Synthesis of Fluorescent Amino Acids via Palladium-Catalyzed Allylic Alkylations

Article abstract of DOI:10.1055/s-0035-1561628

Coumarin-derived allylic carbonates are found to be suitable electrophiles for the synthesis of fluorescent amino acids via palladium-catalyzed allylic alkylation of chelated glycine enolates. The formation of regioisomers can be suppressed by proper choice of the allyl carbonate.

Full text of DOI:10.1055/s-0035-1561628

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2016, 48, A–J
A
paper
Synthesis
L. Schmidt et al.
Paper
Synthesis of Fluorescent Amino Acids via Palladium-Catalyzed
Allylic Alkylations
Lisa Schmidta
Tamara Doroshenkoa
Philipp Barbiea
Andreas Grüterb
TFAHN
COOt-Bu
OCOOEt
LHMDS
ZnCl2
THF, –78 °C
O
Gregor Jungb
Ot-Bu
Et2N
O
O
O
Uli Kazmaier*a
[allylPdCl] , Ph P
2
3
N
O
TFA
THF, −78 °C to r.t.
Zn
a
Universität des Saarlandes, Institut für Organische Chemie,
72%
NEt2
6
6123 Saarbrücken, Germany
b
TFAHN
COOt-Bu
Universität des Saarlandes, Biophysikalische Chemie,
6123 Saarbrücken, Germany
6
+
7 other examples
u.kazmaier@mx.uni-saarland.de
Received: 11.02.2016
Accepted after revision: 06.04.2016
Published online: 19.05.2016
ing different regio- and stereoselectivities. Overall, excel-
lent yields are obtained and the allylic alkylation can also
be used for the highly stereoselective alkylation of pep-
tides.16
DOI: 10.1055/s-0035-1561628; Art ID: ss-2016-t0104-op
Abstract Coumarin-derived allylic carbonates are found to be suitable
electrophiles for the synthesis of fluorescent amino acids via palladium-
catalyzed allylic alkylation of chelated glycine enolates. The formation
of regioisomers can be suppressed by proper choice of the allyl carbon-
ate.
O
O
O
O
N
H
N
COOMe
+
BocHN
Key words allylation, amino acids, chelates, coumarins, fluorescence
labeling, palladium
N3
O
O
Fluorescence microscopy is an important and powerful
N
N
tool in the life sciences since it allows a three-dimensional
N
CuSO4 (10 mol%)
Na ascorbate (10 mol%)
1
N
imaging in living cells. A wide range of fluorescence dyes
O
2
can be used for the labeling, for example, of proteins. Cou-
DMSO–H2O, 80 °C, 16 h
H
N
COOMe
84%
marins play an important role, especially those having elec-
tron-donating groups in 7-position, because of their excel-
BocHN
O
3
lent fluorescence quantum yield. They were found to be
ideal candidates for the development of fluorescence la-
Scheme 1 Fluorescence labeling of peptides via click reaction
4
bels. In general, those labels are coupled to functionalized
5
6
7
amino acids such as lysines, cysteines, or tyrosines. Alter-
natively, those amino acids can also be modified by incor-
poration of either an alkyne or an azide moiety, allowing
the introduction of the fluorescence label via click chemis-
Therefore, we were interested to see, if, for example, the
Pd-catalyzed allylic alkylation might also be suitable for the
incorporation of fluorescence dyes into amino acids. Here-
in, we describe the synthesis of a wide range of different
fluorescence labelled allylic substrates and their reaction
with chelated glycine ester enolates.
We started our investigations with 7-methoxy-substi-
tuted coumarins, since these are easily available. The 4-
methyl derivative 1 can be obtained from resorcin via Pech-
8
try. Since our group is involved in the synthesis of peptidic
9
natural products, we also developed a protocol for peptide
labeling using the Huisgen–Meldal–Sharpless [3+2] cyc-
loaddition, and ‘clickable’ aminocoumarins (Scheme 1).8b
Another focus of our group is the development of new syn-
thetic protocols for the synthesis of unusual amino acids via
reaction of chelated amino acid ester enolates.11 These
highly reactive enolates can be used as nucleophiles, for ex-
10
17
mann condensation and subsequent O-methylation. Oxi-
dation with selenious acid provided 4-formylcoumarin 2 in
good yield (Scheme 2). Compound 2 was used for the syn-
thesis of two different allylic substrates. On the one hand,
vinyl-Grignard addition furnished an allyl alcohol, which
12
ample, in Michael additions or in transition-metal-cata-
13
lyzed reactions. Besides the commonly used Pd-catalyzed
14
15
version, also Ru and Rh catalysts can be applied, show-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

B
Synthesis
L. Schmidt et al.
Paper
was directly acylated to allyl carbonate 3. On the other
hand, 2 was also subjected to a Wittig olefination giving ac-
cess to vinyl ketone 4, which was reduced according to the
Luche protocol. The secondary alcohol 5 was also converted
into the corresponding carbonate 6.
TiCl(Oi-Pr)3
+
N
OH
O
toluene
10 °C, 16 h
N
O
O
1
COOMe
85%
7
8
CHO
H2SeO3 (1.4 equiv)
CHO
O
1
. NMO, OsO4 (5 mol%)
THF–H2O, 60 °C, 3 h
xylene, 140 °C, 20 h
, THF
MgBr
MeO
O
O
85%
MeO
O
O
1
2
2
. Pb(OAc)4, CH2Cl2
°C, 10 min
0%
–78 °C to r.t., 3 h
54%
N
O
0
7
9
1.
MgBr
EtOOCO
(
1.1 equiv)
THF, –78 °C to r.t., 3 h
2
. ClCOOEt (2 equiv)
pyridine, 0 °C to r.t., 16 h
2%
MeO
O
O
OH
O
ClCOOEt
pyridine
OCOOEt
4
3
N
O
0 °C to r.t., 16 h
N
O
O
85%
O
O
10
11
Ph3P
CeCl3•7H2O, NaBH4
2
Scheme 3 Synthesis of 8-hydroxyjulodine-derived allyl carbonate 11
THF, 65 °C, 23 h
6%
MeOH, r.t., 5 min
(quant)
9
MeO
O
O
malonate to the 4-hydroxycoumarin 13, which was con-
verted into triflate 14 in high yield. To get an allylic sub-
strate with the dye directly substituted at the allyl moiety,
4
HO
EtOOCO
1
4 was subjected to a Stille coupling with vinylstannane to
ClCOOEt
pyridine
give 4-vinylcoumarin 15 in almost quantitative yield. Oxi-
dative cleavage of the double bond provided aldehyde 16,
which was converted into the carbonate 17 as described be-
fore. It should be mentioned that we failed to get aldehyde
0
°C to r.t.
7
3% (2 steps)
MeO
O
O
MeO
O
O
5
6
16 directly from the triflate via Pd-catalyzed carbonylation.
Scheme 2 Synthesis of 7-methoxycoumarin-derived allyl carbonates
OH
During our synthesis of clickable fluorescence labels8b
we developed a mild version of the Pechmann condensa-
tion, which was also suitable for the sensitive 8-hydroxyju-
lodine (7) (Scheme 3). We used this approach also for the
synthesis of allylic carbonate 11 containing this amino
functionalized coumarin dye. Compound 7 was refluxed in
toluene with methyl-3-oxo-6-heptenoate in the presence of
ClTi(Oi-Pr)3 affording the coumarin derivative 8 in high
yield. The terminal double bond was subjected to dihydrox-
ylation followed by an oxidative cleavage. The aldehyde 10
obtained was also subjected to a vinyl-Grignard addition
and acylation as described before.
COOAr
toluene
+
Et2N
OH
COOAr
110 °C, 16 h
70%
Et2N
O
O
1
2
Ar = 2,4,6-Cl3C6H2
13
OTf
O
SnBu3
(CF3SO2)2O
[allylPdCl]2, Ph3P
CH2Cl2, Et3N
THF, 60 °C, 2 h
95%
–20 °C, 2 h
Et2N
O
96%
14
O
OsO4, NaIO4
1
,4-dioxane–H2O, r.t., 2 h
Although 8-hydroxyjulodine (7) is commercially avail-
able, it is rather an expensive compound. Therefore, we
tried to replace it by 3-diethylaminophenol (12). Surpris-
ingly, the modified Pechmann condensation, which worked
perfect in the case of 7 failed almost completely with the
diethylamino phenol 12. Therefore, we had to develop an
independent synthetic route (Scheme 4). According to liter-
Et2N
O
O
65%
Et N
O
O
2
15
16
EtOOCO
1.
