Visible-Light Photoredox Alkylation of Heteroaromatic Bases Using Ethyl Acetate as Alkylating Agent

Article abstract of DOI:10.1002/ejoc.202001113

An efficient room-temperature visible-light photoredox α-acyloxyalkylation reaction of N-heteroarenes is reported, which relies on the use of ethyl acetate as a cheap and non-conventional radical source. The direct C(sp²)-C(sp³) coupling was extended to a diverse set of mono-, bi-, and tricyclic of N-heteroaromatics, and the optimized photoredox protocol was successfully performed on a multigram scale. The scope of the alkylating agent was also explored and a plausible mechanism was proposed, involving photoinduced single-electron transfer and hydrogen-atom transfer processes.

Full text of DOI:10.1002/ejoc.202001113

Communication
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Photoredox Catalysis
Visible-Light Photoredox Alkylation of Heteroaromatic Bases
Using Ethyl Acetate as Alkylating Agent
Nándor Győrfi,[a,b] András Kotschy,[a] and Márió Gyuris*[a][‡]
Abstract: An efficient room-temperature visible-light photo- clic of N-heteroaromatics, and the optimized photoredox proto-
redox α-acyloxyalkylation reaction of N-heteroarenes is re- col was successfully performed on a multigram scale. The scope
ported, which relies on the use of ethyl acetate as a cheap of the alkylating agent was also explored and a plausible mech-
and non-conventional radical source. The direct C(sp2)-C(sp3) anism was proposed, involving photoinduced single-electron
coupling was extended to a diverse set of mono-, bi-, and tricy- transfer and hydrogen-atom transfer processes.
The strategy of using common organic solvents as radical
precursors, however appealing, is only infrequently applied in
organic synthesis.[1] Some examples utilizing toluene,[2–7] vari-
ous ether and alcohol,[8–19] acetonitrile,[20–25] and N,N-dimethyl-
formamide[26–30] derived radical synthons were reported. The
common features of these transformations, besides the radical-
chain mechanism, are the use of strong external oxidants, a
stoichiometric amount of transition metals, and elevated tem-
peratures respectively, resulting in narrow substrate scope and
poor isolated yields.[1] It should be noted, that ethyl acetate as
a radical source in organic reactions has barely been exploited
so far.[31,32]
The pioneering work of Minisci and co-workers described
the oxidative radical functionalization of lepidine via a cross-
dehydrogenative coupling (CDC) using ethyl acetate, 1,4-diox-
ane, and methanol as coupling agents.[33] In general, solvents
possessing a C(sp3)-H bond adjacent to an oxygen atom (alco-
Figure 1. Cross-dehydrogenative couplings with solvents.
hol, ether, or ester) can be cleaved via a hydrogen atom transfer
(HAT) process, and the corresponding radical can react with the
heteroarenes directly (Figure 1a).[34–42]
mechanism, resulting in alcohol C–O bond cleavage and the
Visible-light photoredox catalysis permits the mild and effi-
cient generation of radicals. The Merck Research Laboratories
developed a direct C–H functionalization of heteroarenes em-
ploying hydroxymethyl radicals generated from methanol un-
der photoredox conditions (Figure 1b).[43] Upon alkoxyl radical
formation and addition, various alcohols were found to un-
dergo radical elimination of H2O via Spin-Center-Shift (SCS)
formation of a carbon-centered radical. Subsequent proton-
coupled electron transfer (PCET) led to alkylated products in-
stead of hydroxyalkyl derivatives (Figure 1c).[44,45]
Based on this concept, Jin and MacMillan exploited the
SCS-elimination for the photo- and organocatalyzed alkylation
of heteroarenes using primary alcohols.[46] Their studies indi-
cate that alkoxy radical generation under photoredox condi-
tions is a viable option for the direct functionalization of hetero-
arenes. Our objective was to extend the photo-CDC-coupling
to esters and suppressing the SCS-elimination obtain α-acyloxy-
alkylated N-heterocycles that can serve as valuable synthetic
intermediates (Figure 1d).
[a] N. Győrfi, Dr. A. Kotschy, Dr. M. Gyuris
Servier Research Institute of Medicinal Chemistry,
Záhony u 7., 1031 Budapest, Hungary
[b] N. Győrfi
ELTE, Eötvös Loránd University,
Our selected model reaction was the CDC coupling of
lepidine (1a) with ethyl acetate (2a). First, we investigated the
effect of the photocatalysts and the peroxide on the conversion
and selectivity of the transformation in the presence of TFA.
Among the catalysts tested, (Ir[dF(CF3)ppy]2(dtbpy))PF6 (PC-1)
showed the highest activity. Employing 2 equivalents of TFA
Institute of Chemistry, Pázmány Péter stny. 1/A, 1117 Budapest, Hungary
[‡] Present address: Dr. M. Gyuris
Avidin Ltd.,
Alsó Kiköt– Sor 11/D, 6726 Szeged, Hungary
E-mail: m.gyuris@avidinbiotech.com
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202001113.
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Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Peroxide
Acid
3a [%][b]
3a/4a[b]
1[a]
2[a]
3[a]
4[a]
5[a]
6[a]
7[a]
8[d]
9[e]
10[f]
1 % PC-1
1 % PC-1
1 % PC-1
1 % PC-1
1 % PC-1
1 % PC-1
1 % PC-1
1 % PC-1
–
2 equiv. TBHP
2 equiv. CHP
2 equiv. TBPB
2 equiv. TBPB
2 equiv. TBPB
3 equiv. TBPB
4 equiv. TBPB
2 equiv. TBPB
4 equiv. TBPB
4 equiv. TBPB
2 equiv. TFA
2 equiv. TFA
2 equiv. TFA
without TFA
0.2 equiv. TFA
0.2 equiv. CSA
0.2 equiv. CSA
0.2 equiv. CSA
0.2 equiv. CSA
0.2 equiv. CSA
28
34
56
0
67
21
4.6
3.8
3.7
–
17
25
60
–
99 [82][c]
0
12
4
n.d.
n.d.
1 % PC-1
[a] Reactions conditions: 1a (0.5 mmol) in EtOAc (2a) (0.13
M), blue LEDs, N2 atmosphere, room temperature, 1 h. [b] Conversion and selectivity were
determined by HPLC using benzotrifluoride as internal standard. [c] Isolated yield on 3 mmol scale after 1 hour. [d] Absence of LED light, N2 atmosphere,
room temperature, 18 h. [e] Absence of PC-1, blue LEDs, N2 atmosphere, room temperature, 18 h. [f] The reaction was performed in dark at 90 °C (closed
vessel) for 1 h.
and tert-butyl hydroperoxide (TBHP) gave low conversion and rates varied from one substrate to the other, and the time re-
selectivity for 3a (Table 1, entry 1).
quired to reach high conversion (>90 %) is also presented on
Scheme 1. Fortunately, we observed unremarkable levels of side
reactions (SCS) in case of longer reaction times. The first set of
compounds, 2,4-disubstituted, and condensed quinoline deriva-
tives 3a–j were isolated in moderate to good yields. For in-
stance, 4-substituted quinolines (1a–e) were alkylated selec-
tively in the 2-position. It was difficult to draw a direct correla-
tion between the electron-donating ability of the substituents
and the yields that varied in the range of 40–82 %. The best
results were obtained for 4-methylquinoline (1a) and the con-
densed quinoline analog 1d, and the corresponding products
were isolated in 81 % and 65 % yield respectively. In the case
of 2-substituted quinolines, the alkylation occurred in the 4-
position selectively (3f–j). The electron-deficient 2-chloro ana-
log gave the lowest yield (34 % for 3f), while the 2-methyl de-
rivatives gave similar yields (3g–i, 52–60 %) irrespective of the
benzenoid substitution. 2-Phenylquinoline (1j) also fell into this
category. Isoquinoline derivatives (1k–p) also performed well
and showed regioselective coupling at C1, affording products
3k–3p with yields up to 66 %. The isolated yields for most of
the compounds covered a narrow range (48–66 %), while the
most electron-rich dimethoxy analog (1p) was the only outlier
Changing the oxidizing agent to cumene hydroperoxide
(CHP) did not improve the conversion, and the SCS-elimination
as background reaction remained significant (Table 1, entry 2).
