Hydroxymethylation of quinolinesviairon promoted oxidative C-H functionalization: synthesis of arsindoline-A and its derivatives

Article abstract of DOI:10.1039/d0ob02212h

Herein, we report a mild and efficient hydroxymethylation of quinolinesviaan iron promoted cross-dehydrogenative coupling reaction under external acid free conditions. Various hydroxyalkyl substituted quinolines were achieved in excellent yields with well tolerated functional groups. Importantly, a few of the hydroxylmethylated quinolines were further transformed into respective aldehydes, and were successfully utilized for the synthesis of alkaloid arsindoline-A and its derivatives.

Full text of DOI:10.1039/d0ob02212h

Organic &
Biomolecular Chemistry
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Hydroxymethylation of quinolines via iron
promoted oxidative C–H functionalization:
synthesis of arsindoline-A and its derivatives†
Cite this: Org. Biomol. Chem., 2021,
19, 645
Bangarigalla Shantharjun,a,b Damera Vani,a,b Ramanjaneyulu Unnava,a
a,b
Mummadi Sandeepa,b and Kallu Rajender Reddy
*
Herein, we report a mild and efficient hydroxymethylation of quinolines via an iron promoted cross-dehy-
drogenative coupling reaction under external acid free conditions. Various hydroxyalkyl substituted quino-
lines were achieved in excellent yields with well tolerated functional groups. Importantly, a few of the
hydroxylmethylated quinolines were further transformed into respective aldehydes, and were successfully
utilized for the synthesis of alkaloid arsindoline-A and its derivatives.
Received 6th November 2020,
Accepted 8th December 2020
DOI: 10.1039/d0ob02212h
rsc.li/obc
ation of quinolines by using Na2S2O8 in a mixture of methanol
Introduction
and water at 70 °C.8 Later, Wang’s group described a silver pro-
Methanol is one of the most important raw materials in both moted hydroxyalkylation of quinolines by utilizing Selectfluor
organic chemistry and drug discovery. It is also used as a as an oxidant under reflux conditions.9 Recently, Lei et al.
common solvent and reagent in synthetic organic chemistry demonstrated a visible-light-induced protocol for the synthesis
and is a sustainable feedstock for value-added chemicals, of hydroxy alkylated quinoline derivatives in the presence of
pharmaceuticals and materials.1 In addition, it has been suc- Selectfluor and TFA as an additive.10 However, these methods
cessfully used as a C1 source for various organic transform- suffer from the requirement of relatively expensive reagents/
ations such as methylation, methoxylation, formylation and catalysts and the need for longer reaction times. In addition,
hydroxymethylation.2 Among these transformations, hydroxy- the Minisci-type of transformation always requires external
methylation of azaarenes has attracted remarkable interest acid additives and extensive high energetic conditions. Hence,
from medicinal chemists due to the common occurrence of eco-friendly/green-chemistry protocols for the development of
hydroxymethyl(alkyl)units in various important pharmaceuti- hydroxyalkylated heterocycles using inexpensive, environmen-
cally active compounds (Fig. 1).3–5 Along similar lines, tally benign and easy handling reagents would be highly
N-heterocycles are also key scaffolds in several biologically desirable.
active natural products and pharmaceutical agents.6 Owing to
On the other hand, iron-catalyzed/-mediated oxidative C–H
the significance of these units, the hydroxymethylation of bond functionalization is a powerful strategy for the construc-
N-heteroarenes has gained much attention in modern syn- tion of C–C and C-hetero atom bonds.11 This promising strat-
thetic chemistry.
egy is more economic and doesn’t require pre-functionalized
Despite the significance of hydroxymethylated heteroar- starting materials. In continuation of our efforts towards the
enes, only a few reports on their synthesis have been documen- development of iron-catalyzed/-mediated organic transform-
ted so far. For example, in 1971, Minisci and co-workers pro- ations,12 herein, we wish to report an efficient iron mediated
posed a method for the introduction of the hydroxymethyl rapid hydroxyalkylation of heteroarenes, in which H2O2 is used
group into 4-methylquinoline by employing (NH4)2S2O8 as an as a cheap and mild oxidant under external acid free con-
oxidant and H2SO4 as an additive under thermal conditions.7
Interestingly, Togo et al. reported a metal free hydroxymethyl-
aCatalysis and Fine Chemicals Division, CSIR-Indian Institute of Chemical
Technology, Tarnaka, Hyderabad - 500007, India. E-mail: rajender@iict.res.in,
rajenderkallu@gmail.com; Fax: (+91)-040-2716-0921
bAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, U.P.,
India
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
Fig. 1 Examples of bioactive compounds possessing hydroxyalkyl
d0ob02212h
groups.
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Table 1 Screening of the reaction conditions for the hydroxyl methyl-
ation of 2-methyl quinolinea
Scheme 1 Hydroxy alkylation of heteroarenes.
Entry
Catalyst
Oxidant
Yieldb (%)
1
2
3
4
5
6
7
8
Fe(ClO4)2·xH2O
Fe(ClO4)2·xH2O
FeCl2
FeBr2
FeSO4
Fe(acac)2
FeCl3
Fe(ClO4)3
Fe(acac)3
TBHP
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
H2O2
DTBP
DCP
PhI(OAc)2
O2
H2O2
—
H2O2
H2O2
66
78
33
28
Trace
Trace
13
18
Trace
0c
0
0
0
0
ditions. Notably, this reaction was complete within 10 minutes
at room temperature (Scheme 1).
Results and discussion
9
To find the optimum reaction conditions, we initiated our
investigation with 2-methylquinoline (1a) as the model sub-
strate in excess quantity of methanol (2a), which acted as both
as a hydroxymethylating agent and solvent. First, we per-
formed the reaction of 1a and excess amount of 2a in the pres-
ence of Fe(ClO4)2·xH2O (1.0 equiv.) and TBHP (70% in water,
2.0 equiv.) as an oxidant at room temperature for 10 min,
giving the desired product (2-methylquinolin-4-yl)methanol
(3a) in 66% yield (Table 1, entry 1), whereas the use of H2O2
(50% in water) instead of TBHP increased the yield of the
10
11
12
13
14
15
16
17
18
19
20
21
CuCl2
Cu(ClO4)2
PdCl2
Co(ClO4)2
Fe(ClO4)2·xH2O
Fe(ClO4)2·xH2O
Fe(ClO4)2·xH2O
Fe(ClO4)2·xH2O
—
Fe(ClO4)2·xH2O
Fe(ClO4)2·xH2O
Fe(ClO4)2·xH2O
0
0
0
0
0
59d
76e
product (3a) up to 78% (Table 1, entry 2). Encouraged by these a Reactions were performed with 1a (1.0 mmol), catalyst (1.0 equiv.),
and oxidant (2.0 equiv.) in methanol 2a (2.0 mL) at rt for 10 min.
results, a series of iron salts, namely, FeCl2, FeBr2, FeSO4 and
b Isolated yields. c 0% yield means no reaction. d Under reflux con-
ditions. e Reaction time increased to 12 h.