MgBr, THF
–78 °C to r.t., 2 h
2
. ClCOOEt, pyridine
°C to r.t., 16 h
7%
0
Et2N
O
O
5
17
18
ature,
12 was reacted with bis-2,4,6-trichlorophenol
Scheme 4 Synthesis of 7-diethylamino-derived allyl carbonate 17
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

C
Synthesis
L. Schmidt et al.
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To incorporate a spacer between the dye and the allyl
fragment, and to get substrates analogous to 11, 14 was
subjected to a Sonogashira coupling with propargyl alcohol,
which provided alcohol 18 in almost quantitative yield
X
O
O
TFAHN
COOt-Bu
(Scheme 5). Hydrogenation of the triple bond and Dess–
3, 17
Martin oxidation afforded the aldehyde 19, which was con-
verted into carbonate 20 as described. To introduce an even
larger spacer, triflate 14 was also subjected to a Sonogashi-
ra coupling with butenediol-derived alkyne 21. Subsequent
acylation provided carbonate 22 in overall good yield.
LHMDS
ZnCl2
THF, –78 °C
TFAHN
COOt-Bu
Ot-Bu
[allylPdCl]2
Ph3P, THF
23 X = OMe 68%
24 X = NEt2 72%
N
O
TFA
–78 °C to r.t.
Zn
OMe
OH
A
OH
1. H2, Pd/C
Pd(PPh3)4, CuI
MeOH, r.t., 16 h
O
6
14
Et3N, THF, r.t., 2 h
2. DMP, CH2Cl2
r.t., 2 h
O
80%
76%
Et2N
O
O
*
*
18
TFAHN
COOt-Bu
25
EtOOCO
63% dr 2:1
CHO
1
.
–
MgBr, THF
78 °C to r.t., 2 h
Scheme 6 Allylic alkylations using carbonates 3, 6, and 17
2
. ClCOOEt, pyridine
°C to r.t., 16 h
5%
0
such terminal allyl complexes. Instead, a 6:4 mixture of lin-
ear and branched products 26a and 26b was obtained in
the case of 11 (80% yield). The regioselectivity in the case of
Et2N
O
O
5
Et2N
O
O
19
20
2
0 was 6:1 (27a:27b), while the yield was the same. Also,
1
.
the diastereoselectivities of the branched products b were
in the same range as the results obtained with the second-
ary carbonate 6.
O
HO
O
21
Pd(PPh3)4, CuI, Et3N
THF, r.t., 2 h
OCOOEt
14
2
. ClCOOEt, pyridine
°C to r.t., 16 h
9%
O
0
6
O
Et2N
O
O
R1
22
Scheme 5 Synthesis of 7-diethylamino-derived allyl carbonates via So-
nogashira coupling
R2N
R1
TFAHN
COOt-Bu
With those allylic substrates in hand, we next investi-
gated allylic alkylations of chelated glycine ester enolate A
to get access to fluorescence labeled amino acids (Scheme
11, 20
[allylPdCl]2
Ph3P, THF
6a R = R1 = -(CH2)3-
7a R = Et, R = H
2
2
Ot-Bu
1
+
O
N
O
TFA
–78 °C to r.t.
Zn
6). With the allylic substrates 3 and 17 bearing the dye di-
80%
O
A
rectly at the allyl moiety only one regioisomer 23 and 24
was obtained, respectively, resulting from an attack of the
enolate at the sterically least hindered position. The double
bond was in conjugation to the coumarin and was formed
as the E-isomer exclusively. The same regioselectivity was
also observed in the allylation using secondary carbonate 6.
In this case also, the product 25 with the trans double bond
was obtained as a 2:1 diastereomeric mixture.
R1
NR2
*
*
R1
TFAHN
COOt-Bu
2
6b dr 7:3
27b dr 2:1
Scheme 7 Allylic alkylations using carbonates 11 and 20
An interesting observation was made in reactions using
the substrates with the ‘short spacer’ between the dye and
the allyl moiety (Scheme 7). In the case of the terminal allyl
carbonates 11 and 20, we expected to get also the linear al-
lylation products with high preference, which is typical for
The moderate regioselectivity was the reason why we
also investigated allylations of substrates with the larger
spacer bearing an oxygen between the dye and the allyl
moiety 22. In general, such oxygen-substituted allylic sub-
strates react under Pd-catalyzed conditions preferentially at
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

D
Synthesis
L. Schmidt et al.
Paper
the allylic position distal to the O-functionality.19 Indeed,
with this substrate only the linear product 28 was obtained
as a 7:3 E/Z-mixture (Scheme 8).
by flash chromatography on silica gel columns (Macherey-Nagel 60,
0
.063–0.2 mm) and with a flash chromatography system [Reveleris
Grace), RediSep-columns 4 g, 12 g, 24 g, and 40 g from Axel Semrau].
Mixtures of EtOAc, PE, or CH Cl and MeOH were generally used as
(
2
2
eluents. Analytical TLC was performed on precoated silica gel plates
Et2N
(Macherey-Nagel, Polygram® SIL G/UV254). Visualization was accom-
2
2
O
Ot-Bu
[allylPdCl]2
Ph3P, THF
plished with UV light, aq KMnO , or ninhydrin solution. Melting
4
points were determined with a Dr. Tottoli (Büchi) melting point appa-
O
N
O
TFA
–78 °C to r.t.
1
13
Zn
ratus and are uncorrected. H and C NMR spectra were recorded
69%
O
1
13
A
with a Bruker AC-400 [400 MHz ( H) and 100 MHz ( C)] spectrome-
TFAHN
COOt-Bu
ter in CDCl . Chemical shifts are reported in ppm relative to TMS;
3
28
CHCl3 was used as the internal standard. Diastereomeric ratios were
determined by NMR spectroscopy. Mass spectra were recorded with a
Finnigan MAT 95 spectrometer using the CI technique. A Jasco V-650
spectrophotometer was used to measure the absorptions spectra,
while a Jasco FP-6500 was used for the fluorescence spectra. Elemen-
tal analyses were performed at Saarland University.
Scheme 8 Allylic alkylation using carbonate 22
The formation of E/Z-mixture is a little surprising, since
in most cases the E-isomers are formed with high prefer-
ence, but it is not a serious issue, because the double bond
can easily be removed by catalytic hydrogenation, as illus-
trated with the hydrogenation of 24 (Scheme 9). Closely re-
lated coumarin-substituted amino acids have been report-
ed by Schultz et al. as genetically encoded fluorescent ami-
7
-Methoxy-2-oxo-2H-chromene-4-carbaldehyde (2)17
Selenious acid (1.47 g, 11.4 mmol) was added to a solution of 7-me-
thoxy-4-methylcoumarin (1; 1.61 g, 8.46 mmol) in xylene (22 mL).
The reaction mixture was refluxed for 20 h and filtered hot. On cool-
ing, yellow crystals precipitated, which were separated and dried;
20
no acids.
yield: 1.47 g (7.19 mmol, 85%); yellow crystals; mp 193–195 °C; R =
f
0
.55 (PE–EtOAc, 1:1).
NEt2
NEt2
1
H NMR (400 MHz, CDCl ): δ = 3.89 (s, 3 H), 6.71 (s, 1 H), 6.89 (d, J =
3
2.6 Hz, 2 H), 6.92 (dd, J = 9.0, 2.6 Hz, 1 H), 8.49 (d, J = 9.0 Hz, 1 H),
1
0.07 (s, 1 H).
O
H2, Pd/C
O
13
C NMR (100 MHz, CDCl ): δ = 55.8, 101.1, 112.2, 113.3, 127.4, 143.8,
3
O
MeOH, r.t., 2 h
O
156.5, 160.8, 163.4, 166.4, 191.8.
60%
Ethyl [1-(7-Methoxy-2-oxo-2H-chromen-4-yl)allylcarbonate (3)
TFAHN
COOt-Bu
TFAHN
COOt-Bu
Aldehyde 2 (613 mg, 3.00 mmol) was dissolved in THF (55 mL) and
24
24'
was cooled to –20 °C before vinylmagnesium bromide (1 M, 3.6 mL,
Scheme 9 Catalytic hydrogenation of 24
3.6 mmol) in THF was added. The cooling bath was removed and the
mixture was allowed to warm to r.t.. After stirring for 3 h, the solution
was diluted with CH Cl (50 mL) and hydrolyzed with aq 1 M NH Cl
2
2
4
In conclusion, we could show that the Pd-catalyzed al-
lylic alkylation is a powerful tool for the introduction of
coumarin fluorescence labels into amino acids. Although
terminal allylic carbonates give mixtures of linear and
branched allylation products, this problem can be solved by
either removing the spacer between the dye and the allyl
moiety, or by introducing an oxygen into the spacer. In this
case, the linear allylation products are formed preferential-
ly. So far, the fluorescent amino acids are formed as racemic
mixtures. For a stereoselective protocol one might use ei-
ther chiral glycine esters, or chiral peptides as nucleophiles.