In contrast, the treatment of 1a with 2a in the presence of tert-
butyl peroxybenzoate (TBPB) and 2 equivalents of TFA under
photoredox conditions resulted in an improved conversion,
however, no further improvement of selectivity for 3a was de-
tected (Table 1, entry 3). Moreover, the reaction did not occur
in the absence of TFA (Table 1, entry 4).
By decreasing the amount of TFA to 0.2 equivalent led to
slightly improved conversion and good selectivity, although we
still detected the formation of the SCS by-product 4a (Table 1,
entry 5). Furthermore, the application of 20 mol-% (1S)-(+)-10-
camphorsulfonic acid (CSA) in the presence of 3 equivalents of
TBPB led to lower conversion compared to entry 5 with moder-
ately higher selectivity (Table 1, entry 6). By further increasing
the amount of TBPB up to 4 equivalents, complete conversion,
and an excellent product distribution profile was obtained, and
3a was isolated in 82 % yield (Table 1, entry 7). Additional con-
trol experiments indicated that blue LED-light irradiation is es-
sential for the α-acyloxyalkylation reaction, and in the absence
of the photocatalyst a much slower conversion was observed providing product 3p with a mediocre yield of 23 %. The proce-
(Table 1, entries 8–9). It should also be mentioned, that the dure was also extended to the alkylation of bicyclic heteroarene
alkylation occurs under thermal conditions with the exclusion scaffolds bearing two nitrogens (1q–u). 4-Chloroquinazoline de-
of light, although at a significantly slower pace (Table 1, entry rivatives with an electron-rich benzenoid part gave good yields
10). Further details on the optimization studies including the (59 % for 3q and 49 % for 3r), whereas the less electron-rich
photocatalyst, the nature and amount of the oxidant, the choice
of the acid, and additional concentration studies are discussed
in the Supporting Information.
With the optimized conditions in hand, we evaluated the
scope of the photoredox α-acyloxyalkylation protocol. As
analog (3s) was isolated in 33 % yield. Interestingly, we ob-
served sequential radical alkylations during the photo CDC re-
actions in cases of 1t and 1u bearing two reactive positions.
Quinazoline (1t) gave complete conversion after 18 hours, and
a 1:20 mixture of monoalkylated and dialkylated products was
shown in Scheme 1, a representative range of N-heteroaromat- formed along with a small amount of SCS side-products (less
ics was successfully converted to α-acyloxyalkylated products than 10 %) confirmed by LCMS. We were unable to isolate the
under mild conditions. It is important to note that the reaction monoalkylated product and 3t was obtained in mediocre yield
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Scheme 1. Scope of the cross-dehydrogenative coupling of heteroarenes with EtOAca,b; aReactions conditions: 1 (2 mmol), TBPB (8 mmol) PC-1 (0.02 mmol,
1 mol-%), CSA (0.2 mmol, 0.2 equiv.), EtOAc (12 mL), room temperature, 10 W blue LEDs, N2. bIsolated yield.
(40 %). The reaction of 1u was complete in 6 hours and a
37:63 mixture of monoalkylated and dialkylated products was
formed, but only the dialkylated compound 3u could be
isolated in 32 % yield. Finally, six-membered α-acyloxyalkylated
N-heterocycles, such as pyridine derivatives 3v and 3w, as well
as pyrimidine derivatives 3x and 3y were isolated in 40–66 %
yield. It is interesting to note that sequential dialkylation of 1y
that could have been anticipated following the example of 3t
was not observed; only the monoalkylated product 3y was de-
tected and isolated.
Scheme 2. Alkylations with methyl-, butyl acetate, and ethyl propionate.
Having explored the scope of heteroaromatics we also exam-
ined the scope of esters as alkylating agents (Scheme 2.). Run- mixture. The product distribution (10 % Cα, 7 % Cꢀ, 37 % Cγ) is
ning the photo-CDC coupling of 1a in methyl acetate furnished in line with the fact that the less activated is the sp3 CH-bond,
the expected α-acyloxyalkylated derivative 4 in 32 % yield.
the more preferred is the C-H abstraction.[47]
However, when butyl acetate was employed as solvent and
We also ran some control experiments to prove the radical
radical source, the photoalkylation resulted in a regioisomeric nature of the transformation. In the presence of one equivalent
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Scheme 3. Control experiments.
of TEMPO as a radical scavenger we didn't observe the forma- tion, a diverse collection of α-acyloxyalkylated N-heterocyclic
tion of 3a (Scheme 3.). To assess the robustness of the CDC compounds was synthesized and characterized. While methyl
photoalkylation reaction we devised a simple experimental acetate gave a single product, using butyl acetate we obtained
setup (see Supporting Information for details) and performed a multicomponent product mixture highlighting the limitations
the transformation of 1a on the 5 g scale. The expected product of this transformation. The robustness of the protocol was also
(3a) was isolated in 58 % yield and 4-methyl-2-phenylquinoline demonstrated successfully running the transformation on the
(7) as minor by-product was isolated and confirmed by NMR 5 g scale. Based on our observations and some control experi-
and HRMS, supporting our proposed mechanism.
ments a plausible mechanism was proposed, involving photo-
induced SET and HAT processes.
Based on the obtained experimental evidence and literature
precedents we propose the mechanism for this coupling shown
in Scheme 4. The excited state of Ir(III) complex may induce the
photodecompostion of TBPB via single electron transfer (SET),
resulting in the formation of a reactive phenyl radical species
9 and a transition Ir(IV) complex. Subsequent hydrogen atom
transfer between 9 and ethyl acetate (2a) gives the α-acyloxy-
alkyl radical 2b. Radical addition of 2b to the heterocycle 1b
(activated by protonation), followed by a proton-coupled single
Experimental Section
General Information: All reagents, solvents, and catalysts were
commercially available and used without further purification. Purifi-
cations were carried out by forced-flow flash chromatography using
pre-packed silica gel cartridges (RediSep Rf Gold) on a Teledyne
CombiFlash RF 200 device. Thin-layer chromatography (TLC) was
electron transfer leads to product 3a along with the regenera- performed on TLC Silica gel 60 F254 0.25 mm silica gel plates from
tion of the Ir(III) complex.[43]
Merck. Visualization of the developed chromatogram was per-
formed by fluorescence quenching or KMnO4 stain. Analytical
LC-MS: Agilent HP1200 LC with Agilent 6140 quadrupole MS, oper-
ating in positive or negative ion electrospray ionization mode.