Fe(acac)2, were examined for this reaction. But they were found
to be ineffective for this transformation, and provided very low
yields (Table 1, entries 3–6). Furthermore FeIII catalysts
resulted in low yields (Table 1, entries 7–9). Among all the
tested iron catalysts, Fe(ClO4)2·xH2O showed the best results
for this transformation. Other metal salts like CuCl2, Cu
(ClO4)2, PdCl2 and Co(ClO4)2 proved to be inadequate for this
protocol (Table 1, entries 10–13). Meanwhile, the reaction
could not be induced in the presence of other oxidants, for
instance DTBP, DCP, PhI(OAc)2 and O2 (Table 1, entries
14–17). Furthermore, the absence of either Fe(ClO4)2·xH2O or
H2O2 did not produce the desired product (Table 1, entries 18
and 19).
Table 2 Scope of the quinoline derivativesa,b
These results explain that both Fe(ClO4)2·xH2O and H2O2
are necessary for this transformation. In addition, the reaction
under reflux conditions resulted in 59% yield (Table 1, entry
20). Although the reaction time was prolonged up to 12 h, a
satisfactory increment in the yield was not observed (Table 1,
entry 21). Based on the optimization studies, we conclude that
1.0 equivalent of Fe(ClO4)2·xH2O and 2.0 equivalents of H2O2
(50% in water) at room temperature are the optimal conditions
for this transformation.
With these optimal reaction conditions in hand, the scope
of the quinolines was investigated and the results are shown in
Table 2. Quinolines bearing electron-donating (–Me and
–OMe) and electron-withdrawing (–F, –Cl, and –Br) groups
a Reaction conditions: 1 (1.0 mmol), 2 (2.0 mL), H2O2 (2.0 equiv.), Fe
(ClO4)2·xH2O (1.0 equiv.), rt, 10 min. b Isolated yields.
were well tolerated in the reaction and afforded the corres- 2-phenyl substituted quinoline 1h smoothly furnished the
ponding products (3a–3n) in good yields. Electron-withdrawing respective product (3h) in excellent yield. 7-Fluoro-2-methyl-
groups on 2-methyl quinolines (1e–1g) gave 3e–3g in slightly quinoline and 8-chloro-2-methylquinolines (1i and 1j) reacted
higher yields than electron-donating groups (3a–3d). Notably, well and gave the corresponding products (3i and 3j) in good
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yields. However, 2-chloroquinoline (1k) gave the desired
product 3k in 23% yield. Furthermore, unsubstituted quino-
line (1l) gave three regioisomers, namely, quinolin-2-ylmetha-
nol (3la), quinolin-4-ylmethanol (3lb) and quinoline-2,4-diyldi-
methanol (3lc), in 21%, 23% and 19% (overall yield 63%) yield
respectively. Moreover, these isomers were separated by
column chromatography. Similarly, 8-methylquinoline (1m)
and benzo[h]quinoline (1n) gave a mixture of regioisomers
(3ma–3mc) in 85% and (3na–3nc) 67% overall yields respect-
ively. 2-Phenyl pyridine (1o) also produced two regioisomers
(3oa and 3ob) in 37% overall yield. Subsequently, 2,6-diphenyl
pyridine (1p) furnished the desired product (3p) in low yield.
Furthermore, we also extended our investigation to explore
the possibility of this strategy using higher alcohols (like
ethanol 2b, propanol (2c), butanol (2d), isobutanol (2e), and
hexanol (2f)) other than methanol and the results are summar-
ised in Table 3. In this sequence, the reaction with 2-methyl qui-
noline 1a in ethanol 2b under the standard conditions failed to
give the expected product 4a, and the starting materials
remained as such. A longer reaction time (12 h) also failed to
give product 4a. Gratifyingly, switching over to other oxidants,
like TBHP (2.0 equiv.) instead of H2O2, under the same reaction
conditions gave the desired product 4a in 66% yield. In order to
improve the yield of the reaction, the reaction time was pro-
longed to 12 h, and we observed a trace amount of acylated qui-
noline (4a′) along with the desired product (4a). Furthermore,
reactions with 2-phenyl quinoline and 8-chloro-2-methyl quino-
line (1h and 1j) in ethanol 2b afforded 4b and 4c in 57% and
52% yields, respectively. Later, substituted quinolines with pro-
panol 2c produced 4d–4f in 34–42% yields. Similarly, 4-methyl/
2,6-dimethyl quinolines (1b/1c) with butanol 2d gave the corres-
ponding products 4g–4h in low yields. These results explain
that increasing the chain lengths of alcohols decreases their
reactivity for this transformation. Furthermore, the reaction of
2-methyl quinoline 1a with a branched alcohol, iso-butanol 2e,
successfully afforded the product 4i in 33% yield. Similarly,
reaction with hexanol gave 4j in 31% yield.
Scheme 2 Gram scale synthesis.
methanol 2a under the optimized conditions and obtained 3a
in 69% yield (Scheme 2).
Quinoline bearing a formyl group at the 4-position is a key
intermediate for the synthesis of various bioactive compounds13
and sensing agents,14 for example, arsindoline-A alkaloid,
which is a representative molecule of anticancer agents.15
Owing to the importance of this intermediate, some of the
4-hydroxymethyl quinolines 3 were successfully converted into
the corresponding 4-formyl quinolines 5 using the Dess–
Martin oxidant.
Furthermore, the formyl group (compound 5) was involved in
a mineral acid (conc. H2SO4 (1.0 equiv.) mediated condensation
reaction with indole (6) in H2O at room temperature for 1 h,
giving the arsindoline-A alkaloid 7a in 83% yield and its deriva-
tives 7b and 7c in 73 and 76% yields, respectively (Table 4).