In this case, the stereochemical outcome of the allylic al-
kylation can nicely be controlled by the stereogenic centers
(
20 mL) at 0 °C. The aqueous layer was extracted with CH Cl (2 ×), the
2 2
organic layers were dried (Na SO ), and the solvent was evaporated in
2
4
vacuo. The crude allyl alcohol was dissolved in anhyd pyridine (3 mL)
and ethyl chloroformate (0.6 mL, 1.95 g, 6.00 mmol) was added at 0
°
C. The reaction mixture was allowed to warm to r.t. overnight, before
it was diluted with CH Cl (20 mL). The organic layer was washed
2
2
with aq 1 N CuSO to remove the excess pyridine and dried (Na SO ).
4
2
4
The solvent was removed in vacuo and the crude product was puri-
fied by flash chromatography (PE–EtOAc, 9:1 to EtOAc); yield: 3.83 g
(
1.26 mmol, 42%); yellow oil; R = 0.24 (PE–EtOAc, 7:3).
f
1
H NMR (400 MHz, CDCl ): δ = 1.33 (t, J = 7.1 Hz, 3 H), 3.87 (s, 3 H),
3
4.23 (q, J = 7.1 Hz, 2 H), 5.42 (dd, J = 10.2, 0.7 Hz, 1 H), 5.36 (dd, J =
17.2, 0.7 Hz, 1 H), 5.89 (m, 1 H), 6.28 (m, 1 H), 6.41 (s, 1 H), 6.81–6.88
(m, 2 H), 7.55 (d, J = 9.2 Hz, 1 H).
16
13
of the peptide chain. Applications to the fluorescence la-
beling of peptides and natural products are currently under
investigation.
C NMR (100 MHz, CDCl ): δ = 14.2, 55.8, 64.8, 74.9, 101.2, 110.3,
3
112.6, 112.7, 120.8, 125.6, 132.7, 151.6, 154.0, 155.9, 160.9, 162.8.
+
HRMS (CI): m/z (M) calcd for C16H16O : 304.0941; found: 304.0970.
6
(E)-7-Methoxy-4-(3-oxobut-1-en-1-yl)-2H-chromen-2-one (4)
All air- and moisture-sensitive reactions were carried out in dried
Aldehyde 2 (163 mg, 0.8 mmol) was added to a suspension of 1-triph-
enylphosphanylidene-2-propenone (261 mg, 0.82 mmol) in THF (50
mL) and the reaction mixture was refluxed for 23 h. After cooling to
glassware (>100 °C) under an atmosphere of N or argon. Anhyd sol-
2
vents were distilled before use: THF was distilled from LiAlH , CH Cl
4
2
2
was dried with CaH2 before distillation. The products were purified
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

E
Synthesis
L. Schmidt et al.
Paper
r.t. and removal of the solvent, the crude product was purified by
flash chromatography (PE–EtOAc, 9:1 to EtOAc); yield: 187 mg (0.77
was purified by flash chromatography (hexanes–EtOAc, 7:3); yield:
2.60 g (8.80 mmol, 85%); ochre solid; mp 99–101 °C; R = 0.52 (hex-
f
mmol, 96%); yellow solid; mp 135–138 °C; R = 0.14 (PE–EtOAc, 7:3).
anes–EtOAc, 1:1).
f
1
1
H NMR (400 MHz, CDCl ): δ = 2.44 (s, 3 H), 3.89 (s, 3 H), 6.40 (s, 1 H),
H NMR (400 MHz, CDCl ): δ = 1.94–2.00 (m, 4 H), 2.41 (m, 2 H), 2.71–
3
3
6
7
.81 (d, J = 15.9 Hz, 1 H), 6.86–6.89 (m, 2 H), 7.58 (d, J = 8.9 Hz, 1 H),
.72 (d, J = 15.9 Hz, 1 H).
2.79 (m, 4 H), 2.88 (t, J = 6.5 Hz, 2 H), 3.22–3.27 (m, 4 H), 5.07 (m, 2 H),
5.82–5.92 (m, 2 H), 6.99 (s, 1 H).
13
13
C NMR (100 MHz, CDCl ): δ = 28.8, 55.8, 101.4, 110.1, 112.7, 112.8,
C NMR (100 MHz, CDCl ): δ = 20.5, 20.7, 21.6, 27.8, 31.0, 32.5, 49.5,
3
3
1
25.4, 133.7, 134.9, 152.9, 155.7, 160.8, 163.2, 196.7.
49.9, 107.0, 107.2, 108.0, 115.8, 117.9, 121.3, 136.9, 145.7, 151.3,
156.0, 162.6.
+
HRMS (CI): m/z (M) calcd for C14H12O : 244.0730; found: 244.0766.
4
UV (DMSO): λmax (abs) = 393 nm; λmax (em) = 455 nm.
Anal. Calcd for C14H12O (244.07): C, 68.85; H, 4.95; found: C, 68.95; H,
4
5.01.
Anal. Calcd for C19H21NO (295.38): C, 77.26; H, 7.17; N, 4.74. Found:
2
C, 77.02; H, 7.29; N, 4.57.
(E)-4-(3-Hydroxybut-1-en-1-yl)-7-methoxy-2H-chromen-2-one
(
5)
3-(11-Oxo-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyri-
do[3,2,1-ij]quinolin-9-yl)propanal (9)
Unsaturated ketone 4 (184 mg, 0.75 mmol) was dissolved in MeOH (2
mL) and CeCl ·7H O (279 mg, 0.75 mmol) was added. During a period
Alkene 8 (331 mg, 1.12 mmol) was dissolved in a 2:1 mixture of THF
3
2
of 5 min, NaBH (28 mg, 0.75 mmol) was added and after stirring for
and H O (45 mL) and NMO (211 mg, 1.80 mmol) and OsO (15 mg, 60
4
2
4
an additional 5 min at r.t., aq 1 N KHSO (3 mL) was added. The aque-
μmol) were added. The solution was stirred at 60 °C for 3 h. After
4
ous layer was extracted with CH Cl (2 ×). The combined organic lay-
cooling to r.t., NaHSO3 (500 mg) and sat. aq NaHCO3 (10 mL) were
2
2
ers were washed with H O and brine, and dried (Na SO ); yield: 185
added. The mixture was extracted with Et O (2 ×) and the combined
2
2
4
2
mg (0.75 mmol, 100%); R = 0.16 (PE–EtOAc, 1:1).
organic layers were dried (Na SO ) and evaporated in vacuo. The
f
2
4
1
crude diol (396 mg, 1.12 mmol) was directly subjected to the subse-
H NMR (400 MHz, CDCl ): δ = 1.41 (d, J = 6.5 Hz, 3 H), 1.88 (br s, 1 H,
3
2
quent oxidative cleavage as follows. The diol was dissolved in CH Cl2
OH), 3.87 (s, 3 H), 4.52 (qd, J = 6.5, 6.5 Hz, 1 H), 6.21 (s, 1 H), 6.43 (dd,
J = 15.6, 6.5 Hz, 1 H), 6.70–6.83 (m, 3 H), 7.56 (d, J = 8.8 Hz, 1 H).
(
90 mL) and the solution was cooled to 0 °C before Pb(OAc) (497 mg,
4
1
.12 mmol) was added. After 15 min, H O (30 mL) was added, and the
2
13
C NMR (100 MHz, CDCl ): δ = 28.3, 55.8, 68.0, 101.1, 107.9, 112.3,
3
organic layer was washed with aq 10% K CO and dried (MgSO ). After
2
3
4
1
12.4, 121.5, 128.5, 132.0, 150.5, 155.6, 161.6, 162.8.
evaporation in vacuo the crude product was purified by flash chro-
matography (CH Cl –EtOAc, 98:2); yield: 234 mg (0.78 mmol, 70%);
+
HRMS (CI): m/z (M) calcd for C14H14O : 246.0886; found: 246.0861.
4
2
2
yellow solid; mp 146–149 °C; R = 0.08 (CH Cl –EtOAc, 98:2).
The crude allyl alcohol 5 was directly used in the next step to form
the carbonate 6.
f
2
2
1
H NMR (400 MHz, CDCl ): δ = 1.96–2.00 (m, 4 H), 2.77 (t, J = 6.3 Hz, 2
3
H), 2.83–2.90 (m, 4 H), 2.98 (t, J = 6.5 Hz, 2 H), 3.23–3.28 (m, 4 H), 5.88
Ethyl (E)-[4-(7-Methoxy-2-oxo-2H-chromen-4-yl)but-3-en-2-
(s, 1 H), 6.97 (s, 1 H), 9.87 (br s, 1 H).
yl]carbonate (6)
13
C NMR (100 MHz, CDCl ): δ = 20.5, 20.6, 21.5, 23.6, 27.8, 42.3, 49.5,
3
According to the preparation of 3, the crude alcohol 5 (185 mg, 0.75
mmol) was reacted with ethyl chloroformate (0.14 mL, 163 mg, 1.5
mmol) in pyridine (0.75 mL) to give 6; yield: 175 mg (0.55 mmol,
49.9, 107.0, 107.1, 107.6, 118.1, 121.0, 145.9, 151.3, 154.7, 162.3,
199.9 (d).
