Coumaryl Triflate, a Versatile Building Block for the Modification of Coumarins and for Fluorescence Labeling

Article abstract of DOI:10.1055/s-0036-1588159

Coumaryl triflate can be used for a wide range of substitution reactions, either under Pd-catalyzed conditions or via direct nucleophilic substitutions, and is therefore an ideal substrate for the fluorescence labeling of functionalized compounds, such as amino acids.

Full text of DOI:10.1055/s-0036-1588159

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–F
paper
A
U. Kazmaier et al.
Paper
Synthesis
Coumaryl Triflate, a Versatile Building Block for the Modification
of Coumarins and for Fluorescence Labeling
Uli Kazmaier*a
CONu
Nu: ROH, RNH2
4 examples (71–96%)
Tamara Doroshenkoa
Kevin Bauera
Et2N
O
O
Isabel Filbricha
Andreas Grueterb
Gregor Jungb
Nu, CO
Pd0
Ar
O
OTf
O
ArB(OH)2
Pd0
3 examples (94–99%)
Angelika Ullricha
Et2N
O
Et2N
O
Nu
Nu
O
a Universität des Saarlandes, Organische Chemie, 66123 Saarbrücken,
Germany
u.kazmaier@mx.uni-saarland.de
b Universität des Saarlandes, Biophysikalische Chemie, 66123 Saarbrücken,
Germany
Nu: RSH, RNH2
8 examples (56–98%)
Et2N
O
Received: 11.01.2017
Accepted after revision: 06.03.2017
Published online: 23.03.2017
N
N
N
CuSO4 (10 mol%)
DOI: 10.1055/s-0036-1588159; Art ID: ss-2017-t0021-op
MeOOC
MeOOC
N3
Na-ascorbate (10 mol%)
DMSO/H2O, 80 °C, 16 h
77%
+
Abstract Coumaryl triflate can be used for a wide range of substitu-
tion reactions, either under Pd-catalyzed conditions or via direct nucle-
ophilic substitutions, and is therefore an ideal substrate for the fluores-
cence labeling of functionalized compounds, such as amino acids.
N
O
O
N
O
O
Ot-Bu
Key words amino acids, carbonylation, coumarins, fluorescence la-
Et2N
[allylPdCl]2
PPh3, THF
beling, palladium, substitution
N
O
O
TFA
Zn
+
Et2N
–78 °C to r.t.
O
In the life sciences, fluorescence labeling plays an im-
portant role for the investigation of cellular processes and
the three-dimensional imaging of tissues and living cells.1
For the labeling of proteins, for example, a wide range of
fluorescence dyes can be used.2 Besides BODIPYs3 and fluo-
rescein derivatives,4 coumarins also play an important role,
especially those with electron-donating groups at the 7-po-
sition.5 In general, these coumarins show an excellent fluo-
rescence quantum yield, making them extremely suitable
for fluorescence microscopy and the development of fluo-
rescence labels.6 Recently, we could show that 7-dialkyl-
amino-substituted fluorescence labels can be introduced
into functionalized amino acids and peptides7 via the popu-
lar azide-alkyne click chemistry,8 or as backbone modifica-
tion via Pd-catalyzed allylic alkylation9 using coumaryl-
substituted allylic carbonates such as 1 (Scheme 1).10
A key building block in the synthesis of 1 and related
structures was coumaryl triflate 2 (Figure 1), which could
be converted into 1 via Sonogashira coupling. With this in-
teresting building block 2 in hand, we were interested to
study its properties and examine its uses for other reac-
tions.
O
69%
O
TFAHN
COOt-Bu
O
OCOOEt
1
O
Scheme 1 Fluorescence labeling of amino acids via click reaction and
Pd-catalyzed allylic alkylation
OTf
Et2N
O
O
2
Figure 1 Coumaryl triflate 2
described Sonogashira coupling10 also Suzuki coupling pro-
ceeded nicely and in almost quantitative yields (Scheme 2).
These aryl-substituted derivatives are interesting building
blocks used, for example, in fluorescent neurosensors.12
Enlarging the π-system by introduction of an additional
phenyl ring resulted in a bathochromic shift of the absorp-
tion maximum (λabs) from 351 nm (2) to ~375 nm (3), while
the emission maximum (λem) shifted from 384 nm (2) to
454–464 nm (3).
Triflate 2 can easily be obtained in two steps from m-
N,N-diethylaminophenol.10,11 Comparable to the previously
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

B
U. Kazmaier et al.
Paper
Synthesis
(entries 3–5). But even ephedrine could be fluorescence-la-
beled in acceptable yield (entry 5). This is also true for Leu-
OMe as a representative of the amino acid derivatives (en-
try 6). Fluorescence is maintained in all 4-amino-substitut-
ed derivatives with little spectral shifts compared to 2.
