One-Pot Amberlyst 15-Controlled Cyclocondensation of Piperidines and Arylaldehydes: Synthesis of 3,5-Diarylmethylpyridines

Article abstract of DOI:10.1021/acs.joc.9b03315

Amberlyst 15-controlled one-pot easy-operational intermolecular cyclocondensation of substituted piperidines with arylaldehydes provides diversified 3,5-diarylmethylpyridines in high to excellent yields under refluxing toluene conditions. The uses of various acidic solid supports and reaction solvents are investigated for facile and efficient transformation. A plausible mechanism has been proposed.

Full text of DOI:10.1021/acs.joc.9b03315

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One-Pot Amberlyst 15-Controlled Cyclocondensation of Piperidines
and Arylaldehydes: Synthesis of 3,5-Diarylmethylpyridines
Meng-Yang Chang* and Yu-Lin Tsai
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ABSTRACT: Amberlyst 15-controlled one-pot easy-operational intermolecular cyclocondensation of substituted piperidines with
arylaldehydes provides diversified 3,5-diarylmethylpyridines in high to excellent yields under refluxing toluene conditions. The uses
of various acidic solid supports and reaction solvents are investigated for facile and efficient transformation. A plausible mechanism
has been proposed.
However, the isolated yields were not high (for Poirier, 43%;
for Burrows, 25%).
unctionalized pyridines, having a nitrogen-containing six-
Fmembered ring, are one of the most prevalent topics to
date, and the core template is widely present in pharmaceutical
molecules.1,2 They exhibit many biological activities, such as
anticancer and antimicrobial activities.3 Therefore, attempts to
construct pyridine skeletons have been reported via various
elegant protocols. Among the routes, syntheses of pyridines
containing 3,5-disubstituent have been focused on through the
combination of small components, especially in nanoparticle
palladium complex-promoted Suzuki−Miyaura cross-coupling
reactions.4−7 Recent synthetic efforts toward 3,5-dialkyl or
diarylpyridines are divided into two classes, including (1)
transition metal-catalyzed inter- or intramolecular multi-
component cyclization of small molecules8−19 and (2)
Brønsted acid, base, or oxidant-mediated combination of
small fragments.20−27 While seeking a facile high-yield
synthetic route for 3,5-diarylmethylpyridines, we explored a
commercially available Amberlyst 15-controlled one-pot facile-
operational intermolecular cyclocondensation of substituted
piperidines with arylaldehydes that provide diversified 3,5-
diarylmethylpyridines under the refluxing toluene conditions
Following the literature, there are three synthetic reports on
the Ru
̈
gheimer−Poirier−Burrows reaction.22,29a,b One possible
reason is that the isolated yield was not easy to improve. For
the involvement of spinel aluminates, in 1996, Kameswari and
Pillai monitored the reaction of piperidine with formaldehyde
under high temperature (250−450 °C) conditions.29a In 2014,
Neves et al. investigated one La(OTf)3-promoted formation of
a 3,5-bisporphyrinylpyridine derivative with a 54% yield for the
application of a fluorescent ratiometric probe.29b Until 2016,
the Seidel group utilized the microwave irradiation method to
revisit this reaction procedure, and the provided yields were
enhanced in a range of ∼53−95% for the PhCO2H-mediated
formation of 3,5-diarylmethylpyridines.22 Thus, development
of one direct, practical, and general method for the
construction of 3,5-diarylmethylpyridines still represents a
continuing need in the organic synthetic field. On the basis of
this idea, we adopted Amberlyst 15 as the reusable sulfonic
acid support to increase the isolated yields of 3,5-diary-
lmethylpyridines via the Rugheimer−Poirier−Burrows process.
̈
The involvement of this solid support could allow mild and
highly selective transformations and synthesis in an easy-
operational and environmentally friendly manner.30,31
(Scheme 1). Traditionally, Ru
̈
gheimer,28a Poirier,28b and
Burrows28c have reported a rapid access to 3,5-dibenzylpyr-
idines via HOAc-mediated β-condensation of piperidine with
benzaldehyde using a Dean−Stark distillation apparatus.
Considering that there are no reports on the synthesis of 3,5-
diarylmethylpyridines, the initial study commenced with the
combination of model substrates, 2-formyl N-methylpyrrole 1a
(3.0 equiv) and piperidine 2a (1.0 mmol), in the presence of
Scheme 1. Retrosynthetic Route of 3,5-
Diarylmethylpyridines
Received: December 10, 2019
Published: March 25, 2020
https://dx.doi.org/10.1021/acs.joc.9b03315
© XXXX American Chemical Society
J. Org. Chem. XXXX, XXX, XXX−XXX
A

The Journal of Organic Chemistry
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Note
Amberlyst 15 (1.1 g, loading >4.7 equiv/kg)32 at 25 or 60 °C
for 5 or 10 h in toluene (Table 1, entries 1−3). However, no
skeleton having two pyrrolylmethylenyl groups conjugated to
one pyridine, including two new carbon−carbon (C−C) bond
formations (green) via double dehydration.
Based on our experimental results, a plausible mechanism for
the formation of 3a is illustrated in Scheme 2. Initially, the
a
Table 1. Reaction Conditions
Scheme 2. Plausible Mechanism
b
entry solid support (g) solvent (mL) temp (°C) time (h)
%
c
1
2
3
4
5
6
7
8
Amberlyst 15
Amberlyst 15
Amberlyst 15
Amberlyst 15
Amberlyst 15
Amberlyst 15
Amberlyst 15
Amberlyst 15
Amberlyst 15
Amberlyst 15
Amberlyst 15
Amberlyst 15
Dowex 50Wx8
Amberlite 200C
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DME
dioxane
C6H5Cl
xylene
DMF
toluene
toluene
25
60
60
5
5
−
−
−
c
c
10
10
20
30
40
20
20
20
20
20
20
20
d
111
111
111
111
85
101
131
140
154
111
111
65
87
75
54
60
52
40
72
e
e
9
10
11
12
13
14
f
−
38
10
a
The reactions were run on a 1.0 mmol scale with 2a, 1a (3.0 equiv),
b
c
solvent (15 mL), and solid support (1.1 g). Isolated yields. No
reaction. 1a was recovered (entry 4, 20%). Unidentified products
(entry 6, 10%; entry 7, 21%). Complex results.
d
e
f
reaction was observed, and only 1a was recovered. By elevating
the temperature to reflux (111 °C), the yield of 3a was
increased to 65% along with a 20% yield of 1a (entry 4) via a
tandem double β-dehydration process. Furthermore, while
controlling the temperature at 111 °C, different reaction times
were examined. After elongating the time from 10 to 20, 30,
and then 40 h, the isolated yields of 3a were decreased from
65% and 87% to 75% and then 54%, respectively (entries 5−
7). We found that the combination of 20 h provided an 87%
yield of 3a along with trace amounts of 1a in refluxing toluene.
From this phenomenon, we understood that the factors of
reflux temperature and time could affect the yield of 3a.
However, there were still an unreacted starting material 1a and
an unknown mixture generated from the obtained products.
To solely generate 3a, we utilized different reaction solvents to
optimize the conditions. Through control of the reflux
temperature and use of a 20 h reaction time, entries 8−12
show that DME (dimethoxyethane), dioxane, chlorobenzene,
xylene, and DMF did not obtain better yields than toluene for
a temperature range of 85−154 °C. Especially, the boiling
DMF provided only complex results (entry 12). On the basis
of our observation, we concluded that refluxing toluene was an
optimal reaction condition to yield 3a in 20 h.
intermolecular sulfonic acid resin (Amberlyst 15)-mediated
Knoevenagel condensation of 1a with 2a provides A1 having
an iminium ion. After the olefin migration from A1 to A2,
tautomerization of A2 converts to B. Then, by the involvement
of the second equivalent of 1a, C can be generated via
intermolecular Stork enamine addition of B with 1a. Next,
intramolecular proton transfer of C leads to D. By the lone pair
of nitrogen atom promoting dehydration, D can be trans-
formed to E. Furthermore, after 1,3-hydride shifts between E
and F, the third equivalent of 1a can deprotonate to stabilize
the iminium ion. Subsequently, by intermolecular addition of
1a with the nitrogen atom of dienamine on G, H is generated.
