Copper-catalyzed direct ortho-alkylation of N-iminopyridinium ylides with N-tosylhydrazones

Article abstract of DOI:10.1021/jo4002883

Copper-catalyzed cross-coupling of N-tosylhydrazones with N-iminopyridinium ylides leads to the direct C-H alkylation. This direct C-H bond alkylation transformation uses inexpensive CuI as the catalyst without any ligand. The reaction is operationally simple and conducted under mild conditions, giving the corresponding alkylated pyridines in moderate to good yields. DFT calculation provides insights into the reaction mechanism, suggesting that the reaction proceeds through the Cu carbene migratory insertion process.

Full text of DOI:10.1021/jo4002883

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Article
Copper-Catalyzed Direct ortho-Alkylation of N-
Iminopyridinium Ylides with N-Tosylhydrazones
Qing Xiao, Lin Ling, Fei Ye, Renchang Tan, Leiming Tian, Yan Zhang, Yuxue Li, and Jianbo Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4002883 • Publication Date (Web): 19 Mar 2013
Downloaded from http://pubs.acs.org on March 21, 2013
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CopperꢀCatalyzed Direct orthoꢀAlkylation of NꢀIminopyridinium
Ylides with NꢀTosylhydrazones
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Qing Xiao,† Lin Ling,‡ Fei Ye,† Renchang Tan,† Leiming Tian,† Yan Zhang,† Yuxue Li‡,*, Jianbo
Wang†,‡,*
†Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking
University, Beijing 100871, China
‡State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032,
China
liyuxue@sioc.ac.cn; wangjb@pku.edu.cn
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
ABSTRACT. Copperꢀcatalyzed crossꢀcoupling of Nꢀtosylhydrazones with Nꢀiminopyridinium ylides
leads to the direct CꢀH alkylation. This direct CꢀH bond alkylation transformation use cheap CuI as the
catalyst without any ligand. The reaction is operationally simple and under mild conditions, giving the
corresponding alkylated pyridines in moderate to good yields. DFT calculation provides insights into the
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reaction mechanism, suggesting that the reaction proceeds through the Cu carbene migratory insertion
process.
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INTRODUCTION
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Pyridine core is important structure unit which exists widely in various natural products,
pharmaceuticals, ligands, and synthetic building blocks.1 The development of synthetic methodologies
toward substituted pyridine derivatives, especially through direct CꢀH functionalization, has attracted
great attentions in recent years.2ꢀ10 Early efforts in this area were focused on C2 lithiation of pyridines,
followed by alkylation.2a,c.4b Other strategy involves the reaction of Grignard reagents with pyridine Nꢀ
oxide as described by Almvist and Olsson.4c More recently, transitionꢀmetalꢀcatalyzed approach has
become the mainstream of the study. In this context, Fagnou, Charette, Hiyama and other groups have
disclosed their pioneering work on transitionꢀmetalꢀcatalyzed orthoꢀarylation or ꢀalkenylation through
CꢀH functionalization of pyridine Nꢀoxides or Nꢀiminopyridinium ylides.5,6 These remarkable progresses
have made 2ꢀaryl and 2ꢀalkenyl pyridine derivatives easily available. In sharp contrast, the
corresponding orthoꢀalkylation of pyridines with similar strategy remains a challenging problem, largely
due to the β hydride elimination of transition metal alkyl species involved in the reaction pathway.
Recently, Bergman and Ellman have developed an approach toward orthoꢀalkylation of pyridines by
using Rh(I)ꢀphosphine complexesꢀcatalyzed CꢀH bond addition to olefins.7,8 Moreover, Hou and
coworkers have reported that halfꢀsandwich rareꢀearth dialkyl complexes and B(C6F5)3 can serve as
excellent catalyst system for similar transformations (Scheme 1).9,10 Although significant breakthrough
has been made for orthoꢀalkylation of pyridines, some drawbacks still remain. First, both reactions
require expensive and/or complicated catalyst systems. Besides, the regioselectivity is a problem in the
reaction with substituted olefins. Thus, the development of more general method for highly selective
orthoꢀalkylation of pyridines, ideally by using simple and inexpensive metal catalysts, is highly
demanded.