R
R
B(OH)2
(1.2 equiv)
2
Pd(PPh3)4 ( 2 mol%)
K2CO3 (2.0 equiv)
toluene, Δ, 1 h
Et2N
O
O
Table 1 Direct Aminations of Coumaryl Triflate 2
3a R = H
99%
3b R = Me 99%
3c R = OMe 94%
NRR'
HNRR' (1.2 equiv)
Et3N (2.0 equiv)
Scheme 2 Suzuki couplings of coumaryl triflate 2
2
Et2N
O
O
toluene, Δ, 16 h
6
With these good results in hand, carbonylation reac-
tions13 of 2 were next investigated. Our initial experiment
was carried out in absolute methanol at room temperature.
However, at a CO pressure of 1 atm, only 13% of the desired
methyl ester 4 was obtained, while most of the triflate 2
could be recovered. Significantly better yields could be ob-
tained if the pressure was increased to 15 bar (Scheme 3).
Under these conditions ester 4 could be obtained in excel-
lent yield.
Entry
HNRR′
Product
Yield (%)
1
2
3
4
5
6
morpholine
piperidine
6a
6b
6c
6d
6e
6f
95
98
68
60
56
62
diethylamine
dibenzylamine
ephedrine
Leu-OMe
COOMe
One of the highly nucleophilic functionalities found in
nature is the SH group of cysteine, which should also be a
good candidate for fluorescence labeling with 2. Therefore,
we also investigated substitutions with aromatic and ali-
phatic thiols. The reaction of 2,6-dichlorothiophenol under
the previous reaction conditions provided the expected
product 7a in almost quantitative yield, even at room tem-
perature (Scheme 4). To prove whether triflate 2 might also
survive aqueous conditions, generally used for peptide and
protein labeling, the labeling of N-protected cysteine was
investigated in an aqueous 1,4-dioxane solution. Also under
these conditions, the reaction proceeded nicely at room
temperature, and the somewhat lower yield of 7b can be
explained by a competitive oxidation of the cysteine to cys-
tine under the reaction conditions.
Et2N
O
O
CO (15 bar)
PdCl2(PPh3)2 (6 mol%)
Et3N (2 equiv)
.
4 96%
2
CONHR
Et2N
O
O
5a R = Bn 83%
5b R = CH2COOMe 86%
5c R = CH(Me)COOMe 71%
Scheme 3 Carbonylative couplings of coumaryl triflate 2
The reaction probably proceeds via an acyl–Pd interme-
diate,13 which is attacked by the nucleophilic solvent.
Therefore, one might expect also good results with other
good nucleophiles, for example, amines. And indeed, good
yields of 5 were obtained with primary amines, including
amino acid esters (Scheme 3). These could be used as salts
if an excess of base was added. Therefore, triflate 2 is also
suitable for amino acid fluorescence labeling. Incorporation
of CO resulted also in a dramatic bathochromic shift of the
absorption and emission maxima (compared to 2) by 33–35
nm (λabs) and 133–141 nm (λem), respectively.
Cl
S
SH
Cl
Cl
Cl
(1.0 equiv)
Et2N
O
O
7a 97%
2
COOH
S
NHAc
O
Interestingly, a different reaction behavior was observed
with more nucleophilic secondary amines such as morpho-
line. In this case, no CO insertion was observed and the
amine directly replaced the triflate. Therefore, also no Pd
catalyst is required in this reaction, and best results were
obtained by refluxing the reaction mixture in toluene over-
night (Table 1). While cyclic secondary amines gave almost
a quantitative yield of 6 (Table 1, entries 1, 2), the results
were little worse with the more flexible secondary amines
Et2N
O
7b 80%
Scheme 4 Fluorescence labeling of thiols using coumaryl triflate 2
In conclusion, we have shown that coumaryl triflate 2
can be subjected to a wide range of modifications, either
under Pd-catalyzed conditions or via direct nucleophilic
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

C
U. Kazmaier et al.
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Synthesis
substitutions. Thiols are found to be significantly more re-
active than amines, and chemoselective peptide labelings
are currently under investigation.
refluxed for 1 h. After workup and column chromatography (silica gel,
PE–EtOAc 7:3), 3b was isolated as a yellow solid; yield: 61 mg (0.20
mmol, 99%); mp 121–123 °C; Rf = 0.22 (CH2Cl2–EtOAc 98:2).
1H NMR (400 MHz, CDCl3): δ = 1.23 (t, J = 7.1 Hz, 6 H), 2.46 (s, 3 H),
3.43 (q, J = 7.1 Hz, 4 H), 6.02 (s, 1 H), 6.53 (dd, J = 9.0, 2.5 Hz, 1 H), 6.59
(d, J = 2.4 Hz, 1 H), 7.28–7.38 (m, 5 H).