Following the repeated process, proton exchange (G → H),
dehydration (H → I → J), and 1,3-hydride shift (J → K)
provides K. Finally, the construction of 3a can be furnished via
the aromatization of K. By the involvement of in situ formed
water, the releasing aza-fulvene intermediate could convert into
the hydrated N-methylpyrrole.34 From the possible mecha-
nism, we found that Amberlyst 15 organizes a continuous
sequence of intermolecular/intramolecular bond formations or
cleavage. To the best of our knowledge, no sulfonic acid resin-
Next, two commercially available sulfonic acidic solid
supports were examined. However, Dowex 50Wx833a and
Amberlite 200C33b showed that 3a was isolated in low yields
(38 and 10%), as shown in entries 13 and 14. By using two
acidic resins, attempts to enhance the yields failed, and the
major starting substrate 1a was recovered. From the above-
mentioned results, we concluded that entry 5 provided optimal
conditions for synthesizing 3a via the Amberlyst 15-mediated
dependent Ru
reported.
̈
gheimer−Poirier−Burrows reaction has been
To study the scope and limitations of this approach,
substituted 2-formylpyrroles 1a−1o were investigated under
refluxing toluene conditions, as shown in Table 2. With
optimal conditions established (Table 1, entry 5) and a
plausible mechanism proposed (Scheme 2), we found that this
route allowed direct double dehydration in good yields (68−
90%). Among entries 1−23, efficient formation of 3a−3w
showed that substituents (1, R1, and R2) did not affect the
̈
Rugheimer−Poirier−Burrows reaction under refluxing toluene
conditions. This expeditious synthetic route sets up a core
B
https://dx.doi.org/10.1021/acs.joc.9b03315
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Note
a
Table 2. Synthesis of 3a−3w
Scheme 3. Synthesis of 3x−3al
b
entry
1, R1 = , R2 =
1a, H, Me
1b, H, i-Pr
1c, H, allyl
1d, H, nBu
1e, H, cC5H9
1f, H, crotyl
2, R =
3 (%)
1
2
3
4
5
6
7
8
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2b, Me
2c, Ph
2b, Me
2c, Ph
2b, Me
2c, Ph
2b, Me
2c, Ph
3a, 87
3b, 90
3c, 89
3d, 82
3e, 88
3f, 73
3g, 86
1g, Br, Me
c
1h, Ph(CO), Me
1i, H, cinnamyl
1j, H, prenyl
3h, −
c
9
3i, −
c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3j, −
1k, H, Bn
3k, 78
3l, 70
3m, 80
3n, 80
3o, 68
3p, 89
3q, 82
3r, 88
3s, 84
3t, 83
3u, 78
3v, 84
3w, 80
1l, H, 4-NO2C6H4CH2
1m, H, 3-ClC6H4CH2
1n, H, 1-naphthyl
1o, H, PhCH(Me)
1g, Br, Me
1g, Br, Me
1d, H, nBu
1d, H, nBu
moiety (in situ derived from 1t and Amberlyst 15) having high-
reactivity and low-aromaticity properties to obtain major
complex furan ring-opening products such that a low yield of
3ab was generated.
On the other hand, a one-pot reaction of formylcyclohexane
1ae (an aliphatic ring) and a 3 equiv of 2a were examined next.
Surprisingly, no isolation of 3am was detected, and only an
enamine skeleton was observed (Scheme 4, eq 1). The possible
1m, H, 3-ClC6H4CH2
1m, H, 3-ClC6H4CH2
1a, H, Me
1a, H, Me
Scheme 4. Reaction of 1ae−1af with 2a and 1a with 2d
a
The reactions were run on a 1.0 mmol scale with 2a−2c, 1a−1o (3.0
equiv), toluene (15 mL), Amberlyst 15 (1.1 g), 110 °C, 20 h.
b
c
Isolated yields. Complex results.
yields except for 3h−3j. In particular, only a complex unknown
mixture was observed due to complex intermolecular
condensation of piperidine 2a and a 4-carbonyl group on 1h
(entry 8) or intramolecular electrophilic annulation of 1i and
1j with its side benzylic and tertiary olefin (entries 9 and 10).
The molecular structure of compound 3k was determined by
single-crystal X-ray crystallography.35
For the R substituent of 2b−2c, not only aliphatic (R= Me)
but an aromatic group (R= Ph) were appropriate (entries 16−
23). On the basis of the above conditions, different 2-
formylarenes 1p−1ad were examined. These carbocycles and
heterocycles included monocyclic phenyl, dimethoxylphenyl
furyl, thienyl, pyridyl groups, bicyclic naphthyl, benzothienyl
and indolyl groups, and the tricyclic carbazolyl group, as shown
in Scheme 3. Among these ring systems, 3x−3al were isolated
in a range of 32−70% yields. The given yields of these
mentioned formylarenes were lower than those for 2-
formylpyrroles shown in Table 2. Specifically, 3- or 4-pyridyl
(for 3z, 3ad) and 2-furyl (for 3ab) groups provided only 8, 3,
and 10% yields, respectively. However, attempts to increase the
yields of 3z, 3ad, and 3ab failed. For the formation of 3z and
3ad, the possible reason could be that the lone pair of nitrogen
atoms on the pyridine ring (for 3-formylpyridine 1r and 4-
formylpyridine 1v) initially blocked Amberlyst 15 to form a
pyridinium intermediate such that there was not a sufficient
proton source to initiate the following reaction pathway. For
the formation of 3ab, one reasonable explanation could be that
the refluxing toluene condition promoted the protonated-furyl
reason should be that an enolization of 1ae occurred such that
the cyclocondensation was not triggered. By use of the
Amberlyst 15-mediated reaction conditions, 1af with an
electron-donating 4-methoxy group was studied (eq 2).
However, only complex and unidentified mixture was observed
due to 1af with a pull-push structure being unstable in the
presence of acidic conditions. As shown in eq 3, when
changing 2a to 2,6-lutidine 2d (a hindered piperidine), the
results were similar to those in eq 1. We believe that two
bulkier methyl groups provided a steric strain inhibiting the
formation of 3ao. Furthermore, two piperidine derivatives, 4-
hydroxypiperidine (2e, a hydroxyl) or piperidine-4-carboxylic
C
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Note
column chromatography on silica gel (hexanes/EtOAc = 8/1−4/1);
yield = 90% (289 mg); brown liquid; HRMS (ESI-TOF) m/z: [M +
acid ethyl ester (2f, a carboxyl), could not produce the desired
products 3ap and 3aq (eq 4).
1
H]+ calcd for C21H28N3 322.2283, found 322.2279; H NMR (400
In summary, we developed a solid support-controlled
synthesis of 3,5-diarylmethylpyridines via one-pot easy-opera-
tional intermolecular cyclocondensation of substituted piper-
idines with arylaldehydes under refluxing toluene reaction
conditions in moderate to good yields. The process provides a
cascade pathway for two carbon−carbon bond formations.
Related plausible mechanisms have been proposed. The
structures of the key products were confirmed by X-ray
crystallography. Further investigations regarding the synthetic
applications of Amberlyst 15 will be conducted and published
in due course.
