Palladium-Catalyzed Direct Arylation of Alkylpyridine via Activated N-Methylpyridinium Salts

Article abstract of DOI:10.1021/acs.joc.9b02694

An efficient Pd-catalyzed arylation of alkylpyridine based on the pyridinium activation strategy has been developed for synthesis of mixed aryl alkylpyridines. It was found that (1) the N-methyl group in the pyridinium salts acted as a transient activator and could be automatically departed after the reaction, (2) CuBr was an indispensable additive for achieving the C₆-selective arylation, (3) the α-branched alkyl chain on the alkylpyridine greatly increased the yield of the product. Deuterium labelling experiment revealed that in the case of the α-branched alkylpyridine, the presence of CuBr completely inhibited the H/D exchange at the benzylic position and thus enabled the selective arylation at the C₆ position. This protocol demonstrates a broad substrate scope, and with respect to both the aryl iodides and the α-branched alkylpyridine, the desired mixed aryl alkylpyridines were obtained in generally good to excellent yields.

Full text of DOI:10.1021/acs.joc.9b02694

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Article
Palladium-Catalyzed Direct Arylation of
Alkylpyridine via Activated N-methylpyridinium Salts
Xue Chen, Wen-Jing Li, Shun Li, Juan Tang, Xi Du, Xue-
Li Zheng, Mao-Lin Yuan, Hai-yan Fu, Rui-Xiang Li, and Hua Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02694 • Publication Date (Web): 04 Dec 2019
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Palladium-Catalyzed Direct Arylation of Alkylpyridine via Activated N-
methylpyridinium Salts
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Xue Chen,† Wen-jing Li,† Shun Li,† Juan Tang,† Xi Du,‡ Xue-li Zheng,† Mao-lin Yuan,†
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Hai-yan Fu,†* Rui-xiang Li† and Hua Chen†*
†Key lab of Green Chemistry and Technology, Ministry of Education; College of Chemistry, Sichuan
University, Chengdu 610064, People’s Republic of China.
‡Department of Chemistry, School of Basic Medical Science, Southwest Medical University, Luzhou 6
46000, China.
Fax: (+86)-28-8541-2904; e-mail: scufhy@scu.edu.cn; scuhchen@scu.edu.cn.
ArI
R2
R2
Pd Cu
Ar
N
H
I-
N
Me
R1
R1
+N-Methyl group as the transient activator
alfa branched alkyl chain
+Promoted by
Cu(I)
+
as indispensible additive
94
+ 40 examples, up to % yield
ABSTRACT: An efficient Pd-catalyzed arylation of alkylpyridine based on
pyridinium activation strategy has been developed for synthesis of mixed arylalkyl
pyridines. It was found that: (1) the N-methyl group in the pyridinium salts acted as a
transient activator and could be automatically departed after the reaction; (2) CuBr was
an indispensable additive for achieving the C6-selective arylation; (3) the alfa branched
alkyl chain on the alkylpyridine greatly increased the yield of the product. Deuterium
labelling experiment revealed that in the case of the alfa branched alkylpyridine, the
presence of CuBr completely inhibited the H/D exchange at the benzylic position and
thus enabled the selective arylation at the C6 position. This protocol demonstrates a
broad substrate scope, with respect to both the aryl iodides and the alfa branched
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alkylpyridine, the desired mixed arylalkyl pyridines were obtained in generally good to
excellent yields.
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INTRODUCTION
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The aryl- and alkyl-disubstituted pyridines are very important pharmaceutical
precursors and building blocks which are found in many biologically active compounds
and functional materials.1 Both the alkyl and the aryl groups play important roles in
tuning the intriguing properties of pyridine construction unit-based materials, such as
organic optoelectronic,2a,3b electron-transport materials (ETMs),2b-f nanostructured
hybrid materials.2g For example, the aryl unit is beneficial to the construction of π-
extended backbones,3 while the alkyl chain enhances the solubility of molecule in
nonpolar solvents, and hence its processability in material sciences and industrial
applications.4 The aryl and alkyl substituents can be installed to the pyridine ring,
through traditional-metal catalyzed direct C–H activation6,9,10 or cross-coupling
reaction5,7 from pyridine and its pre-functionalized derivatives. Compared with the
latter method, direct C–H activation is very attractive, due to the avoidance of
preliminary synthesis of organometallic pyridine derivatives.7 Although pyridines
bearing both aryl and alkyl substituents can also be synthesized by the direct alkylation
of arylpyridines, the alkylated organometal species involved in the process usually
suffers greatly from β-H elimination, which competes against the alkylation and instead
gives the undesired olefin side-product.8 For this reason, various versions of Minisci
alkylation have been developed in recent years in order to achieve the direct C–H
alkylation of pyridine.9 Alternatively, the aryl-alkyl-disubstituted pyridines could also
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be prepared from alkylpyridines via the arylation process. However, only a few
examples have been reported to date,6 and most of them relied on the pyridine N-oxide10
and N-iminopyridinium ylide11 activation strategies to increase the acidity of pyridyl
C–H bond (Scheme 1).
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Scheme 1. Transitional Metal Catalyzed Arylation of Alkylpyridines.
Previous works
a)
: via Pyridine N-oxide, Ylide preactivation strategies
ArX
Pd or Cu
Alk
N
A
Ar
Alk
N
A
X=BF3K, I, COOH, B(OH)2, Br
The type of alkyl group was less explored
Alk
A=O, NBz
This work
Only Me and n-Pr were investigated, moderate
yield
b)
: via Pyridinium preactivation strategies
ArI
Activated
Pd
Cu
I-
H
N
Ar
N
α
R
Me
Alkyl group
R
R = H, lower yields, up to 40%
, higher yields, up to 94%
R
≠H
The pyridine arylation employing pyridine N-oxides or N-iminopyridinium ylides
often requires additional steps to remove the activating groups from products, which
impairs their atom- and step-economy10,11. On the other hand, the capability of these
two activation strategies for arylation of alkylpyridine has been less studied, and to the
best of our knowledge, only 2-methyl and 2-propylpyridines have been demonstrated
C6–H arylation using pyridine N-oxides or N-iminopyridinium ylide10,11 in moderate
yields (Scheme 1a). Although an excellent site-selective system developed by Fagnou’s
group could achieve C6–H arylation of 2-methylpyridine N-oxide in good yield.10c
Previously, our group have developed an efficient pyridine arylation system based on
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an N-methylpyridinium salts activation strategy.12 The advantages of this approach
include: (1) methyl group as the activator could be automatically eliminated along with
the reaction; (2) The C–H acidity of N-methylpyridinium salts is stronger than the N-
oxide and N-iminopyridinium ylide counterparts, which enables the successful
arylation of some challenging substrates.12 But ongoing studies showed that the lower
yields are encountered with the 2-methylpyridine.
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Toward the goal to developed an efficient protocol for the syntheses of mixed
alkyl/aryl pyridines, we are promoted to re-evaluate the intrinsic arylation activity of
the 2-alkyl pyridine. During the C–H bond transformation process, a base is often
required to facilitate the C–H abstraction, whereas besides the Csp2–H, the benzylic
Csp3–H bond on the alkyl chain is also potentially deprotonated.10c,13,14 This issue
becomes even more serious, when the alkyl pyridine is quaternized and becomes more
acidic. The competitive C–H abstraction complicates the reaction product, leading to
low yield and poor selectivity of the desired C6-arylation. It helps to rationalize the
unsatisfied results of direct arylation when 2-methylpyridine as substrate was employed
at the very first beginning (Scheme 1b, R = H). In such a situation, we envisioned that
this problem could be solved via reducing the acidity of the benzylic protons by
introducing the electron-donating alkyl group there. Herein, we demonstrate our
systematic investigations on the effect of alkyl groups on C6 arylation reactivity, which
enable us to develop an efficient and practical protocol for the synthesis of the mixed
alkyl aryl pyridines (Scheme 1b, R
H).
