carbonitrile (4i). Physical state: White solid; Yield:
29 .86 mg (48%). 1H NMR (300 MHz, CDCl3) δ 7.84 – 7.75 (m, 4H), 7.68-7.61 (m, 2H), 7.51 – 7.45 (m,
2H), 7.41 - 7.38 (m, 2H), 7.30 (d, J = 9.0 Hz, 1H), 4.64 (s, 2H). 13C{1H} NMR (75 MHz, CDCl3) δ 163.4,
156.9, 154.0, 135.2, 133.5, 132.6, 129.3, 127.8, 127.8, 127.1, 127.0, 126.8, 126.5, 126.0, 125.6, 118.0,
117.6, 113.8, 103.51, 37.9. HRMS (ESI/QTOF), m/z: [M+K]+ Calcd for C21H13NO2K, 350.0578;
Found: 350.0591.
2-Oxo-4-(thiophen-3-ylmethyl)-2H-chromene-3-carbonitrile (4j). Physical state: White solid; Yield:
29.90 mg (56%). 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 7.9 Hz, 1H), 7.68 (t, J = 7.4 Hz, 1H), 7.42-
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7.37 (m, 2H), 7.35 – 7.31 (m, 1H), 7.15 (s, 1H), 7.04 (d, J = 6.0 Hz, 1H), 4.46 (s, 2H). 13C{1H} NMR (75
MHz, CDCl3) δ 163.3, 156.9, 154.0, 135.3, 134.3, 127.4, 127.4, 127.1, 126.7, 125.6, 123.2, 118.0, 117.4,
113.6, 102,7, 32.5. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for C15H9NO2SNa, 290.0246; Found:
290.0245.
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4-((1H-Indol-3-yl)methyl)-2-oxo-2H-chromene-3-carbonitrile (4k). Physical state: White solid; Yield:
45.0 mg (75%). 1H NMR (300 MHz, DMSO) δ 11.05 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 7.9
Hz, 2H), 7.50 (d, J = 8.3 Hz, 1H), 7.35 (t, J = 7.1 Hz, 2H), 7.20 (d, J = 1.5 Hz, 1H), 7.15 – 7.04 (m, 2H),
4.53 (s, 2H). 13C{1H} NMR (75 MHz, DMSO) δ 164.3, 157.1, 153.44, 136.1, 135.1, 127.3, 126.3, 125.2,
124.2, 121.5, 119.0, 118.26, 117.5, 117.2, 114.5, 111.6, 108.9, 102.1, 33.4. HRMS (ESI/QTOF), m/z:
[M+Na]+ Calcd for C19H12N2O2Na, 323.0791; Found: 323.0795.
4-(3-(1H-Indol-3-yl)propyl)-2-oxo-2H-chromene-3-carbonitrile (4l). Physical state: White solid;
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Yield: 28.21 mg (43%). H NMR (300 MHz, CDCl3) δ 11.05 (s, 1H), 7.63-7.59 (m, 1H), 7.40 (d, J =
8.0 Hz, 1H), 7.39- 7.35 (M, 1H) 7.34 (dd, J = 4.8, 3.6 Hz, 2H),7.22 (t, J = 7.3 Hz, 1H), 7.16 (d, J = 8.1
Hz, 1H) 7.15-7.06 (m, 2H), 3.15-3.10 (m, 2H), 3.03 (t, J = 7.0 Hz, 2H), 2.21-2.17 (m, 2H). 13C{1H} NMR
(75 MHz, CDCl3) δ 167.0, 156.9, 156.7, 153.7, 131.5, 136.0, 127.1, 126.0, 125.4, 122.3, 122.2, 119.5,
118.8, 117.9, 117.3, 114.5, 113.6, 111.4, 101.7, 31.6, 30.6, 25.4. HRMS (ESI/QTOF), m/z: [M+Na]+
Calcd for C21H16N2O2Na, 351.1104; Found: 351.1107.
tert-Butyl (2-(3-cyano-2-oxo-2H-chromen-4-yl)ethyl)carbamate (4m). Physical state: White solid;
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Yield: 30.77 mg (49%). H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 7.7 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H),
7.43 (dd, J = 18.4, 8.1 Hz, 2H), 4.96 (s, 1H), 3.52 (q, J = 6.6 Hz, 2H), 3.35 (t, J = 6.7 Hz, 2H), 1.42 (s,
13
9H). C{1H} NMR (75 MHz, CDCl3) δ 163.7, 156.8, 156.1, 153.8, 135.4, 126.5, 125.8, 117.9, 113.6,
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102.7, 80.2, 40.2, 32.9, 33.07, 28.4. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for C17H18N2O4Na,
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337.1159; Found: 337.1172.