MHz, CDCl3): δ 8.35 (d, J = 2.0 Hz, 2H), 7.31 (br t, J = 2.0 Hz, 1H),
6.75 (dd, J = 2.0, 2.8 Hz, 2H), 6.13 (t, J = 3.2 Hz, 2H), 5.81 (dd, J =
2.0, 3.2 Hz, 2H), 4.20−4.13 (m, 2H), 3.94 (s, 4H), 1.30 (d, J = 6.8
Hz, 12H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.7 (2x), 136.1
(2x), 134.7 (2x), 128.9, 116.0 (2x), 107.5 (2x), 107.0 (2x), 46.7 (2x),
29.9 (2x), 23.6 (4x).
3,5-Bis(1-allyl-1H-pyrrol-2-ylmethyl)pyridine (3c). 3c was
synthesized according to the general synthetic procedure from 1c
(405 mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3c was purified by
column chromatography on silica gel (hexanes/EtOAc = 8/1−4/1);
yield = 89% (282 mg); brown liquid; HRMS (ESI-TOF) m/z: [M +
1
H]+ calcd for C21H24N3 318.1970, found 318.1967; H NMR (400
MHz, CDCl3): δ 8.33 (d, J = 2.0 Hz, 2H), 7.29 (s, 1H), 6.62 (dd, J =
2.0, 2.8 Hz, 2H), 6.10 (t, J = 2.8 Hz, 2H), 5.89−5.79 (m, 4H), 5.13
(dq, J = 1.6, 10.0 Hz, 2H), 4.90 (dd, J = 1.6, 16.8 Hz, 2H), 4.34 (dt, J
= 1.6, 4.8 Hz, 4H), 3.88 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3):
δ 147.8 (2x), 136.5 (2x), 134.6 (2x), 134.1 (2x), 129.9, 121.1 (2x),
116.6 (2x), 108.2 (2x), 107.0 (2x), 49.1 (2x), 29.7 (2x).
EXPERIMENTAL SECTION
■
General. All reagents and solvents were obtained from commercial
sources and used without further purification. Reactions were
routinely carried out under an atmosphere of dry air with magnetic
stirring. The heating mantle was used to provide a stable heat source.
Products in organic solvents were dried with anhydrous magnesium
sulfate before concentration in vacuo. Melting points were determined
with a SMP3 melting apparatus. 1H and 13C NMR spectra were
recorded on a Varian INOVA-400 spectrometer operating at 400 and
at 100 MHz, respectively. Chemical shifts (δ) are reported in parts per
million (ppm), and the coupling constants (J) are given in Hertz.
High resolution mass spectra (HRMS) were recorded on a Bruker
Solarix mass spectrometer operating in ESI-TOF mode. X-ray crystal
structures were obtained with an Enraf-Nonius FR-590 diffractometer
(CAD4, Kappa CCD).
3,5-Bis(1-n-butyl-1H-pyrrol-2-ylmethyl)pyridine (3d). 3d was
synthesized according to the general synthetic procedure from 1d
(453 mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3d was purified by
column chromatography on silica gel (hexanes/EtOAc = 6/1−4/1);
yield = 82% (286 mg); brown liquid; HRMS (ESI-TOF) m/z: [M +
1
H]+ calcd for C23H32N3 350.2596, found 350.2589; H NMR (400
MHz, CDCl3): δ 8.33 (d, J = 2.0 Hz, 2H), 7.30 (br t, J = 2.0 Hz, 1H),
6.62 (t, J = 2.0 Hz, 2H), 6.07 (t, J = 3.2 Hz, 2H), 5.77−5.76 (m, 2H),
3.89 (s, 4H), 3.70 (t, J = 7.6 Hz, 4H), 1.63−1.55 (m, 4H), 1.32−1.23
(m, 4H), 0.89 (t, J = 7.6 Hz, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 147.9 (2x), 136.4 (2x), 134.7 (2x), 129.7, 120.7 (2x),
107.9 (2x), 106.8 (2x), 46.4 (2x), 33.3 (2x), 30.0 (2x), 19.9 (2x), 13.7
(2x).
For the starting compounds 1a−1af and 2a−2f, these reagents
were obtained from commercial sources and used without further
purification.
3,5-Bis(1-cyclopentyl-1H-pyrrol-2-ylmethyl)pyridine (3e). 3e
was synthesized according to the general synthetic procedure from 1e
(489 mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3e was purified by
column chromatography on silica gel (hexanes/EtOAc = 8/1−4/1);
yield = 88% (328 mg); brown liquid; HRMS (ESI-TOF) m/z: [M +
General Synthetic Procedure of Compounds 3a−3g and 3k−
3al. Commercially available Amberlyst 15 (1.1 g, >4.7 equiv/kg) was
added to a solution of arylaldehydes 1 (3.0 mmol) in toluene (15 mL)
at 25 °C. The reaction mixture was stirred at 25 °C for 10 min.
Substituted piperidines 2 (1.0 mmol) were added to the reaction
mixture at 25 °C. The reaction mixture was stirred at reflux for 20 h.
The heating mantle was used to provide a stable heat source. The
reaction mixture was cooled to 25 °C; Amberlyst 15 was filtered, and
the solvent was concentrated. The residue was diluted with water (10
mL), and the mixture was extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were washed with brine, dried, filtered, and
evaporated to afford crude product under reduced pressure.
Purification on silica gel (hexanes/EtOAc = 8/1−4/1) afforded
compounds 3a−3g and 3k−3al. Amberlyst 15 could be activated by
6N H2SO4 and recovered for the next reaction cycle of the
cyclocondensation process.
1
H]+ calcd for C25H32N3 374.2596, found 374.2590; H NMR (400
MHz, CDCl3): δ 8.33 (d, J = 2.0 Hz, 2H), 7.28 (br t, J = 2.0 Hz, 1H),
6.71 (dd, J = 2.0, 2.8 Hz, 2H), 6.10 (t, J = 2.8 Hz, 2H), 5.79−5.78 (m,
2H), 4.31−4.23 (m, 2H), 3.94 (s, 4H), 1.95−1.55 (m, 16H);
13C{1H} NMR (100 MHz, CDCl3): δ 147.8 (2x), 136.3 (2x), 134.8
(2x), 129.9, 116.8 (2x), 107.7 (2x), 107.1 (2x), 56.7 (2x), 33.7 (4x),
30.2 (2x), 24.1 (4x).
3,5-Bis(1-but-2-enyl-1H-pyrrol-2-ylmethyl)pyridine (3f). 3f
was synthesized according to the general synthetic procedure from 1f
(447 mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3f was purified by
column chromatography on silica gel (hexanes/EtOAc = 8/1−4/1);
Three isomers (cis/cis + cis/trans + trans/trans); yield = 73% (252
mg); brown liquid; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
General Procedure for the Recovery of Amberlyst 15. 6N H2SO4
(100 mL) was added to a solution of the used Amberlyst 15 (5−6 g)
in water (50 mL) at 25 °C. The reaction mixture was stirred at 25 °C
for 10 h. Amberlyst 15 was filtered, washed using water (5 × 10 mL),
and dried by vacuum oven (60 °C) to afford refreshed Amberlyst 15
(5−6 g).
1
C23H28N3 346.2283, found 346.2277; For major product, H NMR
(400 MHz, CDCl3): δ 8.32 (d, J = 2.0 Hz, 2H), 7.27 (br s, 1H),
6.64−6.61 (m, 2H), 6.09 (t, J = 3.2 Hz, 2H), 5.82−5.80 (m, 2H),
5.49−5.39 (m, 4H), 4.27 (dt, J = 1.2, 4.4 Hz, 4H), 3.88 (s, 4H), 1.66
(d, J = 6.8 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.9 (2x),
136.4 (2x), 134.6 (2x), 129.9, 128.3 (2x), 126.9 (2x), 120.9 (2x),
108.1 (2x), 106.9 (2x), 48.6 (2x), 29.9 (2x), 17.5 (2x).