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We have recently reported a series of Cuꢀcatalyzed crossꢀcoupling reactions using Nꢀtosylhydrazones
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as coupling partners.11 These reactions presumably proceed through migratory insertion process of the
Cuꢀcarbene intermediate.12 As a continuation of our interest in this area, herein we report the first Cuꢀ
catalyzed direct alkylation of Nꢀiminopyridinium ylides6,13 with Nꢀtosylhydrazones and inexpensive CuI
as the catalyst. The reaction represents an efficient and highly selective approach toward both primary
and secondary orthoꢀalkylꢀsubstituted pyridine derivatives (Scheme 1).
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Scheme 1. TransitionꢀMetalꢀCatalyzed orthoꢀAlkylation of Pyridines
cat. M
+
R'
R
N
H
R
R'
N
M = Rh (ref. 7)
M = Sc or Y (ref. 9)
cat. Cu
NNHTs
R'
+
R'
this study
N
H
N
R
NBz
NBz R
RESULTS AND DISCUSSIONS
Based on the reports by Charette and coworkers,6 we employed Nꢀiminopyridinium ylide 1a as the
substrate and studied its reaction with Nꢀtosylhydrazones 2a (Table 1). After some initial experiments
(Table 1, entries 1ꢀ6), we observed that in the presence of LiOtBu in toluene,14 Cuꢀcatalyzed coupling of
1a and 2a could afford 2ꢀalkyl substituted pyridine 3a in 66% isolated yield (Table 1, entry 3).
Encouraged by these initial results, we proceeded to optimize the reaction conditions by screening the
temperature and copper salts (Table 1, entries 7ꢀ10). We found that the initially used CuI provided better
results as compared with other Cu salts. We then went on to screen other reaction parameters and
observed that the reaction was significantly affected by the copper catalyst loading and the ratio of
substrates. The optimal yield could be achieved by using 20 mol% of the CuI catalyst and LiOtBu (3.5
equiv) in toluene, and the ratio of pyridinium ylide to Nꢀtosylhydrazone is 1:2 (Table 1, entry 11).
Table 1. Optimization of the Reaction Conditionsa
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1
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3
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NNHTs
[Cu], Base
Solvent, T
Ph
+
N
N
Ph
NBz
NBz
5
2a
3a
6
1a
7
8
9
entry CuX (mol%) base
solvent
T(oC)
yield (%)b
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1
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuBr (10)
CuCl (10)
CuI (20)
LiOtBu
LiOtBu
LiOtBu
NaOtBu
Cs2CO3
K2CO3
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
dioxane
DCE
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110
80
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66
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81
2
3
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
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11c
a Reactions were carried out with pyridinium ylides (0.4 mmol), Nꢀtosylhydrazones (0.6 mmol) and base
(1.2 mmol) in solvent (2 mL) for 5 h, unless otherwise noted. b Isolated yield. c The reaction was carried
out with 0.8 mmol Nꢀtosylhydrazone and 1.4 mmol LiOtBu.
With the optimized reaction conditions in hand, the scope of this transformation was explored by
using various pyridinium ylides and Nꢀtosylhydrazones. Treatment of pyridinium ylide 1a with a series
of Nꢀtosylhydrazones 2a–q furnished the corresponding products 3a–q in moderate to good yields
(Scheme 2). The reaction was not significantly affected by the substituents on the aromatic ring of the
tosylhydrazones. Both electronꢀrich (Scheme 2, 3b, c, g, n) and electronꢀdeficient arylꢀsubstituted
tosylhydrazones (Scheme 2, 3bꢀe) were effective. Notably, alkoxyl, cyclopropyl, ester, bromo groups are
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all tolerated under the given reaction conditions. Besides, the reaction also worked well with
tosylhydrazones generated from alkyl aldehydes or ketones (Scheme 2, 3k, l, p-u).