Molecular weight scan range was 100 to 1350 m/z. Parallel UV de-
tection was done at 210 nm and 254 nm. LCMS measurements
Gemini-NX, 3 μm, C18, 50 mm × 3.00 mm i.d. column at 40 °C, at a
flow rate of 1 mL/min using 5 mM aqueous NH4HCO3 solution and
MeCN as eluents. Gas chromatography and low-resolution mass
spectrometry were performed on Agilent 6850 gas chromatograph
and Agilent 5975C mass spectrometer using 15 m × 0.25 mm col-
umn with 0.25 μm HP-5MS coating and helium as carrier gas. Ion
source: EI+, 70 eV, 230 °C, quadrupole: 150 °C, interface: 300 °C. UV
purity of new compounds are >95 % unless otherwise noted. 1H
and 13C NMR spectra were recorded on a Bruker Avance Ultrashield
500 (500 MHz 1H and 124 MHz 13C) instrument with Bruker Cryo
Probe ATM and are internally referenced to residual protium solvent
signals (note: [D6]DMSO referenced at 2.52 and 39.98 ppm respec-
tively). Data for 1H NMR are reported as follows: chemical shift (δ
ppm), integration, multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, br = broad), coupling constant (Hz) and
assignment. Data for 13C NMR are reported in terms of chemical
shift and no special nomenclature is used for equivalent carbons.
IR spectra were recorded with ATR mode on a Bruker Tensor 27
spectrometer and the spectra were reported in wavenumbers
(cm–1). High-resolution mass spectra were obtained on a Shimadzu
IT-TOF mass spectrometer system, ion source temperature 200 °C,
Scheme 4. Proposed mechanism for the HAT-induced α-acyloxyalkylation of
heteroaromatic bases.
In summary, we have developed a photoredox α-oxyalkyl-
ation procedure using ethyl acetate as an unconventional radi-
cal source. Following the establishment of the optimal condi-
tions and suppressing the undesired spin-center-shift elimina- ESI +/–, ionization voltage: (+/–) 4.5 kV, mass resolution min. 10000.
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OptiMelt MPA100 melting point apparatus was used for melting
point measurements.
tained the title compound as white solid (204 mg, 40 % yield). 1H
NMR (500 MHz, DMSO): δ 7.89 (d, J = 9.2 Hz, 1H), 7.41–7.38 (m, 2H),
7.32 (d, J = 2.7 Hz, 1H), 5.84 (q, J = 6.7 Hz, 1H), 3.93 (s, 3H), 2.66 (s,
3H), 2.1 (s, 3H), 1.55 (d, J = 6.7 Hz, 3H); 13C NMR (124 MHz, DMSO):
δ = 170.3, 157.9, 157.7, 144.4, 142.9, 131.2, 128.5, 122, 119.4, 102.9,
73.5, 56, 21.5, 20.9, 19.1; IR: νmax C=O 1735 cm–1; HRMS: m/z ([M +
H]+) calcd. for C15H18NO3: 260.1281, found 260.1287; Mp: 82.05–
84.04 °C.
General Synthetic Procedure for Small Scale Reactions: An oven-
dried 20 mL vial equipped with a septum and a Teflon magnetic
stir bar was charged with Ir[dF(CF3)ppy)]2(dtbbpy)PF6 (23.2 mg,
0.02 mmol, 0.01 equiv.), (1S)-(+)-10-camphorsulfonic acid (139 mg,
0.4 mmol, 0.2 equiv.) and heteroarene (2.00 mmol, 1.0 equiv.). The
vial was evacuated and refilled with nitrogen three times before
12 mL of EtOAc (MeOAc or BuOAc) and tert-butyl peroxybenzoate
(2.33 g, 2.3 mL, 8 mmol, 4 equiv.) were added by a syringe under
constant nitrogen flow. The reaction mixture was degassed by
sparging with nitrogen for 15 minutes at 10–15 °C. The mixture was
then stirred vigorously and irradiated by a 10 W blue LED (approxi-
mately 0.5 cm between the light source and the vial) at room tem-
perature. The progression of the reaction was monitored by LC-MS
until no further conversion was detected (typically 18 hours). The
reaction mixture was diluted with EtOAc (20 mL) and extracted with
K2CO3 solution (20 mL, 10 m/m %). Then the aqueous phase was
extracted with EtOAc (3 x 20 mL). The combined organic layers were
washed with brine (1 × 20 mL), dried with Na2SO4, filtered and the
solvent was evaporated under reduced pressure. The crude product
was purified by flash chromatography on silica gel using a gradient
program starting with heptane and gradually increasing the
amount of added ethyl acetate to 20 % to afford the desired prod-
uct.
1-(4,6-Dichloro-2-quinolyl)ethyl Acetate (3c): Following the
General Synthetic Procedure starting from 4,6-dichloroquinoline
(396 mg, 2 mmol), after 3 hours reaction time we obtained the title
1
compound as white solid (334 mg, 59 % yield). H NMR (500 MHz,
DMSO): δ 8.19 (d, J = 2.3 Hz, 1H), 8.11–8.10 (m, 1H), 7.91 (dd, J =
2.3 Hz, J = 9.0 Hz, 1H), 7.89 (s, 1H), 5.87 (q, J = 6.7 Hz, 1H), 2.13 (s,
3H), 1.58 (d, J = 6.3 Hz, 3H); 13C NMR (124 MHz, DMSO): δ = 170.4,
162.1, 146.6, 141.6, 133.3, 132.2, 132.1, 126.1, 122.9, 120.2, 72.9, 21.4,
20.6; IR: νmax C=O 1740cm–1; HRMS: m/z ([M + H]+) calcd. for
C13H12Cl2NO2: 284.0240, found 284.0241; Mp: 97.11–99.14 °C.
1-Phenanthridin-6-ylethyl Acetate (3d): Following the General
Synthetic Procedure starting from phenantridine (358 mg, 2 mmol),
after 18 hours reaction time we obtained the title compound as
1
white solid (343 mg, 65 % yield). H NMR (500 MHz, DMSO): δ 8.92
(d, J = 8.3 Hz, 1H), 8.81 (dd, J = 1.3 Hz and 8.2 Hz, 1H), 8.37 (d, J =
8.1 Hz, 1H), 8.08 (dd, J = 1.3 Hz and 8.2 Hz, 1H), 8.00–7.96 (m, 1H),
7.85–7.81 (m, 1H), 7.81–7.78 (m, 1H), 7.76–7.72 (m, 1H), 6.64 (q, J =
6.6 Hz, 1H), 2.1 (s, 3H), 1.72 (d, J = 6.6 Hz, 3H); 13C NMR (124 MHz,
DMSO): δ = 131.1, 129.7, 129.0, 128.0, 127.4, 125.3, 123.1, 122.7,
70.0, 20.9, 19.3; IR: νmax C=O 1733 cm–1; HRMS: m/z ([M + H]+) calcd.
for C17H16NO2: 266.1175, found 266.1182.