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tert-Butyl (3-(3-cyano-2-oxo-2H-chromen-4-yl)propyl)carbamate (4n). Physical state: White solid;
Yield: 46.58 mg (71%). 1H NMR (300 MHz, CDCl3) δ 7.76-7.66 (m, 2H), 7.40 (t, J = 1.0 Hz, 2H), 4.94
(s, 1H), 3.31 (d, J = 6.2 Hz, 2H), 3.31 (d, J = 6.2 Hz, 2H) 3.15 – 3.10 (m, 2H), 1.43 (s, 9H). 13C{1H} NMR
(75 MHz, CDCl3) δ 166.2, 156.8, 156.2, 153.9, 135.9, 126.0, 125.7, 118.1, 117.3, 113.5, 101.9, 79.7,
40.2, 33.8, 30.0, 28.4. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for C18H20N2O4Na, 351.1315; Found:
351.1321.
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6-Methyl-2-oxo-4-propyl-2H-chromene-3-carbonitrile (4o). Physical state: White solid; Yield: 43.13
mg (95%). 1H NMR (300 MHz, CDCl3) δ 7.49 (d, J = 9.0 Hz, 2H), 7.30 (d, J = 9.0 Hz, 1H), 3.10  3.05
(m, 2H), 2.47 (s, 3H), 1.85  1.78 (m, 2H), 1.14 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ
166.4, 157.2, 152.1, 136.3, 135.4, 125.6, 117.8, 117.2, 113.7, 101.6, 33.7, 23.7, 21.2, 14.3. HRMS
(ESI/QTOF), m/z: [M+Na]+ Calcd for C14H13NO2Na, 250.0838; Found: 250.0840.
7-methoxy-2-oxo-4-propyl-2H-chromene-3-carbonitrile (4p). Physical state: White solid; Yield: 40.33
mg (84%). 1H NMR (300 MHz, CDCl3) δ 7.63 (d, J = 9.0 Hz, 1H), 6.95 (dd, J = 9.0, 2.5 Hz, 1H), 6.83
(s, 1H), 3.92 (s, 3H), 3.10-2.93 (m, 2H), 1.77 (dt, J = 14.9, 7.5 Hz, 2H), 1.11 (t, J = 7.3 Hz, 3H). 13C{1H}
NMR (75 MHz, CDCl3) δ 166.4, 165.4, 157.7, 156.2, 127.3, 114.2, 114.0, 111.2, 101.36, 98.1, 56.2,
33.7, 23.5, 14.2. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for C14H13NO3Na, 266.0787, Found:
266.0790.
Ethyl 2-oxo-4-propylchromane-3-carboxylate (4q). Physical state: White solid; Yield: 41 mg (72%). 1H
NMR (300 MHz, CDCl3) δ 7.31-7.26 (m, 1H), 7.11 – 7.07 (m, 3H), 4.16 – 3.97 (m, 2H), 3.78 (d, J = 2.4
Hz, 1H), 3.41 – 3.36 (m, 1H), 1.61 – 1.55 (m, 2H), 1.42 – 1.34 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H). 0.94 (t,
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J = 7.2 Hz, 3H). C{1H} NMR (75 MHz, CDCl3) δ 167.3, 164.8, 150.8, 128.8, 128.7, 124.7, 124.4,
117.1, 62.2, 52.2, 39.8, 36.6, 19.9, 13.9, 13.8. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for
C15H18O4Na, 285.1097; Found: 285.1107.
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4-(3-(Biphenyl-4-yl)-3-oxopropyl)-2-oxo-2H-chromene-3-carbonitrile (4r). Physical state: White
solid; Yield: 35.37 mg (44%). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 2H), 7.85 (dd, J = 8.3,
1.2 Hz, 1H), 7.22 - 7.69 (m, 3H), 7.64 – 7.61(m, 2H), 7.49 – 7.41(m, 5H), 3.59 (dd, J = 8.4, 6.4 Hz, 2H),
3.47 (t, J = 8.0 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 195.9, 166.1, 154.0, 146.7, 135.5, 129.1,
128.9, 128.6, 127.6, 127.2, 126.0, 125.8, 118.2, 117.3, 113.41, 102.6, 37.5, 25.9. HRMS (ESI/QTOF),
m/z: [M+Na]+ Calcd for C25H17NO3Na, 402.1100; Found: 402.1080.
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2-Oxo-4-pentadecyl-2H-chromene-3-carbonitrile (4s). Physical state: White solid; Yield: 60.12 mg
(79%). 1H NMR (CDCl3, 300 MHz) δ 7.75 – 7.67 (m, 2H). 7.42 (t, J = 9 Hz, 2H), 3.12 – 3.07 (m, 2H),
1.80 – 1.70 (m, 2H), 1.52 – 1.47 (m, 2H), 1.25 (m, 22H), 0.87 (t, J = 6.6 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 166.9, 157.0, 154.0, 135.2, 126.0, 125.6, 118.1, 117.6, 113.5, 101.9, 77.5, 77.2, 76.9,
32.1, 30.1, 29.8, 29.5, 29.4, 22.8, 14.3. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for C25H35NO2Na,
404.2560; Found: 404.2546.