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Next, the scope of Nꢀiminopyridinium ylide was investigated. The reaction was examined with Nꢀ
iminopyridinium ylides 1b–e, which were treated with tosylhydrazones 2n (R' = H, R" = tBu) under the
optimized reaction conditions. NꢀIminopyridinium species with substituents at the 2ꢀ, and 4ꢀpositions
underwent the alkylation reaction smoothly and provided the corresponding ortho alkylated products in
moderate to good yields (Scheme 2, 3r-t). Notably, this reaction could also be applied to other similar
structures. For example, the reaction with Nꢀiminoquinolinium afforded the alkylated product in good
yield (Scheme 2, 3u). Finally, it is noteworthy that in all cases, 2,6ꢀdialkylated products were not
detected.
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Scheme 2. Direct Alkylation of NꢀIminopyridinium Ylides with NꢀTosylhydrazonesa
R
R
CuI (20 mol%)
LiOtBu (3.5 equiv)
NNHTs
R"
+
R"
N
N
R'
PhMe, 90 oC
NBz R'
NBz
1a-e
2a-q
3a-u
X
N
NBz
N
3a, X = H, 81%a
NBz
3b, X = 4-CF3, 77%
3c, X = 4-OMe, 72%
3d, X = 4-Br, 64%
3f, 76%
3e, X = 4-CO2Me, 76%
O
O
N
N
N
NBz
NBz
NBz
3h
3i
, 72%
, 88%
3g, 68%
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N
N
N
NBz
5
NBz Ph
NBz
6
7
c
3j
3k
3l
, 82%
, 66%
, 56% (80%)
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X
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Ph
N
N
N
NBz
NBz
NBz
3n, 91%
3m
3o
, 70%
, X = 4-OMe, 85%
tBu
N
N
NBz
NBz
3p
, 81%
3q, 71%
X
N
N
N
NBz
NBz
NBz
3s
3t
, X = 4-Me, 71%
, X = 4-Ph, 78%
c
3r
3u
, 70%
, 66% (90%)
a
Reaction conditions if not otherwise noted: 1aꢀe (0.3 mmol), 2aꢀq (0.6 mmol), CuI (20 mol %),
LiOtBu (1.05 mmol), PhMe (2 mL), 5ꢀ8 h. b Isolated yield. c The yields in parentheses are these based on
recovered starting materials.
Based on our understanding of the copperꢀcatalyzed crossꢀcoupling reaction of Nꢀ
tosylhydrazones, a plausible mechanism proposed for this novel direct CꢀH bond alkylation has been
depicted in Scheme 3.6c,11 The key step in the reaction is proposed to be the migratory insertion of Cu
carbene species. In the presence of base and Cu(I) salt, the copper pyridinium ylides A is formed via
direct CꢀH activation. The reaction of copper pyridinium ylides A with diazo substrate B, which is
generated in situ from Nꢀtosylhydrazone in the presence of base, leads to the formation of copper–
carbene species C. Migratory insertion of alkynyl group to the carbenic carbon gives intermediate D.
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Finally, the alkylated product is formed by protonation of intermediate D, in conjunction with the
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regeneration of the Cu(I) catalyst.
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Scheme 3. Mechanistic Rationale
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N
LiOtBu
NBz
I
N
N
Cu
O
CuI
NNHTs
Ph
R'
A
R
R
R'
N
R
NBz
LiOtBu
H
N2
R'
R
R'
R
N
N
B
I
Cu
N2
N
N
Cu
R'
O
O
I
Ph
D
C
Ph
To have a better understanding of the reaction mechanism, density functional theory (DFT)15 studies
have been performed with Gaussian 09 program16 using B3LYP17 method. Based on an extensive
computational study on many possible mechanisms, the whole reaction pathway was obtained.18 For C,
H, O, N and Li, the 6ꢀ311+G** basis set was used. For Cu and I, the SDD19 basis set with Effective
Core Potential (ECP) was used. The structures were optimized with SMD20 method in toluene
(ε=2.374). Harmonic vibration frequency calculations confirmed that the optimized structures are either
minima (having no imaginary vibration) or transition states (having one imaginary vibration).