≠
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RESULTS AND DISCUSSION
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We have previously developed a protocol for synthesis of 2,6-diarylpyridines,
starting from 2-phenyl pyridine via N-methylpyridinium activator strategy.12 However,
the system appears not applicable to 2-methylpyridines. When the optimal condition
was applied with N-methyl-2-methylpyridinium salts (1a; 0.6 mmol), p-tolyl iodide (2a;
1.2 mmol), being reacted in N,N-dimethylformamide at 150 °C in the presence of
Pd(PhCN)2Cl2 (5 mol%), Cu2O (50 mol%), and trifuryl phosphine (10 mol%), the
desired 6-phenyl-2-methyl pyridine was obtained in merely 10% yield. An equal
amount of p-tolyl (6-(p-tolyl) pyridin-2-yl) methanone 3a′ (Scheme 2. Eq.1) was
furnished along with the reaction, which probably resulted from the successive
arylation and oxidation at benzylic Csp3–H bond. A higher C6-arylation selectivity was
achieved under the condition of Pd(PhCN)2Cl2 (5 mol%), PPh3 (5 mol%), CuBr (1 equiv)
and PivOK (2.0 equiv), CTAB (cetyltrimethyl ammonium bromide) (0.5 equiv) at
120 °C in DMAc (Table 1), affording the desired C6-arylation product in 22% yield,
together with 11% yield of 3a′ (Scheme 2. Eq. 2). CTAB may serve as the stabilizer for
the possible in situ generated palladium nanopaticles.15
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Scheme 2. Arylation of N-methyl-2-methylpyridinium Salt
Pd(PhCN)2Cl2 (5 mol%), TFP (10 mol%)
10%
10%
N
(1)
(2)
Cu2O (0.5 eq), PivOK (2 eq)
16 h, N2, DMAc (1 M)
I
+
N
N
I
O
3a'
3a
Pd(PhCN)2Cl2 (5 mol%), PPh3 (5 mol%)
1a
2a
22%
11%
CuBr (1.0 eq), PivOK (2 eq), CTAB (0.5 eq)
16 h, N2, DMAc (1 M)
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Table 1. Substrate Scope in Term of Alkyl Substituted Pyridinium Saltsa
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9
Alk
I
Pd(PhCN)2Cl2, CuBr, PivOK
Alk
+
N
N
I
PPh3, CTAB, DMAc(1 M), N2, 16 h
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2a
1a-o
3a-o
N
N
N
N
n
3c,
: 22%
n=0
n=1: 28%
: 20%
n=4: 24%
n=2
3a,
3b,
3f: 71%
3g: 80%
N
3e: 39%
3d,
N
N
N
3h: 82%
3i: 70%
3j: 63%
3k: 85%
tBu
N
N
N
2
N
6
3l: 67%
3m: 63%
3n: 55%
3o: 52%
di(3ob) : mono(3oa) = 2:1
a Reaction conditions: 1a-1o (0.25 mmol), 2a (109 mg, 0.5 mmol), Pd(PhCN)2Cl2 (4.7
mg, 0.0125 mmol), CuBr (35.8 mg, 0.25 mmol), PPh3 (3.7 mg, 0.0125 mmol), PivOK
(70 mg, 0.5 mmol), CTAB: cetylrimethylammonium bromide (45.5 mg, 0.125 mmol),
DMAc (1 M, 0.25 mL), 120 oC, 16 h, N2; b Isolated yields.
However, the attempts to further improve the yield and selectivity by extensive
screening of reaction condition was unsuccessful (see the Supporting Information,
Table S1). The yield and selectivity were generally low due to formation of the by-
product 3a′as well as significant quantities of unidentifiable by-products. Notably,
CuBr served as an important additive, and without it led to no reaction. The selectivity
of arylation at C6 position over benzylic site was better in N2 atmosphere than in air.
We speculated that the formation of the by-product 3a′ is most likely due to the small
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difference pKa value of C6–H and benzylic C–H bonds, which led to non-selective
reaction. Accordingly, we reasoned that the C6-selective arylation should be achievable
if these two types of C–H bonds were well distinguished. It is obvious that the
incorporation of electron-donating alkyl groups at benzylic position of 2-
methylpyridine would electronically and sterically decrease its C–H acidity and thus
favor C6–H bond arylation.
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With these considerations in mind, we systemically studied the effect of different
type of alkyl groups at the benzylic carbon on reaction efficiency, with PivOK as base
and CuBr as additive under N2 atmosphere, as shown in Table 1. As depicted in the
previous work, the bulkier PivOK as base would be beneficial for the selective arylation
at the less hindered C6–H position of the pyridinium salt.16 Initially, the alkyl
pyridinium salts 1a-1e bearing different alkyl groups, such as, methyl, ethyl, propyl,
pentyl, iso-butyl group was reacted with 1-iodo-4-methylbenzene 2a, and the yields are
still low (20-39%). This meant that the pKa value of the benzylic C–H bond was not
yet high enough after one alkyl group was introduced. But a remarkable increase of
yield was observed when substrate with iso-propyl group at the benzylic site (3e) was
employed. This observation revealed that the steric bulkiness of the side chain was
helpful for improving the yield. On this basis, we hypothesized that the yield would be
further increased by increasing the number of the alkyl groups at the benzylic site.
Accordingly, a series of pyridinium salts 1f-1l with two alkyl groups at the benzylic
site were subjected to the catalytic conditions. As expected, these additional alkyl
groups gave a significant rise in yield, and the desired products 3f-3l could be acquired
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in good yields (67-82%). In addition, pyridines bearing cycloalkyl groups at the C2
position were also suitable substrates. For example, the N-methyl-2-
cyclohexylpyridinium salt 1m could afford the expected C6-arylation product 3m in 63%
yield. The N-methyl-2-cyclopropylpyridinium salts 1n could also produce 3n in 55%
yield. Finally, the influence of the position of alkyl group on the pyridine ring was also
investigated. For example, 4-tert-butylpyridinium salts 1o gave a mixture of mono- and
di-arylation product 3o in 52% combined yield, with di/mono ratio being 2:1.
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Table 2. Substrate Scope in Term of Aryl Iodidesa
I
Pd(PhCN)2Cl2, CuBr, PivOK
R
+
R
N
N
I
PPh3, CTAB, DMAc (1 M), 16 h,
1k
2a-y
4a-y
R
R
N
N
N
N
R
R
4o: R=Cl:80%
4i : R=OCH3:61%
4j : R=CH3:79%
4k : R=CN:84%
4l : R=F:89%
4m: R=CO2CH3:33%
4n : R=CF3:N.R
4a: R=CH(CH3)2:73%
4b: R=OCH3:83%
4c: R=F:83%
4e: R=COOCH3:71%
4f : R=CF3:84%
4g: R=CN:94%
4p: R=CF3:73%
4q: R=CH3:85%
4r: R=OCH3:91%
4d: R=Cl:78%
4h: R=NO2:76%
O
F
F
N
N
N
N
N
Cl
F
4s: 79%
4w: 80%
4u: 81%
4v: 68%
4t: 82%
+
I
N
N
N
N
N
+
N
I
4ya
4yb
4xa
4xb
1k:2y=1:2 4y: 35% (4ya:4yb = 0.75:1)
1k:2y=2:1 4y: 40% (4ya:4yb =1.85:1)
1k:2x=1:2 4x: 68% (4xa:4xb=1:1)
1k:2x=2:1 4x: 64% (4xa:4xb=2.4:1)
a Reaction conditions: 1k (72.7 mg, 0.25 mmol), 2a-2y (0.5 mmol), Pd(PhCN)2Cl2 (4.7
mg, 0.0125 mmol), CuBr (35.8 mg, 0.25 mmol), PPh3 (3.7 mg, 0.0125 mmol), PivOK
(70 mg, 0.5 mmol), CTAB: cetylrimethylammonium bromide (45.5 mg, 0.125 mmol),
DMAc (0.25 mL), 120 oC, N2, 16 h; b Isolated yields.