All air- or moisture-sensitive reactions were carried out in dried
glassware (>100 °C) under an atmosphere of N2 or argon. The prod-
ucts were purified by flash chromatography on silica gel columns
(Macherey-Nagel 60, 0.063–0.2 mm). Mixtures of CH2Cl2 and EtOAc
were generally used as eluents. Analytical TLC was performed on pre-
coated silica gel plates (Macherey-Nagel, Polygram® SIL G/UV254). Vi-
sualization was accomplished with UV-light, KMnO4 solution, or nin-
hydrin solution. Melting points were determined with a Dr. Tottoli
(Büchi) melting point apparatus and are uncorrected. 1H and 13C NMR
spectra were recorded with a Bruker AVII-400 [400 MHz (1H) and 100
MHz (13C)] spectrometer in CDCl3. Chemical shifts are reported in
ppm relative to TMS; CHCl3 was used as the internal standard. Mass
spectra were recorded with a Finnigan MAT 95Q spectrometer using
the CI technique. A Jasco V-650 spectrophotometer was used to mea-
sure the absorption spectra, while a Jasco FP-6500 was used for the
fluorescence spectra. Quantum yields of selected compounds (5 μM in
DMSO) were determined on a Quantaurus-QY Absolute PL Quantum
Yield Spectrometer C 11347 (Hamamatsu). Elemental analyses were
performed at Saarland University.
13C NMR (100 MHz, CDCl3): δ = 12.5, 21.4, 44.8, 97.9, 108.0, 108.2,
108.4, 128.0, 128.4, 129.3, 133.4, 139.4, 150.6, 156.2, 156.8, 162.3.
HRMS (CI): m/z calcd for C20H21NO2 (M)+: 307.1567; found: 307.1578.
UV (DMSO): λmax (abs) = 373 nm; λmax (em) = 454 nm.
Anal. Calcd for C20H21NO2 (307.39): C, 78.15; H, 6.89; N, 4.56. Found:
C, 77.82; H, 6.94; N, 4.50.
7-(N,N-Diethylamino)-4-(4-methoxyphenyl)-2H-chromen-2-one
(3c)12
According to the general procedure for Suzuki coupling, 4-methoxy-
phenylboronic acid (36 mg, 0.24 mmol) was added to a solution of tri-
flate 2 (73 mg, 0.20 mmol), Pd(PPh3)4 (4.6 mg, 4 μmol, 2 mol%), and
K2CO3 (33 mg, 0.24 mmol) in anhyd toluene (1 mL). The reaction mix-
ture was refluxed for 1 h. After workup and column chromatography
(silica gel, hexanes–EtOAc 7:3), 3c was isolated as a yellow solid;
yield: 61 mg (0.19 mmol, 94%); mp 121–123 °C; Rf = 0.59 (CH2Cl2–
EtOAc 95:5).
1H NMR (400 MHz, CDCl3): δ = 1.21 (t, J = 7.1 Hz, 6 H), 3.41 (q, J = 7.1
Hz, 4 H), 3.88 (s, 3 H), 5.99 (s, 1 H), 6.52 (dd, J = 9.0, 2.6 Hz, 1 H), 6.56
(d, J = 2.6 Hz, 1 H), 7.01 (dt, J = 8.8, 2.8 Hz, 2 H), 7.31 (d, J = 9.1 Hz, 1
H), 7.39 (dt, J = 8.8, 2.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 12.4, 44.7, 55.4, 97.9, 107.9, 108.0,
108.4, 114.1, 127.9, 128.5, 129.8, 150.5, 155.8, 156.8, 160.5, 162.3.
Suzuki Coupling of Coumaryl Triflate 2; General Procedure
To a solution of Pd(PPh3)4 (2 mol%), K2CO3 (2 equiv), and triflate 210 (1
equiv) in toluene (5 mL/mmol) was added arylboronic acid (1.2
equiv) under N2 atmosphere at r.t. and the reaction mixture was re-
fluxed until complete conversion of the coumarin was observed
(TLC). Afterwards, the reaction was quenched with aq 1 M NH4Cl and
extracted with EtOAc. The combined organic layers were dried (an-
hyd Na2SO4), concentrated, and the crude product was purified by
flash chromatography (silica gel).
HRMS (CI): m/z calcd for C20H21NO (M)+: 323.1516; found: 323.1488.
UV (DMSO): λmax (abs) = 390 nm; λmax (em) = 482 nm; ΦF = 0.71.
Methyl 7-(N,N-Diethylamino)-2-oxo-2H-chromene-4-carboxylate
(4)
7-(N,N-Diethylamino)-4-phenyl-2H-chromen-2-one (3a)14
Pd(PPh3)2Cl2 (8.4 mg, 12 μmol, 10 mol%) and Et3N (33 μL, 24.3 mg,
0.24 mmol) were added to a solution of triflate 2 (44 mg, 0.12 mmol)
in anhyd toluene (1.6 mL) containing MeOH (0.2 mL). The reaction
mixture was stirred under CO atmosphere (15 bar) in an autoclave at
r.t. overnight. Afterwards, the reaction was quenched with aq 1 N KH-
SO4, and extracted with EtOAc (3 ×). The combined organic layers
were filtered through Celite and dried (anhyd Na2SO4). The solvent
was removed in vacuo and the crude product was purified by column
chromatography (silica gel, CH2Cl2) to furnish 4 as a yellow solid;
yield: 32 mg (0.115 mmol, 96%); mp 119–120 °C; Rf = 0.33 (PE–EtOAc
7:3).