As shown in Scheme 4, from the reactant complex R, the deprotonation occurs via the transition state
TS-DP (15.4 kcal/mol), leading to INT1 (9.6 kcal/mol). Then, a CuꢀLi exchange happened via the 1,3ꢀ
Cu shift transition state TS-Cu-1,3-Shift over a small barrier of 2.4 kcal/mol, leading to the copper
pyridinium ylide A'. Subsequently, the copperꢀcarbene species C' formed via transition state TS-
Carbene over a barrier of 19.2 kcal/mol, releasing a nitrogen molecule. In C', migratory insertion of the
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alkynyl group to the carbenic carbon via transition state TS-Ins leading to intermediate D'. After a CꢀC
single bond rotation (TS-Rot) and 1,4ꢀCu shift (TS-Cu-1,4-Shift), another conformation of D', INT3 is
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8
Scheme 4. The Calculated Full Reaction Pathway. The relative free energies in solvent ꢀGsol are in
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kcal/mol, calculated at B3LYP/6ꢀ311+G**/SDD level
Me
H
Ph
N
N
OtBu
Ph
N
N
N
Me
Li
N
Cu I Li OtBu
N
I
N
Cu
O
H
O
Cu
I
TS-DP
15.4
N
N
Ph
N
Ph
O
Li
N
OtBu
Ph
TS-Cu-1,3-Shift
12.0
Ph
TS-Carbene
11.5
H
Me
Me
9.6
Ph
INT1
Cu
I
N
N
H
Li
OtBu
O
OtBu
Li
O
N
N
H
Ph
0.0
TS-Ins
-1.3
I
Cu
R
Ph
Me
N
-7.7
A'
OtBu
Li
Ph
H
N
N
N
N
N
N2
O
Me
I
Ph
Ph
Cu
Ph
Cu
I
N
N
Ph
N
Cu
N
-13.8
Me
O
I
Li
O
N
N
Me
Cu
N
OtBu
C'
Li
I
Ph
Ph
H
OtBu
Ph
Me
N
O
Li
H
OtBu
Ph
H
-45.2
D'
Carbene formation &
& Transmetallation
Migratory Insertion
C-H activation
I
Me
TS-Rot
-28.1
Me
Ph
Cu
I
H
N
N
N
N
N
Me
Ph
OtBu
Cu
Ph
Cu
-30.3
I
N
O
Li
O Li OtBu
O
Li OtBu
TS-PT
Ph
H
H
Ph
Ph
TS-Cu-1,4-Shift
-38.3
-39.3
INT2
-43.5
INT3
I
Ph
-45.2
D'
Cu
Me
N
Cu
Me
H
I
Me
N
N
N
N
Me
-47.1
3a
Ph
O
Li
Ph
O Li OtBu
N
OtBu
Cu
I
N
OtBu
Li
Ph
O Li OtBu
Ph
H
H
I
Cu
N
Ph
Ph
H
O
Ph
Conformational Change
Protonation
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generated. Then the protonation of INT3 by HOtBu occurs via transition state TS-PT over a barrier of
13.2 kcal/mol, leading to the final product 3a and regenerating the Cu(I) catalyst. For transition states
TS-DP and TS-Carbene, the Nꢀcoordinated structures are also calculated and shown to be
unfavorable.18 The key transition states along the reaction coordinate are shown in Figure 1.
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Figure 1. The Optimized Important Transition States on the Full Reaction Pathways. Bond lengths are
in Å and relative free energies in solvent ꢀGsol are in kcal/mol, calculated at B3LYP/6ꢀ311+G**/SDD
level.