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To examine the applicability of this protocol to synthesize mixed aryl alkyl
disubstituted pyridines, we further investigated the substrate scope in terms of the aryl
iodides by reacting with 2-(3′-pentyl) pyridinium salt 1k. The results are summarized
in Table 2. To our delight, the protocol is applicable to a wide range of aryl iodides (2a-
2y). Different substituted aryl iodides could selectively arylate the C6–position of 1k to
afford the corresponding products 4a-4y in 33-94% yields, irrespective of electronic
and steric properties of the substituents. Notably, meta-OMe-substituted phenyl iodide
afforded higher yield of product, than its ortho- and para- analogues (91% for 4r,
versus 83% and 61% for 4b and 4i, respectively). The results are well consistent with
the observed trends in our previously reported pyridinium arylation system. In addition,
the aryl iodides showed good compatibility with various functional groups. Besides the
OMe group, F, Cl, CF3, CN, NO2, and COOCH3 were all well-tolerated with the
reaction conditions. Especially noteworthy was that excellent yields could be obtained
with aryl iodides containing CN and NO2 groups, which only led to a modest level of
yield in our previous studies on the arylation of 2-arylpyridinium salts12a. Generally,
the steric hindrance from the ortho substituent decreases the yields to some extent (4i-
4k, 4m), and ortho-CF3 (4n) completely inhibited the reaction. Pleasantly, the
disubstituted iodobenzenes 2s-2v could also undergo the reaction smoothly, affording
the corresponding products in good yields of 68-82%. Furthermore, the 1-
iodonaphthalene was found to be a reactive arylating reagent for this reaction (4w, 80%
yield). To our delight, the 1,4- or 1,3- diiodobenzenes also underwent the reaction
smoothly and gave a mixture of di- and mono- arylated product 4xa and 4xb, or 4ya
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and 4yb, in 68% and 35% combined yields, respectively. Increasing the amount of
pyridinium salts 1k could significantly improve the yields of di-arylation product, thus
providing a facile synthetic approach for NCN-pincer-type ligand, such as 4ya.
Furthermore, the mono-arylation products 4xb and 4yb could also serve as important
synthetic intermediates, since the remaining iodine atom of which allowed the further
functionalization.
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Scheme 3. Deuterated Experiment
PivOK, D2O
H
H
H/D
H/D
(1)
N
H
N
D/H
N2
I
I
I
H
D/H
T=80 o
C
C
C
D:96%
D:96%
D:96%
D:0%
D:65%
D:37%
T=120 o
T=120 o
1a
CuBr(1.0eq)
PivOK, D2O
N2
(2)
(3)
N
H
N
D/H
H
H/D
D/H
I
H
T=80 o
C
C
C
D:97%
D:95%
D:96%
D:0%
D:94%
D:49%
T=120 o
T=120 o
1c
CuBr(1.0eq)
H/D
H
PivOK, D2O
N2
N
H
N
D/H
I
I
T=80 o
C
C
C
D:0%
D:87%
D:0%
D:0%
D:97%
D:26%
1h
T=120 o
T=120 o
CuBr(1.0eq)
In order to better understand the role of the alfa branched alkyl group as well as
the additive CuBr in the reaction, a series of deuterated experiments were conducted.
In the first place, we treated the pyridiniums 1a, 1c and 1h, respectively, with 2 equiv
o
of PivOK at 80 C in D2O for 16 h. In the cases of 1a and 1c, the D incorporation
occurred exclusively at benzylic sites in 96% and 97% yields, respectively (Scheme 3,
Eq. 1, 2), whereas no D incorporation was detected in 1h (Eq. 3). This observation
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indicated: (1) the benzylic C–H bonds of 1a and 1c were more acidic than their
corresponding C6–H bonds; (2) the bulkiness and electron richness at benzylic site in
1h precluded the H/D exchange. The observed trend was well consistent with our
previous assumptions that the C–H bond acidity would be reduced via the incorporation
of alkyl groups. We further found that the H/D exchange at the C6 position was enabled
by increasing the temperature from 80 oC to 120 oC, and the D incorporation of 1a and
1c was significantly improved from none to 65% and 94%, respectively. It was also
noteworthy that both the C6–H and benzylic C–H bonds of pyridinium 1h were
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deuterated at 120 C (87% and 97%, respectively) (Eq. 3). These phenomena again
revealed that the C6–H bond is less acidic than benzylic C–H bond, thus requiring high
temperature to achieve H/D exchange. Furthermore, at the reaction temperature (120
oC), the extent of the H/D exchange of the C6–H and the benzylic C–H was in a
comparable level, which indicated that the selective C6–H arylation still remained
challenging. Surprisingly, the situations were significantly changed with the addition
of CuBr. Although the D incorporation of C6–H were reduced for all three pyrdinium
compounds in the presence of CuBr, the D incorporation at benzylic position was
completely inhibited for 1h, in sharp contrast to 1a and 1c. In other words, the added
CuBr significantly increased the opportunity of H/D exchange in 1h at the C6–H rather
than benzylic C–H, thus the excellent C6 arylation selectivity.
CONCLUSIONS
In summary, we have disclosed a Pd-catalyzed and operationally simple protocol for
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the direct arylation of N-methyl alkylpyridium salts. This protocol provides a facile
route for the synthesis of a wide range of mixed aryl alkyl pyridine compounds in good
to excellent yields, with outstanding functional group tolerance. The success of this
approach is attributed to (1) using the pyridinium salt as the substrates, which is an
important pyridine activation strategy; (2) the presence of the alfa branched alkyl group
in the alkylpyridine molecule and (3) the addition of CuBr as an effective additive to
achieve the selective C6–H bond arylation.
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EXPERIMENTAL SECTION
General Information: All chemicals were purchased from Aldrich, Adamas, Alfa and
TCI. Column chromatography was performed with silica gel (Merck, 300-400 mesh).
1H NMR spectra were recorded on Bruker Avance 400 or 600 MHz spectrometers.
Chemical shifts were reported in ppm referenced to 7.26 ppm of chloroform-d (2.50
ppm of DMSO-d6). The following abbreviations (or combination of thereof) were used
to explain multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, br = broad.
Coupling constants, J, were reported in Hertz unit (Hz). 13C NMR spectra were
recorded on Bruker Avance 101 MHz spectrometers, and were fully decoupled by broad
band proton decoupling. Chemical shifts were reported in ppm referenced to the center
line of a triplet at 77.16 ppm of chloroform-d (a multiplet at 39.52 ppm of DMSO-d6).
HRMS was recorded on a commercial apparatus (ESI Source, TOF). Melting points
were obtained by XT4A micro Melting-point Measurement Instruments.
General procedures for the Preparation of 2-Alkylpyridine (A):17b To a 20 ml ether
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solution of (1-(pyridin-2-yl)alkyl)lithium, prepared from methyllithium 1.6 M (diethyl
ether solution, 37.5ml, 60 mmol, 2 equiv) and 2-alkylpyridine (60 mmol, 2 equiv), was
added bromoalkane (30 mmol, 1 equiv) dissolved in 20 ml of anhydrous Et2O, over a
10 minutes period. The reaction mixture was stirred at room temperature for an
additional 30 min. The reaction mixture was poured onto 50 g of crushed ice. The
phases were separated and the aqueous layer was extracted with three 100 ml portions
of diethyl ether. The combined ether extracts were dried over sodium sulfate. The
solvent was removed by vacumm rotary evaporation. The crude mixture was purified
by column chromatography (silica gel, petroleum ether/ethyl acetate 100:1) to afford 2-
alkylpyridine as a colorless oil.