According to the general procedure for Suzuki coupling, phenylboron-
ic acid (29 mg, 0.24 mmol) was added to a solution of triflate 2 (73
mg, 0.20 mmol), Pd(PPh3)4 (4.6 mg, 4 μmol, 2 mol%), and K2CO3 (33
mg, 0.24 mmol) in anhyd toluene (1 mL). The reaction mixture was
refluxed for 1 h. After workup and column chromatography (silica gel,
PE–EtOAc 7:3), 3a was isolated as a yellow solid; yield: 59 mg (0.20
mmol, 99%); mp 119–120 °C; Rf = 0.25 (PE–EtOAc 7:3).
1H NMR (400 MHz, CDCl3): δ = 1.20 (t, J = 7.1 Hz, 6 H), 3.41 (q, J = 7.1
Hz, 4 H), 6.01 (s, 1 H), 6.51 (dd, J = 9.0, 2.4 Hz, 1 H), 6.57 (d, J = 2.4 Hz,
1 H), 7.25 (d, J = 9.1 Hz, 1 H), 7.40–7.49 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 12.5, 44.8, 97.9, 108.0, 108.3, 108.5,
127.9, 128.4, 128.6, 129.2, 136.3, 150.6, 156.2, 156.8, 162.2.
HRMS (CI): m/z calcd for C19H19NO2 (M)+: 293.1410; found: 293.1410.
1H NMR (400 MHz, CDCl3): δ = 1.21 (t, J = 7.1 Hz, 6 H), 3.42 (q, J = 7.1
Hz, 4 H), 3.96 (s, 3 H), 6.51 (d, J = 2.6 Hz, 1 H), 6.52 (s, 1 H), 6.60 (dd,
J = 9.2, 2.6 Hz, 1 H), 8.00 (d, J = 9.2 Hz, 1 H).
UV (DMSO): λmax (abs) = 376 nm; λmax (em) = 464 nm.
13C NMR (100 MHz, CDCl3): δ = 12.6, 44.8, 52.8, 97.7, 105.0, 109.1,
111.4, 127.7, 150.8, 157.1, 160.8, 165.1. Signal for the CO2Me group
was not observed.
Anal. Calcd for C19H19NO2 (293.37): C, 77.79; H, 6.53; N, 4.77. Found:
C, 77.76; H, 6.71; N, 4.62.
HRMS (CI): m/z calcd for C15H17NO4 (M)+: 275.1158; found: 275.1171.
7-(N,N-Diethylamino)-4-(p-tolyl)-2H-chromen-2-one (3b)
UV (DMSO): λmax (abs) = 396 nm; λmax (em) = 536 nm.
According to the general procedure for Suzuki coupling, p-tolylboron-
ic acid (33 mg, 0.24 mmol) was added to a solution of triflate 2 (73
mg, 0.20 mmol), Pd(PPh3)4 (4.6 mg, 4 μmol, 2 mol%), and K2CO3 (33
mg, 0.24 mmol) in anhyd toluene (1 mL). The reaction mixture was
Anal. Calcd for C15H17NO4 (275.30): C, 65.44; H, 6.22; N, 5.09. Found:
C, 65.49; H, 6.11; N, 4.92.
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D
U. Kazmaier et al.
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Synthesis
Palladium-Catalyzed Aminocarbonylations of Coumaryl Triflate 2;
General Procedure
0.40 mmol) were added to a solution of triflate 2 (73 mg, 0.20 mmol)
and (S)-alanine methyl ester hydrochloride (33 mg, 0.24 mmol) in an-
hyd toluene (2 mL). The reaction mixture was stirred under CO atmo-
sphere (15 bar) at r.t. overnight. After workup and column chroma-
tography (silica gel, CH2Cl2–EtOAc 95:5), 5c was isolated as a yellow
solid; yield: 49 mg (0.14 mmol, 71%); mp 144–146 °C; Rf = 0.19 (CH2-
Cl2–EtOAc 9:1).
1H NMR (400 MHz, CDCl3): δ = 1.18 (t, J = 7.1 Hz, 6 H), 1.53 (d, J = 7.2
Hz, 3 H), 3.38 (q, J = 7.1 Hz, 4 H), 3.78 (s, 3 H), 4.74 (qd, J = 7.2, 7.2 Hz,
1 H), 6.09 (s, 1 H), 6.43 (d, J = 2.3 Hz, 1 H), 6.55 (dd, J = 9.1, 2.4 Hz, 1
H), 6.93 (d, J = 7.2 Hz, 1 H), 7.59 (d, J = 9.1 Hz, 1 H).
Pd(PPh3)2Cl2 (10 mol%) and Et3N (2 equiv) were added to a solution of
triflate 2 (1 equiv) and the corresponding amine (1.2 equiv) in anhyd
toluene (10 mL/mmol). The reaction mixture was stirred under CO at-
mosphere (15 bar) overnight before it was diluted with CH2Cl2 and
quenched with aq 1 M NH4Cl. The aqueous layer was extracted with
CH2Cl2 (3 ×) and the combined organic layers were dried (anhyd
Na2SO4). The solvent was evaporated in vacuo and the crude product
was purified by column chromatography.