The results of DFT calculation is generally in accordance with the simplified mechanistic rationale
depicted in Scheme 3, although the DFT calculation indicates the initial deprotonation and the last
protonation steps require the participation of lithium. However, it should be mentioned that an
alternative mechanism which involves a direct Cu carbene insertion into CꢀH bond of heterocycles
cannot be strictly eliminated.21 To verify such possible pathway, a control experiment has been carried
out. Thus, diphenyldiazomethane 4 was prepared and was submitted to CuIꢀcatalyzed reaction with Nꢀ
iminopyridinium ylide 1a (Scheme 5). In the absence of base, only trace product could be identified,
while the expected product 3a could be isolated in 58% yield in the presence of the base. For metal
carbene CꢀH insertion base is not needed, therefore, these results do not support a direct Cu carbene CꢀH
insertion mechanism. DFT calculation also suggests that Cu carbene CꢀH insertion mechanism can be
ruled out due to unfavorable energy barrier.18
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1
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3
4
5
6
Scheme 5. Control experiments with diphenyldiazomethane 4.
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9
N2
CuI (20 mol%)
+
Ph
PhMe, 90 oC
40 min
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N
N
Ph
Ph
NBz Ph
NBz
4
2 equiv
3a
1a
Base
none
LiOtBu (1.5 equiv)
Yield
trace
58%
Charette and coworkers have carried out deuterium exchange experiments in their Cuꢀcatalyzed orthoꢀ
alkenylation of Nꢀiminopyridinium ylides.6c The study indicates that deprotonation occurs at the 2,6ꢀ
positions of the pyridinium ring in the presence of CuBr2 (10 mol%) and K2CO3 (2 equiv). Our
deuterium exchange experiments also suggest preferential deprotonation at 2,6ꢀpositions in the presence
of CuI (20 mol%) and LiOtBu (3.5 equiv). Furthermore, DFT calculation shows protons at 2,6ꢀpositions
of pyridinium ring are more acidic than those at 3,4ꢀpositions.18
To gain further insights, the effect of substituents on the reaction was studied (eq 1). The competition
experiment of Nꢀiminopyridinium ylides 1a and 1c in the reaction with Nꢀtosylhydrazone 2n shows that
1a is more reactive than 1c.
+
CuI (20 mol%)
LiOtBu (3.5 equiv)
N
tBu
N
tBu
N
N
(1)
NBz
+
NBz
PhMe, 90 oC
1a:1c:2n = 1:1:2
NBz
NBz
1a
1c
3n
3s
<15%
NNHTs
+
76%
H
tBu
2n
The calculated pathways show that the deprotonation step is irreversible. Therefore, the barriers of
the deprotonation step can affect the ratio of 3n and 3s. Thus, the barriers of the deprotonation step of 1a
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and 1c were calculated. The results show that the barrier of 1c is 0.2 kcal/mol in ꢀGsol (1.0 kcal/mol in
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ꢀEsol) higher than that of 1a, which qualitatively agrees with the experimental results (Scheme 6). This
result can be rationalized by the fact that electronꢀdonation of the methyl group makes the pyridine ring
more electronic rich, which is unfavorable for the deprotonation.
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Scheme 6. Calculation on Substituent Effects. The relative free energies in solvent ꢀGsol are in kcal/mol,
calculated at B3LYP/6ꢀ311+G**/SDD level.
Me
H
Li
O
H
OtBu
OtBu
N
N
N
N
Li
O
I
I
Cu
Cu
15.6
15.4
Ph
Ph
N
N
TS-DP-Me
N
TS-DP
N
Ph
Ph
Me
Me
Me
OtBu
Li
OtBu
Li
N
N
N
0.0
0.0
R-Me
O
N
O
R
I
I
Cu
Cu
Ph
Ph
N
N
N
N
Ph
Ph
Me
Me
CONCLUSION
In this paper, we have reported an efficient crossꢀcoupling of Nꢀiminopyridinium ylides with Nꢀ
tosylhydrazones through direct CꢀH bond functionalization by using cheap CuI as the catalyst without
adding ligand. This direct CꢀH bond alkylation transformation, which is operationally simple and under
mild conditions, affords the corresponding alkylated pyridines in moderate to good yields. Since Nꢀ
tosylhydrazones are easily prepared from the corresponding aldehydes or ketones, this reaction
represents a practical access toward various 2ꢀalkyl pyridines. Computational study provides insights
into the reaction mechanism, in particular the deprotonation and the Cu carbene migratory insertion
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processes. This information is useful for the further development of CꢀH bond functionalization based
on Cu carbene transformations.