Synthesis of Compound 3a on 5 g Scale: An oven-dried 250 mL
Schlenk-tube equipped with a magnetic stir bar was charged with
Ir[dF(CF3)ppy)]2(dtbbpy)PF6 (392 mg, 0.35 mmol, 0.01 equiv.) and
(1S)-(+)-10-camphorsulfonic acid (1.62 g, 7 mmol, 0.2 equiv.). The
tube was sealed with a rubber septum, evacuated and refilled with
nitrogen three times before adding dry EtOAc (250 mL), 4-methyl-
quinoline (1a) (5.00 g, 4.6 mL, 35.0 mmol, 1.0 equiv.) and tert-butyl
peroxybenzoate (27.2 g, 26.6 mL, 140 mmol, 4 equiv.) by a syringe
under constant nitrogen flow. The reaction mixture was degassed
by sparging with nitrogen for 15 minutes at 10–15 °C. The mixture
was then stirred vigorously and irradiated by a blue LED source (see
device B, approximately 5 cm between the light source and the
Schlenk-tube) at room temperature. The reaction was monitored by
LC-MS until no further conversion was detected (2–3 hours). The
majority of the volatiles were removed to the volume of the mixture
to 50 mL (Caution: although we never experienced problem it is
advised to carry out this operation behind a shield!). The crude
mixture was purified by flash chromatography on silica gel eluting
with ethyl acetate/n-heptane gradient. Fractions containing 3a were
collected and evaporated to give the title compound 3a (4.67 g,
20.3 mmol, 58 %) as a yellow oil.
Ethyl 2-(1-Acetoxyethyl)-4-chloro-quinoline-3-carboxylate (3e):
Following the General Synthetic Procedure starting from 4-chloro-
quinoline-3-carboxylate (472 mg, 2 mmol), after 1 hour reaction
time we obtained the title compound as white solid (343 mg, 53 %
yield). 1H NMR (500 MHz, DMSO): δ 8.28–8.26 (m, 1H), 8.14–8.12 (m,
1H), 7.99–7.96 (m, 1H), 7.87–7.84 (m, 1H), 5.91 (q, J = 6.7 Hz, 1H),
4.51–4.40 (m, 2 H), 2.04 (s, 3H), 1.63 (d, J = 6.7 Hz, 3H), 1.37 (t, J =
7.1 Hz, 3H); 13C NMR (124 MHz, DMSO): δ = 170.2, 165.4, 156.7,
147.3, 140, 132.8, 129.9, 129.8, 125.5, 124.6, 124.3, 72.5, 63.0, 21.1,
19.9, 14.3; IR: νmax C=O 1740, 1722 cm–1; HRMS: m/z ([M + H]+)
calcd. for C16H17ClNO4: 322.0840, found 322.0843; Mp: >300 °C (de-
composition).
1-(2-Chloro-4-quinolyl)ethyl Acetate (3f): Following the General
Synthetic Procedure starting from 2-chloroquinoline (326 mg,
2 mmol), after 18 hours reaction time we obtained the title com-
pound as colourless oil (170 mg, 34 % yield). 1H NMR (500 MHz,
DMSO): δ 8.23 (d, J = 8.7 Hz, 1H), 8.00 (dd, J = 0.8 Hz and 8.5 Hz,
1H), 7.88–7.84 (m, 1H), 7.74–7.70 (m, 1H), 7.53 (s, 1H), 6.47 (q, J =
Hz 6.7 Hz, 1H), 2.15 (s, 3H), 1.6 (d, J = 6.5 Hz, 3H); 13C NMR (124 MHz,
DMSO): δ = 170.2, 152.4, 150.4, 148, 131.5, 129.3, 128.1, 124.3, 124,
118.4, 68.3, 21.9, 21.3; IR: νmax C=O 1733 cm–1; HRMS: m/z ([M +
H]+) calcd. for C13H13ClNO2: 250.0629, found 250.0628; Mp: 83.00–
86.34 °C.
Characterization Data for Compounds 3a–y, 4, and 5a–c
1-(4-Methyl-4-quinolyl)ethyl Acetate (3a): Following the General
Synthetic Procedure starting from 4-methylquinoline (429 mg,
396 μL, 3 mmol), after 1 hour reaction time we obtained the title
compound as yellow oil (563 mg, 82 % yield). 1H NMR (500 MHz,
DMSO): δ 8.10 (dd, J = 8.4 Hz and 1.0 Hz, 1H), 7.99 (dd, J = 8.4 Hz
and 0.7 Hz, 1H), 7.77–7.74 (m, 1H), 7.63–7.60 (m, 1H), 7.44 (d, J =
0.8 Hz, 1H), 5.87 (q, J = 6.7 Hz, 1H), 2.71 (d, J = 0.9 Hz, 3H), 2.13 (s,
3H), 1.58 (d, J = 6.7 Hz, 3H); 13C NMR (124 MHz, DMSO): δ = 170.6,
161.0, 147.1, 145.9, 130, 129.8, 127.5, 126.8, 124.6, 119.1, 73.5, 21.5,
20.9, 18.8; IR: νmax C=O 1734 cm–1; HRMS: m/z ([M + H]+) calcd. for
C14H16NO2: 230.1175, found 230.1175.
1-(2-Methyl-4-quinolyl)ethyl Acetate (3g): Following the General
Synthetic Procedure starting from 2-methylquinoline (286 mg,
2 mmol), after 3 hours reaction time we obtained the title com-
pound as yellow oil (274 mg, 60 % yield). 1H NMR (500 MHz, DMSO):
δ 8.10 (d, J = 8.5 Hz, 1H), 7.96 (dd, J = 8.5 Hz and 0.9 Hz, 1H), 7.75–
7.71 (m, 1H), 7.59–7.56 (m, 1H), 7.41 (s, 1H), 6.45 (q, J = 6.6 Hz, 1H),
2.65 (s, 3H), 2.13 (s, 3H), 1.59 (d, J = 6.6 Hz, 3H); 13C NMR (124 MHz,
DMSO): δ = 170.2, 159.2, 148.0, 147.8, 129.7, 129.6, 126.4, 123.6,
1-(6-Methoxy-4-methyl-2-quinolyl)ethyl Acetate (3b): Following
the General Synthetic Procedure starting from 6-methoxy-4-methyl- 123.4, 118.0, 68.4, 25.4, 22.0, 21.4; IR: νmax C=O 1736 cm–1; HRMS:
quinoline (346 mg, 2 mmol), after 5 hours reaction time we ob-
m/z ([M + H]+) calcd. for C14H16NO2: 230.1175, found 230.1174.
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1-(7-Chloro-2-methyl-4-quinolyl)ethyl Acetate (3h): Following 135.1, 134.7, 129.1, 126.7, 124.9, 121.9, 119.4, 70.0, 21.3, 20.2; IR:
the General Synthetic Procedure starting from 7-chloro-2-methyl-
νmax C=O 1721 cm–1, -CH 2985 cm-1; HRMS: m/z ([M + H]+) calcd.
quinoline (354 mg, 2 mmol), after 18 hours reaction time we for C13H13BrNO2: 294.0124, found 294.0118; Mp: 70.63–72.96 °C.
obtained the title compound as white solid (280 mg, 54 % yield).