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General procedures for the Preparation of 2-Alkylpyridine (B):18 To a suspension
of 2-bromopyridine (0.22 ml, 2.3 mmol, 1 equiv) and tri-tert-butylphosphonium
tetrafluoroborate (41 mg, 0.14 mmol, 0.06 equiv) in THF (2.5 mL) under N2 were added
Pd(OAc)2 (25 mg, 0.11 mmol, 0.05 equiv) and zinc bromide solution (27.6 wt%
solution in THF, 0.57 g, 0.7 mmol, 0.3 equiv). Cycloalkylmagnesium bromide (1 M in
THF, 3.68 mL, 3.68 mmol, 1.6 equiv) was added slowly over 30 min while maintaining
the temperature at 20–25 oC. The reaction mixture was stirred at room temperature for
an additional 2 h and monitored by TLC. Upon completion (>99% conversion), the
reaction was cooled to 0 oC, and water (8.0 mL) was added slowly while maintaining
the temperature below 15 oC. Ethyl acetate (10 mL) was added, and the aqueous layer
was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried
over sodium sulfate, filtered, and concentrated. The crude mixture was purified by
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column chromatography (silica gel, petroleum ether/ethyl acetate 100:1) to afford the
pure product.
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General procedures for the Preparation of N-methylpyridinium Salt (C): To a
solution of appropriate pyridine (15.0 mmol, 1 equiv) in acetonitrile (5 mL) was added
CH3I (45.0 mmol, 3 equiv) under argon in a two-necked flask. The mixture was heated
at 80 °C (heated by oil bath) for 16 h, and then cooled to room temperature. After
removal of the solvent under reduced pressure to afford the crude product, which was
purified by recrystallization in CH3CN/EtOAc co-solvent system.
General procedures for the Synthesis of 3a–3r (D): An oven-dried 25 mL Schlenk
tube equipped with magnetic stirring bar were charged with 4-tolyl iodide (109 mg, 0.5
mmol, 2 equiv), appropriate N-methylpyridinium salt (0.25 mmol, 1 equiv), and
Pd(PhCN)2Cl2 (4.7 mg, 0.0125 mmol, 5 mol%), PPh3 (3.7 mg, 0.0125 mmol, 5 mol%),
PivOK (70 mg, 0.5 mmol, 2 equiv), CuBr (35.8 mg, 0.25 mmol, 1 equiv), CTAB (45.5
mg, 0.125 mmol, 0.5 equiv). The tube was sealed and the mixture was charged with
nitrogen gas three times, then dry DMAc (1 M, 0.25 ml) was added to the sealed
reaction vessel by syringe. The resulting solution was stirred at 120 °C (heated by
heating plate magnetic stirrer) for 16–48 h. After cooling to room temperature, the
mixture was diluted with ethyl acetate and filtered through a short pad of celite, the
volatiles were removed under vacuum and the residue was purified by preparative thin
layer chromatography (silica gel, petroleum ether/ethyl acetate 50:1) to give pure
product.
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General procedures for the Synthesis of 4a–4y (E): An oven-dried 25 mL Schlenk
tube equipped with magnetic stirring bar were charged with aryl iodide (0.5 mmol),
appropriate N-methyl-2-(3′-pentyl) pyridinium salt (72.7 mg, 0.25 mmol), and
Pd(PhCN)2Cl2 (4.7 mg, 0.0125 mmol), PPh3 (3.7 mg, 0.0125 mmol), PivOK (70 mg,
0.5 mmol), CuBr (35.8 mg, 0.25 mmol), CTAB (45.5 mg, 0.125 mmol). The tube was
sealed and the mixture was charged with nitrogen gas three times, then dry DMAc (1
M, 0.25 ml) was added to the sealed reaction vessel by syringe. The resulting solution
was stirred at 120 °C (heated by heating plate magnetic stirrer) for 16 h. After cooling
to room temperature, the mixture was diluted with ethyl acetate and filtered through a
short pad of celite, the volatiles were removed under vacuum and the residue was
purified by preparative thin layer chromatography (silica gel, petroleum ether/ethyl
acetate 50:1) to give pure product.
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General procedure for deuterium experiments: An oven-dried 25 mL Schlenk tube
equipped with magnetic stirring bar were charged with N-methyl-2-alkylpyridinium
salt (0.25 mmol), and PivOK (70.0 mg, 0.5 mmol), and/or CuBr (35.8 mg, 0.25 mmol).
The tube was sealed and the mixture was charged with nitrogen gas three times, then
D2O (0.6 mL) was added to the sealed reaction vessel by syringe. The resulting solution
was stirred at 80 or 120 °C (heated by heating plate magnetic stirrer) for 16 h. After
cooling to room temperature, the mixture was filtrated and detected by 1H NMR.
General procedures for Gram-Scale Reaction : An oven-dried 25 mL pressure tube
equipped with magnetic stirring bar were charged with 4-tolyl iodide (1.74 g, 8 mmol),
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appropriate N-methyl-2-(3′-pentyl) pyridinium salt (1.16 g, 4 mmol), and
Pd(PhCN)2Cl2 (75.2 mg, 0.2 mmol), PPh3 (59.2 mg, 0.2 mmol), PivOK (1.12 g, 8
mmol), CuBr (572.8 mg, 4 mmol), CTAB (728 mg, 2 mmol). The tube was sealed and
the mixture was charged with nitrogen gas three times, then dry DMAc (1 M, 4 ml) was
added to the sealed reaction vessel by syringe. The resulting solution was stirred at 120
°C (heated by heating plate magnetic stirrer) for 72 h. After cooling to room temperature,
the mixture was diluted with ethyl acetate and filtered through a short pad of celite, the
volatiles were removed under vacuum and the residue was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate 200:1) to give pure product
(726.6 mg, 76% yield).
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Physical Data of 1E-1J, 1L, 1M and 1N.
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2-isobutylpyridine (1E)17: 2-picoline (0.79 ml, 8 mmol) and 2-bromopropane (0.38ml,
4 mmol) were subjected to general procedure A. A colorless oil (217.7 mg, 40% yield).
1H NMR (400 MHz, CDCl3) δ 8.46 – 8.41 (m, 1H), 7.46 (td, J = 7.6, 1.8 Hz, 1H), 7.02
– 6.95 (m, 2H), 2.56 (d, J = 7.3 Hz, 2H), 2.07 – 1.94 (m, 1H), 0.84 (d, J = 6.7 Hz, 6H).
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2-(4-methylpentan-2-yl)pyridine (1F): 2-ethylpyridine (0.91 ml, 8 mmol) and 1-
bromo-2-methylpropane (0.43ml, 4 mmol) were subjected to general procedure A. A
colorless oil (512.4 mg, 78% yield). 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.48
– 7.40 (m, 1H), 7.04 – 6.97 (m, 1H), 6.97 – 6.89 (m, 1H), 2.93 – 2.80 (m, 1H), 1.63 –
1.51 (m, 1H), 1.40 – 1.27 (m, 2H), 1.19 – 1.10 (m, 3H), 0.81 – 0.76 (m, 3H), 0.76 –
0.71 (m, 3H). 13C NMR {1H} (101 MHz, CDCl3) δ 166.7, 149.1, 136.1, 121.4, 120.9,
46.3, 39.6, 25.6, 22.7, 22.5, 21.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H18N,
164.1434; Found 164.1435.
2-(3-methylpentan-2-yl)pyridine (1G): 2-ethylpyridine (0.91 ml, 8 mmol) and 2-
bromobutane (0.43ml, 4 mmol) were subjected to general procedure A. A colorless oil
(386.3 mg, 59% yield). 1H NMR (400 MHz, CDCl3) δ 8.51 – 8.42 (m, 1H), 7.52 – 7.43
(m, 1H), 7.07 – 6.94 (m, 2H), 2.74 – 2.58 (m, 1H), 1.77 – 1.63 (m, 1H), 1.51 – 1.14 (m,
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4H), 1.11 – 0.91 (m, 1H), 0.82 – 0.64 (m, 6H). C NMR {1H} (101 MHz, CDCl3) δ
166.4, 166.2, 149.0, 149.0, 136.0, 135.9, 122.3, 122.1, 120.9, 120.8, 47.0, 46.5, 39.9
39.89, 27.8, 25.9, 17.6, 17.1, 16.0, 15.3, 11.6, 11.2. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C11H18N 164.1434; Found 164.1433.