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EXPERIMENTAL SECTION
9
All reactions were performed under a nitrogen atmosphere in a flameꢀdried reaction flask. All solvents
were distilled prior to use. Toluene and dioxane were dried over Na with benzophenoneꢀketyl
intermediate as indicator. DCE was dried over CaH2. 200ꢀ300 Mesh silica gel was used for the
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chromatography. H NMR (400 MHz) and C NMR (100 MHz) spectra were recorded in ppm using
tetramethylsilane (TMS) as the internal standard. IR spectra are reported in wave numbers, cmꢀ1. For
HRMS measurements, the mass analyzer is FTꢀICR.
The preparation of Nꢀtosylhydrazones (2aꢀq). The literature procedure was followed.11 A solution of
o
pure TsNHNH2 (5 mmol) in methanol (5 mL) was stirred and heated to 60 C until the TsNHNH2
dissolved. The mixture was cooled to room temperature. Then carbonyl compounds were dropped into
the mixture slowly. After approximately 5 minutes the crude products could be obtained as solid
precipitations. The precipitations were washed by Petroleum ether then removed in vacuo to give the
pure products. In general the yields were around 95%. Because of the relatively low activity of diarylꢀ
substituted ketones, their reactions at room temperature may be incomplete. They should be reacted in
refluxing methanol for approximately 1 h. The reaction could be monitored by TLC.
The preparation of Nꢀiminopyridinium ylides (1aꢀe). Literature procedure was followed.6 Pyridine
(0.100 mL, 1.24 mmol) and Oꢀ(2,4ꢀdinitrophenyl)hydroxylamine (272 mg, 1.36 mmol) were added to
H2O/THF (1:1 mixture, 1.0 mL). The reaction flask was sealed with a septum, and the resulting
suspension was stirred at 40 °C for 16 h. During this period, the reaction mixture turned dark red. The
reaction was poured into aqueous NaOH (2.5 N, 6 mL) at room temperature, stirred for 5 min, and then
benzoyl chloride (0.215 mL, 1.84 mmol) was added in one portion. After 5 h, the reaction was diluted
with H2O (5 mL) and extracted with CHCl3 (3x10 mL). The combined organic phases were washed with
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NaOH (2.5 N, 5 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under
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1
reduced pressure affording the Nꢀiminopyridinium ylides 1a-e. The H NMR spectra data of 1a-e were
4
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found consistent with those previously reported in the literature.6
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9
Typical procedure for the reaction between Nꢀiminopyridinium ylides and Nꢀtosylhydrazones. Under a
nitrogen atmosphere, Nꢀiminobenzoylpyridinium ylide (1a, 59.4 mg, 0.3 mmol) and 4ꢀmethylꢀN'ꢀ(1ꢀ
phenylethylidene)benzenesulfonohydrazide (2a, 172.8 mg, 0.6 mmol) were added to a mixture of CuI
(11.5 mg, 0.06 mmol), LiOtBu (84.0 mg, 1.05 mmol) in PhMe (2 mL). The mixture was then stirred at
90 °C for 6 h. The reaction could be monitored with TLC. Upon completion of the reaction, the solvent
was removed in vacuo, and the crude product was purified by column chromatography (CH2Cl2/MeOH
= 40:1) to afford pure 3a as a yellow oil (73 mg, 81%).