+
HRMS (CI): m/z (M) calcd for C18H19NO : 297.1365; found: 297.1398.
3
7
3%); yellow solid; mp 76–77 °C; R = 0.26 (PE–EtOAc, 7:3).
f
UV (DMSO): λmax (abs) = 393 nm; λmax (em) = 456 nm.
1
H NMR (400 MHz, CDCl ): δ = 1.34 (t, J = 7.1 Hz, 3 H), 1.50 (d, J = 6.7
3
Anal. Calcd for C18H19NO (297.35): C, 72.71; H, 6.44; N, 4.71. Found:
3
Hz, 3 H), 3.88 (s, 3 H), 4.23 (q, J = 7.1 Hz, 2 H), 5.42 (qd, J = 6.5, 6.5 Hz,
C, 72.84; H, 6.68; N, 4.58.
1
7
H), 6.28 (s, 1 H), 6.39 (dd, J = 15.7, 6.5 Hz, 1 H), 6.83–6.90 (m, 3 H),
.56 (d, J = 8.8 Hz, 1 H).
9-(3-Hydroxypent-4-en-1-yl)-2,3,6,7-tetrahydro-1H,5H,11H-pyra-
13
C NMR (100 MHz, CDCl ): δ = 14.2, 20.2, 55.8, 64.2, 73.7, 101.1,
3
no[2,3-f]pyrido[3,2,1-ij]quinolin-11-one (10)
108.9, 112.2, 112.3, 124.5, 125.6, 137.4, 143.0, 149.9, 155.6, 161.3,
Aldehyde 9 (500 mg, 1.68 mmol) was reacted according to the prepa-
ration of 3 with 1 M vinylmagnesium bromide (2.0 mL, 2.0 mmol) in
THF (20 mL). Flash chromatography (CH Cl –EtOAc, 98:2) provided
162.8.
+
HRMS (CI): m/z (M) calcd for C17H18O : 318.1103; found: 318.1132.
6
2
2
1
=
1
0; yield: 302 mg (0.89 mmol, 54%); yellow solid; mp 104–106 °C; Rf
0.23 (PE–EtOAc, 1:1);
9
-(But-3-en-1-yl)-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyr-
ido[3,2,1-ij]quinolin-11-one (8)
H NMR (400 MHz, CDCl ): δ = 1.87 (m, 2 H), 1.94–2.00 (m, 5 H), 2.70–
3
To a suspension of 8-hydroxyjulodine (7; 1.95 g, 10.3 mmol) and
methyl-3-oxo-6-heptenate (1.63 g, 10.3 mmol) in toluene (30 mL)
was added ClTi(Oi-Pr) (1 M in hexane, 20 mL, 20 mmol). The mixture
was refluxed overnight. After cooling to r.t., the mixture was diluted
with CH Cl and sat. aq Na/K-tartrate solution was added. Stirring
2.84 (m, 4 H), 2.89 (t, J = 6.5 Hz, 2 H), 3.22–3.27 (m, 4 H), 4.22 (m, 1 H),
5.18 (ddd, J = 10.4, 1.2, 1.2 Hz, 1 H), 5.29 (ddd, J = 17.2, 1.2, 1.2 Hz, 1
3
H), 5.88–5.96 (m, 2 H), 7.04 (s, 1 H).
13
C NMR (100 MHz, CDCl ): δ = 20.5, 20.7, 21.6, 27.4, 27.8, 35.6, 49.5,
3
2
2
49.9, 72.3, 107.0, 107.1, 108.0, 115.5, 118.0, 121.5, 140.5, 145.7, 151.3,
was continued until the layers separated and the aqueous layer was
extracted with CH Cl (2 ×). The combined organic layers were dried
156.6, 162.7.
2
2
+
(Na SO ) and after removal of the solvent in vacuo, the crude product
HRMS (CI): m/z (M) calcd for C20
H
23NO
3
: 325.1672; found: 325.1680.
2
4
UV (DMSO): λmax (abs) = 392 nm; λmax (em) = 454 nm.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

F
Synthesis
L. Schmidt et al.
Paper
1
Ethyl [5-(11-Oxo-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyri-
do[3,2,1-ij]quinolin-9-yl)pent-1-en-3-yl]carbonate (11)
H NMR (400 MHz, CDCl ): δ = 1.21 (t, J = 7.1 Hz, 6 H), 3.41 (q, J = 7.1
3
Hz, 4 H), 5.63 (dd, J = 11.0, 1.0 Hz, 1 H), 5.94 (dd, J = 17.3, 1.0 Hz, 1 H),
.12 (s, 1 H), 6.52 (d, J = 2.6 Hz, 1 H), 6.58 (dd, J = 9.0, 2.6 Hz, 1 H), 6.93
6
According to the preparation of 3, allyl alcohol 10 (3.05 g, 9.0 mmol)
was reacted with ethyl chloroformate (1.7 mL, 1.95 g, 18.0 mmol) in
pyridine (9 mL). Flash chromatography (hexanes–EtOAc, 7:3) afforded
(dd, J = 17.4, 11.0 Hz, 1 H), 7.45 (d, J = 9.0 Hz, 1 H).
13
C NMR (100 MHz, CDCl ): δ = 12.5 (2 q), 44.8 (2 t), 97.2, 104.7, 108.5,
3
1
0
1
1; yield: 3.04 g (7.65 mmol, 85%); yellow solid, mp 89–93 °C; R =
.16 (PE–EtOAc, 7:3).
110.0, 115.8, 130.8, 150.6, 151.1, 153.2, 156.5, 162.5.
f
UV (DMSO): λmax (abs) = 372 nm; λmax (em) = 422 nm.
H NMR (400 MHz, CDCl ): δ = 1.31 (t, J = 7.1 Hz, 3 H), 1.91–2.06 (m, 6
+
3
HRMS (CI): m/z (M) calcd for C15H17NO : 243.1254; found: 243.1263.
2
H), 2.68–2.78 (m, 4 H), 2.85 (t, J = 6.5 Hz, 2 H), 3.21–3.26 (m, 4 H), 4.20
(
1
(
1
q, J = 7.1 Hz, 2 H), 5.15 (ddd, J = 12.7, 12.7, 6.5 Hz, 1 H), 5.28 (ddd, J =
0.5, 1.1, 1.1 Hz, 1 H), 5.36 (ddd, J = 17.3, 1.1, 1.1 Hz, 1 H), 5.80–5.88
m, 2 H), 6.96 (s, 1 H).
7
-(Diethylamino)-2-oxo-2H-chromene-4-carbaldehyde (16)23
To a solution of alkene 15 (300 mg, 1.2 mmol) in a mixture of H O (1.5
mL) and 1,4-dioxane (1.6 mL) was added OsO (6 μL 2.5 wt% solution
in n-hexane, 1.68 mg, 6.6 μmol, 0.55 mol%). The reaction mixture was
stirred for 5 min. During this period the mixture became dark orange
2
3
4
C NMR (100 MHz, CDCl ): δ = 14.2, 20.4, 20.6, 21.5, 27.0, 27.7, 33.0,
3
4
1
9.4, 49.8, 64.0, 77.8, 106.9, 107.0, 107.7, 118.0, 118.2, 121.2, 135.2,
45.7, 151.3, 154.4, 155.6, 162.4.
(due to osmate ester formation). While maintaining the temperature
+
HRMS (CI): m/z (M) calcd for C 3H NO : 397.1883; found: 397.1905.
2
27
5
of the stirred mixture at 24–26 °C, finely powdered NaIO4 (513 mg,
2.4 mmol) was added in portions over a period of 30 min. The slurry
was stirred for an additional 1.5 h. The mixture (now pale yellow)
was extracted thoroughly with Et O and the combined organic layers
were filtered through Celite, dried (Na SO ), and the solvent was
UV (DMSO): λmax (abs) = 396 nm; λmax (em) = 456 nm.
Anal. Calcd for C23H27NO (397.46): C, 69.50; H, 6.85; N, 3.52. Found: C,
6
5
2
9.60; H, 6.84; N, 3.40.