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2-(3-methylbutan-2-yl)pyridine (1H)17: 2-ethylpyridine (0.91 ml, 8 mmol) and 2-
bromopropane (0.38ml, 4 mmol) were subjected to general procedure A. A colorless
oil (498.7 mg, 83% yield). 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 4.3 Hz, 1H), 7.45
(td, J = 7.7, 1.5 Hz, 1H), 7.00 – 6.93 (m, 2H), 2.54 – 2.45 (m, 1H), 1.93 – 1.81 (m, 1H),
1.16 (d, J = 7.0 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H), 0.66 (d, J = 6.8 Hz, 3H).
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2-(4-methylhexan-3-yl)pyridine (1I): 2-propylpyridine (1.06 ml, 8 mmol) and 2-
bromobutane (0.43ml, 4 mmol) were subjected to general procedure A. A colorless oil
(398 mg, 56% yield). 1H NMR (400 MHz, CDCl3) δ 8.51 – 8.45 (m, 1H), 7.51 – 7.42
(m, 1H), 7.02 – 6.94 (m, 2H), 2.46 – 2.36 (m, 1H), 1.80 – 1.41 (m, 4H), 1.21 – 1.03 (m,
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1H), 0.95 – 0.76 (m, 3H), 0.76 – 0.67 (m, 2H), 0.64 – 0.59 (m, 4H). C NMR {1H}
(101 MHz, CDCl3) δ 164.7, 164.3, 149.1, 149.0, 135.6, 135.5, 123.7, 123.5, 120.8 (2),
55.0, 54.6, 39.3, 38.9, 27.4, 26.8, 24.9, 24.0, 16.8, 16.2, 12.4, 12.3, 11.4, 11.2. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C12H20N, 178.1590; Found 178.1594.
2-(2-methylpentan-3-yl)pyridine (1J)17: 2-propylpyridine (1.06 ml, 8 mmol) and 2-
bromopropane (0.38ml, 4 mmol) were subjected to general procedure A. A colorless
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oil (328 mg, 50% yield). H NMR (400 MHz, CDCl3) δ 8.56 – 8.47 (m, 1H), 7.57 –
7.45 (m, 1H), 7.08 – 6.96 (m, 2H), 2.37 – 2.24 (m, 1H), 1.98 – 1.86 (m, 1H), 1.86 –
1.74 (m, 1H), 1.74 – 1.62 (m, 1H), 0.97 – 0.90 (m, 3H), 0.70 – 0.61 (m, 6H).
2-(hexan-2-yl)pyridine (1L): 2-ethylpyridine (0.91 ml, 8 mmol) and 1-bromobutane
(0.42ml, 4 mmol) were subjected to general procedure A. A colorless oil (400 mg, 61%
yield). 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 4.8 Hz, 1H), 7.49 – 7.43 (m, 1H),
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7.01 (dd, J = 7.9, 0.7 Hz, 1H), 6.99 – 6.93 (m, 1H), 2.83 – 2.69 (m, 1H), 1.71 – 1.59
(m, 1H), 1.55 – 1.43 (m, 1H), 1.21 – 1.13 (m, 6H), 1.10 – 0.98 (m, 1H), 0.75 (t, J = 7.1
Hz, 3H). 13C NMR {1H} (101 MHz, CDCl3) δ 166.7, 149.1, 136.1, 121.4, 120.9, 42.0,
36.8, 29.8, 22.7, 20.8, 14.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H18N,
164.1434; Found 164.1431.
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2-cyclohexylpyridine (1M)22: Cyclohexylmagnesium bromide (1 M in THF, 3.68 mL,
3.68 mmol) was subjected to general procedure B. A colorless oil (111.9 mg, 30%
yield). 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.8 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H),
7.14 (d, J = 7.8 Hz, 1H), 7.10 – 7.06 (m, 1H), 2.69 (tt, J = 11.8, 3.3 Hz, 1H), 1.97 –
1.92 (m, 2H), 1.88 – 1.83 (m, 2H), 1.78 – 1.71 (m, 1H), 1.57 – 1.47 (m, 2H), 1.46 –
1.36 (m, 2H), 1.34 – 1.25 (m, 1H).
2-cyclopropylpyridine (1N)18: Cyclopropylmagnesium bromide (1 M in THF, 3.68
mL, 3.68 mmol) was subjected to general procedure B. A colorless oil (91.2 mg, 33%
yield). 1H NMR (400 MHz, CDCl3) δ 8.45 – 8.39 (m, 1H), 7.53 – 7.46 (m, 1H), 7.09
(d, J = 7.8 Hz, 1H), 7.03 – 6.97 (m, 1H), 2.05 – 1.96 (m, 1H), 1.01 – 0.94 (m, 4H).
Physical Data of 1a−1o.
1,2-dimethylpyridin-1-ium iodide (1a)19: 2-methylpyridine (0.79 ml, 8 mmol) was
subjected to general procedure C. A yellowish solid (2.82 g, 80% yield). 1H NMR (400
MHz, D2O) δ 8.83 – 8.75 (m, 1H), 8.50 – 8.42 (m, 1H), 8.05 – 7.98 (m, 1H), 7.96 –
7.89 (m, 1H), 4.35 – 4.29 (m, 3H), 2.92 – 2.87 (m, 3H).
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subjected to general procedure C. A yellow solid (3.06 g, 82% yield). H NMR (400
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(m, 3H), 3.15 – 3.09 (m, 2H), 1.40 – 1.36 (m, 3H).
1-methyl-2-propylpyridin-1-ium iodide (1c)20: 2-propylpyridine (1.06 ml, 8 mmol)
was subjected to general procedure C. A yellowish solid (3.36 g, 85% yield). 1H NMR
(400 MHz, D2O) δ 8.86 – 8.75 (m, 1H), 8.56 – 8.50 (m, 1H), 8.10 – 8.05 (m, 1H), 7.97
– 7.92 (m, 1H), 4.46 – 4.34 (m, 3H), 3.24 – 3.13 (m, 2H), 2.01 – 1.85 (m, 2H), 1.19 –
1.10 (m, 3H).
1-methyl-2-pentylpyridin-1-ium iodide (1d): 2-pentylpyridine (1.33 ml, 8 mmol) was
subjected to general procedure C. A yellow solid (2.55 g, 60% yield). Mp = 68 – 70 oC.
1H NMR (400 MHz, D2O) δ 8.71 (d, J = 6.2 Hz, 1H), 8.43 (t, J = 7.9 Hz, 1H), 7.98 (d,
J = 8.1 Hz, 1H), 7.86 (t, J = 6.9 Hz, 1H), 4.32 (s, 3H), 3.18 – 3.10 (m, 2H), 1.88 – 1.80
(m, 2H), 1.51 – 1.39 (m, 4H), 0.93 (t, J = 7.2 Hz, 3H). 13C NMR {1H} (101 MHz, D2O)
δ 159.3, 145.9, 145.1, 128.4, 125.1, 45.4, 32.4, 30.5, 26.3, 21.7, 13.3. HRMS (ESI-
TOF) m/z: M+ Calcd for [C11H18N]+, 164.1434; Found 164.1435.