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Benzoyl(2ꢀ(1ꢀphenylethyl)pyridiniumꢀ1ꢀyl)amide (3a).6b (73 mg, 81%); Rf = 0.3 (CH2Cl2:MeOH = 40:1),
1
brown oil. H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 6.0 Hz, 1H), 8.19 (dd, J = 1.6 Hz, 7.2 Hz, 2H),
7.82 (t, J = 7.2 Hz, 1H), 7.49ꢀ7.42 (m, 5H), 7.35ꢀ7.24 (m, 5H), 5.23 (q, J = 7.2 Hz, 1H), 1.70 (d, J = 7.2
13
Hz, 3H); C NMR (100 MHz, CDCl3) δ 170.0, 160.2, 145.6, 141.1, 137.3, 137.2, 130.0, 128.8, 128.1,
128.0, 127.8, 127.2, 125.5, 123.1, 39.6, 19.1.
Benzoyl(2ꢀ(1ꢀ(4ꢀ(trifluoromethyl)phenyl)ethyl)pyridiniumꢀ1ꢀyl)amide (3b).6b (85 mg, 77%); Rf = 0.4
(CH2Cl2:MeOH = 30:1), brown oil. 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 1.2 Hz, 1H), 8.13 (d, J =
6.4 Hz, 2H), 7.87 (t, J = 7.6 Hz, 1H), 7.57ꢀ7.49 (m, 4H), 7.43ꢀ7.37 (m, 5H), 5.23 (q, J = 6.8 Hz, 1H),
1.71 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.7, 159.7, 146.9, 146.2, 138.3, 137.8, 131.0,
130.2 (q, J = 32 Hz), 129.2, 128.9, 128.7, 126.5,126.1, 124.5, 121.1 (q, J = 272 Hz), 40.6, 20.2.
Benzoyl(2ꢀ(1ꢀ(4ꢀmethoxyphenyl)ethyl)pyridiniumꢀ1ꢀyl)amide (3c).6b (72 mg, 72%); Rf = 0.35
(CH2Cl2:MeOH = 40:1), brown oil. 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 6.0 Hz, 1H), 8.21 (d, J =
6.0 Hz, 2H), 7.81 (t, J = 7.6 Hz, 1H), 7.49ꢀ7.41 (m, 5H), 7.23 (m, 2H), 6.87, (d, J = 8.4 Hz, 2H), 5.19 (q,
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J = 7.2 Hz, 1H), 3.79 (s, 3H), 1.67 (d, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3) δ 170.8, 161.6,
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159.6, 146.5, 138.1, 134.0, 130.9, 130.0, 129.0, 128.7, 126.3, 123.9, 115.0, 56.1, 39.7, 19.9.
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Benzoyl(2ꢀ(1ꢀ(4ꢀbromophenyl)ethyl)pyridiniumꢀ1ꢀyl)amide (3d). (73 mg, 64%); Rf = 0.3 (CH2Cl2:MeOH
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= 40:1), brown oil. H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 4.8 Hz, 1H), 8.16 (d, J = 6.4 Hz, 2H),
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7.84 (t, J = 7.6 Hz, 1H), 7.51ꢀ7.48 (m, 2H), 7.45ꢀ7.42 (m , 5H), 7.16ꢀ7.14 (m, 2H), 5.14 (q, J = 7.2 Hz,
1H), 1.66 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.0, 159.5, 145.9, 140.3, 137.5, 137.1,
131.9, 130.2, 129.7, 128.1, 127.9, 125.3, 123.5, 121.3, 39.3, 19.1; FTIR (film) 3342.0, 2973.3, 2890,
1593.6, 1554.9, 1487.1, 1330.8 cmꢀ1; ESIꢀMS (m/z, relative intensity): 382.1 (21), 381.1 [(M+H)+, 100],
380.1 (21), 379.1 (99), 281.5 (3), 190.5 (5); HRMS (ESI) m/e calcd for C20H18BrN2O (M+H)+ 381.0597,
found 381.0603.