In order to gain insights into the reaction mechanism, we
performed a control experiment with 1a and 2a in the presence
of the radical scavenger TEMPO under optimized reaction con-
ditions, and product 3a was not obtained (Scheme 3). This
result suggests that the reaction proceeds through a radical
pathway. Furthermore, the reaction was also examined with
different catalytic systems, such as 10 mol% of Fe(ClO4)2·xH2O
and 2.0 equiv. of H2O2, at room temperature; we did not
observe any desired product, and the starting material (95%)
was recovered (Scheme 3b). Similarly, loading of 30 mol% and
50 mol% of catalyst gave low yields (Scheme 3c and d),
whereas the use of 75 mol% of Fe(ClO4)2·xH2O resulted in 58%
isolated yield along with 30% of the unreacted starting
material (Scheme 3e). These catalytic experiments suggest that
the reaction necessarily required a stoichiometric amount of
Fe(ClO4)2·xH2O.
Moreover, due to the easy availability of the starting
materials and the operational simplicity of this protocol, we
performed a gram scale reaction with 2-methylquinoline 1a in
Based on previous reports9,16 and our own control experi-
mental results, we have proposed a plausible mechanism as
shown in Scheme 4. Initially, Fe(II) is oxidised to Fe(III) via a
single electron transfer (SET) process in the presence of H2O2,
Table 3 Scope of various alcoholsa,b
Table 4 Synthesis of arsindoline-A alkaloid and its derivativesa,b
a Reaction conditions for compounds
(1.0 mmol), Dess–Martin (1.2 equiv.), DCM (2.0 mL), rt, 1 h. (ii)
5 and 7: (i) Compound 3
a Reaction conditions: 1 (1.0 mmol), 2 (2.0 mL), TBHP (2.0 equiv.), Fe Compound 5 (0.5 mmol), indole 6 (1.0 mmol), conc. H2SO4 (1.0 equiv.),
(ClO4)2·xH2O (1.0 equiv.), rt, 15 min. b Isolated yields.
H2O (2.0 mL), rt, 1 h. b Isolated yields are provided.
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iron mediated oxidative CDC strategy under ambient con-
ditions. The main features of the present transformation are
that it does not require external acid additives, uses in-
expensive and commercially available H2O2 as an oxidant, and
has shorter reaction time. In addition, various alcohols were
also tolerated by this reaction to furnish the respective hydro-
xylalkylated N-heteroarenes. Moreover, we have shown syn-
thetic utility of the isolated hydroxymethylated quinolines for
the generation of the corresponding formyl quinolines, which
were further employed for the synthesis of bioactive arsindo-
line-A alkaloid and its derivatives.
Experimental section
All the chemicals and solvents were purchased from Sigma-
Aldrich, Alfa Aesar and S. D. Fine Chemicals Pvt. Ltd, India
and used without further purification. Silica gel
(100–200 mesh) was used for column chromatography, and
thin-layer chromatography was performed on pre-coated silica
gel 60-F254 plates and visualized by UV-light and developed by
iodine. The IR values are reported in reciprocal centimeters
Scheme 3 Control experiments of 3a–3e.
1
(cm−1). All the H and 13C {1H} NMR spectra were recorded on
Avance-300, Avance-400, and Avance-500 MHz spectrometers.
Chemical shifts (δ) are reported in ppm, using TMS (δ = 0) as
an internal standard in CDCl3. The peak patterns are indicated
as follows: bs, broad singlet; s, singlet; d, doublet; t, triplet;
dd, doublet of doublets; sep, septet; and m, multiplet. The
coupling constants (J) are reported in hertz (Hz). LC–MS
measurements were carried out with an Agilent 1200 series
(DAD; diode array detector) instrument using
a Zorbax
(SB-C18, 3.0 mm × 50 mm × 1.8 μm) column. Low- and high-
resolution mass spectrometry was carried out using the elec-
trospray ionisation method.
Scheme 4 Plausible mechanism.
generating a hydroxyl radical and a hydroxyl ion. The corres-
ponding hydroxyl radical abstracts the hydrogen radical from
the α-CH of methanol and generates a hydroxymethyl radical
(A). Meanwhile, Fe(III) coordinates with the N-atom of quino-
line to form a more electron deficient intermediate (B).
Afterwards, hydroxymethyl radical (A) attacks the 4th position
of intermediate B to afford the radical cation intermediate C.
Intermediate D is obtained from intermediate C via the
removal of Fe(III). Furthermore, intermediate D is oxidised by
Fe(III) to generate a cationic intermediate E, which is similar to
that reported by Wang et al. in the Ag-promoted α-C–H aryla-
tion of alcohols.9 Finally, intermediate E readily undergoes
rearomatization followed by the loss of a proton, resulting in
product 3a. Probably, the corresponding proton is abstracted
by an in situ generated hydroxyl anion.
General procedure and characterization data for the
hydroxymethylation of quinolines (3a–3p)
To a stirring solution of quinolines (1) (1.0 mmol) and Fe
(ClO4)2·xH2O (1.0 equiv.) in 2.0 mL of methanol (2a) was
added dropwise 2.0 equivalents of 50% H2O2 at room tempera-
ture. The progress of the reaction was monitored by TLC. After
the completion of the reaction (10 min), the reaction mixture
was extracted with ethyl acetate and washed with saturated
NaHCO3 and brine solution. The organic layer was dried over
Na2SO4 and concentrated in vacuum. The mixture was purified
by column chromatography over silica gel (100–200 mesh size),
and using a hexane/ethyl acetate mixture as the eluent gave the
desired products 3.
(2-Methylquinolin-4-yl)methanol (3a). White solid (136 mg,
1
78% yield), mp 143–145 °C; H NMR (400 MHz, CDCl3) δ 8.03
(d, J = 8.3 Hz, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.67 (t, J = 8.4 Hz,
1H), 7.49 (t, J = 8.2 Hz, 1H), 7.41 (s, 1H), 5.19 (s, 2H), 2.70 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 159.0, 147.4, 146.4, 129.3,
Conclusions
In summary, we have developed a simple, mild and efficient 128.9, 125.8, 124.1, 122.7, 119.1, 61.4, 25.2. HRMS (ESI): calcd
protocol for the hydroxymethylation of N-heteroarenes via an for [M + H]+ C11H12NO: 174.0913, found: 174.0917.
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(4-Methylquinolin-2-yl)methanol (3b). Yellow solid (121 mg, 160.5, 149.0, 146.0, 124.9 (d, J = 9.9 Hz), 121.2, 118.7, 116.0 (d,
69% yield), mp 78–80 °C; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 24.2 Hz), 113.1, 112.9 61.8, 25.4. 19F NMR (377 MHz,
J = 8.4 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.71 (t, J = 8.4 Hz, 1H), CDCl3)
7.55 (t, J = 8.2 Hz, 1H), 7.12 (s, 1H), 4.87 (s, 2H), 2.70 (s, 3H). C11H11FNO: 192.0819, found: 192.0829.