3,5-Bis(4-bromo-1-methyl-1H-pyrrol-2-ylmethyl)pyridine
(3g). 3g was synthesized according to the general synthetic procedure
from 1g (561 mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3g was
purified by column chromatography on silica gel (hexanes/EtOAc =
8/1−4/1); yield = 86% (362 mg); brown liquid; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C17H18Br2N3 421.9868, found 421.9861; 1H
NMR (400 MHz, CDCl3): δ 8.32 (d, J = 2.0 Hz, 2H), 7.21 (s, 1H),
6.56 (d, J = 2.0 Hz, 2H), 5.80 (d, J = 2.0 Hz, 2H), 3.85 (s, 4H), 3.40
(s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 148.1 (2x), 136.2 (2x),
133.9 (2x), 131.0, 121.6 (2x), 110.6 (2x), 94.1 (2x), 33.9 (2x), 29.7
(2x).
3,5-Bis(1-methyl-1H-pyrrol-2-ylmethyl)pyridine (3a). 3a was
synthesized according to the general synthetic procedure from 1a
(327 mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3a was purified by
column chromatography on silica gel (hexanes/EtOAc = 8/1−4/1);
yield = 87% (231 mg); brown liquid; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C17H20N3 266.1657, found 266.1652; H NMR (400
1
MHz, CDCl3): δ 8.36 (d, J = 2.4 Hz, 2H), 7.31 (br t, J = 2.0 Hz, 1H),
6.61 (dd, J = 2.0, 2.4 Hz, 2H), 6.09 (dd, J = 2.8, 3.6 Hz, 2H), 5.86−
5.84 (m, 2H), 3.93 (s, 4H), 3.47 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 147.8 (2x), 136.3 (2x), 134.5 (2x), 130.0, 121.9 (2x),
107.8 (2x), 106.6 (2x), 33.6 (2x), 29.8 (2x).
3,5-Bis(1-isopropyl-1H-pyrrol-2-ylmethyl)pyridine (3b). 3b
was synthesized according to the general synthetic procedure from 1b
(411 mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3b was purified by
D
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Note
3,5-Bis(1-benzyl-1H-pyrrol-2-ylmethyl)pyridine (3k). 3k was
synthesized according to the general synthetic procedure from 1k
(555 mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3k was purified by
column chromatography on silica gel (hexanes/EtOAc = 8/1−4/1);
yield = 78% (325 mg); brown solid; mp = 95−98 °C (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C29H28N3 418.2283, found 418.2276; 1H NMR (400 MHz,
CDCl3): δ 8.28 (s, 2H), 7.35−7.28 (m, 6H), 7.16 (s, 1H), 6.98−6.95
(m, 4H), 6.73 (dd, J = 2.0, 2.8 Hz, 2H), 6.21 (t, J = 3.6 Hz, 2H),
5.95−5.94 (m, 2H), 4.96 (s, 4H), 3.78 (s, 4H); 13C{1H} NMR (100
MHz, CDCl3): δ 147.6 (2x), 137.8 (2x), 136.2 (2x), 134.3, 130.0
(2x), 128.5 (4x), 127.2 (2x), 126.0 (4x), 121.9 (2x), 108.6 (2x), 107.1
(2x), 50.3 (2x), 29.7 (2x). Single-crystal X-ray diagram: crystal of
compound 3k was grown by slow diffusion of EtOAc into a solution
of compound 3k in CH2Cl2 to yield colorless prisms. The compound
crystallizes in the monoclinic crystal system, space group P n, a =
6.2091(7) Å, b = 11.4310(14) Å, c = 31.863(4) Å, V = 2254.4(5) Å3,
Z = 4, dcalcd = 1.230 g/cm3, F(000) = 888, 2θ range 1.282−26.397°, R
indices (all data) R1 = 0.0691, wR2 = 0.1236.
3,5-Bis-[1-(4-nitrobenzyl)-1H-pyrrol-2-ylmethyl]pyridine
(3l). 3l was synthesized according to the general synthetic procedure
from 1l (690 mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3l was
purified by column chromatography on silica gel (hexanes/EtOAc =
8/1−4/1); yield = 70% (355 mg); brown liquid; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C29H26N5O4 508.1985, found 508.1992; 1H
NMR (400 MHz, CDCl3): δ 8.14 (d, J = 2.0 Hz, 2H), 8.07 (d, J = 8.8
Hz, 4H), 7.04 (t, J = 2.0 Hz, 1H), 6.97 (d, J = 9.2 Hz, 4H), 6.88 (dd, J
= 2.0, 2.8 Hz, 2H), 6.18 (t, J = 3.2 Hz, 2H), 5.90 (dd, J = 1.6, 3.6 Hz,
2H), 5.02 (s, 4H), 3.66 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3):
δ 147.7 (2x), 147.2, 145.7 (2x), 136.1 (2x), 134.1 (2x), 129.9 (2x),
126.7 (4x), 123.8 (4x), 122.1 (2x), 109.5 (2x), 108.1 (2x), 49.8 (2x),
29.7 (2x).
3,5-Bis-[1-(3-chlorobenzyl)-1H-pyrrol-2-ylmethyl]pyridine
(3m). 3m was synthesized according to the general synthetic
procedure from 1m (657 mg, 3.0 mmol) and 2a (85 mg, 1.0
mmol); 3m was purified by column chromatography on silica gel
(hexanes/EtOAc = 8/1−4/1); yield = 80% (388 mg); brown liquid;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C29H26Cl2N3 486.1504,
found 486.1499; 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 2.0 Hz,
2H), 7.22−7.17 (m, 4H), 7.08 (t, J = 2.0 Hz, 1H), 6.87 (d, J = 0.8 Hz,
2H), 6.77−6.74 (m, 2H), 6.67 (dd, J = 2.0, 2.8 Hz, 2H), 6.17 (t, J =
3.2 Hz, 2H), 5.92 (dd, J = 1.6, 3.6 Hz, 2H), 4.89 (s, 4H), 3.72 (s,
4H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.7 (2x), 140.0 (2x),
136.1 (2x), 134.6 (2x), 134.2 (2x), 130.0 (2x), 129.9, 127.5 (2x),
126.2 (2x), 124.2 (2x), 121.9 (2x), 109.1 (2x), 107.6 (2x), 49.8 (2x),
29.8 (2x).
3,5-Bis(1-naphthalen-1-ylmethyl-1H-pyrrol-2-ylmethyl)-
pyridine (3n). 3n was synthesized according to the general synthetic
procedure from 1n (705 mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol);
3n was purified by column chromatography on silica gel (hexanes/
EtOAc = 8/1−4/1); yield = 80% (414 mg); brown liquid; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C37H32N3 518.2596, found
518.2590; 1H NMR (400 MHz, CDCl3): δ 8.20 (d, J = 1.6 Hz, 2H),
7.90−7.88 (m, 2H), 7.80−7.75 (m, 4H), 7.54−7.50 (m, 4H), 7.32
(dd, J = 7.2, 8.0 Hz, 2H), 7.10 (br s, 1H), 6.66 (dd, J = 2.0, 2.8 Hz,
2H), 6.56 (dd, J = 0.8, 7.2 Hz, 2H), 6.21 (t, J = 3.6 Hz, 2H), 5.94 (dd,
J = 1.6, 3.2 Hz, 2H), 5.36 (s, 4H), 3.69 (s, 4H); 13C{1H} NMR (100
MHz, CDCl3): δ 147.8 (2x), 136.3 (2x), 134.2 (2x), 133.3 (2x), 130.5
(2x), 130.2, 128.8 (2x), 127.9 (2x), 126.5 (2x), 125.8 (2x), 125.6
(2x), 123.7 (2x), 122.1 (2x), 122.0 (4x), 108.6 (2x), 107.4 (2x), 48.1
(2x), 29.8 (2x).