2
4
evaporated in vacuo. The crude product was purified by column chro-
matography (silica gel, PE–EtOAc, 7:3); yield: 190 mg (0.78 mmol,
7
-(Diethylamino)-2-oxo-2H-chromen-4-yl Trifluoromethanesul-
21
fonate (14)
6
5%); red solid; mp 78–80 °C; R = 0.20 (PE–EtOAc, 6:4).
f
Under a N2 atmosphere, 4-hydroxycoumarin 1322 (3.2 g, 13.8 mmol)
was dissolved in anhyd CH Cl (70 mL) and Et N (3.8 mL, 27.6 mmol)
1
H NMR (400 MHz, CDCl ): δ = 1.22 (t, J = 7.1 Hz, 6 H), 3.43 (q, J = 7.1
3
2
2
3
Hz, 4 H), 6.45 (s, 1 H), 6.52 (d, J = 2.6 Hz, 1 H), 6.63 (dd, J = 9.2, 2.6 Hz,
was added. The solution was cooled to –20 °C, and treated dropwise
with triflic anhydride (5.0 mL, 5.0 g, 18 mmol). The resulting mixture
was stirred for additional 2 h, and then passed through a pad of silica
gel, which was washed with EtOAc–hexane (1:30). The filtrate was
concentrated in vacuo. The crude product was purified by column
chromatography (silica gel, CH Cl ); yield: 4.8 g (13.2 mmol, 96%);
1
H), 8.30 (d, J = 9.2 Hz, 1 H), 10.03 (s, 1 H).
13
C NMR (100 MHz, CDCl ): δ = 12.4 (2 q), 44.8 (2 t), 97.6, 109.5, 117.3,
3
127.0, 127.1, 143.9, 151.0, 157.4, 161.9, 192.5.
+
HRMS (CI): m/z (M) calcd for C14H15NO : 245.1045; found: 245.1050.
3
2
2
UV (DMSO): λmax (abs) = 441 nm; λmax (em) = 432 nm.
yellow solid; mp 77–79 °C; R = 0.15 (CH Cl –EtOAc, 98:2).
f
2
2
1
H NMR (400 MHz, CDCl ): δ = 1.22 (t, J = 7.1 Hz, 6 H), 3.43 (q, J = 7.1
3
1-[7-(Diethylamino)-2-oxo-2H-chromen-4-yl]allyl Ethyl Carbon-
ate (17)
Hz, 4 H), 6.05 (s, 1 H), 6.51 (d, J = 2.4 Hz, 1 H), 6.64 (dd, J = 9.1, 2.5 Hz,
H), 7.42 (d, J = 9.1 Hz, 1 H).
1
According to the preparation of 3, aldehyde 16 (1.0 g, 4.3 mmol) was
dissolved in THF (45 mL) and 1 M vinylmagnesium bromide solution
in THF (5.72 mL, 5.72 mmol) was slowly added at –20 °C and the reac-
tion mixture was stirred for 3 h. After work up, the crude product was
13
C NMR (100 MHz, CDCl ): δ = 12.3 (2 q), 45.0 (2 t), 97.4, 98.5 (s)
3
1
02.0, 109.4, 116.9 (s) 123.5, 152.1, 156.3, 158.1, 161.3.
HRMS (CI): m/z (M)+ calcd for C14H14F NO S: 365.0538; found:
3
5
365.0531.
dissolved in CH Cl (10 mL) and pyridine (5 mL) and treated with eth-
2 2
yl chloroformate (1 mL, 8.6 mmol) at 0 °C. The reaction mixture was
allowed to warm to r.t. overnight. Workup and column chromatogra-
phy (silica gel, PE–EtOAc, 7:3) provided 17; yield; 848 mg (2.5 mmol,
UV (DMSO): λmax (abs) = 351 nm; λmax (em) = 384 nm.
Anal. Calcd for C14H14F NO S (365.3249): C, 46.03; H, 3.86; N, 3.83.
3
5
Found: C, 46.30; H, 3.69, N, 3.88.
5
7%); yellow oil; R = 0.38 (PE–EtOAc, 7:3);
f
1
H NMR (400 MHz, CDCl ): δ = 1.13 (t, J = 7.1 Hz, 6 H), 1.26 (t, J = 7.1
3
7
-(Diethylamino)-4-vinyl-2H-chromen-2-one (15)
Hz, 3 H), 3.34 (q, J = 7.1 Hz, 4 H), 4.16 (q, J = 7.1 Hz, 2 H), 5.32 (d, J =
10.4 Hz, 1 H), 5.42 (d, J = 17.2 Hz, 1 H), 5.95 (ddd, J = 16.7, 10.4, 6.1 Hz,
[AllylPdCl] (5.4 mg 15 μmol, 0.5 mol%) and PPh (7.9 mg 30 μmol, 1
2
3
mol%) were dissolved in anhyd THF (10 mL) and the solution was
stirred for 15 min at r.t., before it was added to a solution of tributyl-
vinylstannane (0.9 mL, 813 mg, 2.5 mmol) and triflate 14 (1 g, 3
mmol) in THF (20 mL) at 60 °C. The reaction mixture was refluxed for
1
H), 6.12 (s, 1 H), 6.18 (d, J = 6.1 Hz, 1 H), 6.44 (d, J = 2.5 Hz, 1 H), 6.50
(dd, J = 9.1, 2.6 Hz, 1 H), 7.36 (d, J = 9.1 Hz, 1 H).
13
C NMR (100 MHz, CDCl ): δ = 12.4 (2 q), 14.2, 44.7 (2 t), 64.7, 75.1,
3
97.9, 105.8, 106.4, 108.6, 120.2, 125.5, 133.2, 150.6, 154.1, 156.6,
2
h, cooled to r.t. and diluted with EtOAc. After addition of sat. aq KF,
161.9, 162.0.
the mixture was stirred overnight at r.t.. The aqueous layer was ex-
tracted with CH Cl , the organic layer was washed with H O, and
+
HRMS (CI): m/z (M) calcd for C19H NO : 345.1570; found: 345.1575.
23
5
2
2
2
dried (Na SO ). The solvent was removed in vacuo and the crude
UV (DMSO): λmax (abs) = 377 nm; λmax (em) = 436 nm.
2
4
product was purified by column chromatography (silica gel, CH Cl –
2
2
Et O, 95:5) to furnish 15. The compound is sensitive to light; yield:
2
7-(Diethylamino)-4-(3-hydroxyprop-1-yn-1-yl)-2H-chromen-2-
one (18)
579 mg (2.38 mmol, 95%); yellow solid; mp 50–53 °C; Rf = 0.33
(
CH Cl –Et O, 95:5).
2
2
2
To a solution of Pd(PPh ) (23 mg, 20 μmol, 2 mol%), CuI (4.5 mg, 23
3
4
μmol, 4 mol%), and triflate 14 (365 mg, 1 mmol) in THF (5 mL) were
added Et N (0.15 mL, 1 mmol) and propargylic alcohol (0.1 mL, 2
3
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

G
Synthesis
L. Schmidt et al.
Paper
+
mmol) under N2 at r.t.. The reaction mixture was stirred for 2 h.
Workup as usual and column chromatography (silica gel, CH Cl –EtO-
HRMS (CI): m/z (M) calcd for C21H27NO : 373.1883; found: 373.1850.
5
2
2
UV (DMSO): λmax (abs) = 371 nm; λmax (em) = 420 nm.
Ac, 95:5) afforded 18; yield: 218 mg (0.8 mmol, 80%); yellow solid;
mp 144–145 °C; R = 0.24 (CH Cl –EtOAc, 9:1).
f
2
2
(
Z)-4-({3-[7-(Diethylamino)-2-oxo-2H-chromen-4-yl]prop-2-yn-1-
yl}oxy)but-2-en-1-yl Ethyl Carbonate (22)
1
H NMR (400 MHz, CDCl ): δ = 1.20 (t, J = 7.1 Hz, 6 H), 2.15 (m, 1 H),
3
3.41 (q, J = 7.1 Hz, 4 H), 4.60 (s, 2 H), 6.17 (s, 1 H), 6.45 (d, J = 2.5 Hz, 1
According to the preparation of 18, Et N (1.7 mL, 1.3 g, 12.4 mmol)
and propargyl ether 21 (3.0 g 24.8 mmol) were added to a suspen-
sion of Pd(PPh ) (311 mg, 248 μmol, 2 mol%), CuI (94.5 mg, 496 μmol,
3
H), 6.57 (dd, J = 9.0, 2.5 Hz, 1 H), 7.57 (d, J = 9.0 Hz, 1 H).
24
13
C NMR (100 MHz, CDCl ): δ = 12.4 (2 q), 44.8 (2 t), 51.5, 80.0, 97.4,
3
3 4
9
8.6, 107.8, 108.8, 111.7 (d) 127.5, 136.8, 151.1, 156.1, 161.7.
4 mol%), and triflate 14 (4.5 g, 12.4 mmol) in THF (60 mL) at r.t. The
reaction mixture was stirred at this temperature for 2 h. Workup and
column chromatography (silica gel, CH Cl –MeOH, 95:5) furnished
+
HRMS (CI): m/z (M) calcd for C16H17NO : 271.1202; found: 271.1209.
3
2
2
UV (DMSO): λmax (abs) = 399 nm; λmax (em) = 479 nm.
the desired allyl alcohol (3.3 g, 9.8 mmol, 79%) as a yellow oil. The al-
lyl alcohol (3.3 g, 9.8 mmol) was dissolved in CH Cl (20 mL), and pyr-
Anal. Calcd for C16H17NO (271.32): C, 70.83; H, 6.32; N, 5.16. Found:
C, 70.95; H, 6.41; N, 4.87.