13C NMR (101 MHz, CDCl3) δ 158.6, 146.4, 145.3, 129.5, 129.1,
(8-Chloro-2-methylquinolin-4-yl)methanol (3j). Pale yellow
127.6, 126.1, 123.8, 119.0, 64.0, 18.8. HRMS (ESI): calcd for [M solid (151 mg, 78% yield), mp 141–143 °C; 1H NMR (500 MHz,
δ −110.3 (s). HRMS (ESI): calcd for [M +
H]+
+ H]+ C11H12NO: 174.0913, found: 174.0920.
CDCl3) δ 7.82–7.77 (m, 2H), 7.44–7.37 (m, 2H), 5.15 (s, 2H),
(2,6-Dimethylquinolin-4-yl)methanol (3c). White solid 2.76 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.3, 146.3, 144.0,
(119 mg, 63% yield), mp 150–152 °C; 1H NMR (400 MHz, 133.3, 129.5, 125.6, 125.5, 121.9, 120.0, 61.7, 25.8. HRMS (ESI):
CDCl3) δ 7.92 (d, J = 8.6 Hz, 1H), 7.63 (s, 1H), 7.49 (d, J = 10.4 calcd for [M + H]+ C11H11ClNO: 208.0524, found: 208.0530.
Hz, 1H), 7.36 (s, 1H), 5.14 (s, 2H), 2.66 (s, 3H), 2.51 (s, 3H). 13
C
(2-Chloroquinolin-4-yl)methanol (3k). Yellow solid (46 mg,
1
NMR (101 MHz, CDCl3) δ 158.0, 146.0, 145.6, 135.6, 131.4, 23% yield), mp 148–150 °C; H NMR (400 MHz, CDCl3) δ 8.05
128.7, 124.1, 121.7, 119.1, 61.5, 25.1, 21.8. HRMS (ESI): calcd (d, J = 8.5 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.74 (t, J = 8.4 Hz,
for [M + H]+ C12H14NO: 188.1070, found: 188.1069.
1H), 7.61–7.55 (m, 2H), 5.22 (s, 2H). 13C NMR (101 MHz,
(6-Methoxy-2-methylquinolin-4-yl)methanol (3d). Yellow CDCl3) δ 151.1, 149.5, 147.7, 130.4, 129.3, 127.1, 124.4, 122.7,
1
solid (98 mg, 48% yield), mp 163–165 °C; H NMR (400 MHz, 119.2, 61.3. HRMS (ESI): calcd for [M + H]+ C10H9ClNO:
CDCl3) δ 7.95 (d, J = 9.2 Hz, 1H), 7.36–7.32 (m, 2H), 7.14 (d, J = 194.0367, found: 194.0369.
2.8 Hz, 1H), 5.11 (s, 2H), 3.92 (s, 3H), 2.68 (s, 3H). 13C NMR
Quinolin-2-ylmethanol (3la). Pale yellow oil (34 mg, 21%
(101 MHz, CDCl3 + DMSO) δ 161.7, 160.9, 150.7, 148.2, 135.1, yield); 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.5 Hz, 1H),
129.9, 125.8, 124.2, 106.2, 65.6, 60.3, 29.7. HRMS (ESI): calcd 8.07 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.75–7.69 (m,
for [M + H]+ C12H14NO2: 204.1019, found: 204.1019.
1H), 7.53 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 4.92 (s,
(6-Fluoro-2-methylquinolin-4-yl)methanol (3e). White solid 2H). 13C NMR (101 MHz, CDCl3) δ 158.2, 145.7, 135.9, 128.8,
(167 mg, 86% yield), mp 162–164 °C; 1H NMR (500 MHz, 127.5, 126.6, 126.5, 125.3, 117.4, 63.2. HRMS (ESI): calcd for
CDCl3) δ 8.04 (dd, J = 9.2, 5.5 Hz, 1H), 7.52 (dd, J = 9.8, 2.8 Hz, [M + H]+ C10H10NO: 160.0757, found: 160.0765.
1H), 7.48–7.42 (m, 2H), 5.12 (s, 2H), 2.73 (s, 3H). 13C NMR
Quinolin-4-ylmethanol (3lb). Pale yellow oil (37 mg, 23%
1
(75 MHz, CDCl3 + DMSO) δ 159.7 (d, J = 244.5 Hz), 158.2, 146.6 yield); H NMR (300 MHz, CDCl3) δ 8.10–8.76 (m, 1H), 8.10 (d,
144.5, 144.6, 131.3, 131.2, 124.9 (d, J = 9.4 Hz), 119.9, 118.8 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H),
J = 25.5 Hz), 106.9, 106.6, 60.8, 25.1. 19F NMR (377 MHz, 7.58–7.50 (t, J = 6.3 Hz, 2H), 5.23 (s, 2H). 13C NMR (101 MHz,
CDCl3)
δ
−109.3 (s). HRMS (ESI): calcd for [M
+
H]+ CDCl3 + DMSO) δ 160.5, 146.3, 136.1, 136.07, 129.0, 127.9,
127.1, 125.5, 118.2, 64.3. HRMS (ESI): calcd for [M + H]+
C11H11FNO: 192.0819, found: 192.0827.
(6-Chloro-2-methylquinolin-4-yl)methanol (3f). Pale yellow C10H10NO: 160.0757, found: 160.0765.
solid (166 mg, 79% yield), mp 158–160 °C; 1H NMR (500 MHz,
Quinoline-2,4-diyldimethanol (3lc). Brown oil (36 mg, 19%
CDCl3) δ 7.96 (d, J = 9.0 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.60 yield); 1H NMR (500 MHz, CDCl3) δ 8.11 (d, J = 8.3 Hz, 1H),
(dd, J = 9.0, 2.3 Hz, 1H), 7.43 (s, 1H), 5.13 (s, 2H), 2.70 (s, 3H). 7.92 (d, J = 9.2 Hz, 1H), 7.73 (t, J = 8.4 Hz, 1H), 7.57 (t, J = 7.6
13C NMR (101 MHz, CDCl3) δ 159.4, 146.0, 145.3, 131.7, 130.7, Hz, 1H), 7.45 (s, 1H), 5.23 (s, 2H), 4.92 (s, 2H). 13C NMR
130.2, 124.9, 122.0, 120.0, 61.5, 25.3. HRMS (ESI): calcd for [M (101 MHz, CDCl3 + DMSO) δ 161.5, 147.4, 146.0, 128.4, 128.3,
+ H]+ C11H11ClNO: 208.0524, found: 208.0529.