Methyl 1-(1-Acetoxyethyl)isoquinoline-3-carboxylate (3n): Fol-
lowing the General Synthetic Procedure starting from methyl iso-
quinoline-3-carboxylate (402 mg, 2 mmol), after 2 hours reaction
1H NMR (500 MHz, DMSO): δ ppm 8.17 (d, J = 9.0 Hz, 1H), 8.00 (d,
J = 2.2 Hz, 1H), 7.61 (dd, J = 9.0 and 2.2 Hz, 1H), 7.44 (s, 1H), 6.42
(q, J = 6.7 Hz, 1H), 2.66 (s, 3H), 2.13 (s, 3H), 1.57 (d, J = 6.7 Hz, 3H);
time we obtained the title compound as white solid (313 mg, 57 %
13C NMR (124 MHz, DMSO): δ = 170.2, 160.9, 148.6, 148.2, 134.4,
1
yield). H NMR (500 MHz, DMSO): δ 8.62 (s, 1H), 8.39–8.37 (m, 1H),
128.1, 127, 125.9, 122.1, 118.6, 68.4, 25.4, 22.0, 21.4; IR: νmax C=O
8.27–8.25 (m, 1H), 7.92–7.86 (m, 2H), 6.58 (q, J = 6.7 Hz, 1H), 3.93
1736 m–1; HRMS: m/z ([M + H]+) calcd. for C14H15ClNO2: 264.784,
(s, 3H), 2.06 (s, 3H), 1.67 (d, J = 6.7 Hz, 3H); 13C NMR (124 MHz,
found 264.0787; Mp: 98.80–100.90 °C.
DMSO): δ = 170.4, 165.9, 159.3, 140.2, 136.4, 131.6, 130.7, 129.7,
126.8, 125.0, 124.4, 70.5, 52.9, 21.3, 19.9; IR: νmax C=O 1734 cm–1
;
1-(6-Bromo-2-methyl-4-quinolyl)ethyl Acetate (3i): Following the
General Synthetic Procedure starting from 6-bromo-2-methyl-quin-
oline (440 mg, 2 mmol), after 7 hours reaction time we obtained
the title compound as white solid (319 mg, 52 % yield). 1H NMR
(500 MHz, DMSO): δ 8.34 (d, J = 2.0 Hz, 1H), 7.9 (d, 1H), 7.86 (dd,
J = 8.9 Hz and 2.0 Hz, 1H), 7.45 (s, 1H), 6.43 (q, J = 6.7 Hz, 1H), 2.65
(s, 3H), 2.13 (s, 3H), 1.56 (d, J = 6.7 Hz, 3H); 13C NMR (124 MHz,
DMSO): δ = 170.2, 160.0, 147.6, 146.7, 132.9, 131.8, 125.9, 124.8,
119.7, 119.0, 68.2, 25.4, 22.1, 21.4; IR: νmax C=O 1731 cm–1; HRMS:
m/z ([M + H]+) calcd. for C14H15BrNO2: 308.0281, found 308.0275;
Mp: 82.30–84.80 °C.
HRMS: m/z ([M + H]+) calcd. for C15H16NO4: 274.1074, found
274.1071; Mp: 113.45–115.62 °C.
1-(3-Chloro-1-isoquinolyl)ethyl Acetate (3o): Following the
General Synthetic Procedure starting from 3-chloroisoquinoline
(326 mg, 2 mmol), after 18 hours reaction time we obtained the
1
title compound as light yellow solid (240 mg, 48 % yield). H NMR
(500 MHz, DMSO): δ 8.32 (d, J = 8.7 Hz, 1H), 8.02 (s, 1H), 8.00 (s,
1H), 7.86–7.83 (m, 1H), 7.75–7.72 (m, 1H), 6.54 (q, J = 6.6 Hz, 1H),
2.06 (s, 3H), 1.62 (d, J = 6.6 Hz, 3H); 13C NMR (124 MHz, DMSO): δ =
170.3, 160.4, 143.8, 138.9, 132.0, 128.8, 127.5, 125.1, 124.3, 120.4,
69.6, 21.3, 20.0; IR: νmax C=O 1732 cm–1; HRMS: m/z ([M + H]+) calcd.
for C13H13ClNO2: 250.0629, found 250.0634; Mp: 86.24–89.34 °C.
1-(2-Phenyl-4-quinolyl)ethyl Acetate (3j): Following the General
Synthetic Procedure starting from 2-phenylquinoline (410 mg,
2 mmol), after 18 hours reaction time we obtained the title com-
pound as yellow oil (283 mg, 49 % yield). 1H NMR (500 MHz, DMSO):
δ 8.28–8.26 (m, 2 H), 8.21 (d, J = 7.8 Hz, 1H), 8.13 (dd, J = 8.2 Hz
and 0.8 Hz, 1H), 8.05 (s, 1H), 7.83–7.80 (m, 1H), 7.68–7.64 (m, 1H),
7.59–7.50 (m, 3H), 6.55 (q, J = 6.7 Hz, 1H), 2.16 (s, 3H), 1.68 (d, J =
6.7 Hz, 3H); 13C NMR (124 MHz, DMSO): δ = 169.8, 156.0, 148.6,
147.8, 138.5, 130.0, 129.9, 129.7, 128.9, 127.3, 126.8, 123.7, 123.3,
114.4, 68.4, 21.5, 20.9; IR: νmax C=O 1737 cm–1; HRMS (GC-TOF): m/z
([M]+) calcd. for C19H17NO2: 292.1259, found 292.1264.
1-(6,7-Dimethoxy-1-isoquinolyl)ethyl Acetate (3p): Following the
General Synthetic Procedure starting from 6,7-dimethoxyisoquin-
oline (378 mg, 2 mmol), after 18 hours reaction time we obtained
1
the title compound as colourless oil (127 mg, 23 % yield). H NMR
(500 MHz, DMSO): δ 8.29 (d, J = 5.5 Hz, 1H), 7.63 (d, J = 5.5 Hz, 1H),
7.45 (s, 1H), 7.38 (s, 1H), 6.55 (q, J = 6.6 Hz, 1H), 3.93 (s, 3H), 3.91 (s,
3H), 2.05 (s, 3H), 1.63 (d, J = 6.6 Hz, 3H); 13C NMR (124 MHz, DMSO):
δ = 170.4, 155.8, 152.8, 150.4, 140.7, 133.5, 121.6, 120.1, 106.2, 103.0,
70.3, 56.2, 56.0, 21.3, 19.6; IR: νmax C=O 1717 cm–1; HRMS: m/z ([M
+ H]+) calcd. for C15H18NO4: 276.1230, found 276.1227.
1-(1-Isoquinolyl)ethyl Acetate (3k): Following the General Syn-
thetic Procedure starting from isoquinoline (258 mg, 2 mmol), after
2 hours reaction time we obtained the title compound as colourless
oil (248 mg, 58 % yield). 1H NMR (500 MHz, DMSO): δ 8.47 (d, J =
5.7 Hz, 1H), 8.27 (d, J = 8.6 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.81–
7.78 (m, 2H), 7.74–7.70 (m, 1H), 6.59 (q, J = 6.6 Hz, 1H), 2.04 (s, 3H),
1.64 (d, J = 6.6 Hz, 3H); 13C NMR (124 MHz, DMSO): δ = 170.3, 158.7,
141.9, 130.8, 128.3, 128.0, 124.7, 121.2, 70.1, 21.3, 20.0; IR: νmax
C=O 1732 cm–1; HRMS: m/z ([M + H]+) calcd. for C13H14NO2:
216.1019, found 216.1016.