13C NMR (100 MHz, CDCl3): δ = 12.4, 18.0, 44.8, 48.5, 52.7, 97.6, 105.0,
106.6, 109.2, 127.5, 149.0, 151.1, 157.0, 161.8, 165.1, 172.8.
N-Benzyl-7-(N,N-diethylamino)-2-oxo-2H-chromene-4-carbox-
amide (5a)
According to the general procedure for Pd-catalyzed aminocarbonyla-
tions, Pd(PPh3)2Cl2 (14 mg, 20 μmol, 10 mol%) and Et3N (55 μL, 40 mg,
0.40 mmol) were added to a solution of triflate 2 (73 mg, 0.20 mmol)
and benzylamine (26 μL, 25.7 mg, 0.24 mmol) in anhyd toluene (2
mL). The reaction mixture was stirred under CO atmosphere (15 bar)
at r.t. overnight. After workup and column chromatography (silica gel,
CH2Cl2–EtOAc 100:0, 95:5), 5a was isolated as a yellow solid; yield: 67
mg (0.17 mmol, 83%); mp 169–170 °C; Rf = 0.45 (CH2Cl2–EtOAc 95:5).
1H NMR (400 MHz, CDCl3): δ = 1.19 (t, J = 7.1 Hz, 6 H), 3.39 (q, J = 7.1
Hz, 4 H), 4.61 (d, J = 5.9 Hz, 2 H), 6.03 (s, 1 H), 6.41 (d, J = 2.5 Hz, 1 H),
6.54 (dd, J = 9.1, 2.5 Hz, 1 H), 6.83 (t, J = 5.4 Hz, 1 H), 7.26–7.37 (m, 5
H), 7.59 (d, J = 9.1 Hz, 1 H).
HRMS (CI): m/z calcd for
346.1525.
C
18H22N2O5 (M)+: 346.1523; found:
UV (DMSO): λmax (abs) = 386 nm; λmax (em) = 520 nm.
Aminations of Coumaryl Triflate 2; General Procedure
Et3N (2 equiv) was added to a solution of triflate 2 (1 equiv) and the
corresponding amine (1.2–1.5 equiv) in anhyd toluene (10 mL/mmol).
The reaction mixture was refluxed overnight. After cooling to r.t., the
mixture was diluted with CH2Cl2 and quenched with aq 1 M NH4Cl.
The aqueous layer was extracted with CH2Cl2 (3 ×) and the combined
organic layers were dried (anhyd Na2SO4). The solvent was evaporat-
ed in vacuo and the crude product was purified by column chroma-
tography.
13C NMR (100 MHz, CDCl3): δ = 12.5, 43.8, 44.8, 97.6, 105.1, 106.4,
109.2, 127.5, 127.8, 127.8, 128.9, 137.5, 149.4, 151.1, 157.0, 161.9,
165.3.
7-(N,N-Diethylamino)-4-morpholino-2H-chromen-2-one (6a)
HRMS (CI): m/z calcd for
C
21H22N2O3 (M)+: 350.1625; found:
According to the general procedure for aminations, triflate 2 (44 mg,
0.12 mmol) was reacted with morpholine (12 μL, 15.8 mg, 0.18
mmol) and Et3N (33 μL, 24 mg, 0.24 mmol). After workup and column
chromatography (silica gel, CH2Cl2–EtOAc 95:5), 6a was isolated as a
yellow solid; yield: 34 mg (0.11 mmol, 95%); mp 132–133 °C; Rf = 0.32
(CH2Cl2–EtOAc 9:1).
350.1631.
UV (DMSO): λmax (abs) = 395 nm; λmax (em) = 542 nm; ΦF = 0.47.
Anal. Calcd for C21H22N2O3 (350.42): C, 71.98; H, 6.33; N, 7.99. Found:
C, 72.01; H, 6.41; N, 7.89.
[7-(N,N-Diethylamino)-2-oxo-2H-chromene-4-carbonyl]glycine
Methyl Ester (5b)
1H NMR (400 MHz, CDCl3): δ = 1.20 (t, J = 7.1 Hz, 6 H), 3.22 (m, 4 H),
3.40 (q, J = 7.1 Hz, 4 H), 3.89 (m, 4 H), 5.45 (s, 1 H), 6.48 (d, J = 2.6 Hz, 1
H), 6.54 (dd, J = 9.1, 2.6 Hz, 1 H), 7.36 (d, J = 9.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 12.5, 44.7, 51.5, 66.5, 92.9, 98.1, 104.3,
107.9, 125.6, 150.3, 156.7, 162.0, 163.6.