1.723 (d, J = 6.8 Hz, 3H), 1.718 (d, J = 6.8 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 147.7 (2x), 143.5, 143.4, 136.3 (2x), 134.5
(2x), 130.42, 130.38, 128.6 (3x), 127.2 (2x), 125.40 (2x), 125.39
(2x), 117.9 (2x), 108.7 (2x), 107.0 (2x), 54.9 (2x), 30.0 (2x), 22.59,
22.56.
3,5-Bis(4-bromo-1-methyl-1H-pyrrol-2-ylmethyl)-4-methyl-
pyridine (3p). 3p was synthesized according to the general synthetic
procedure from 1g (561 mg, 3.0 mmol) and 2b (99 mg, 1.0 mmol);
3p was purified by column chromatography on silica gel (hexanes/
EtOAc = 8/1−4/1); yield = 89% (387 mg); brown solid; mp = 40−
43 °C (recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C18H20Br2N3 436.0024, found 436.0019; 1H
NMR (400 MHz, CDCl3): δ 8.16 (s, 2H), 6.58 (d, J = 1.6 Hz, 2H),
5.58 (d, J = 1.6 Hz, 2H), 3.85 (s, 4H), 3.51 (s, 6H), 2.18 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 148.8 (2x), 144.7, 132.5 (2x),
130.7 (2x), 121.4 (2x), 110.3 (2x), 94.1 (2x), 33.9 (2x), 28.2 (2x),
14.8.
3,5-Bis(4-bromo-1-methyl-1H-pyrrol-2-ylmethyl)-4-phenyl-
pyridine (3q). 3q was synthesized according to the general synthetic
procedure from 1g (561 mg, 3.0 mmol) and 2c (161 mg, 1.0 mmol);
3q was purified by column chromatography on silica gel (hexanes/
EtOAc = 8/1−4/1); yield = 82% (408 mg); brown liquid; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C23H22Br2N3 498.0181, found
1
498.0176; H NMR (400 MHz, CDCl3): δ 8.33 (s, 2H), 7.37−7.34
(m, 3H), 6.91−6.88 (m, 2H), 6.43 (d, J = 1.6 Hz, 2H), 6.58 (d, J =
2.0 Hz, 2H), 3.54 (s, 4H), 3.12 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 149.0, 148.9 (2x), 136.2, 132.2 (2x), 131.4, 128.5 (2x),
127.9 (2x), 127.8 (2x), 120.8 (2x), 110.6 (2x), 94.0 (2x), 33.5 (2x),
27.8 (2x).
3,5-Bis(1-n-butyl-1H-pyrrol-2-ylmethyl)-4-methylpyridine
(3r). 3r was synthesized according to the general synthetic procedure
from 1d (453 mg, 3.0 mmol) and 2b (99 mg, 1.0 mmol); 3r was
purified by column chromatography on silica gel (hexanes/EtOAc =
7/1−4/1); yield = 88% (320 mg); brown liquid; HRMS (ESI-TOF)
1
m/z: [M + H]+ calcd for C24H34N3 364.2753, found 364.2747; H
NMR (400 MHz, CDCl3): δ 8.23 (s, 2H), 6.65 (dd, J = 2.0, 2.4 Hz,
2H), 6.04 (t, J = 3.2 Hz, 2H), 5.55−5.33 (m, 2H), 3.91 (s, 4H), 3.83
(t, J = 7.2 Hz, 4H), 2.19 (s, 3H), 1.75−1.67 (m, 4H), 1.41−1.28 (m,
4H), 0.95 (t, J = 7.2 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ
148.9 (2x), 144.6, 132.0 (2x), 129.3 (2x), 120.5 (2x), 107.4 (2x),
106.7 (2x), 46.3 (2x), 33.4 (2x), 28.3 (2x), 18.9 (2x), 14.6, 13.6 (2x).
3,5-Bis(1-n-butyl-1H-pyrrol-2-ylmethyl)-4-phenylpyridine
(3s). 3s was synthesized according to the general synthetic procedure
from 1d (453 mg, 3.0 mmol) and 2c (161 mg, 1.0 mmol); 3s was
purified by column chromatography on silica gel (hexanes/EtOAc =
8/1−6/1); yield = 84% (357 mg); brown liquid; H HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C29H36N3 426.2909, found 426.2904;
1H NMR (400 MHz, CDCl3): δ 8.39 (s, 2H), 7.33−7.31 (m, 3H),
6.98−6.96 (m, 2H), 6.53 (t, J = 2.0 Hz, 2H), 6.02 (t, J = 2.8 Hz, 2H),
5.59−5.58 (m, 2H), 3.61 (s, 4H), 3.48 (t, J = 7.2 Hz, 4H), 1.40−1.33
(m, 4H), 1.18−1.09 (m, 4H), 0.83 (t, J = 7.2 Hz, 6H); 13C{1H} NMR
(100 MHz, CDCl3): δ 148.9 (2x), 136.5, 132.6 (2x), 130.2 (2x),
128.1 (2x), 127.9 (2x), 127.6 (2x), 120.1 (2x), 107.9 (2x), 106.5 (2x),
46.0 (2x), 33.0 (2x), 28.1 (2x), 19.7 (2x), 13.5 (2x).
3,5-Bis-[1-(3-chlorobenzyl)-1H-pyrrol-2-ylmethyl]-4-methyl-
pyridine (3t). 3t was synthesized according to the general synthetic
procedure from 1m (657 mg, 3.0 mmol) and 2b (99 mg, 1.0 mmol);
3t was purified by column chromatography on silica gel (hexanes/
EtOAc = 8/1−4/1); yield = 83% (414 mg); brown liquid; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C30H28Cl2N3 500.1660, found
1
500.1656; H NMR (400 MHz, CDCl3): δ 8.13 (s, 2H), 7.24−7.23
3,5-Bis-[1-(1-phenylethyl)-1H-pyrrol-2-ylmethyl]pyridine
(3o). 3o was synthesized according to the general synthetic procedure
from 1o (597 mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3o was
purified by column chromatography on silica gel (hexanes/EtOAc =
8/1−4/1); yield = 68% (303 mg); brown liquid; HRMS (ESI-TOF)
(m, 4H), 6.94 (s, 2H), 6.86−6.83 (m, 2H), 6.71 (t, J = 2.0 Hz, 2H),
6.13 (t, J = 3.6 Hz, 2H), 5.61 (t, J = 1.6 Hz, 2H), 5.02 (s, 4H), 3.71 (s,
4H), 1.89 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 148.9 (2x),
144.7, 140.1 (2x), 134.6 (2x), 132.6 (2x), 130.0 (2x), 129.8 (2x),
127.6 (2x), 126.2 (2x), 124.2 (2x), 121.8 (2x), 108.6 (2x), 107.5 (2x),
49.9 (2x), 28.2 (2x), 14.3.