1-(4-Chloro-6,7-dimethoxy-quinazolin-2-yl)ethyl Acetate (3q):
Following the General Synthetic Procedure starting from 4-chloro-
6,7-dimethoxyquinazoline (449 mg, 2 mmol), after 18 hours reaction
time we obtained the title compound as white solid (364 mg, 59 %
yield). 1H NMR (500 MHz, DMSO): δ 7.45 (s, 1H), 7.39 (s, 1H), 5.76 (q,
J = 6.8 Hz, 1H), 4.01 (s, 3H), 3.99 (s, 3H), 2.10 (s, 3H), 1.58 (d, J =
6.8 Hz, 3H); 13C NMR (124 MHz, DMSO): δ = 170.4, 162.5, 158.8,
157.5, 151.8, 149.1, 117.7, 107.4, 102.8, 72.8, 57.1, 56.7, 21.3, 19.9; IR:
νmax C=O 1735 cm–1; HRMS: m/z ([M + H]+) calcd. for C14H16ClN2O4:
311.0793, found 311.0802; Mp: 115.36–119.15 °C.
1-(4-Bromo-1-isoquinolyl)ethyl Acetate (3l): Following the Gen-
eral Synthetic Procedure starting from 4-bromoisoquinoline
(416 mg, 2 mmol), after 18 hours reaction time we obtained the
title compound as light yellow oil (310 mg, 53 % yield). 1H NMR
(500 MHz, DMSO): δ 8.74 (s, 1H), 8.37 (d, J = 8.5 Hz, 1H), 8.18 (d, J =
8.5 Hz, 1H), 8.00–7.97 (m, 1H), 7.87–7.83 (m, 1H), 6.57 (q, J = 6.6 Hz,
1H), 2.04 (s, 3H), 1.63 (d, J = 6.6 Hz, 3H); 13C NMR (124 MHz, DMSO):
δ = 170.3, 159.0, 143.5, 134.6, 132.7, 129.6, 126.8, 126.6, 125.5, 119.2,
69.8, 21.3, 20; IR: νmax C=O 1736 cm–1; HRMS: m/z ([M + H]+) calcd.
for C13H13BrNO2: 294.0124, found 294.0115.
1-(4-Chloro-6-methyl-quinazolin-2-yl)ethyl Acetate (3r): Follow-
ing the General Synthetic Procedure starting from 4-chloro-6-meth-
ylquinazoline (357 mg, 2 mmol), after 18 hours reaction time we
obtained the title compound as white solid (257 mg, 49 % yield).
1H NMR (500 MHz, DMSO): δ 8.05 (s, 1H), 7.99–7.95 (m, 2H), 5.80 (q,
J = 6.8 Hz, 1H), 2.58 (s, 3H), 2.11 (s, 3H), 1.60 (d, J = 6.8 Hz, 3H); 13C
NMR (124 MHz, [D6]DMSO) δ = 170.4, 163.2, 161.7, 149.6, 140.4,
138.5, 128.5, 124.5, 122.3, 72.8, 21.7, 21.3, 19.8; IR: νmax C=O
1734 cm–1; HRMS: m/z ([M + H]+) calcd. for C13H14ClN2O2: 265.0738,
found 265.0733; Mp: 166.00–181.63 °C.
1-(5-Bromo-1-isoquinolyl)ethyl Acetate (3m): Following the Gen-
eral Synthetic Procedure starting from 5-bromoisoquinoline 1-(4,6-Dichloropyrido[3,4-d]pyrimidin-2-yl)ethyl Acetate (3s):
(416 mg, 2 mmol), after 18 hours reaction time we obtained the
title compound as pale white solid (390 mg, 66 % yield). 1H NMR
(500 MHz, DMSO): δ 8.63 (d, J = 5.9 Hz, 1H), 8.35 (d, J = 8.6 Hz, 1H),
8.18 (dd, J = 7.6 Hz and 0.8 Hz, 1H), 7.95 (dd, J = 5.9 Hz and 0.8 Hz,
Following the General Synthetic Procedure starting from 4,6-di-
chloropyrido[3,4-d]pyrimidine (400 mg, 2 mmol), after 18 hours re-
action time we obtained the title compound as light yellow solid
(146 mg, 33 % yield). 1H NMR (500 MHz, DMSO): δ 9.33 (s, 1H), 8.22
1H), 7.67–7.64 (m, 1H), 6.6 (q, J = 6.6 Hz, 1H), 2.05 (s, 3H), 1.63 (d, (s, 1H), 6.77 (q, J = 6.7 Hz, 1H), 2.08 (s, 3H), 1.60 (d, J = 6.7 Hz, 3H);
J = 6.6 Hz, 3H); 13C NMR (124 MHz, DMSO): δ = 170.3, 159.7, 143.7,
13C NMR (124 MHz, DMSO): δ = 170.2, 163, 162/141.6, 155.2, 146.9,
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129.6, 117.4, 67.8, 21.2, 19.9; IR: νmax C=O 1731 cm–1; HRMS: m/z 56.0, 21.3, 19.9; IR: νmax C=O 1738 cm–1; HRMS: m/z ([M + H]+) calcd.
([M + H]+) calcd. for C11H10Cl2N3O2 286.0144, found 286.0144; Mp: for C15H16ClN2O3: 307.0844, found 307.0849.
163.66–177.08 °C (decomposition).
1-(2-Quinolyl)ethyl Acetate (3aa): Following the General Synthetic
1-[2-(1-Acetoxyethyl)quinazolin-4-yl]ethyl Acetate (3t): Follow-
ing the General Synthetic Procedure starting from quinazoline
(260 mg, 2 mmol), after 18 hours reaction time we obtained the
title compound as yellow oil (242 mg, 40 % yield); 1H NMR
(500 MHz, DMSO): δ 8.34 (d, J = 8.4 Hz, 1H), 8.04–7.99 (m, 2H), 7.78–
7.74 (m, 1H), 6.54–6.47 (m, 1H), 5.92–5.82 (m, 1H), 2.13 (d, J = 5.5 Hz,
3H) 2.09 (s, 3H), 1.67–1.59 (m, 6H); 13C NMR (124 MHz, DMSO): δ =
170.4/170.3/170.2, 169.6/169.3, 164.2/164.0, 150.4/150.3, 135.0/
129.0, 128.6/128.5, 124.9/124.8, 120.6/120.5, 73.1/73.0, 69.7/69.6,
21.3/21.1/21.0, 20/19.8; IR: νmax C=O 1736 cm–1; HRMS: m/z ([M +
H]+) calcd. for C16H19N2O4: 303.1339, found 303.1341.
Procedure starting from quinoline (258 mg, 2 mmol), after 3 hours
reaction time we obtained the title compound as yellow oil
(131 mg, 30 % yield). 1H NMR (500 MHz, [D6]DMSO) δ 8.40 (d, J =
8.5, 1H), 8.00–7.94 (m, 2H), 7.78–7.75 (m, 1 H), 7.62–7.59 (m, 1 H),
7.57 (d, J = 8.6 Hz, 1 H), 5.91 (q, J = 6.8 Hz, 1 H), 2.12 (s, 3 H), 1.58
(d, J = 6.8 Hz, 3H); 13C NMR (124 MHz, [D6]DMSO) δ = 170.4, 161.1,
147.2, 137.7, 130.3, 129.1, 128.4, 127.6, 127.0, 118.8, 73.5, 21.4, 20.9.
IR νmax C=O 1737 cm–1. HRMS: m/z ([M + H]+) calcd. for C13H14NO2:
216.1019, found 216.1019.