According to the general procedure for Pd-catalyzed aminocarbonyla-
tions, Pd(PPh3)2Cl2 (14 mg, 20 μmol, 10 mol%) and Et3N (55 μL, 40 mg,
0.40 mmol) were added to a solution of triflate 2 (73 mg, 0.20 mmol)
and glycine methyl ester hydrochloride (30 mg, 0.24 mmol) in anhyd
toluene (2 mL). The reaction mixture was stirred under CO atmo-
sphere (15 bar) at r.t. overnight. After workup and column chroma-
tography (silica gel, CH2Cl2–EtOAc 95:5 then 90:10), 5b was isolated
as a yellow solid; yield: 57 mg (0.17 mmol, 86%); mp 141–142 °C;
Rf = 0.19 (CH2Cl2–EtOAc 8:2).
HRMS (CI): m/z calcd for
C
17H22N2O3 (M)+: 302.1625; found:
302.1626.
UV (DMSO): λmax (abs) = 356 nm; λmax (em) = 412 nm.
7-(N,N-Diethylamino)-4-(piperidin-1-yl)-2H-chromen-2-one (6b)
1H NMR (400 MHz, CDCl3): δ = 1.20 (t, J = 7.1 Hz, 6 H), 3.41 (q, J = 7.1
Hz, 4 H), 3.81 (s, 3 H), 4.24 (d, J = 5.5 Hz, 2 H), 6.13 (s, 1 H), 6.47 (d,
J = 2.3 Hz, 1 H), 6.58 (dd, J = 9.1, 2.6 Hz, 1 H), 6.69 (br s, 1 H), 7.64 (d,
J = 9.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 12.4, 41.4, 44.8, 52.7, 97.7, 104.9,
106.7, 109.2, 127.5, 148.7, 151.2, 157.1, 161.7, 165.6, 169.7.
According to the general procedure for aminations, triflate 2 (73 mg,
0.20 mmol) was reacted with piperidine (24 μL, 20.7 mg, 0.24 mmol)
and Et3N (55 μL, 40 mg, 0.4 mmol). After workup and column chro-
matography (silica gel, CH2Cl2–EtOAc 98:2, 95:5, 9:1), 6b was isolated
as a yellow solid; yield: 59 mg (0.20 mmol, 98%); mp 100–101 °C;
Rf = 0.19 (CH2Cl2–EtOAc 9:1).
1H NMR (400 MHz, CDCl3): δ = 1.12 (t, J = 7.1 Hz, 6 H), 1.61–1.71 (m, 6
H), 3.12 (m, 4 H), 3.32 (q, J = 7.1 Hz, 4 H), 5.35 (s, 1 H), 6.40 (d, J = 2.6
Hz, 1 H), 6.47 (dd, J = 9.1, 2.6 Hz, 1 H), 7.30 (d, J = 9.1 Hz, 1 H).
HRMS (CI): m/z calcd for
C
17H20N2O5 (M)+: 332.1367; found:
332.1361.
UV (DMSO): λmax (abs) = 386 nm; λmax (em) = 525 nm.
13C NMR (100 MHz, CDCl3): δ = 12.4, 24.4, 25.7, 44.6, 52.2, 91.9, 98.0,
105.0, 107.7, 125.9, 150.0, 156.6, 162.8, 164.0.
[7-(N,N-Diethylamino)-2-oxo-2H-chromene-4-carbonyl]-(S)-ala-
nine Methyl Ester (5c)
HRMS (CI): m/z calcd for
C
18H24N2O2 (M)+: 300.1832; found:
300.1838.
According to the general procedure for Pd-catalyzed aminocarbonyla-
tions, Pd(PPh3)2Cl2 (14 mg, 20 μmol, 10 mol%) and Et3N (55 μL, 40 mg,
UV (DMSO): λmax (abs) = 362 nm; λmax (em) = 430 nm; ΦF = 0.64.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

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U. Kazmaier et al.
Paper
Synthesis
Anal. Calcd for C18H24N2O2 (300.40): C, 71.97; H, 8.05, N, 9.33. Found:
C, 71.99; H, 8.27; N, 9.04.
7-(N,N-Diethylamino)-2-oxo-2H-chromen-4-yl-(S)-leucine Methyl
Ester (6f)
According to the general procedure for aminations, triflate 2 (73 mg,
0.20 mmol) was reacted with (S)-leucine methyl ester hydrochloride
(44 mg, 0.24 mmol) and Et3N (110 μL, 80 mg, 0.80 mmol). After work-
up and column chromatography (silica gel, CH2Cl2–EtOAc 95:5), 6f
was isolated as a yellow solid; yield: 45 mg (0.12 mmol, 62%); mp
198–200 °C; Rf = 0.51 (CH2Cl2–EtOAc 9:1).
1H NMR (400 MHz, CDCl3): δ = 0.91 (d, J = 6.2 Hz, 3 H), 0.96 (d, J = 6.2
Hz, 3 H), 1.17 (t, J = 7.1 Hz, 6 H), 1.69–1.82 (m, 3 H), 3.31–3.41 (m, 4
H), 3.79 (s, 3 H), 4.18 (td, J = 7.7, 6.1 Hz, 1 H), 4.98 (s, 1 H), 5.82 (d,
J = 7.9 Hz, 1 H), 6.29 (d, J = 2.5 Hz, 1 H), 6.42 (dd, J = 9.0 2.5 Hz, 1 H),
7.23 (d, J = 9.1 Hz, 1 H).