2-isobutyl-1-methylpyridin-1-ium iodide (1e): 2-isobutylpyridine (1.19 ml, 8 mmol)
was subjected to general procedure C. After removal of the solvent under reduced
pressure to afford the crude product, which was purified by preparative thin layer
chromatography (silica gel, ethyl acetate) to give pure product. A yellow oil (3.32 mg,
80% yield). 1H NMR (400 MHz, D2O) δ 8.71 (d, J = 6.1 Hz, 1H), 8.42 (t, J = 7.8 Hz,
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1H), 7.96 (d, J = 7.9 Hz, 1H), 7.86 (t, J = 6.8 Hz, 1H), 4.33 (s, 3H), 3.04 (d, J = 7.3 Hz,
2H), 2.27 – 2.16 (m, 1H), 1.05 (d, J = 6.6 Hz, 6H). 13C NMR {1H} (101 MHz, D2O) δ
158.2, 146.2, 144.9, 129.6, 125.3, 45.6, 41.1, 27.1, 21.5. HRMS (ESI-TOF) m/z: M+
Calcd for [C10H16N]+, 150.1277; Found 150.1280.
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1-methyl-2-(4-methylpentan-2-yl)pyridin-1-ium iodide (1f): 2-(4-methylpentan-2-
yl)pyridine (1.30 g, 8 mmol) was subjected to general procedure C. A yellow-green
solid (3.43 g, 75% yield). Mp = 106 – 108 oC. 1H NMR (400 MHz, DMSO-d6) δ 8.96
(d, J = 5.5 Hz, 1H), 8.52 (t, J = 7.8 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.95 (t, J = 6.9
Hz, 1H), 4.33 (s, 3H), 3.48 – 3.36 (m, 1H), 1.67 – 1.48 (m, 3H), 1.32 (d, J = 6.7 Hz,
3H), 0.90 (t, J = 5.6 Hz, 6H). 13C NMR {1H} (101 MHz, DMSO-d6) δ 163.1, 146.6,
145.4, 126.0, 125.1, 45.6, 44.2, 32.8, 25.1, 23.0, 21.7, 19.2. HRMS (ESI-TOF) m/z: M+
Calcd for [C12H20N]+, 178.1590; Found 178.1591.
1-methyl-2-(3-methylpentan-2-yl)pyridin-1-ium iodide (1g): 2-(3-methylpentan-2-
yl)pyridine (1.30 g, 8 mmol) was subjected to general procedure C. A yellow solid (3.80
g, 83% yield). Mp = 114 – 116 oC. 1H NMR (400 MHz, CDCl3) δ 9.52 (d, J = 6.3 Hz,
1H), 8.51 (td, J = 7.7, 3.3 Hz, 1H), 7.96 (t, J = 6.5 Hz, 1H), 7.86 (t, J = 8.3 Hz, 1H),
4.59 (s, 3H), 3.39 – 3.21 (m, 1H), 1.80 – 1.67 (m, 1H), 1.44 – 1.36 (m, 3H), 1.31 – 1.16
(m, 2H), 0.94 – 0.81 (m, 6H). 13C NMR {1H} (101 MHz, CDCl3) δ 163.5, 163.2, 147.7,
147.6, 145.5, 145.4, 126.8, 126.0, 47.6, 47.3, 41.2, 40.3, 39.7, 39.2, 28.1, 25.0, 17.6,
17.5, 15.9, 14.8, 11.9, 11.0. HRMS (ESI-TOF) m/z: M+ Calcd for [C12H20N]+, 178.1590;
Found 178.1589.
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1-methyl-2-(3-methylbutan-2-yl)pyridin-1-ium iodide (1h): 2-(3-methylbutan-2-
yl)pyridine (1.19 g, 8 mmol) was subjected to general procedure C. A yellowish solid
(3.49 g, 80% yield). Mp = 128 – 130 oC. 1H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J =
4.4 Hz, 1H), 8.53 (t, J = 7.9 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.96 (t, J = 6.9 Hz, 1H),
4.35 (s, 3H), 3.27 – 3.16 (m, 1H), 2.07 – 1.98 (m, 1H), 1.30 (d, J = 6.8 Hz, 3H), 0.98
(d, J = 6.6 Hz, 3H), 0.79 (d, J = 6.7 Hz, 3H). 13C NMR {1H} (101 MHz, DMSO-d6) δ
162.8, 146.6, 145.2, 126.5, 125.1, 46.1, 41.1, 32.4, 20.8, 18.8, 16.6. HRMS (ESI-TOF)
m/z: M+ Calcd for [C11H18N]+, 164.1434; Found 164.1439.
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1-methyl-2-(4-methylhexan-3-yl)pyridin-1-ium iodide (1i): 2-(4-methylhexan-3-
yl)pyridine (1.42 g, 8 mmol) was subjected to general procedure C. After removal of
the solvent under reduced pressure to afford the crude product, which was purified by
preparative thin layer chromatography (silica gel, ethyl acetate) to give pure product. A
orange red oil (3.59 g, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 5.7
Hz, 1H), 8.55 (t, J = 7.9 Hz, 1H), 8.16 – 8.11 (m, 1H), 8.01 – 7.95 (m, 1H), 4.38 – 4.31
(m, 3H), 3.27 – 3.16 (m, 1H), 2.02 – 1.87 (m, 1H), 1.86 – 1.68 (m, 2H), 1.67 – 1.17 (m,
1H), 1.18 – 1.08 (m, 1H), 0.95 – 0.85 (m, 3H), 0.84 – 0.66 (m, 6H). 13C NMR {1H}
(101 MHz, DMSO-d6) δ 161.6, 161.2, 147.3, 147.1, 145.2, 145.1, 126.9, 125.17, 47.0,
46.8, 46.5, 46.3, 38.3, 38.2, 27.0, 25.0, 23.9, 22.7, 16.6, 15.1, 11.6, 11.1, 11.0, 10.7.
HRMS (ESI-TOF) m/z: M+ Calcd for [C13H22N]+, 192.1747; Found 192.1749.
1-methyl-2-(2-methylpentan-3-yl)pyridin-1-ium iodide (1j): 2-(2-methylpentan-3-
yl)pyridine (1.30 g, 8 mmol) was subjected to general procedure C. A yellow solid (3.66
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g, 80% yield). Mp = 118 – 120 oC. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 6.0
Hz, 1H), 8.55 (t, J = 7.7 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.98 (t, J = 6.9 Hz, 1H), 4.34
(s, 3H), 3.20 – 3.09 (m, 1H), 2.06 – 1.89 (m, 2H), 1.78 – 1.64 (m, 1H), 1.01 (d, J = 6.6
Hz, 3H), 0.75 (d, J = 6.7 Hz, 3H), 0.68 (t, J = 7.4 Hz, 3H). 13C NMR {1H} (101 MHz,
DMSO-d6) δ 161.6, 147.2, 145.3, 126.8, 125.2, 48.3, 46.6, 32.4, 24.1, 20.7, 19.5, 11.1.
HRMS (ESI-TOF) m/z: M+ Calcd for [C12H20N]+, 178.1590; Found 178.1593.
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1-methyl-2-(pentan-3-yl)pyridin-1-ium iodide (1k): 2-(pentan-3-yl)pyridine (1.32
ml, 8 mmol) was subjected to general procedure C. A yellow solid (3.84 g, 88% yield).
Mp = 150 – 152 oC. 1H NMR (400 MHz, D2O) δ 8.72 (d, J = 6.1 Hz, 1H), 8.48 (t, J =
7.5 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.88 – 7.82 (m, 1H), 4.37 (s, 3H), 3.40 – 3.30 (m,
1H), 2.00 – 1.89 (m, 2H), 1.86 – 1.75 (m, 2H), 0.87 (t, J = 7.5 Hz, 6H). 13C {1H} NMR
(101 MHz, D2O) δ 162.9, 146.3, 145.3, 126.8, 125.0, 46.3, 43.9, 27.2, 10.7. HRMS
(ESI-TOF) m/z: M+ Calcd for [C11H18N]+, 164.1434; Found 164.1437.