(Z)-4-(Heptadec-8-en-1-yl)-2-oxo-2H-chromene-3-carbonitrile (4t). Physical state: White solid; Yield:
56.98 mg (70%). 1H NMR (300 MHz, CDCl3) δ 7.71 (dd, J = 15.5, 7.9 Hz, 2H), 7.42 (t, J = 6.8 Hz, 2H),
5.35 – 5.34 (m, 2 H), 3.13 – 3.08 (m, 2 H), 2.01 (s, 4 H), 1.77 (dd, J = 14.6, 7.1 Hz, 2H), 1.58 – 1.53 (m,
13
2H), 1.34 (s, 9H), 1.26 (s, 9H), 0.87 (t, J = 5.8 Hz, 3H). C{1H} NMR (101 MHz, CDCl3) δ 166.8,
157.0, 153.9, 135.1, 130.2, 129.7, 126.0, 125.5, 118.1, 117.5, 113.5, 101.9, 32.1, 32.0, 30.0, 29.8, 29.7,
29.6, 29.4, 29.2, 29.1, 27.3, 27.2, 22.8, 14.2. HRMS (ESI/QTOF), m/z: [M+Na]+ Calcd for
C27H37NO2Na, 430.2717; Found: 430.2723.
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4-((1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)methyl)-2-oxo-2H-chromene-3-
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carbonitrile (4u). Physical state: Brown solid; Yield: 38.0 mg (44%). H NMR (300 MHz, CDCl3) δ
7.86 (d, J = 7.9 Hz, 1H), 7.70 – 7.64 (m, 3H) 7.43 (dd, J = 14.0, 8.4 Hz, 3H), 7.33 (t, J = 7.6 Hz, 1H),
6.84 (d, J = 9.0 Hz, 1H), 6.75 (s, 1H), 6.66 (d, J = 8.8 Hz, 1H), 5.47 (s, 2H), 3.71 (s, 3H), 2.46 (s, 3H).
13C{1H} NMR (75 MHz, CDCl3) δ 168.4, 163.6, 153.5, 139.8, 136.3, 135.4, 133.4, 131.5, 130.9, 129.5,
129.3, 126.1, 125.6, 118.1, 115.2, 130.0, 112.0, 100.4, 100.8, 55.7, 33.9, 29.1. HRMS (ESI/QTOF), m/z:
[M+Na]+ Calcd for C28H19ClN2O4Na, 505.0925, Found: 505.0921.
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2-Oxo-4-((3S)-3-((3S,5R,7S,8S,10R,12R,13S,14R,17S)-3,7,12-trihydroxy-10,13-
dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)butyl)-2H-chromene-3-carbonitrile
(4v). Physical state: Brown solid; Yield: 57.56 mg (54%). 1H NMR (400 MHz, CDCl3) δ 7.69 – 7.60
(m, 2H), 7.38 – 7.20 (m, 2H), 3.89 (s, 1H), 3.79 (s, 1H), 3.48- 3.33 (m, 4H), 3.11 – 3.07 (m, 1H), 2.98 (s,
1H), 2.22 – 2.10 (m, 1H), 1.97 – 1.82 (m, 3H), 1.66 – 1.46 (m, 10H), 1.21 – 1.18 (m, 9H), 0.92 – 0.87 (m,
2H), 0.79 (s, 3H), 0.69 (s, 3H). C{1H} NMR (75 MHz, CDCl3) δ 168.5, 157.2, 153.9, 135.3, 126.1,
13
125.7, 118.0, 117.5, 113.6, 101.3, 73.2, 72.0, 68.6, 46.6, 45.8, 41.7, 39.8, 39.4, 36.6, 36.4, 35.5, 34.9,
30.5, 29.8, 28.5, 28.2, 27.9, 26.3, 23.5, 22.5, 17.7, 14.3, 12.5. HRMS (ESI/QTOF), m/z: [M+K]+ Calcd
for C33H43NO5K, 572.2773; Found: 572.2772.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the ACS Publications website at DOI:
Mechanistic studies, X-ray crystallography data, CIF files, 1H and 13C NMR spectra
AUTHOR INFORMATION
Corresponding Author
*E-mail: ravips@chemistry.iitd.ac.in
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ORCID:
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Ravi P. Singh: 0000-0001-5323-5979
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Krishna N. Tripathi: 0000-0002-4912-1765
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Author Contributions
‡ KNT and MB contributed equally.
Notes
The authors declare no competing financial interest
Present Addresses
†Department of Chemistry, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi 110016 (India).
ACKNOWLEDGMENT
We are grateful for the generous financial support from DST-India (EMR/2017/000319), CSIR
[02(0254)/16/EMR-II] and DAE (201804BRE02RP04978-BRNS). KNT is grateful to the CSIR, New
Delhi, India, for SRF. We are thankful to Dr. Abhijeet Srivastava, for help in preparing the manuscript
and illustration.
DEDICATION
This work is dedicated to Professor Elias J. Corey on the occasion of his 90th birthday.
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REFERENCES
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V.; Bergamini, G.; Ceroni, P. Light: A Very Peculiar Reactant and Product. Angew. Chem., Int. Ed. 2015,
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MacMillan, D. W. C.) Wiley-VCH, Weinheim, 2018. (b) Wu, J.; Grant, P. S.; Li, X.; Noble, A.; Aggarwal,
V. K. Catalyst‐Free Deaminative Functionalizations of Primary Amines by Photoinduced Single‐Electron
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(24) CCDC 1906778 and 1906813 contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.
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