4,7-Bis(N,N-diethylamino)-2H-chromen-2-one (6c)
According to the general procedure for aminations, triflate 2 (73 mg,
0.20 mmol) was treated with Et2NH (25 μL, 17.6 mg, 0.24 mmol) and
Et3N (55 μL, 40 mg, 0.4 mmol). After workup and column chromatog-
raphy (silica gel, CH2Cl2–EtOAc 9:1), 6c was isolated as a yellow oil;
yield: 39 mg (0.14 mmol, 68%); Rf = 0.19 (CH2Cl2–EtOAc 9:1).
1H NMR (400 MHz, CDCl3): δ = 1.17 (t, J = 7.1 Hz, 6 H), 1.20 (t, J = 7.1
Hz, 6 H), 3.34 (q, J = 7.1 Hz, 4 H), 3.37 (q, J = 7.1 Hz, 4 H), 5.34 (s, 1 H),
6.45 (d, J = 2.6 Hz, 1 H), 6.50 (dd, J = 9.1, 2.7 Hz, 1 H), 7.40 (d, J = 9.1
Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 12.5, 21.9, 22.7, 25.0, 41.0, 44.6, 52.7,
53.8, 80.9, 97.8, 102.2, 107.8, 121.5, 150.5, 153.3, 155.6, 164.1, 174.2.
HRMS (CI): m/z calcd for C20H29N2O4 (M + H)+: 361.2122; found:
361.2120.
13C NMR (100 MHz, CDCl3): δ = 12.2, 12.4, 44.5, 45.3, 90.6, 98.1, 105.0,
107.4, 126.0, 149.8, 156.6, 160.0, 163.8.
HRMS (CI): m/z calcd for
C
17H24N2O2 (M)+: 288.1832; found:
288.1841.
UV (DMSO): λmax (abs) = 345 nm; λmax (em) = 390 nm.
UV (DMSO): λmax (abs) = 352 nm; λmax (em) = 417 nm.
Anal. Calcd for C20H28N2O4 (360.45): C, 66.64; H, 7.83; N, 7.77. Found:
C, 66.54; H, 8.18; N, 7.47.
4-(N,N-Dibenzylamino)-7-(N,N-diethylamino)-2H-chromen-2-one
(6d)
4-[(2,6-Dichlorophenyl)thio]-7-(N,N-diethylamino)-2H-chromen-
2-one (7a)
According to the general procedure for aminations, triflate 2 (73 mg,
0.20 mmol) was reacted with dibenzylamine (46 μL, 47 mg, 0.24
mmol) and Et3N (55 μL, 40 mg, 0.40 mmol). After workup and column
chromatography (silica gel, CH2Cl2–EtOAc 9:1), 6d was isolated as a
pale brown solid; yield: 50 mg (0.12 mmol, 60%); mp 100–101 °C;
Rf = 0.1 (CH2Cl2–EtOAc 9:1).
1H NMR (400 MHz, CDCl3): δ = 1.11 (t, J = 7.1 Hz, 6 H), 3.31 (q, J = 7.1
Hz, 4 H), 4.42 (s, 4 H), 5.32 (s, 1 H), 6.40–6.45 (m, 2 H), 7.15–7.28 (m,
10 H), 7.51 (d, J = 8.8 Hz, 1 H).
In analogy to the general procedure for aminations, triflate 2 (183 mg,
0.50 mmol) was reacted with 2,6-dichlorothiophenol (89.5 mg, 0.50
mmol) and Et3N (140 μL, 103 mg, 1.0 mmol). The reaction mixture
was stirred at r.t. for 24 h. After workup as usual, the crude product
was crystallized from Et2O–PE to provide 7a as a brown solid; yield:
190 mg (0.485 mmol, 97%); mp 154–155 °C; Rf = 0.73 (CH2Cl2–MeOH
95:5).
1H NMR (400 MHz, CDCl3): δ = 1.21 (t, J = 7.0 Hz, 6 H), 3.42 (q, J = 7.1
Hz, 4 H), 5.15 (s, 1 H), 6.48 (d, J = 2.5 Hz, 1 H), 6.62 (dd, J = 9.0, 2.8 Hz,
1 H), 7.39 (m, 1 H), 7.52 (m, 2 H), 7.64 (d, J = 9.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 12.4, 44.8, 97.4, 101.5, 106.5, 108.5,
124.8, 126.2, 129.3, 132.3, 142.2, 150.9, 153.5, 154.9, 160.6.
13C NMR (100 MHz, CDCl3): δ = 12.4, 44.6, 55.2, 93.2, 98.2, 104.6,
107.9, 125.8, 127.5, 127.5, 128.7, 136.3, 150.1, 156.8, 160.6, 163.5.
HRMS (CI): m/z calcd for
C
27H28N2O2 (M)+: 412.2145; found:
412.2161.
UV (DMSO): λmax (abs) 356 nm; λmax (em) = 418 nm.
HRMS (CI): m/z calcd for C19H17Cl2NO2S (M)+: 393.0357; found:
393.0357.