3
2
2
idine (3.2 mL) and ethyl chloroformate (4.5 mL, 19.6 mmol) were add-
ed at 0 °C. The reaction mixture was allowed to warm to r.t. overnight.
Workup and column chromatography (silica gel, CH Cl –EtOAc, 95:5)
3
-[7-(Diethylamino)-2-oxo-2H-chromen-4-yl]propionaldehyde
2
2
(19)
provided 22; yield: 4.4 g (10.7 mmol, 87%); yellow solid; mp 55–56
°
C; R = 0.42 (CH Cl –EtOAc, 95:5).
Alcohol 18 (3.8 g, 14 mmol, 1 equiv) was dissolved in MeOH (40 mL)
and Pd/C (380 mg, 10 wt%) was added. The flask was evacuated and
flushed with H . The mixture was stirred under H atmosphere over-
f 2 2
1
H NMR (400 MHz, CDCl ): δ = 1.21 (t, J = 7.1 Hz, 6 H), 1.30 (t, J = 7.1
3
2
2
Hz, 3 H), 3.41 (q, J = 7.1 Hz, 4 H), 4.19 (q, J = 7.1 Hz, 2 H), 4.28 (d, J = 5.0
Hz, 2 H), 4.47 (s, 2 H), 4.75 (d, J = 5.3 Hz, 2 H), 5.86 (dtt, J = 11.3, 5.3,
2.5 Hz, 2 H), 6.17 (s, 1 H), 6.46 (d, J = 2.5 Hz, 1 H), 6.60 (dd, J = 9.0, 2.5
Hz, 1 H), 7.57 (d, J = 9.0 Hz, 1 H).
night and filtered through Celite. The solvent was removed in vacuo
and the crude product was purified by column chromatography (sili-
ca gel, CH Cl –MeOH, 98:2) providing the saturated alcohol (3.7 g,
2
2
1
3.5 mmol, 96%) as a yellow oil. This alcohol (1.3 g, 4.7 mmol) was
13
C NMR (100 MHz, CDCl ): δ = 12.4 (2 q), 14.3, 44.8 (2 t), 58.1, 63.2,
3
dissolved in CH Cl (90 mL) and Dess–Martin periodinane (2.4 g, 5.64
mmol, 1.2 equiv) was added at r.t.. The reaction mixture was stirred
for 2 h. Workup and column purification (silica gel, CH Cl –EtOAc,
2
2
64.2, 65.6, 80.8, 96.1, 97.4, 107.8, 108.8, 111.9 (d) 127.3, 127.5, 130.1,
136.6, 151.0, 155.0, 156.2, 161.4.
2
2
+
HRMS (CI): m/z (M) calcd for C23H NO : 413.1832; found: 413.1847.
9
0
1
5:5) provided 19; yield: 1.079 g (3.72 mmol, 79%); yellow oil; R =
.29 (CH Cl –EtOAc, 95:5).
27
6
f
UV (DMSO): λmax (abs) = 396 nm; λmax (em) = 478 nm.
2
2
H NMR (400 MHz, CDCl ): δ = 1.20 (t, J = 7.0 Hz, 6 H), 2.86 (t, J = 7.6
Anal. Calcd for C23H27NO (413.46): C, 66.81; H, 6.58; N, 3.39. found:
3
6
Hz, 2 H), 3.01 (t, J = 7.4 Hz, 2 H), 3.40 (q, J = 7.1 Hz, 4 H), 5.92 (s, 1 H),
C, 67.11; H, 6.61; N, 3.13.
6.49 (d, J = 2.5 Hz, 1 H), 6.58 (dd, J = 9.0, 2.6 Hz, 1 H), 7.37 (d, J = 9.0 Hz,
1
H), 9.87 (s, 1 H).
Palladium-Catalyzed Allylic Alkylations of Chelated Glycine Ester
Enolate; General Procedure
13
C NMR (100 MHz, CDCl ): δ = 12.4 (2 q), 23.5, 42.0, 44.7 (2 t), 97.8,
3
1
07.5, 107.7, 108.6, 124.9, 150.6, 154.7, 156.2, 162.0, 199.8 (d).
At –20 °C, a solution of LHMDS was prepared from HMDS (111 mg,
0.69 mmol) and 1.6 M BuLi (0.39 mL, 0.625 mmol) in THF (1 mL). This
solution was cooled to –78 °C and added to a solution of the protected
amino acid ester (0.25 mmol) in THF (1 mL). After 20 min at –78 °C, a
+
HRMS (CI): m/z (M) calcd for C16H19NO : 273.1358; found: 273.1353.
3
UV (DMSO): λmax (abs) = 364 nm; λmax (em) = 419 nm.
solution of ZnCl (38 mg, 0.275 mmol) in THF (1 mL) was added under
vigorous stirring. After an additional 30 min, a solution of [allylPdCl]2
2
5
-[7-(Diethylamino)-2-oxo-2H-chromen-4-yl]pent-1-en-3-yl Ethyl
Carbonate (20)
(1 mg, 2.5 μmol, 1 mol%), PPh3 (3 mg, 11.3 μmol, 4.5 mol%), and the
According to the preparation of 3, aldehyde 19 (2.5 g, 9.4 mmol) was
dissolved in THF (100 mL) and vinylmagnesium bromide (12.2 mL,
corresponding allylic ester (0.5 mmol) in THF (3 mL) was added. The
solution was stirred and warmed up to r.t. in the cooling bath over-
12.2 mmol, 1 M in THF) was added slowly at –20 °C. The reaction
night. Subsequently, the solution was diluted with Et O and hydro-
2
mixture was stirred for 2 h. Workup as usual and column chromatog-
raphy provided the desired allyl acohol (2.03 g, 6.7 mmol, 71%) as a
yellow oil. The allyl alcohol (253 mg, 0.8 mmol) was dissolved in
CH Cl (2 mL) and pyridine (0.8 mL) and ethyl chloroformate (0.2 mL,
lyzed with aq 1 N KHSO . The aqueous phase was extracted with Et O
4
2
(2 ×) and the combined organic phases were dried (Na SO ). After
2
4
evaporation of the solvent, the crude product was purified by silica
gel column chromatography.
2
2
1
74 mg, 1.6 mmol) was added at 0 °C. The reaction mixture was al-
lowed to warm to r.t. overnight. Workup and column chromatography
silica gel, PE–EtOAc, 7:3) provided 20; yield: 238 mg (0.62 mmol,
tert-Butyl (E)-5-(7-Methoxy-2-oxo-2H-chromen-4-yl)-2-(2,2,2-tri-
(
fluoroacetamido)pent-4-enoate (23)
7
8%); yellow oil; R = 0.36 (PE–EtOAc, 7:3).
f
According to the general procedure for allylic alkylations, 23 was ob-
tained from TFA-protected tert-butyl glycinate (64 mg, 0.28 mmol)
and carbonate 3 (76 mg, 0.25 mmol) after flash chromatography
1
H NMR (400 MHz, CDCl ): δ = 1.21 (t, J = 7.1 Hz, 6 H), 1.33 (t, J = 7.1
3
Hz, 3 H), 1.96–2.10 (m, 2 H), 2.71–2.77 (m, 2 H), 3.41 (q, J = 7.1 Hz, 4
H), 4.21 (q, J = 7.2 Hz, 2 H), 5.17 (dd J = 12.7, 6.5 Hz, 1 H), 5.29 (ddd, J =
(Reveleris, Gradient PE–EtOAc, 9:1 to EtOAc); yield: 75 mg (0.17
1
1
0.5, 1.0, 1.0 Hz, 1 H), 5.38 (ddd, J = 17.2, 1.1, 1.1 Hz, 1 H) 5.85 (ddd, J =
7.2, 10.5, 6.6 Hz, 1 H), 5.93 (s, 1 H), 6.50 (d, J = 2.6 Hz, 1 H), 6.58 (dd,
mmol, 68%); yellow oil; R = 0.31 (PE–EtOAc, 7:3).
f
1
H NMR (400 MHz, CDCl ): δ = 1.49 (s, 9 H), 2.81 (m, 1 H), 3.00 (m, 1
3
J = 9.0, 2.6 Hz, 1 H), 7.37 (d, J = 9.0 Hz, 1 H).
H), 3.86 (s, 3 H), 4.65 (m, 1 H), 6.22 (s, 1 H), 6.28 (dt, J = 15.7, 7.4 Hz, 1
H), 6.70 (d, J = 15.7 Hz, 1 H), 6.80–6.85 (m, 2 H), 7.20 (d, J = 6.8 Hz, 1
H), 7.49 (d, J = 8.8 Hz, 1 H).