125.1, 124.2, 122.6, 115.3, 64.5, 59.5. HRMS (ESI): calcd for [M
(6-Bromo-2-methylquinolin-4-yl)methanol (3g). Pale yellow + H]+ C11H12NO2: 190.0863, found: 190.0865.
solid (192 mg, 76% yield), mp 163–165 °C; 1H NMR (500 MHz,
(8-Methylquinolin-2-yl)methanol (3ma). Brick red solid
CDCl3) δ 8.04 (d, J = 2.1 Hz, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.74 (35 mg, 19% yield), mp 121–123 °C; 1H NMR (400 MHz,
(dd, J = 9.0, 2.2 Hz, 1H), 7.43 (s, 1H), 5.13 (s, 2H), 2.71 (s, 3H). CDCl3) δ 8.11 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.58
13C NMR (101 MHz, CDCl3 + DMSO) δ 159.5, 146.2, 132.4, (d, J = 8.0 Hz, 1H), 7.46–7.40 (m, 1H), 7.27–7.22 (m, 1H), 4.92
130.8, 125.6, 125.4, 120.0, 119.5, 60.7, 25.4. HRMS (ESI): calcd (s, 2H), 2.81 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 157.4, 145.5,
for [M + H]+ C11H11BrNO: 252.0019, found: 252.0029.
137.2, 136.4, 130.1, 127.6, 126.1, 125.7, 117.9, 63.9, 17.8.
(2-Phenylquinolin-4-yl)methanol (3h). White solid (219 mg, HRMS (ESI): calcd for [M + H]+ C11H12NO: 174.0913, found:
1
93% yield), mp 106–108 °C; H NMR (400 MHz, CDCl3) δ 8.15 174.0921.
(d, J = 8.5 Hz, 1H), 7.97–7.87 (m, 2H), 7.72 (d, J = 9.2 Hz, 2H),
(8-Methylquinolin-4-yl)methanol (3mb). Pale yellow solid
7.68–7.61 (m, 1H), 7.47–7.33 (m, 4H), 5.00 (s, 2H). 13C NMR (44 mg, 25% yield), mp 134–136 °C; 1H NMR (400 MHz,
(101 MHz, CDCl3) δ 157.4, 147.9, 146.9, 139.5, 130.1, 129.5, CDCl3) δ 8.92 (d, J = 4.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.58
129.4, 128.8, 127.6, 126.4, 122.7, 116.1, 61.7. HRMS (ESI): (d, J = 7.0 Hz, 1H), 7.54 (d, J = 4.3 Hz, 1H), 7.48–7.43 (m, 1H),
calcd for [M + H]+ C16H14NO: 236.1070, found: 236.1081.
5.22 (s, 2H), 2.83 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 149.2,
(7-Fluoro-2-methylquinolin-4-yl)methanol (3i). White solid 147.1, 146.1, 137.8, 129.6, 126.5, 125.7, 120.7, 117.9, 61.9, 18.7.
(151 mg, 78% yield), mp 172–174 °C; 1H NMR (400 MHz, HRMS (ESI): calcd for [M + H]+ C11H12NO: 174.0913, found:
CDCl3) δ 7.92 (dd, J = 9.2, 6.0 Hz, 1H), 7.67 (dd, J = 10.3, 2.6 174.0920.
Hz, 1H), 7.38 (s, 1H), 7.32–7.28 (m, 1H), 5.16 (s, 2H), 2.72 (s,
(8-Methylquinoline-2,4-diyl)dimethanol (3mc). Pale yellow
1
3H). 13C NMR (101 MHz, CDCl3) δ 163.1 (d, J = 250.4 Hz), solid (84 mg, 41% yield), mp 126–128 °C; H NMR (400 MHz,
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CDCl3) δ 7.74 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 7.0 Hz, 2H), progress of the reaction was monitored by TLC. After the com-
7.47–7.42 (m, 2H), 7.40 (s, 2H), 5.20 (s, 4H), 4.90 (s, 5H), 2.80 pletion of the reaction (15 min), the reaction mixture was
(s, 6H). 13C NMR (101 MHz, CDCl3) δ 157.2, 147.0, 145.2, extracted with ethyl acetate and washed with saturated
137.1, 129.9, 126.2, 125.0, 120.5, 114.7, 63.9, 61.8, 18.3. HRMS NaHCO3 and brine solution. The organic layer was dried over
(ESI): calcd for [M
204.1029.
+
H]+ C12H14NO2: 204.1019, found: Na2SO4 and concentrated in vacuum. The mixture was purified
by column chromatography over silica gel (100–200 mesh size),
Benzo[h]quinolin-2-ylmethanol (3na). Pale yellow oil (49 mg, and using a mixture of hexane/ethyl acetate as the eluent gave
23% yield); 1H NMR (300 MHz, CDCl3) δ 9.29 (d, J = 8.9 Hz, the desired product 4.
1H), 8.17 (d, J = 8.2 Hz, 1H), 7.94–7.90 (m, 1H), 7.82 (d, J = 8.8
1-(2-Methylquinolin-4-yl)ethan-1-ol (4a). Pale yellow solid
Hz, 1H), 7.79–7.66 (m, 3H), 7.40 (d, J = 8.2 Hz, 1H), 5.01 (s, (115 mg, 66% yield) mp 109–111 °C; 1H NMR (400 MHz,
2H). 13C NMR (126 MHz, CDCl3) δ 157.4, 144.8, 136.8, 133.9, CDCl3) δ 7.99 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H),
130.8, 128.3, 127.9, 127.5, 127.1, 125.5, 125.1, 124.2, 118.8, 7.67–7.59 (m, 1H), 7.44 (dd, J = 8.9, 5.4 Hz, 2H), 5.59 (s, 1H),
64.2. HRMS (ESI): calcd for [M + H]+ C14H12NO: 210.0913, 2.69–2.58 (m, 3H), 1.67–1.56 (m, 3H). 13C NMR (101 MHz,
found: 210.0922.