1-(4-Quinolyl)ethyl Acetate (3ab): Following the General Synthetic
Procedure starting from quinoline (258 mg, 2 mmol), after 3 hours
reaction time we obtained the title compound as yellow oil (50 mg,
12 % yield). 1H NMR (500 MHz, [D6]DMSO) δ 8.89 (d, J = 4.5 Hz, 1
H), 8.19 (dd, J = 8.7 Hz and J = 0.8 Hz, 1 H), 8.07 (dd, J = 8.4 Hz and
J = 0.8 Hz,1 H), 7.83–7.79 (m, 1 H), 7.70–7.66 (m, 1 H), 7.53 (d, J =
4.5 Hz, 1 H), 6.51 (q, J = 6.4 Hz, 1 H), 2.14 (s, 3 H), 1.61 (d, J = 4.5 Hz,
3 H); 13C NMR (124 MHz, [D6]DMSO) δ = 170.2, 151.0, 148.2, 148.0,
130.3, 129.9, 127.4, 125.0, 123.8, 117.4, 68.4, 22.0, 21.4. IR νmax C=O
1734 cm–1. HRMS: m/z ([M + H]+) calcd. for C13H14NO2: 216.1019,
found 216.1019.
1-[4-(1-Acetoxyethyl)phthalazin-1-yl]ethyl Acetate (3u): Follow-
ing the General Synthetic Procedure starting from phthalazine
(260 mg, 2 mmol), after 6 hours reaction time we obtained the title
compound as yellow oil (195 mg, 32 % yield). 1H NMR (500 MHz,
DMSO): δ 8.37–8.33 (m, 2 H), 8.10–8.07 (m, 2 H), 6.63–6.59 (m, 2 H),
2.07 (s, 6 H), 1.71 (d, J = 6.7 Hz, 6 H); 13C NMR (124 MHz, DMSO):
δ = 170.4, 158.2, 133.4, 124.6, 124.3, 69.7, 21.3, 19.9. IR: νmax C=O
1724 cm–1. HRMS: m/z ([M + H]+) calcd. for C16H19N2O4: 303.1339,
found 303.1331.
1-(4-Phenyl-2-pyridyl)ethyl Acetate (3v): Following the General
Synthetic Procedure starting from 4-phenylpyridine (310 mg,
2 mmol), after 18 hours reaction time we obtained the title com-
pound as yellow oil (192 mg, 40 % yield). 1H NMR (500 MHz, DMSO):
δ 8.59 (dd, J = 5.3 Hz and 0.6 Hz, 1H), 7.81–7.79 (m, 2H), 7.67 (d,
J = 1.6 Hz, 1H), 7.64 (dd, J = 5.2 and J = 1.8 Hz, 1H), 7.56–7.47 (m,
[(1)-1-[2-[(1)-1-Acetoxyethyl]-4-quinolyl]ethyl] Acetate (3ac):
Following the General Synthetic Procedure starting from quinoline
(258 mg, 2 mmol), after 3 hours reaction time we obtained the title
compound as yellow oil (105 mg, 17 % yield). 1H NMR (500 MHz,
[D6]DMSO) δ 8.18 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.82–
7.78 (m, 1H), 7.69–7.65 (m, 1H), 7.53 (d, J = 4.3 Hz, 1H), 6.53–6.48
3H), 5.83 (q, J = 6.7 Hz, 1H), 2.09 (s, 1H), 1.55 (d, J = 6.7 Hz, 3H); 13
NMR (124 MHz, DMSO): δ = 170.3, 161.2, 150.1, 148.5, 137.7, 129.8,
C
(m, 1H), 5.96–5.88 (m, 1H), 2.15–2.13 (m, 6H), 1.62–1.58 (m, 6H). 13
C
NMR (124 MHz, [D6]DMSO) δ = 170.4/170.3, 170.2/170.1, 161.0/
160.8, 149.2/149.0, 147.5/147.5, 130.2/130.1, 129.7/129.0, 127.4/
127.4, 124.4/124.3, 123.8, 114.5/114.1, 73.4, 68.6, 22.0, 21.4/21.3,
20.7. IR νmax C=O 1736 cm–1. HRMS: m/z ([M + H]+) calcd. for
C17H20NO4: 302.1387, found 302.1390.
129.7, 127.4, 120.9, 118.2, 73.0, 21.5, 20.9; IR: νmax C=O 1731 cm–1
;
HRMS: m/z ([M + H]+) calcd. for C15H16NO2: 242.1176, found
242.1176.
1-(4-Cyano-2-pyridyl)ethyl Acetate (3w): Following the General
Synthetic Procedure starting from isonicotinonitrile (208 mg,
2 mmol), after 5 hours reaction time we obtained the title com-
pound as yellow oil (185 mg, 51 % yield). 1H NMR (500 MHz, DMSO):
δ 8.80 (dd, J = 5.0 Hz and 0.8 Hz, 1H), 7.91–7.90 (m, 1H), 7.81 (dd,
J = 5.0 Hz and 1.5 Hz, 1H), 5.79 (q, J = 6.7 Hz, 1H), 2.11 (s, 3H), 1.50
(d, J = 6.7 Hz, 3H); 13C NMR (124 MHz, DMSO): δ = 170.3, 162.1,
150.7, 125.2, 122.6, 120.7, 117.2, 72.3, 21.4, 20.7; IR: νmax C=O
1732 cm–1; HRMS: m/z ([M + H]+) calcd. for C10H11N2O2: 191.0815,
found 191.0814.
(4-Methyl-2-quinolyl)methyl Acetate (4): Following the General
Synthetic Procedure starting from 4-methylquinoline (283 mg,
2 mmol), after 18 hours reaction time we obtained the title com-
pound as colourless oil (138 mg, 32 % yield.). 1H NMR (500 MHz,
DMSO): δ 8.09 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.78–7.74
(m, 1H), 7.64–7.61 (m, 1H), 7.41 (s, 1H), 5.26 (s, 2H), 2.7 (s, 3H), 2.16
(s, 3H); 13C NMR (124 MHz, DMSO): δ = 170.7, 156.5, 147.2, 145.7,
130.1, 129.6, 127.5, 126.9, 124.7, 120.3, 67.1, 21.2, 18.8; IR: νmax C=
O 1737 cm-1; HRMS: m/z ([M + H]+) calcd. for C13H14NO2 216.1019,
found 216.1020.
1-(4,6-Dimethylpyrimidin-2-yl)ethyl Acetate (3x): Following the
General Synthetic Procedure starting from 4,6-dimethylpyrimidine
(316 mg, 2 mmol), after 3 hours reaction time, and using 20 % ethyl
acetate – 80 % heptane as eluent we obtained the title compound
The Reaction of 4-Methylquinoloine with Butyl Acetate
Following the General Synthetic Procedure starting from 4-methyl-
quinoline (283 mg, 2 mmol), after 18 hours of reaction time we
obtained the following compounds.
1
as light yellow oil (258 mg, 66 % yield). H NMR (500 MHz, DMSO):
δ 7.14 (s, 1H), 5.61 (q, J = 6.7 Hz, 1H), 2.39 (s, 6H), 2.05 (s, 3H), 1.48
(d, J = 6.7 Hz, 3H); 13C NMR (124 MHz, DMSO): δ = 170.3, 167.8,
167.1, 119.1, 73.1, 23.9, 21.3, 20; IR: νmax C=O 1734 cm–1. HRMS: m/z
([M + H]+) calcd. for C10H15N2O2: 195.1128, found 195.1130.