2-(hexan-2-yl)-1-methylpyridin-1-ium iodide (1l): 2-(hexan-2-yl)pyridine (1.30 g, 8
mmol) was subjected to general procedure C. After removal of the solvent under
reduced pressure to afford the crude product, which was purified by preparative thin
layer chromatography (silica gel, ethyl acetate) to give pure product. A yellow oil (3.57
g, 78% yield). 1H NMR (400 MHz, D2O) δ 8.88 (d, J = 5.3 Hz, 1H), 8.63 (t, J = 7.3 Hz,
1H), 8.23 (d, J = 7.8 Hz, 1H), 8.06 – 7.93 (m, 1H), 4.51 (s, 3H), 3.67 – 3.54 (m, 1H),
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2.03 – 1.78 (m, 2H), 1.53 (d, J = 6.3 Hz, 3H), 1.49 – 1.28 (m, 4H), 0.95 (s, 3H). C
NMR {1H} (101 MHz, D2O) δ 163.8, 146.4, 145.8, 126.7, 125.4, 46.8, 35.6, 35.5, 29.0,
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22.4, 19.8, 13.9. HRMS (ESI-TOF) m/z: M+ Calcd for [C12H20N]+, 178.1590; Found
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178.1593.
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2-cyclohexyl-1-methylpyridin-1-ium iodide (1m): 2-cyclohexylpyridine (1.31 ml, 8
mmol) was subjected to general procedure C. A yellow solid (3.41 g, 75% yield). Mp
= 191 – 193 oC. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (d, J = 6.1 Hz, 1H), 8.51 (t, J =
7.8 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.93 (t, J = 6.5 Hz, 1H), 4.34 (s, 3H), 3.23 – 3.14
(m, 1H), 1.94 (d, J = 11.1 Hz, 2H), 1.83 (d, J = 11.9 Hz, 2H), 1.74 (d, J = 12.7 Hz, 1H),
1.58 – 1.42 (m, 4H), 1.37 – 1.27 (m, 1H).13C NMR {1H} (101 MHz, DMSO-d6) δ 162.1,
146.6, 145.4, 126.0, 125.0, 45.5, 31.1, 25.4, 25.0. HRMS (ESI-TOF) m/z: [M +] Calcd
for [C12H18N]+ 176.1434; Found 176.1436.
2-cyclopropyl-1-methylpyridin-1-ium iodide (1n): 2-cyclopropylpyridine (0.952 g, 8
mmol) was subjected to general procedure C. After removal of the solvent under
reduced pressure to afford the crude product, which was purified by preparative thin
layer chromatography (silica gel, ethyl acetate) to give pure product. A colourless oil
(2.5 g, 60% yield). 1H NMR (400 MHz, CDCl3) δ 1H NMR (400 MHz, CDCl3) δ 9.42
(d, J = 6.0 Hz, 1H), 8.43 (t, J = 7.9 Hz, 1H), 7.95 – 7.89 (m, 1H), 7.71 (d, J = 8.1 Hz,
1H), 4.66 (s, 3H), 2.57 – 2.46 (m, 1H), 1.51 – 1.44 (m, 2H), 1.19 – 1.13 (m, 2H). 13C
NMR {1H} (101 MHz, CDCl3) δ 159.2, 147.4, 145.5, 126.0, 125.6, 47.3, 14.7, 9.8.
HRMS (ESI-TOF) m/z: M+ Calcd for [C9H12N]+, 134.0964; Found 134.0960.
4-(tert-butyl)-1-methylpyridin-1-ium iodide (1o): 4-(tert-butyl)pyridine (1.18 ml, 8
mmol) was subjected to general procedure C. A yellow solid (3.53 g, 85% yield). Mp
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= 129 – 131 oC. 1H NMR (400 MHz, CDCl3) δ 9.27 (d, J = 6.7 Hz, 2H), 7.97 (d, J =
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6.6 Hz, 2H), 4.62 (s, 3H), 1.37 (s, 9H). C NMR {1H} (101 MHz, CDCl3) δ 171.0,
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145.1, 125.3, 48.5, 36.7, 30.1. HRMS (ESI-TOF) m/z: [M +] Calcd for [C10H16N]+
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150.1277; Found 150.1279.
Physical Data of 3a−3r.
2-methyl-6-(p-tolyl)pyridine (3a)21 (General procedures D): A colourless oil (10.1 mg,
22% yield). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.1 Hz, 2H), 7.61 (t, J = 7.7 Hz,
1H), 7.49 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 7.9 Hz, 2H), 7.07 (d, J = 7.6 Hz, 1H), 2.63
(s, 3H), 2.40 (s, 3H).
p-tolyl(6-(p-tolyl)pyridin-2-yl)methanone (3a') (General procedures D): A colourless
oil (7.8 mg, 22% yield). 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.2 Hz, 2H), 7.98 –
7.90 (m, 5H), 7.33 – 7.26 (m, 4H), 2.46 (s, 3H), 2.41 (s, 3H). 13C NMR {1H} (101 MHz,
CDCl3) δ 193.5, 156.0, 155.2, 143.8, 139.6, 137.8, 135.9, 133.9, 131.7, 129.7, 128.9,
127.0, 122.6, 122.1, 21.9, 21.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H18NO,
288.1383; Found 288.1383.
2-ethyl-6-(p-tolyl)pyridine (3b) (General procedures D): A colourless oil (13.9 mg, 28%
yield). 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.1 Hz, 2H), 7.64 (t, J = 7.7 Hz, 1H),
7.51 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 7.6 Hz, 1H), 2.90 (q, J =
7.6 Hz, 2H), 2.41 (s, 3H), 1.37 (t, J = 7.6 Hz, 3H). 13C NMR {1H} (101 MHz, CDCl3)
δ 163.4, 156.9, 138.7, 137.2, 137.0, 129.5, 127.0, 120.2, 117.6, 31.7, 21.4, 14.0. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C14H16N, 198.1277; Found 198.1277.
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2-propyl-6-(p-tolyl)pyridine (3c) (General procedures D): A colourless oil (10.3 mg,
20% yield). 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.1 Hz, 2H), 7.63 (t, J = 7.7 Hz,
1H), 7.50 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 7.5 Hz, 2H), 7.06 (d, J = 7.6 Hz, 1H), 2.88 –
2.82 (m, 2H), 2.40 (s, 3H), 1.89 – 1.77 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). 13C NMR {1H}
(101 MHz, CDCl3) δ 162.2, 157.0, 138.7, 137.3, 136.9, 129.5, 127.0, 120.9, 117.6, 40.7,
23.1, 21.4, 14.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H18N, 212.1434; Found
212.1434.
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2-pentyl-6-(p-tolyl)pyridine (3d) (General procedures D): A colourless oil (28 mg, 32%
yield). 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.2 Hz, 2H), 7.62 (t, J = 7.7 Hz, 1H),
7.50 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 2H), 7.05 (d, J = 7.6 Hz, 1H), 2.88 – 2.82
(m, 2H), 2.41 (s, 3H), 1.86 – 1.76 (m, 2H), 1.43 – 1.36 (m, 4H), 0.95 – 0.89 (m, 3H).
13C NMR {1H} (101 MHz, CDCl3) δ 162.5, 156.9, 138.7, 137.2, 136.9, 129.5, 127.0,
120.8, 117.5, 38.7, 31.8, 29.6, 22.7, 21.4, 14.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C17H22N, 240.1747; Found 240.1737.
2-isobutyl-6-(p-tolyl)pyridine (3e) (General procedures D): A colourless oil (28 mg,
32% yield). 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.2 Hz, 2H), 7.62 (t, J = 7.7 Hz,
1H), 7.50 (d, J = 7.7 Hz, 1H), 7.27 (d, J = 8.3 Hz, 2H), 7.03 (d, J = 7.5 Hz, 1H), 2.74
(d, J = 7.2 Hz, 2H), 2.40 (s, 3H), 2.28-2.17 (m, 1H), 0.98 (d, J = 6.6 Hz, 6H). 13C NMR
{1H} (101 MHz, CDCl3) δ 161.4, 156.9, 138.8, 136.9, 129.5, 128.8, 127.1, 121.7, 117.7,
47.6, 29.2, 27.3, 22.6, 21.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H20N,
226.1590; Found 226.1585.