13
C NMR (100 MHz, CDCl ): δ = 12.4 (2 q), 14.2 (q) 27.1, 33.0, 44.7 (2
3
t), 60.4, 64.1, 97.8, 107.7, 107.9, 108.4, 118.3, 125.1, 135.2, 150.5,
54.5, 155.5, 156.2, 162.2.
1
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

H
Synthesis
L. Schmidt et al.
Paper
13
C NMR (100 MHz, CDCl ): δ = 28.0 (3 q), 35.5, 55.7, 60.4, 84.1, 101.2,
H), 3.88 (s, 3 H), 4.11 (m, 1 H), 4.21 (dd, J = 7.8, 4.6 Hz, 1 H), 6.25 (s, 1
3
1
1
08.3, 111.8, 112.4, 125.5, 127.5, 132.6, 149.9, 155.6, 161.5, 162.9,
68.8, signals of the TFA group could not be detected.
H), 6.64 (d, J = 15.6 Hz, 1 H), 6.99 (d, J = 7.8 Hz, 1 H), 7.69 (d, J = 8.7 Hz,
1 H).
HRMS (CI): m/z (M)+ calcd for C21H22F NO : 441.1393; found:
13
C NMR (100 MHz, CDCl ): δ (major diastereomer, 66%) = 15.5, 28.1
3
6
3
441.1412.
(3 q), 40.3, 55.8, 59.9, 84.1, 101.2, 108.2, 112.4, 112.5, 124.9, 125.3,
1
39.0, 150.1, 155.7, 161.5, 162.9, 168.4; signals of the TFA group could
not be detected; δ (minor diastereomer, 34%, selected signals) = 15.2,
8.0 (3 q), 35.9, 56.5, 60.4, 73.7, 100.9, 111.8, 137.5.
tert-Butyl (E)-5-[7-(Diethylamino)-2-oxo-2H-chromen-4-yl]-2-
2,2,2-trifluoroacetamido)pent-4-enoate (24)
2
(
HRMS (CI): m/z (M + H)+ calcd for C22
456.1607.
H F NO : 456.1628; found:
According to the general procedure for allylic alkylations, 24 was ob-
tained from TFA-protected tert-butyl glycinate (81 mg, 0.36 mmol)
and carbonate 17 (76 mg, 0.25 mmol) after flash chromatography
25 3 6
(
(
1
PE–EtOAc, 7:3); yield: 86.9 mg (0.18 mmol, 72%); yellow oil; R = 0.25
PE–EtOAc, 7:3).
tert-Butyl (E)-7-(11-Oxo-2,3,6,7-tetrahydro-1H,5H,11H-pyra-
no[2,3-f]pyrido[3,2,1-ij]quinolin-9-yl)-2-(2,2,2-trifluoroacetami-
do)hept-4-enoate (26a) and tert-Butyl 3-[2-(11-Oxo-2,3,6,7-
tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-9-
yl)ethyl]-2-(2,2,2-trifluoroacetamido)pent-4-enoate (26b)
f
H NMR (400 MHz, CDCl ): δ = 1.20 (t, J = 7.1 Hz, 6 H), 1.49 (s, 9 H),
3
2
5
.82 (m, 1 H), 2.95 (m, 1 H), 3.40 (q, J = 7.1 Hz, 4 H), 4.64 (dd, J = 12.4,
.7 Hz, 1 H), 6.03 (s, 1 H), 6.24 (dt, J = 15.1, 7.4 Hz, 1 H), 6.49 (d, J = 2.5
Hz, 1 H), 6.55 (dd, J = 9.0, 2.6 Hz, 1 H), 6.68 (d, J = 15.6 Hz, 1 H), 7.14 (d,
J = 6.7 Hz, 1 H), 7.37 (d, J = 9.0 Hz, 1 H).
According to the general procedure for allylic alkylations, the amino
acid derivatives 26a,b were obtained from TFA-protected tert-butyl
glycinate (64 mg, 0.28 mmol) and carbonate 11 (99 mg, 0.25 mmol)
after flash chromatography (Reveleris, Gradient PE–EtOAc, 9:1 to EtO-
13
C NMR (100 MHz, CDCl ): δ = 12.4 (2 q), 27.8 (3 q), 35.5, 44.7 (2 t),
3
5
1
2.7, 84.1, 97.9, 104.6, 107.2, 108.5, 114.2, 125.3, 128.1, 131.5, 149.9,
50.7, 156.5, 162.4, 162.5, 168.9.
Ac); yield: 111 mg (0.20 mmol, 80%); yellow oil; R (26a/b) = 0.20 (PE–
f
EtOAc, 7:3).
HRMS (CI): m/z (M + H)+ calcd for C24H30F N O : 483.2101; found:
3
2
5
4
83.2101.
2
6a (60%)
UV (DMSO): λmax (abs) = 380 nm; λmax (em) = 443 nm.
1
H NMR (400 MHz, CDCl ): δ = 1.47 (s, 9 H), 1.94–1.97 (m, 4 H), 2.35
3
(
6
5
td, J = 15.1, 7.1 Hz, 2 H), 2.49 (m, 1 H), 2.62–2.70 (m, 3 H), 2.76 (t, J =
.1 Hz, 2 H), 2.87 (t, J = 6.5 Hz, 2 H), 3.21–3.27 (m, 4 H), 4.50 (m, 1 H),
.34 (m, 1 H), 5.61 (dt, J = 15.4, 6.4 Hz, 1 H), 5.86 (s, 1 H), 6.94–6.96
tert-Butyl 5-[7-(Diethylamino)-2-oxo-2H-chromen-4-yl]-2-(2,2,2-
trifluoroacetamido)pentanoate (24′)
To a solution of alkene 24 (20.0 mg, 41.1 μmol) in MeOH was added
(m, 2 H).
1
0% Pd/C (2 mg). The mixture was stirred for 2 h under H2 atmo-
13
C NMR (100 MHz, CDCl ): δ = 20.4, 20.6, 21.5, 27.7, 27.9 (3 q), 31.2
3
sphere and the solvent was removed in vacuo after TLC proved full
conversion. The residue was subjected to flash chromatography (PE–
EtOAc, 7:3); yield: 12.0 mg (27.7 μmol, 60%); yellow oil, R = 0.21 (PE–
(2 t), 35.0, 49.5, 49.9, 52.7, 83.5, 107.0, 107.0, 107.9, 118.0, 121.2,
124.0, 134.1, 145.7, 151.3, 155.8, 162.6, 169.3; signals of the TFA
f
group could not be detected.
EtOAc, 7:3).
1
H NMR (500 MHz, CDCl ): δ = 1.20 (t, J = 7.1 Hz, 6 H), 1.44 (s, 9 H),
3
26b (40%)
1
2
5
6
.64 (m, 1 H), 1.76 (m, 1 H), 1.86 (m, 1 H), 2.04 (m, 1 H), 2.66 (m, 1 H),
.76 (m, 1 H), 3.40 (q, J = 7.1 Hz, 4 H), 4.52 (dt, J = 6.4 Hz, 6.3 Hz, 6 H),
.90 (s, 1 H), 6.50 (d, J = 2.5 Hz, 1 H), 6.57 (dd, J = 9.0 Hz, 2.5 Hz, 1 H),
.99 (d, J = 7.23 Hz, 1 H), 7.35 (J = 9.0 Hz, 1 H).
1
H NMR (400 MHz, CDCl ): δ (major diastereomer, 70%) = 1.47 (s, 9 H),
3
1.95–2.00 (m, 4 H), 2.35 (td, J = 15.1, 7.1 Hz, 2 H), 2.68–2.78 (m, 4 H),
2.85 (t, J = 6.5 Hz, 2 H), 3.22–3.27 (m, 4 H), 4.20 (m, 1 H) 4.61 (m, 1 H),
5.28 (m, 2 H), 5.60 (m, 1 H), 5.86 (s, 1 H), 6.95 (s, 1 H), 6.77 (d, J = 7.9
13
C NMR (125 MHz, CDCl ): δ = 12.4, 23.7, 27.9, 31.0, 31.6, 44.8, 52.7,
3
Hz, 1 H), 6.95 (s, 1 H); δ (minor diastereomer, 30%, selected signals) =
8
1
3.7, 97.9, 107.7, 108.5, 115.6 (q, J = 287.7 Hz), 125.1, 150.5, 155.5,
56.3, 156.7 (q, J = 37.6 Hz), 162.2, 168.7.
1
.46 (s, 9 H), 6.96 (s, 1 H).
13
C NMR (100 MHz, CDCl ): δ (major diastereomer, 70%) = 20.4, 20.6,
3
HRMS (CI): m/z (M + H)+ calcd for C24H32F N O : 485.2258; found:
4
3
2
5
21.5, 27.7, 27.9 (3 q), 31.2 (2t), 46.3, 49.5, 49.9, 55.4, 83.6, 107.1,
07.2, 107.9, 118.0, 120.1, 123.2, 132.7, 145.7, 151.2, 155.7, 162.5,
85.2261.