1
m/z: [M + H]+ calcd for C31H32N3 446.2596, found 446.2591; H
NMR (400 MHz, CDCl3): δ 8.19 (s, 2H), 7.30−7.20 (m, 6H), 7.05
(t, J = 2.4 Hz, 1H), 6.90−6.87 (m, 6H), 6.19 (dd, J = 3.2, 6.4 Hz,
2H), 5.87−5.84 (m, 2H),5.17−5.10 (m, 2H), 3.72−3.62 (m, 4H),
3,5-Bis-[1-(3-chlorobenzyl)-1H-pyrrol-2-ylmethyl]-4-phenyl-
pyridine (3u). 3u was synthesized according to the general synthetic
procedure from 1m (657 mg, 3.0 mmol) and 2c (161 mg, 1.0 mmol);
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Note
3u was purified by column chromatography on silica gel (hexanes/
EtOAc = 8/1−4/1); yield = 78% (438 mg); brown liquid; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C35H30Cl2N3 562.1817, found
3.0 mmol) and 2a (85 mg, 1.0 mmol); 3aa was purified by column
chromatography on silica gel (hexanes/EtOAc = 8/1−4/1); yield =
59% (160 mg); brown liquid; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C15H14NS2 272.0568, found 272.0563; 1H NMR (400 MHz,
CDCl3): δ 8.41 (d, J = 2.0 Hz, 2H), 7.43 (t, J = 2.0 Hz, 1H), 7.16 (d, J
= 1.2, 5.2 Hz, 2H), 6.93 (dd, J = 3.6, 5.2 Hz, 2H), 6.79 (dd, J = 1.2,
3.6 Hz, 2H), 4.13 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ
148.0 (2x), 142.3 (2x), 136.3 (2x), 135.6, 126.9 (2x), 125.5 (2x),
124.3 (2x), 33.0 (2x).
3,5-Bisfuran-2-ylmethylpyridine (3ab). 3ab was synthesized
according to the general synthetic procedure from 1t (288 mg, 3.0
mmol) and 2a (85 mg, 1.0 mmol); 3ab was purified by column
chromatography on silica gel (hexanes/EtOAc = 8/1−4/1); yield =
10% (24 mg); brown liquid; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C15H14NO2 240.1025, found 240.1019; 1H NMR (400 MHz,
CDCl3): δ 8.39 (br s, 2H), 7.42 (br s, 1H), 7.33 (dd, J = 0.4, 1.6 Hz,
2H), 6.29 (dd, J = 1.6, 3.2 Hz, 2H), 6.01 (dd, J = 0.8, 3.2 Hz, 2H),
3.95 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 153.0 (2x), 148.0
(2x), 141.8 (2x), 136.6 (2x), 133.5, 110.3 (2x), 106.7 (2x), 31.6 (2x).
3,5-Bisbenzo[b]thiophen-2-ylmethylpyridine (3ac). 3ac was
synthesized according to the general synthetic procedure from 1u
(486 mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3ac was purified by
column chromatography on silica gel (hexanes/EtOAc = 8/1−4/1);
yield = 58% (215 mg); brown solid; mp = 218−220 °C (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C23H18NS2 372.0881, found 372.0875; 1H NMR (400 MHz,
CDCl3): δ 8.49 (d, J = 2.0 Hz, 2H), 7.75 (dd, J = 0.4, 7.6 Hz, 2H),
7.66 (d, J = 7.2 Hz, 2H), 7.52 (t, J = 1.6 Hz, 1H), 7.34−7.25 (m, 4H),
7.00 (s, 2H), 4.21 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ
148.3 (2x), 143.3 (2x), 139.9 (2x), 139.8 (2x), 136.7 (2x), 135.0,
124.3 (2x), 123.9 (2x), 123.1 (2x), 122.2 (4x), 34.0 (2x).
1
562.1812; H NMR (400 MHz, CDCl3): δ 8.31 (s, 2H), 7.30−7.23
(m, 3H), 7.18−7.10 (m, 4H), 6.86−6.84 (m, 2H), 6.80 (br s, 2H),
6.59 (d, J = 7.2 Hz, 2H), 6.56 (t, J = 2.4 Hz, 2H), 6.09 (t, J = 3.2 Hz,
2H), 5.65−5.64 (m, 2H), 4.65 (s, 4H), 3.46 (s, 4H); 13C{1H} NMR
(100 MHz, CDCl3): δ 148.89, 148.85, 139.9 (2x), 136.1, 134.4 (2x),
132.2 (2x), 130.5 (2x), 129.9 (2x), 128.1 (2x), 127.82 (2x), 127.77
(2x), 127.4 (2x), 126.21 (2x), 124.15 (2x), 121.2 (2x), 109.1 (2x),
107.6 (2x), 49.5 (2x), 28.1 (2x).
4-Methyl-3,5-bis(1-methyl-1H-pyrrol-2-ylmethyl)pyridine
(3v). 3v was synthesized according to the general synthetic procedure
from 1a (327 mg, 3.0 mmol) and 2b (99 mg, 1.0 mmol); 3v was
purified by column chromatography on silica gel (hexanes/EtOAc =
8/1−4/1); yield = 84% (235 mg); brown liquid; HRMS (ESI-TOF)
1
m/z: [M + H]+ calcd for C18H22N3 280.1814, found 280.1806; H
NMR (400 MHz, CDCl3): δ 8.18 (s, 2H), 6.17 (t, J = 2.0 Hz, 2H),
6.04 (t, J = 2.8 Hz, 2H), 5.62 (ddd, J = 0.8, 2.0, 2.8 Hz, 2H), 3.91 (s,
4H), 3.56 (s, 6H), 2.23 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3):
δ 148.8 (2x), 144.5, 132.9 (2x), 129.8 (2x), 121.8 (2x), 107.7 (2x),
106.7 (2x), 33.7 (2x), 28.3, (2x), 14.6.
3,5-Bis(1-methyl-1H-pyrrol-2-ylmethyl)-4-phenylpyridine
(3w). 3w was synthesized according to the general synthetic
procedure from 1a (327 mg, 3.0 mmol) and 2c (161 mg, 1.0
mmol); 3w was purified by column chromatography on silica gel
(hexanes/EtOAc = 8/1−4/1); yield = 80% (273 mg); brown liquid;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H24N3 342.1970,
found 342.1963; 1H NMR (400 MHz, CDCl3): δ 8.37 (s, 2H), 7.40−
7.38 (m, 3H), 7.00−6.98 (m, 2H), 6.50 (t, J = 2.0 Hz, 2H), 6.03 (t, J
= 2.8 Hz, 2H), 5.68−5.66 (m, 2H), 3.64 (s, 4H), 3.21 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3): δ 149.0 (2x), 148.8 (2x), 136.7,
3,5-Bis(4-pyridinyl)-2-ylmethylpyridine (3ad). 3ad was syn-
thesized according to the general synthetic procedure from 1v (321
mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3ad was purified by
column chromatography on silica gel (hexanes/EtOAc = 8/1−4/1);
yield = 3% (8 mg); brown liquid; HRMS (ESI-TOF) m/z: [M + H]+
132.9 (2x), 130.6, 128.4 (2x), 128.1 (2x), 127.8, 121.4 (2x), 108.2
(2x), 106.8 (2x), 33.4 (2x), 28.1 (2x).
3,5-Dibenzylpyridine (3x). 3x was synthesized according to the
general synthetic procedure from 1p (318 mg, 3.0 mmol) and 2a (85
mg, 1.0 mmol); 3x was purified by column chromatography on silica
gel (hexanes/EtOAc = 8/1−7/1); yield = 58% (150 mg); yellow
solid; mp = 84−85 °C (recrystallized from hexanes and EtOAc);
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H18N 260.1439,
1
calcd for C17H16N3 262.1344, found 262.1340; H NMR (400 MHz,
CDCl3): δ 8.51 (dd, J = 1.6, 4.4 Hz, 4H), 8.38 (d, J = 2.0 Hz, 2H),
7.23 (t, J = 2.0 Hz, 1H), 7.06 (dd, J = 1.6, 4.4 Hz, 4H), 3.94 (s, 4H);
13C{1H} NMR (100 MHz, CDCl3): δ 150.1 (4x), 148.7 (2x), 148.4
(2x), 136.8 (2x), 134.5, 124.0 (4x), 38.1 (2x).