CDCl3) δ 159.1, 151.5, 147.7, 129.2, 129.1, 125.6, 123.6, 122.8,
Benzo[h]quinolin-4-ylmethanol (3nb). Yellow oil (60 mg, 117.6, 65.9, 25.9, 24.6. HRMS (ESI): calcd for [M + H]+
28% yield); 1H NMR (300 MHz, CDCl3) δ 9.29 (d, J = 9.1 Hz, C12H14NO: 188.1070, found: 188.1150.
1H), 8.94 (d, J = 4.5 Hz, 1H), 7.93–7.88 (m, 1H), 7.82 (s, 2H),
1-(2-Methylquinolin-4-yl)ethan-1-one (4a′). Yellow liquid
7.78–7.66 (m, 2H), 7.61 (d, J = 4.5 Hz, 1H), 5.23 (s, 2H). 13C (18 mg, 9% yield); H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 8.5
NMR (101 MHz, CDCl3) δ 148.8, 146.1, 145.8, 133.3, 131.6, Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.57 (t,
128.3, 128.0, 127.8, 127.3, 124.7, 123.7, 120.3, 119.2, 62.0. J = 7.7 Hz, 1H), 7.49 (s, 1H), 2.80 (s, 3H), 2.74 (s, 3H). 13C NMR
HRMS (ESI): calcd for [M + H]+ C14H12NO: 210.0913, found: (101 MHz, CDCl3) δ 201.6, 158.5, 148.9, 143.2, 129.9, 129.2,
1
210.0922.
127.4, 125.3, 122.0, 120.8, 30.2, 25.4. HRMS (ESI): calcd for [M
Benzo[h]quinoline-2,4-diyldimethanol (3nc). Brown oil + H]+ C12H12NO: 186.0913, found: 186.0913.
1
(40 mg, 16% yield); H NMR (400 MHz, CDCl3 + DMSO) δ 9.22
1-(2-Phenylquinolin-4-yl)ethan-1-ol (4b). Yellow liquid
1
(d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.78–7.71 (M, 2H), (144 mg, 57% yield); H NMR (400 MHz, CDCl3) δ 8.15 (d, J =
7.66–7.57 (M, 3H), 5.11 (s, 2H), 4.91 (s, 2H). 13C NMR 8.3 Hz, 1H), 7.97 (d, J = 6.2 Hz, 2H), 7.82 (s, 1H), 7.76 (d, J = 8.4
(101 MHz, CDCl3 + DMSO) δ 158.4, 148.2, 144.4, 133.3, 131.1, Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.44–7.38 (m, 4H), 5.42 (q, J =
128.0, 127.7, 127.0, 126.9, 124.5, 122.8, 120.5, 116.3, 64.7, 61.1. 6.4 Hz, 1H), 1.55 (d, J = 6.5 Hz, 3H). 13C NMR (101 MHz,
HRMS (ESI): calcd for [M + H]+ C15H14NO2: 240.1019, found: CDCl3) δ 157.2, 152.3, 148.0, 139.3, 130.1, 129.4, 129.3, 128.7,
240.1030.
(6-Phenylpyridin-2-yl)methanol (3oa). Yellow liquid (26 mg, for [M + H]+ C17H16NO: 250.1226, found: 250.1360.
14% yield); 1H NMR (400 MHz, CDCl3) δ 8.04–8.00 (m, 2H),
1-(8-Chloro-2-methylquinolin-4-yl)ethan-1-ol (4c). White
127.5, 126.1, 124.2, 122.8, 114.4, 66.1, 24.5. HRMS (ESI): calcd
1
7.75 (t, J = 7.7 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.52–7.41 (m, solid (116 mg, 52% yield) mp 124–126 °C; H NMR (400 MHz,
3H), 7.16 (d, J = 8.2 Hz, 1H), 4.82 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 7.83 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.46
CDCl3) δ 158.5, 156.1, 138.8, 137.5, 129.2, 128.8, 126.9, 119.1, (s, 1H), 7.39–7.33 (m, 1H), 5.54 (q, J = 6.2 Hz, 1H), 2.77 (s, 3H).
118.8, 63.9. HRMS (ESI): calcd for [M + H]+ C12H12NO: 13C NMR (101 MHz, CDCl3) δ 160.3, 151.5, 144.2, 133.5, 129.2,
186.0913, found: 186.0923.
(2-Phenylpyridin-4-yl)methanol (3ob). Yellow liquid (44 mg, for [M + H]+ C12H13ClNO: 222.0680, found: 222.0759.
23% yield); 1H NMR (500 MHz, CDCl3) δ 8.60 (d, J = 5.0 Hz,
1-(2-Methylquinolin-4-yl)propan-1-ol (4d). Yellow liquid
125.4, 125.0, 121.9, 118.4, 66.3, 25.9, 24.6. HRMS (ESI): calcd
1
1H), 7.97–7.92 (m, 2H), 7.69 (s, 1H), 7.48–7.38 (m, 3H), 7.18 (d, (82 mg, 42% yield); H NMR (400 MHz, CDCl3) δ 7.99 (d, J =
J = 6.5 Hz, 1H), 4.75 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.62 (t, J = 8.2 Hz, 1H),
157.7, 151.0, 149.6, 139.3, 129.1, 128.8, 127.0, 119.7, 118.1, 7.44 (t, J = 8.2 Hz, 1H), 7.39 (s, 1H), 5.33 (dd, J = 7.7, 4.4 Hz,
63.6. HRMS (ESI): calcd for [M + H]+ C12H12NO: 186.0913, 1H), 2.64 (s, 3H), 2.09–1.91 (m, 1H), 1.89–1.76 (m, 1H), 1.03 (t,
found: 186.0923.
J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 158.9, 150.3,
(2,6-Diphenylpyridin-4-yl)methanol (3p). White solid 147.8, 129.2, 129.0, 125.5, 123.9, 122.8, 118.4, 71.1, 31.3, 25.3,
(75 mg, 28% yield) mp 103–104 °C; 1H NMR (500 MHz, CDCl3) 10.3. HRMS (ESI): calcd for [M + H]+ C13H16NO: 202.1226,
δ 8.15–8.12 (4, 2H), 7.63 (s, 1H), 7.52–7.46 (m, 4H), 7.45–7.40 found: 202.1291.
(m, 2H), 4.78 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 157.1,
1-(6-Fluoro-2-methylquinolin-4-yl)propan-1-ol (4e). Yellow
151.4, 139.4, 129.1, 128.7, 127.1, 116.2, 64.0. HRMS (ESI): liquid (77 mg, 35% yield); 1H NMR (400 MHz, CDCl3) δ
calcd for [M + H]+ C18H16NO: 262.1226, found: 262.1239.