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2-(4-methylpentan-2-yl)-6-(p-tolyl)pyridine (3f) (General procedures D): A
colourless oil (45.2 mg, 71% yield). 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, J = 8.1,
1.5 Hz, 2H), 7.63 (t, J = 7.7 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.9 Hz, 2H),
7.05 (d, J = 7.6 Hz, 1H), 3.12 – 3.03 (m, 1H), 2.42 (s, 3H), 1.81 – 1.73 (m, 1H), 1.55 –
1.43 (m, 2H), 1.32 (dd, J = 6.9, 1.6 Hz, 3H), 0.95 (dd, J = 6.3, 1.6 Hz, 3H), 0.89 (dd, J
= 6.4, 1.5 Hz, 3H). 13C NMR {1H} (101 MHz, CDCl3) δ 166.7, 156.5, 138.6, 137.3,
136.9, 129.5, 127.0, 119.6, 117.4, 46.7, 40.0, 25.9, 23.1, 22.8, 21.4, 21.4. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C18H24N, 254.1903; Found 254.1896.
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2-(3-methylpentan-2-yl)-6-(p-tolyl)pyridine (3g) (General procedures D): A
colourless oil (50.5 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz,
2H), 7.50 (td, J = 7.7, 2.3 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 8.2 Hz, 2H),
6.93 – 6.88 (m, 1H), 2.80 – 2.70 (m, 1H), 2.30 (s, 3H), 1.82 – 1.73 (m, 1H), 1.29 – 1.15
(m, 4H), 1.13 – 0.96 (m, 1H), 0.86 – 0.74 (m, 5H), 0.71 (d, J = 6.8 Hz, 1H). 13C NMR
{1H} (101 MHz, CDCl3) δ 166.2, 165.8, 156.3, 138.6, 137.4, 136.6, 136.5, 129.4, 128.7,
127.0, 126.9, 120.4, 120.2, 117.2, 117.2, 46.9, 46.6, 39.9, 27.9, 26.2, 21.4, 17.8, 17.2,
16.4, 15.6, 11.8, 11.4. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H24N, 254.1903;
Found 254.1899.
2-(3-methylbutan-2-yl)-6-(p-tolyl)pyridine (3h) (General procedures D): A
colourless oil (49.2 mg, 82% yield). 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.2 Hz,
2H), 7.62 (t, J = 7.7 Hz, 1H), 7.51 (dd, J = 7.8, 0.8 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H),
7.02 (dd, J = 7.6, 0.5 Hz, 1H), 2.77 – 2.67 (m, 1H), 2.42 (s, 3H), 2.14 – 2.03 (m, 1H),
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1.34 (d, J = 7.0 Hz, 3H), 1.00 (d, J = 6.7 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H). 13C NMR
{1H} (101 MHz, CDCl3) δ 166.0, 156.4, 138.6, 137.3, 136.6, 129.4, 126.9, 120.3, 117.3,
48.9, 33.6, 21.5, 21.4, 20.0, 17.6. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H22N,
240.1747; Found 240.1740.
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2-(4-methylhexan-3-yl)-6-(p-tolyl)pyridine (3i) (General procedures D): A colourless
oil (46.5 mg, 70% yield). 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.0 Hz, 2H), 7.62
(td, J = 7.7, 2.0 Hz, 1H), 7.52 (dt, J = 7.8, 1.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 6.99
(ddd, J = 7.5, 4.6, 0.6 Hz, 1H), 2.69 – 2.57 (m, 1H), 2.43 (s, 3H), 1.95 – 1.82 (m, 3H),
1.64 – 1.34 (m, 1H), 1.25 – 1.04 (m, 1H), 1.00 – 0.93 (m, 3H), 0.86 (t, J = 7.4 Hz,
2H), 0.82 – 0.77 (m, 4H). 13C NMR {1H} (101 MHz, CDCl3) δ 164.4, 163.9, 156.3,
156.3, 138.6, 137.4, 136.2, 136.1, 129.4, 128.7, 127.0, 126.9, 121.9, 121.7, 117.1, 55.0,
54.3, 39.3, 39.0, 27.5, 27.1, 25.1, 24.1, 21.4, 16.8, 16.5, 12.6, 12.6, 11.7, 11.6. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C19H26N, 268.2060; Found 268.2059.
2-(2-methylpentan-3-yl)-6-(p-tolyl)pyridine (3j) (General procedures D): A
colourless oil (40 mg, 63% yield). 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.2 Hz,
2H), 7.62 (t, J = 7.7 Hz, 1H), 7.53 (dd, J = 7.8, 0.9 Hz, 1H), 7.29 (d, J = 7.9 Hz, 2H),
6.99 (dd, J = 7.6, 0.8 Hz, 1H), 2.51 – 2.44 (m, 1H), 2.43 (s, 3H), 2.11 – 2.03 (m, 1H),
1.94 – 1.83 (m, 2H), 1.03 (d, J = 6.7 Hz, 3H), 0.81 (d, J = 6.7 Hz, 3H), 0.78 (t, J = 7.4
Hz, 3H). 13C NMR {1H} (101 MHz, CDCl3) δ 164.2, 156.4, 138.6, 137.4, 136.2, 129.4,
126.9, 121.8, 117.2, 56.7, 32.6, 25.0, 21.4, 21.1, 20.9, 12.5. HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C18H24N, 254.1903; Found 254.1897.
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The Journal of Organic Chemistry
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2-(pentan-3-yl)-6-(p-tolyl)pyridine (3k) (General procedures D): A colourless oil
(50.9 mg, 85% yield). 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.2 Hz, 2H), 7.63 (t,
J = 7.7 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 7.6 Hz,
1H), 2.70 – 2.60 (m, 1H), 2.43 (s, 3H), 1.87 – 1.74 (m, 4H), 0.86 (t, J = 7.4 Hz, 6H).
13C NMR {1H} (101 MHz, CDCl3) δ 164.9, 156.6, 138.6, 137.4, 136.5, 129.4, 127.0,
120.9, 117.4, 51.5, 28.2, 21.4, 12.3. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C17H22N, 240.1747; Found 240.1749.
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2-(hexan-2-yl)-6-(p-tolyl)pyridine (3l) (General procedures D): A colourless oil (42.3
mg, 67% yield). 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.1 Hz, 2H), 7.64 (t, J = 7.7
Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 7.6 Hz, 1H),
3.02 – 2.93 (m, 1H), 2.43 (s, 3H), 1.90 – 1.82 (m, 1H), 1.69 – 1.61 (m, 1H), 1.39 – 1.32
(m, 6H), 1.28 – 1.19 (m, 1H), 0.90 (t, J = 7.0 Hz, 3H).13C NMR {1H} (101 MHz, CDCl3)
δ 166.6, 156.5, 138.7, 137.3, 136.8, 129.5, 127.0, 119.6, 117.4, 42.2, 37.0, 30.0, 23.0,
21.4, 21.0, 14.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H24N, 254.1903; Found
254.1897.
2-cyclohexyl-6-(p-tolyl)pyridine (3m) (General procedures D): A colourless oil (39.5
mg, 63% yield). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.2 Hz, 2H), 7.64 (t, J = 7.7
Hz, 1H), 7.51 (dd, J = 7.8, 0.7 Hz, 1H), 7.28 (d, J = 7.9 Hz, 2H), 7.07 (d, J = 7.3 Hz,
1H), 2.80 (tt, J = 11.8, 3.4 Hz, 1H), 2.42 (s, 3H), 2.05 (dd, J = 13.3, 1.8 Hz, 2H), 1.94
– 1.86 (m, 2H), 1.83 – 1.76 (m, 1H), 1.68 – 1.57 (m, 2H), 1.53 – 1.41 (m, 2H), 1.39 –
1.28 (m, 1H). 13C NMR {1H} (101 MHz, CDCl3) δ 166.4, 156.5, 138.6, 137.3, 136.9,
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