1
found 260.1435; H NMR (400 MHz, CDCl3): δ 8.35 (br s, 2H),
7.32−7.21 (m, 7H), 7.17−7.15 (m, 4H), 3.94 (s, 4H); 13C{1H} NMR
(100 MHz, CDCl3): δ 148.1 (2x), 139.8 (2x), 136.7 (2x), 136.2,
128.8 (4x), 128.6 (4x), 126.4 (2x), 38.9 (2x).
3,5-Bisnaphthalen-1-ylmethyl-pyridine (3ae). 3ae was syn-
thesized according to the general synthetic procedure from 1w (468
mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3ae was purified by
column chromatography on silica gel (hexanes/EtOAc = 8/1−4/1);
yield = 66% (237 mg); yellow liquid; HRMS (ESI-TOF) m/z: [M +
3,5-Bis(2-naphthalen)-2-ylmethylpyridine (3y). 3y was syn-
thesized according to the general synthetic procedure from 1q (468
mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3y was purified by column
chromatography on silica gel (hexanes/EtOAc = 8/1−7/1); yield =
60% (216 mg); yellow solid; mp = 120−122 °C (recrystallized from
hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C27H22N 360.1752, found 360.1746; 1H NMR (400 MHz, CDCl3): δ
8.43 (d, J = 2.0 Hz, 2H), 7.82−7.73 (m, 6H), 7.59 (br s, 2H), 7.49−
7.43 (m, 4H), 7.36 (dt, J = 0.4, 2.4 Hz, 1H), 7.27 (dd, J = 2.4, 8.4 Hz,
2H), 4.09 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 148.2 (2x),
137.3 (2x), 137.0 (2x), 136.1 (2x), 133.5 (2x), 132.1, 128.3 (2x),
127.6 (2x), 127.5 (2x), 127.2 (2x), 127.1 (2x), 126.2 (2x), 125.6 (2x),
39.0 (2x).
3,5-Bis(3-pyridinyl)-2-ylmethylpyridine (3z). 3z was synthe-
sized according to the general synthetic procedure from 1r (321 mg,
3.0 mmol) and 2a (85 mg, 1.0 mmol); 3z was purified by column
chromatography on silica gel (hexanes/EtOAc = 8/1−4/1); yield =
8% (21 mg); brown liquid; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C17H16N3 262.1344, found 262.1338; 1H NMR (400 MHz,
CDCl3): δ 8.47 (dd, J = 1.6, 6.4 Hz, 2H), 8.45 (d, J = 2.0 Hz, 2H),
8.35 (d, J = 2.4 Hz, 2H), 7.41 (dt, J = 1.6, 8.0 Hz, 2H), 7.23 (dt, J =
0.4, 2.0 Hz, 1H), 7.20 (dd, J = 4.8, 8.4 Hz, 2H), 3.93 (s, 4H);
13C{1H} NMR (100 MHz, CDCl3): δ 149.9 (2x), 148.3 (2x), 148.0
(2x), 136.5 (2x), 136.2 (2x), 135.2 (2x), 135.0, 123.6 (2x), 36.0 (2x).
3,5-Bisthiophen-2-ylmethylpyridine (3aa). 3aa was synthe-
sized according to the general synthetic procedure from 1s (336 mg,
1
H]+ calcd for C27H22N 360.1752, found 360.1747; H NMR (400
MHz, CDCl3): δ 8.60 (br s, 2H), 7.88 (d, J = 8.4 Hz, 4H), 7.78 (d, J =
8.4 Hz, 2H), 7.50 (dt, J = 1.2, 8.0 Hz, 2H), 7.44 (dt, J = 1.2, 8.0 Hz,
2H), 7.40 (d, J = 8.0 Hz, 2H), 7.28 (br s, 1H), 7.21 (d, J = 6.8 Hz,
2H), 4.35 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.8 (2x),
136.2 (2x), 135.2 (2x), 133.8 (2x), 131.6 (3x), 128.7 (2x), 127.4 (2x),
127.1 (2x), 126.0 (2x), 125.6 (2x), 125.4 (2x), 123.7 (2x), 36.0 (2x).
3,5-Bis((9-ethyl-9H-carbazol-3-yl)methyl)pyridine (3af). 3af
was synthesized according to the general synthetic procedure from 1x
(669 mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3af was purified by
column chromatography on silica gel (hexanes/EtOAc = 8/1−4/1);
yield = 68% (335 mg); brown solid; mp = 157−158 °C (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C35H32N3 494.2596, found 494.2591; 1H NMR (400 MHz,
CDCl3): δ 8.48 (d, J = 2.0 Hz, 2H), 8.06 (d, J = 7.6 Hz, 2H), 7.91 (s,
2H), 7.49 (dt, J = 0.8, 8.0 Hz, 2H), 7.46 (t, J = 1.6 Hz, 1H), 7.41 (d, J
= 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.28 (dd, J = 1.6, 8.4 Hz,
2H), 7.23 (t, J = 8.0 Hz, 2H), 4.33 (q, J = 7.2 Hz, 4H), 7.14 (s, 4H),
1.42 (t, J = 7.2 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.8
(2x), 140.1 (2x), 138.6 (2x), 137.2 (2x), 136.8 (2x), 130.2, 126.6
(2x), 125.6 (2x), 123.1 (2x), 122.6 (2x), 120.4 (2x), 120.3 (2x), 118.6
(2x), 108.5 (2x), 108.4 (2x), 38.9 (2x), 37.4 (2x), 13.7 (2x).
3,5-Bis-3-(1-methylindole)-2-ylmethylpyridine (3ag). 3ag
was synthesized according to the general synthetic procedure from
F
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The Journal of Organic Chemistry
pubs.acs.org/joc
Note
1y (477 mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3ag was purified
by column chromatography on silica gel (hexanes/EtOAc = 8/1−4/
1); yield = 68% (248 mg); brown liquid; HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C25H24N3 366.1970, found 366.1965; 1H NMR (400
MHz, CDCl3): δ 8.46 (d, J = 2.0 Hz, 2H), 7.49 (t, J = 2.0 Hz, 1H),
7.47 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.25 (dt, J = 0.8,
8.0 Hz, 2H), 7.09 (dt, J = 0.8, 8.0 Hz, 2H), 6.69 (s, 2H), 4.05 (s, 4H),
3.70 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.7 (2x), 137.1,
136.5 (2x), 136.2 (2x), 124.4 (2x), 127.1 (2x), 121.6 (2x), 118.9 (2x),
118.8 (2x), 113.1 (2x), 109.2 (2x), 32.5 (2x), 28.6 (2x).
hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C23H26NO4 380.1862, found 380.1857; 1H NMR (400 MHz,
CDCl3): δ 8.32 (d, J = 5.0 Hz, 2H), 7.25 (t, J = 2.0 Hz, 1H), 6.77
(d, J = 8.0 Hz, 2H), 6.67 (dd, J = 2.0, 8.4 Hz, 2H), 6.62 (d, J = 2.0 Hz,
2H), 3.86 (s, 4H), 3.84 (s, 6H), 3.78 (s, 6H); 13C{1H} NMR (100
MHz, CDCl3): δ 149.0 (2x), 147.9 (2x), 147.6 (2x), 136.4 (2x),
136.4, 132.3 (2x), 120.7 (2x), 111.9 (2x), 111.2 (2x), 55.8 (2x), 55.7
(2x), 38.4 (2x).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.9b03315.