8.02–7.94 (m, 1H), 7.53 (d, J = 10.2 Hz, 1H), 7.45–7.35 (m, 2H),
5.24–5.16 (m, 1H), 2.66 (s, 3H), 2.00–1.89 (m, 1H), 1.89–1.77 (m,
1H), 1.03 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 159.8
(d, J = 247.5 Hz), 158.5, 150.0, 144.8, 131.3, 131.2, 124.5 (d, J =
General procedure and characterization data for the
hydroxyalkylated quinolines (4a–4j)
To a stirring solution of quinolines (1) (1.0 mmol) and Fe 9.1 Hz), 119.2, 119.0 (d, J = 25.3 Hz), 107.0, 106.8, 71.3, 31.0,
(ClO4)2·xH2O (1.0. equiv.) in 2.0 mL of alcohols (2b–f) was 25.0, 10.3. 19F NMR (377 MHz, CDCl3) δ −113.6 (s). HRMS (ESI):
dropwise added TBHP (4.0 equiv.) at room temperature. The calcd for [M + H]+ C13H15FNO: 220.1132, found: 220.1236.
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1-(6-Chloro-2-methylquinolin-4-yl)propan-1-ol (4f). Yellow chromatography over silica gel (100–200 mesh size) and using
liquid (81 mg, 34% yield); 1H NMR (400 MHz, CDCl3) δ 7.89 a hexane/ethyl acetate mixture as the eluent gave the desired
(dd, J = 7.8, 5.6 Hz, 2H), 7.55 (dd, J = 9.0, 2.3 Hz, 1H), 7.39 (s, product 5.
1H), 5.22 (dd, J = 7.7, 4.6 Hz, 1H), 2.65 (s, 3H), 1.99–1.88 (m,
Quinoline-4-carbaldehyde (5a). White solid (114 mg, 72%
1H), 1.86–1.77 (m, 1H), 1.03 (t, J = 7.4 Hz, 3H). 13C NMR yield), mp 79–81 °C; 1H NMR (400 MHz, CDCl3) δ 10.53 (s,
(101 MHz, CDCl3) δ 158.2, 148.4, 145.2, 130.4, 129.8, 128.9, 1H), 9.21 (d, J = 4.2 Hz, 1H), 9.03 (d, J = 9.5 Hz, 1H), 8.23 (d, J =
123.6, 121.1, 118.3, 30.1, 24.3, 9.2. HRMS (ESI): calcd for [M + 9.0 Hz, 1H), 7.83 (m, 2H), 7.75 (t, J = 8.4 Hz, 1H). 13C NMR
H]+ C13H15ClNO: 236.0837, found: 236.0895.
(101 MHz, CDCl3) δ 192.9, 150.5, 149.3, 136.8, 130.2, 130.1,
1-(4-Methylquinolin-2-yl)butan-1-ol (4g). Brown liquid 129.4, 125.9, 124.5, 123.9. HRMS (ESI): calcd for [M + H]+
1
(61 mg, 28% yield); H NMR (400 MHz, CDCl3) δ 7.98 (dd, J = C10H8NO: 158.0600, found: 158. 158.0601.
22.7, 8.4 Hz, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.55–7.48 (m, 1H),
2-Methylquinoline-4-carbaldehyde
(5b).
White
solid
1
7.20 (s, 1H), 3.72–3.64 (m, 2H), 3.41–3.29 (m, 1H), 2.69 (s, 3H), (117 mg, 68% yield), mp 84–86 °C; H NMR (400 MHz, CDCl3)
2.13–2.04 (m, 1H), 2.03–1.94 (m, 1H), 1.41 (d, J = 7.1 Hz, 3H). δ 10.48 (s, 1H), 8.95 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.5 Hz, 1H),
13C NMR (101 MHz, CDCl3) δ 165.7, 146.9, 145.2, 129.3, 129.0, 7.78 (t, J = 8.4 Hz, 1H), 7.71–7.63 (m, 2H), 2.86 (s, 3H). 13C
126.9, 125.8, 123.6, 120.7, 60.1, 40.0, 38.2, 20.5, 18.9. HRMS NMR (101 MHz, CDCl3) δ 193.0, 159.2, 149.0, 137.1, 130.2,
(ESI): calcd for [M + H]+ C14H18NO: 216.1382, found: 216.1382.
129.2, 128.3, 127.1, 124.2, 122.3, 25.3. HRMS (ESI): calcd for
1-(2,6-Dimethylquinolin-4-yl)butan-1-ol (4h). Brown liquid [M + H]+ C11H10NO: 172.0757, found: 172.0757.
1
(85 mg, 36% yield); H NMR (400 MHz, CDCl3) δ 7.89 (d, J =
6-Chloro-2-methylquinoline-4-carbaldehyde (5c). Pale yellow
8.6 Hz, 1H), 7.65 (s, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.36 (s, 1H), solid (178 mg, 86% yield), mp 113–115 °C; 1H NMR (500 MHz,
5.38 (dd, J = 7.9, 4.3 Hz, 1H), 2.65 (s, 3H), 2.51 (s, 3H), CDCl3) δ 10.37 (s, 1H), 8.99 (s, 1H), 8.02 (d, J = 9.0 Hz, 1H),
1.91–1.73 (m, 2H), 1.62–1.44 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 7.73–7.66 (m, 2H), 2.85 (s, 3H). 13C NMR (126 MHz, CDCl3) δ
13C NMR (101 MHz, CDCl3) δ 157.9, 149.9, 146.4, 135.2, 131.2, 192.7, 159.5, 147.4, 136.2, 134.7, 131.2, 130.6, 128.5, 123.7,
128.9, 123.8, 121.8, 118.2, 69.6, 40.4, 25.2, 21.9, 19.2, 14.0. 122.6, 25.2. HRMS (ESI): calcd for [M + H]+ C11H9ClNO:
HRMS (ESI): calcd for [M + H]+ C15H20NO: 230.1539, found: 206.0367, found: 206.0368.
230.1539.