1-(4-Methyl-2-quinolyl)butyl Acetate (5a): colourless oil (51 mg,
1
10 % yield). H NMR (500 MHz, DMSO): δ 8.08 (dd, J = 8.3 Hz and
0.8 Hz, 1H), 7.97 (dd, J = 8.4 Hz and 0.7 Hz, 1H), 7.77–7.73 (m, 1H),
7.63–7.60 (m, 1H), 7.39 (d, J = 0.8 Hz, 1H), 5.77–5.74 (m, 1H), 2.70
(d, J = 0.9 Hz, 3H), 2.12 (s, 3H), 1.92–1.87 (m, 2H), 1.41–1.28 (m, 2H),
0.90 (t, J = 7.5 Hz, 3H); 13C NMR (124 MHz, DMSO): δ = 170.6, 145.7,
129.9, 129.7, 124.6, 119.3, 76.8, 36.9, 21.4, 18.9, 18.7, 14.1; IR: νmax
C=O 1740 cm–1; HRMS: m/z ([M + H]+) calcd. for C16H20NO2
258.1489, found 258.1481.
1-[4-Chloro-6-(4-methoxyphenyl)pyrimidin-2-yl]ethyl Acetate
(3y): Following the General Synthetic Procedure starting from 4-
chloro-5-(4-methoxyphenyl)pyrimidine (440 mg, 2 mmol), after 18
hours reaction time we obtained the title compound as yellow oil
(132 mg, 30 % yield). 1H NMR (500 MHz, DMSO): δ 8.24–8.22 (m,
2H), 8.13 (s, 1H), 7.12–7.09 (m, 2H), 5.69 (q, J = 6.8 Hz, 3H), 3.81 (s,
3H), 2.13 (s, 3H), 1.57 (q, J = 6.8 Hz, 3H); 13C NMR (124 MHz, DMSO):
δ = 170.4, 169.4, 165.4, 162.9, 161.8, 129.9, 127.5, 115.0, 114.9, 72.6,
2-(4-Methyl-2-quinolyl)butyl Acetate (5b): colourless oil (36 mg,
7 % yield). 1H NMR (500 MHz, DMSO): δ 8.06 (dd, J = 8.3 Hz and
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[6] G. Qin, X. Chen, L. Yang, H. Huang, ACS Catal. 2015, 5, 2882–2885.
[7] L.-N. Guo, S. Wang, X.-H. Duan, S.-L. Zhou, Chem. Commun. 2015, 51,
4803–4806.
0.9 Hz, 1H), 7.95 (dd, J = 8.4 Hz and 0.7 Hz, 1H), 7.73–7.70 (m, 1H),
7.60–7.56 (m, 1H), 7.34 (d, J = 0.8 Hz, 1H), 4.36 (d, J = 7.1 Hz, 2H),
3.19–3.12 (m, 1H), 2.67 (d, J = 0.9 Hz, 3H), 1.91 (s, 3H), 1.83–1.75 (m,
2H), 0.77 (t, J = 7.4 Hz, 3H); 13C NMR (124 MHz, DMSO): δ = 170.8,
162.1, 147.7, 144.7, 129.6, 129.6, 127.2, 126.3, 124.6, 122.4, 67.1, 48.5,
24.8, 21.1, 18.7, 12.0; IR: νmax C=O 1742 cm–1; HRMS: m/z ([M + H]+)
calcd. for C16H20NO2 258.1489, found 258.1493.
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3-(4-Methyl-2-quinolyl)butyl Acetate (5c): colourless oil (190 mg,
1
37 % yield). H NMR (500 MHz, DMSO): δ 8.04 (dd, J = 8.3 Hz and
0.9 Hz, 1H), 7.93 (dd, J = 8.4 Hz and 0.7 Hz, 1H), 7.72–7.69 (m, 1H),
7.58–7.54 (m, 1H), 7.33 (d, J = 0.8 Hz, 1H), 3.99–3.91 (m, 2H), 3.14–
3.07 (m, 1H), 2.66 (d, J = 0.8 Hz, 3H), 2.19–2.12 (m, 1H), 1.97–1.90
(m, 4H), 1.30 (d, J = 7.1 Hz, 3H); 13C NMR (124 MHz, DMSO): δ =
170.8, 165.5, 147.5, 144.9, 129.6, 129.5, 127.1, 126.1, 124.5, 121.4,
62.8, 39.0, 35.0, 21.2, 21.1, 18.7; IR: νmax C=O 1739 cm–1; HRMS: m/z
([M + H]+) calcd. for C16H20NO2 258.1489, found 258.1492.
1-(4-Methyl-2-quinolyl)ethyl Propanoate (6): Following the Gen-
eral Synthetic Procedure starting from 4-methylquinoline (283 mg,
2 mmol), after 3 hours reaction time we obtained the title com-
pound as colourless oil (235 mg, 48 % yield). 1H NMR (500 MHz,
[D6]DMSO) δ 8.09 (dd, J = 8.4 Hz and J = 1.0 Hz, 1H), 7.98 (dd, J =
8.4 Hz and J = 0.7 Hz, 1H), 7.78–7.74 (m, 1H), 7.64–7.61 (m, 1H),
7.42 (d, J = 0.8 Hz, 1H), 5.88 (q, J = 6.7 Hz, 1H), 2.71 (d, J = 0.8 Hz,
3H), 2.47–2.41 (m, 2H), 1.57 (d, J = 6.7 Hz, 3H), 1.06 (t, J = 6.7 Hz,
3H); 13C NMR (124 MHz, [D6]DMSO) δ = 173.6, 160.8, 147.1, 145.8,
130.0, 129.7, 127.5, 126.8, 124.6, 119.0, 73.4, 27.4, 21.0, 18.9, 9.5. IR
νmax C=O 1736 cm–1, -CH 2982 cm–1. HRMS: m/z ([M + H]+) calcd.
for C15H18NO2: 244.1332, found 244.1332.
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1
oil (31 mg, 0.4 % yield). H NMR (500 MHz, [D6]DMSO) δ 8.29–8.27
(m, 2H), 8.12–8.05 (m, 3H), 7.80–7.76 (m, 1H), 7.65–7.61 (m, 1H),
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156.1, 147.9, 145.7, 139.2, 130.1, 130.0, 129.3, 127.6, 127.4, 126.8,
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This research has been implemented in the frame of project no.
FIEK_16-1–2016- 0005 “Development of molecular biomarker
research and service center”, with the support provided from
the National Research, Development, and Innovation Fund of
Hungary, financed under the FIEK_16 funding scheme.
Keywords: Alkylation · C–H activation · Minisci reaction ·
Photocatalysis · Synthetic methods
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Received: August 14, 2020
Eur. J. Org. Chem. 0000, 0–0
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© 2020 Wiley-VCH GmbH

Communication
doi.org/10.1002/ejoc.202001113
EurJOC
European Journal of Organic Chemistry
Photoredox Catalysis
The direct Csp2-Csp3 visible-light
photoredox cross-dehydrogenative
N. Győrfi, A. Kotschy,
coupling of N-heteroaromatics with
ethyl acetate via the generation of
1-acetoxyethan-1-yl radical is reported.
This approach also uncovers ethyl
acetate as a cheap and non-conven-
tional radical source in photoredox re-
lated organic synthesis.
M. Gyuris* ............................................. 1–9
Visible-Light Photoredox Alkylation
of Heteroaromatic Bases Using Ethyl
Acetate as Alkylating Agent
doi.org/10.1002/ejoc.202001113
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
9
© 2020 Wiley-VCH GmbH