Anal. Calcd C27H28N2O2 (412.53): C, 78.61; H, 6.84; N, 6.79. Found: C,
78.99; H, 6.96; N, 6.69.
UV (DMSO): λmax (abs) = 385 nm; λmax (em) = 503 nm; ΦF = 0.63.
7-(N,N-Diethylamino)-4-{[(1R,2S)-1-hydroxy-1-phenylpropan-2-
yl]-N-methylamino}-2H-chromen-2-one (6e)
N-Acetyl-S-[7-(N,N-diethylamino)-2-oxo-2H-chromen-4-yl]-(R)-
cysteine (7b)
According to the general procedure for aminations, triflate 2 (73 mg,
0.20 mmol) was reacted with ephedrine (40 mg, 0.24 mmol) and Et3N
(55 μL, 40 mg, 0.4 mmol). After workup and column chromatography
(silica gel, CH2Cl2–EtOAc 9:1), 6e was isolated as a yellow solid; yield:
42 mg (0.11 mmol, 56%); mp 100–102 °C; Rf = 0.1 (CH2Cl2–MeOH
95:5).
1H NMR (400 MHz, CDCl3): δ = 1.19 (t, J = 7.1 Hz, 6 H), 1.51 (d, J = 6.7
Hz, 3 H), 2.44 (br s, 1 H), 2.82 (s, 3 H), 3.38 (q, J = 7.1 Hz, 4 H), 4.26 (dq,
J = 6.9, 6.7 Hz, 1 H), 4.75 (d, J = 6.9 Hz, 1 H), 4.91 (s, 1 H), 6.40 (d,
J = 2.6 Hz, 1 H), 6.44 (dd, J = 9.1, 2.6 Hz, 1 H), 7.14–7.25 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 12.4, 13.5, 33.4, 44.5, 61.9, 76.5, 90.5,
98.0, 104.6, 107.3, 126.1, 126.3, 128.4, 141.7, 149.8, 156.4, 161.5,
163.7.
HRMS (CI): m/z calcd for C23H29N2O3 (M + H)+: 381.2173; found:
381.2164.
Triflate 2 (73 mg, 0.20 mmol), N-acetyl-(R)-cysteine (98 mg, 0.60
mmol), and Et3N (55 μL, 40 mg, 0.4 mmol) were dissolved in a 7:3
H2O–1,4-dioxane mixture (1 mL) and the mixture was allowed to stir
overnight at r.t. The solution was adjusted to pH 3 with aq 1 N KHSO4
before it was extracted with CH2Cl2 (3 ×). The combined organic lay-
ers were dried (anhyd MgSO4), concentrated in vacuo, and purified by
flash chromatography (silica gel, CH2Cl2–MeOH–AcOH 94:5:1) to pro-
vide 7b as a colorless solid; yield: 60 mg (0.16 mmol, 80%); mp 106–
108 °C; Rf = 0.35 (CH2Cl2–MeOH–AcOH 91:8:1).
1H NMR (400 MHz, DMSO-d6): δ = 1.11 (t, J = 6.9 Hz, 6 H), 1.86 (s, 3 H),
3.30 (dd, J = 13.6, 8.5 Hz, 1 H), 3.41 (q, J = 6.8 Hz, 4 H), 3.52 (dd,
J = 13.4, 4.4 Hz, 1 H), 4.53 (m, 1 H), 5.95 (s, 1 H), 6.49 (d, J = 1.8 Hz, 1
H), 6.69 (dd, J = 9.0, 2.0 Hz, 1 H), 7.46 (d, J = 9.0 Hz, 1 H), 8.44 (d, J = 8.0
Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 12.3, 22.3, 31.4, 44.0, 50.9, 96.6,
100.3, 105.9, 108.7, 124.7, 150.7, 154.2, 155.1, 159.0, 169.6, 171.4.
UV (DMSO): λmax (abs) = 351 nm; λmax (em) = 410 nm.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

F
U. Kazmaier et al.
Paper
Synthesis
HRMS (CI): m/z calcd for C18H21N2O4S (M – OH)+: 361.1217; found:
361.1224.
(6) McFarland, J. M.; Francis, M. B. J. Am. Chem. Soc. 2005, 127,
13490.
(7) (a) Yee, D. Y.; Balsanek, V.; Sames, D. J. Am. Chem. Soc. 2004, 126,
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UV (DMSO): λmax (abs) = 382 nm; λmax (em) = 482 nm.
Acknowledgment
Financial support from the Deutsche Forschungsgemeinschaft is
gratefully acknowledged.
(8) Wirtz, L.; Auerbach, D.; Jung, G.; Kazmaier, U. Synthesis 2012,
44, 2005.
Supporting Information
(9) (a) Palomo, J. M. Org. Biomol. Chem. 2012, 10, 9309. (b) Tang, W.;
Becker, M. L. Chem. Soc. Rev. 2014, 43, 7013. (c) Karmann, L.;
Kazmaier, U. Eur. J. Org. Chem. 2013, 7101.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588159.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F