2,6-Dimethylquinoline-4-carbaldehyde (5d). Pale yellow solid
2-Methyl-1-(2-methylquinolin-4-yl)propan-1-ol (4i). Brown (145 mg, 77% yield), mp 118–120 °C; 1H NMR (400 MHz,
liquid (71 mg, 33% yield); 1H NMR (400 MHz, CDCl3) δ 8.01 (d, CDCl3) δ 10.44 (s, 1H), 8.72 (s, 1H), 8.00 (d, J = 8.6 Hz, 1H),
J = 8.4 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.63–7.57 (m, 2H), 2.83 (s, 3H), 2.58 (s, 3H). 13C NMR
7.45 (t, J = 8.2 Hz, 1H), 7.38 (s, 1H), 5.19 (d, J = 5.2 Hz, 1H), (101 MHz, CDCl3) δ 193.2, 158.0, 147.7, 138.7, 136.5, 132.4,
2.69 (s, 3H), 2.23–2.13 (m, 1H), 1.00 (d, J = 6.9 Hz, 3H), 0.95 (d, 128.8, 127.2, 123.2, 122.30, 25.1, 22.0. HRMS (ESI): calcd for
J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 158.7, 149.6, [M + H]+ C12H12NO: 186.0913, found: 186.0913.
147.9, 129.3, 129.0, 125.4, 124.2, 123.1, 119.3, 74.8, 34.4, 25.4,
General procedure characterization data for the arsindoline-A
and its derivatives (7a–c)
20.1, 16.7. HRMS (ESI): calcd for [M + H]+ C14H18NO: 216.1383,
found: 216.1429.
1-(2-Methylquinolin-4-yl)hexane-1-ol (4j). Brown liquid To a stirred solution of quinoline-4-carbaldehyde 5 (0.5 mmol)
1
(76 mg, 31% yield); H NMR (400 MHz, CDCl3) δ 7.99 (d, J = and indole 6 (1.0 equiv.) in H2O (2 mL), H2SO4 (1.0 equiv.) was
8.5 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), added dropwise at 0 °C. After the completion of the reaction,
7.44 (t, J = 7.6 Hz, 1H), 7.39 (s, 1H), 5.38 (dd, J = 8.2, 4.0 Hz, the reaction mixture was diluted with water and extracted with
1H), 2.63 (s, 3H), 1.92–1.73 (m, 2H), 1.62–1.40 (m, 2H), DCM twice. The organic layer was washed with saturated
1.39–1.23 (m, 4H), 0.87 (t, J = 7.0 Hz, 3H). 13C NMR (126 MHz, sodium bicarbonate solution, dried with anhydrous Na2SO4
CDCl3) δ 158.8, 151.2, 147.5, 129.1, 129.0, 125.6, 123.8, 122.8, and concentrated. The crude reaction mixture was purified by
118.3, 69.8, 38.5, 31.7, 25.8, 25.1, 22.6, 14.1. HRMS (ESI): calcd column chromatography using EtOAc/hexane as eluents to
for [M + H]+ C16H22NO: 244.1696, found: 244.1813.
obtain the product 7.
4-(Di(1H-indol-3-yl)methyl)quinoline (7a). Pale yellow solid
(313 mg, 83% yield), mp 108–110 °C; 1H NMR (400 MHz,
CDCl3) δ 8.74 (d, J = 4.5 Hz, 1H), 8.16 (d, J = 8.3 Hz, 2H), 8.06
General procedure and characterization data for the quinoline-
4-carbaldehydes (5)
To a stirring solution of hydroxymethylated quinoline 3a (s, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.37 (dd,
(1.0 mmol) in 2.0 mL of DCM, Dess–Martin periodinane (1.2 J = 8.2, 2.8 Hz, 4H), 7.20 (t, J = 7.6 Hz, 2H), 7.16 (d, J = 4.5 Hz,
equiv.) was added slowly at 0 °C, and the reaction mixture was 1H), 7.02 (t, J = 7.6 Hz, 2H), 6.65 (s, 1H), 6.58 (s, 2H). 13C NMR
stirred at room temperature for 1 h. The progress of the reac- (126 MHz, CDCl3) δ 150.4, 149.8, 148.4, 136.8, 129.9, 129.0,
tion was monitored by TLC. After the completion of the reac- 127.4, 126.8, 126.6, 124.4, 124.2, 122.3, 121.0, 119.6, 119.5,
tion, the reaction mixture was quenched with saturated 117.7, 111.3, 35.6. HRMS (ESI): calcd for [M + H]+ C26H20N3:
sodium thiosulphate solution and extracted with DCM (5.0 mL 374.1651, found: 374.1654.
× 3). The organic layer was washed with saturated sodium
4-(Di(1H-indol-3-yl)methyl)-2-methylquinoline (7b). Brick
bicarbonate solution, dried with anhydrous Na2SO4 and con- red solid (286 mg, 73% yield), mp 251–252 °C; 1H NMR
centrated. The crude product was purified by silica gel column (400 MHz, CDCl3) δ 8.10 (dd, J = 7.9, 4.4 Hz, 2H), 8.02 (s, 2H),
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7.64 (t, J = 7.7 Hz, 1H), 7.42–7.34 (m, 5H), 7.21 (t, J = 7.2 Hz,
2H), 7.04 (dd, J = 15.4, 8.4 Hz, 3H), 6.66–6.57 (m, 3H), 2.59 (s,
3H). 13C NMR (101 MHz, CDCl3 + DMSO) δ 158.6, 150.3, 147.6,
136.8, 128.8, 128.6, 126.6, 125.6, 125.4, 124.6, 123.9, 121.5,
121.4, 119.0, 118.7, 116.8, 111.4, 35.4, 25.2. HRMS (ESI): calcd
for [M + H]+ C27H22N3: 388.1808, found: 388.1811.
J. K. Tibenderana, F. N. Baliraine, P. J. Rosenthal and
U. D’Alessandro, Malar. J., 2011, 10, 144.
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1
Brick red solid (324 mg, 76% yield), mp 163–165 °C; H NMR
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1H), 7.36 (dd, J = 12.2, 8.1 Hz, 4H), 7.20 (t, J = 7.6 Hz, 2H), 7.09
(s, 1H), 7.02 (t, J = 7.3 Hz, 2H), 6.58 (d, J = 1.6 Hz, 2H), 6.51 (s,
1H), 2.56 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.3, 149.1,
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Conflicts of interest
There are no conflicts to declare.
9 S. Wang, S. Xing, Y. Zhang, Y. Fan, H. Zhao, J. Wang,
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10 L. Niu, J. Liu, X.-A. Liang, S. Wang and A. Lei, Nat.
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Acknowledgements
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sincerely thank DST INSPIRE and SERB-NPDF India for fellow-
ships, respectively. Dr KRR thanks the Director, CSIR-IICT for
financial support. Communication No: IICT/Pubs./2020/276.
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