■
3,5-Bis-3-(1-allylindole)-2-ylmethylpyridine (3ah). 3ah was
synthesized according to the general synthetic procedure from 1z
(555 mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3ah was purified by
column chromatography on silica gel (hexanes/EtOAc = 8/1−4/1);
yield = 63% (263 mg); brown liquid; HRMS (ESI-TOF) m/z: [M +
sı
X-ray analysis data of 3k (CIF)
Copies of NMR, MS, and HRMS spectral data for all
compounds (PDF)
1
H]+ calcd for C29H28N3 418.2283, found 418.2277; H NMR (400
MHz, CDCl3): δ 8.46 (d, J = 2.4 Hz, 2H), 7.50 (t, J = 2.0 Hz, 1H),
7.48 (d, J = 7.6 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.23 (dt, J = 1.2,
8.4 Hz, 2H), 7.09 (dt, J = 1.2, 8.0 Hz, 2H), 6.75 (s, 2H), 6.01−5.91
(m, 2H), 5.20 (dq, J = 1.6, 10.4 Hz, 2H), 5.08 (dq, J = 1.6, 16.8 Hz,
2H), 4.65 (dt, J = 1.6, 5.2 Hz, 4H), 4.07 (s, 4H); 13C{1H} NMR (100
MHz, CDCl3): δ 147.7 (2x), 136.5, 136.4 (2x), 136.1 (2x), 133.4
(2x), 127.6 (2x), 126.0 (2x), 121.7 (2x), 119.0 (4x), 117.1 (2x), 113.5
(2x), 109.6 (2x), 45.6 (2x), 28.7 (2x).
AUTHOR INFORMATION
Corresponding Author
■
Meng-Yang Chang − Department of Medicinal and Applied
Chemistry, Kaohsiung Medical University, Kaohsiung 807,
Taiwan; Department of Medical Research, Kaohsiung Medical
University Hospital, Kaohsiung 807, Taiwan; orcid.org/
0000-0002-1983-8570; Email: mychang@kmu.edu.tw
3,5-Bis-3-(1-n-butylindole)-2-ylmethylpyridine (3ai). 3ai was
synthesized according to the general synthetic procedure from 1aa
(603 mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3ai was purified by
column chromatography on silica gel (hexanes/EtOAc = 8/1−4/1);
yield = 66% (297 mg); brown liquid; HRMS (ESI-TOF) m/z: [M +
Author
1
H]+ calcd for C31H36N3 450.2909, found 450.2905; H NMR (400
Yu-Lin Tsai − Department of Medicinal and Applied Chemistry,
Kaohsiung Medical University, Kaohsiung 807, Taiwan
MHz, CDCl3): δ 8.49 (d, J = 2.0 Hz, 2H), 7.53 (t, J = 2.0 Hz, 1H),
7.50 (d, J = 7.6 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.26 (dt, J = 1.2,
8.4 Hz, 2H), 7.11 (dt, J = 1.2, 8.0 Hz, 2H), 6.78 (s, 2H), 4.09 (s, 4H),
4.06 (t, J = 6.8 Hz, 4H), 1.84−1.77 (m, 4H), 1.41−1.32 (m, 4H),
0.98 (t, J = 7.6 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.7
(2x), 136.42 (2x), 136.38, 136.2 (2x), 127.5 (2x), 126.0 (2x), 121.4
(2x), 118.9 (2x), 118.7 (2x), 112.9 (2x), 109.3 (2x), 45.8 (2x), 32.2
(2x), 28.7 (2x), 20.1 (2x), 13.6 (2x).
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.9b03315
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
3,5-Bis-3-(1-benzylindole)-2-ylmethylpyridine (3aj). 3aj was
synthesized according to the general synthetic procedure from 1ab
(705 mg, 3.0 mmol) and 2a (85 mg, 1.0 mmol); 3aj was purified by
column chromatography on silica gel (hexanes/EtOAc = 8/1−4/1);
yield = 69% (357 mg); brown liquid; HRMS (ESI-TOF) m/z: [M +
■
The authors would like to thank the Ministry of Science and
Technology of the Republic of China for financial support
(MOST 106-2628-M-037-001-MY3).
1
H]+ calcd for C37H32N3 518.2596, found 518.2591; H NMR (400
REFERENCES
MHz, CDCl3): δ 8.49 (d, J = 2.4 Hz, 2H), 7.54 (dt, J = 2.4 Hz, 2H),
7.51 (d, J = 7.6 Hz, 1H), 7.33−7.26 (m, 8H), 7.21 (dt, J = 1.2, 8.4 Hz,
2H), 7.11−7.07 (m, 6H), 6.80 (s, 2H), 5.22 (s, 4H), 4.10 (s, 4H);
13C{1H} NMR (100 MHz, CDCl3): δ 147.7 (2x), 137.5 (2x), 136.8,
136.4 (2x), 136.1 (2x), 128.6 (4x), 127.7 (2x), 127.5 (2x), 126.6 (4x),
126.5 (2x), 121.9 (2x), 119.1 (2x), 119.0 (2x), 113.7 (2x), 109.7 (2x),
49.8 (2x), 28.7 (2x).
■
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m/z: [M + H]+ calcd for C33H36N3 474.2909, found 474.2904; H
NMR (400 MHz, CDCl3): δ 8.44 (d, J = 2.0 Hz, 2H), 7.49 (t, J = 2.0
Hz, 1H), 7.46 (d, J = 7.6 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.21 (dt, J
= 0.8, 8.0 Hz, 2H), 7.06 (dt, J = 0.8, 7.6 Hz, 2H), 6.87 (s, 2H), 4.77−
4.70 (m, 2H), 4.06 (s, 4H), 2.21−2.14 (m, 4H), 1.91−1.80 (m, 8H),
1.79−1.73 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 147.7
(2x), 137.6 (2x), 136.4, 136.3 (2x), 127.6 (2x), 122.8 (2x), 121.4
(2x), 118.9 (2x), 118.9 (2x), 113.0 (2x), 109.8 (2x), 56.8 (2x), 32.5
(4x), 28.8 (2x), 24.0 (4x).
3,5-Bis(3,4-dimethoxybenzyl)pyridine (3al). 3al was synthe-
sized according to the general synthetic procedure from 1ad (498 mg,
3.0 mmol) and 2a (85 mg, 1.0 mmol); 3al was purified by column
chromatography on silica gel (hexanes/EtOAc = 8/1−4/1); yield =
63% (239 mg); brown solid; mp = 84−86 °C (recrystallized from
G
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H
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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
regenerated and used several times. The concentration of active sites
is >4.7equiv/kg.
(33) For Dowex 50Wx8, see: (a) Ali, S. H.; Merchant, S. Q. Kinetic
Study of Dowex 50 Wx8-Catalyzed Esterification and Hydrolysis of
Benzyl Acetate. Ind. Eng. Chem. Res. 2009, 48, 2519−2532 For
Amberlite 200C, see:. (b) Lahyani, A.; Chtourou, M.; Frikha, M. H.;
Trabelsi, M. Amberlyst-15 and Amberlite-200C: Efficient Catalysts for
Aldol and Cross-Aldol Condensation under Ultrasound Irradiation.
Ultrason. Sonochem. 2013, 20, 1296−1301.
(34) To demonstrate the plausible mechanism (Scheme 2), the final
resulting byproduct N-methylpyrrolylmethyl alcohol could be
detected by LC-MS technique.
(35) CCDC 1891810 (3k) contains the supplementary crystallo-
graphic data for this paper. This data can be obtained free of charge
via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC,
12 Union Road, Cambridge CB2 1EZ, UK; fax: 44-1223-336033, e-
mail: deposit@ccdc.cam.ac.uk).
I
https://dx.doi.org/10.1021/acs.joc.9b03315
J. Org. Chem. XXXX, XXX, XXX−XXX