1
UV (DMSO): λmax (abs) = 380 nm; λmax (em) = 441 nm.
168.6; signals of the TFA group could not be detected.
HRMS (CI): m/z (M)+ calcd for C28H33F N O : 534.2336; found:
3
2
5
tert-Butyl (E)-5-(7-Methoxy-2-oxo-2H-chromen-4-yl)-3-methyl-2-
534.2336.
(2,2,2-trifluoroacetamido)pent-4-enoate (25)
UV (DMSO): λmax (abs) = 385 nm; λmax (em) = 455 nm.
According to the general procedure for allylic alkylations, 25 was ob-
tained from TFA-protected tert-butyl glycinate (64 mg, 0.28 mmol)
and carbonate 6 (80 mg, 0.25 mmol) after flash chromatography
tert-Butyl (E)-7-[7-(Diethylamino)-2-oxo-2H-chromen-4-yl]-2-
(
[
2,2,2-trifluoro-acetamido)hept-4-enoate (27a) and tert-Butyl 3-
2-(7-(Diethylamino)-2-oxo-2H-chromen-4-yl)ethyl]-2-(2,2,2-tri-
(Reveleris, Gradient PE–EtOAc, 9:1 to EtOAc); yield: 72 mg (0.16
mmol, 63%); yellow oil; R = 0.40 (PE–EtOAc, 7:3).
f
fluoroacetamido)pent-4-enoate (27b)
1
H NMR (400 MHz, CDCl ): δ (major diastereomer, 66%) = 1.22 (d, J =
3
According to the general procedure for allylic alkylations, the amino
acid derivatives 27a/b were obtained from TFA-protected tert-butyl
glycinate (134 mg, 0.59 mmol) and carbonate 20 (154 mg, 0.41 mmol)
after flash chromatography (PE–EtOAc, 7:3) as an inseparable mix-
ture of regio- and stereoisomers; yield: 170 mg (0.32 mmol, 80%);
6
.7 Hz, 3 H), 1.49 (s, 9 H), 3.09 (m, 1 H), 3.87 (s, 3 H), 4.63 (dd, J = 7.8,
.6 Hz, 1 H), 6.26 (s, 1 H), 6.38 (dd, J = 15.6, 7.8 Hz, 1 H), 6.71 (d, J =
5.6 Hz, 1 H), 6.82–6.91 (m, 2 H), 7.01 (d, J = 7.8 Hz, 1 H), 7.52 (d, J =
.7 Hz, 1 H); δ (minor diastereomer, 34%, selected signals) = 1.50 (s, 9
4
1
8
yellow oil; R (27a/b) = 0.23 (PE–EtOAc, 7:3).
f
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

I
Synthesis
L. Schmidt et al.
Paper
2
7a
Supporting Information
1
H NMR (400 MHz, CDCl ): δ (major rotamer, 82%) = 1.19 (t, J = 7.1 Hz,
3
Supporting information for this article (copies of NMR spectra) is
available online at http://dx.doi.org/10.1055/s-0035-1561628.
6
H), 1.46 (s, 9 H), 2.31–2.41 (m, 2 H), 2.49 (m, 1 H), 2.61–2.76 (m, 3
S
u
p
p
o
nrtIo
i
g
f
rm oaitn
S
u
p
p
ortioIgnfmr oaitn
H), 3.39 (q, J = 7.1 Hz, 4 H), 4.50 (m, 1 H), 7.56 (dt, J = 15.3, 7.6 Hz, 1 H),
5
6
.60 (dt, J = 15.3, 6.9 Hz, 1 H), 5.88 (s, 1 H), 6.47 (d, J = 2.5 Hz, 1 H),
.56 (m, 1 H), 6.98 (d, J = 7.3 Hz, 1 H), 7.34 (d, J = 9.0 Hz); δ (minor
References
rotamer, selected signals): 1.45 (s, 9 H), 7.03 (d, J = 7.0 Hz, 1 H).
(
1) (a) Valeur, B.; Brochon, J.-C. New Trends in Fluorescence Spec-
2
7b
troscopy: Applications to Chemical and Life Sciences; Springer:
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technology and life science; Wiley: Hoboken, New Jersey, 2009.
1
H NMR (400 MHz, CDCl ): δ (minor rotamer, 18%, selected signals) =
3
1
5
1
.45 (s, 9 H), 4.61 (dd, J = 8.7, 4.4 Hz, 1 H), 5.21 (d, J = 17.1 Hz, 1 H),
.29 (d, J = 10.9 Hz, 1 H), 5.62 (m, 1 H), 5.89 (s, 1 H), 6.83 (d, J = 8.6 Hz,
H), 7.36 (d, J = 8.9 Hz, 1 H).
(2) (a) Hama, Y.; Urano, Y.; Koyama, Y.; Gunn, A. J.; Choyke, P. L.;
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13
C NMR (100 MHz, CDCl ): δ (isomeric mixture) = 12.3, 20.0, 24.2,
3
26.0, 27.8, 27.8, 29.1, 29.3, 29.5, 31.1, 31.1, 31.2, 32.9, 33.5, 34.8, 44.6,
46.2, 51.4, 51.5, 52.6, 52.6, 55.4, 82.3, 83.4, 83.6, 97.7, 107.4, 107.6,
107.7, 107.8, 108.8, 107.9, 108.4, 108.5, 115.5 (q, J = 287.6 Hz), 115.6
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2
282.
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1
50.4, 150.4, 155.5, 155.6, 155.7, 156.2, 156.3, 156.4 (q, J = 33.5 Hz),
56.2 (q, J = 32.2 Hz), 162.1, 162.1, 162.2, 168.5, 169.2, 173.3, 173.6.
(
(
1
HRMS (CI): m/z (M)+ calcd for C26H33F N O : 510.2342; found:
3
2
5
6) (a) Bernardes, G. J. L.; Chalker, J. M.; Errey, J. C.; Davis, B. G. J. Am.
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Weinrich, D.; Köhn, M.; Engelkamp, H.; Christianen, P. C. M.;
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UV (DMSO): λmax (abs) = 364 nm; λmax (em) = 420 nm.
tert-Butyl 6-({3-[7-(Diethylamino)-2-oxo-2H-chromen-4-yl]prop-
2-yn-1-yl}oxy)-2-(2,2,2-trifluoroacetamido)hex-4-enoate (28)
According to the general procedure for allylic alkylations, 28 was ob-
tained from TFA-protected tert-butyl glycinate (227 mg, 1.0 mmol)
and carbonate 22 (206 mg, 0.5 mmol) after flash chromatography
(CH Cl –EtOAc, 95:5, 9:1) as a 7:3 E/Z-mixture; yield: 189 mg (0.34
2 2
(
7) (a) Kodadek, T.; Duroux-Richard, I.; Bonnafous, J. C. Trends Phar-
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mmol, 69%); yellow oil; R = 0.41 (CH Cl –EtOAc, 95:5).
f
2
2
(
E)-28 (70%)
1
H NMR (400 MHz, CDCl ): δ =1.20 (t, J = 7.1 Hz, 6 H), 1.48 (s, 9 H),
3
2
.55 (m, 1 H), 2.72 (m, 1 H), 3.40 (q, J = 7.1 Hz, 4 H), 3.83 (s, 2 H), 3.99
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(d, J = 4.9 Hz, 2 H), 4.55 (m, 1 H), 5.54–5.70 (m, 2 H), 5.98 (s, 1 H), 6.49
d, J = 2.5 Hz, 1 H), 6.56 (dd, J = 9.0, 2.6 Hz, 1 H), 7.09 (d, J = 7.2 Hz, 1
(
H), 7.28 (d, J = 9.0 Hz, 1 H).
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367. (d) Karmann, L.; Schulz, K.; Herrmann, J.; Müller, R.;
(
1
Z)-28 (30%)
H NMR (400 MHz, CDCl ): δ (selected signals) = 1.47 (s, 9 H), 3.80 (s,
H), 4.17 (d, J = 2.59 Hz, 2 H), 4.78 (m, 1 H), 5.80 (m, 1 H), 7.41 (d, J =
.1 Hz, 1 H).
3
2
2
7
6
1
3
C NMR (100 MHz, CDCl ): δ (E/Z mixture) = 12.4 (2 q), 28.0, 34.7,
3
Kazmaier, U. Angew. Chem. Int. Ed. 2015, 54, 4502; Angew.
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4
1
2
3.0, 44.8 (2 t), 52.6, 71.4, 74.5, 83.7, 97.7, 108.0, 108.7, 110.0, 110.4,
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03.6.
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5
3
2
6
51.2340.
UV (DMSO): λmax (abs) = 372 nm; λmax (em) = 446 nm.
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Financial support from the Deutsche Forschungsgemeinschaft is
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J