Benzoyl(2ꢀ(1ꢀ(4ꢀ(methoxycarbonyl)phenyl)ethyl)pyridiniumꢀ1ꢀyl)amide (3e).6b (82 mg, 76%); Rf = 0.3
(CH2Cl2:MeOH = 20:1), brown oil. 1H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 6.0 Hz, 1H), 8.16 (t, J =
6.0 Hz, 2H), 7.99 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.86 (q, J = 6.0 Hz, 1H), 7.54ꢀ7.50 (m,
1H), 7.46ꢀ7.42 (m, 4H), 7.35 (d, J = 8.4 Hz, 2H), 5.25 (q, J = 6.8 Hz, 1H), 3.90 (s, 3H), 1.71 (d, J = 7.2
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 169.9, 166.7, 159.1, 146.4, 145.9, 137.3, 137.0, 130.10,
130.00, 129.1, 128.0, 128.0, 127.8, 125.3, 123.5, 52.1, 39.3, 19.1.
Benzoyl(2ꢀ(1ꢀ(naphthalenꢀ2ꢀyl)ethyl)pyridiniumꢀ1ꢀyl)amide (3f). (80 mg, 76%); Rf = 0.3 (CH2Cl2:MeOH
= 30:1), brown oil. 1H NMR (400 MHz, CDCl3) δ 8.61 (br, 1H), 8.21 (d, J = 6.0 Hz, 2H), 7.78 (m, 5H),
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7.43ꢀ7.35 (m, 8H), 5.35 (d, J = 3.6 Hz, 1H), 1.78 (d, J = 6.0 Hz, 3H); C NMR (100 MHz, CDCl3) δ
170.1, 160.2, 145.7, 138.6, 137.6, 137.2, 133.4, 132.6, 130.2, 128.6, 128.2, 127.9, 127.8, 126.7, 126.6,
126.4, 126.1, 125.8, 123.4, 39.9, 18.9; FTIR (film) 3068.7, 2975.3, 2878.2, 1682.1, 1555.5, 1488.6,
1330.8 cmꢀ1; ESIꢀMS (m/z, relative intensity): 354.2 (26), 353.2 [(M+H)+, 100], 335.2 (7), 176.6 (3);
HRMS (ESI) m/e calcd for C24H21N2O (M+H)+ 353.1648, found 353.1648.
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(2ꢀ(1ꢀ(Benzo[d][1,3]dioxolꢀ5ꢀyl)butyl)pyridiniumꢀ1ꢀyl)(benzoyl)amide (3g). (76 mg, 68%); Rf = 0.35
(CH2Cl2:MeOH = 20:1), brown oil. 1H NMR (400 MHz, CDCl3) δ 8.49 (br, 1H), 8.13 (br, 2H), 7.72 (m,
1H), 7.45ꢀ7.24 (m, 5H), 6.71ꢀ6.50 (m, 3H), 5.81 (s, 2H), 4.92 (br, 1H), 1.90 (m, 2H), 1.10 (m, 2H), 0.78
(t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.8, 159.2, 148.0, 146.7, 145.8, 137.4, 137.3,
133.3, 130.0, 128.0, 127.8, 125.2, 123.1, 122.0, 108.9, 108.5, 101.1, 44.4, 35.8, 20.6, 13.8; FTIR (film)
2980.0, 2927.7, 2850, 1593.8, 1555.0, 1486.6, 1442.0, 1331.5 cmꢀ1; ESIꢀMS (m/z, relative intensity):
375.2 [(M+H)+, 100], 310.7 (3), 167.6 (8), 177.1 (5); HRMS (ESI) m/e calcd for C23H23N2O3 (M+H)+
375.1703, found 375.1709.
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Benzoyl(2ꢀ(1ꢀphenylbutyl)pyridiniumꢀ1ꢀyl)amide (3h). (87 mg, 88%); Rf = 0.3 (CH2Cl2:MeOH = 40:1),
brown oil. 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 5.2 Hz, 1H), 8.14 (d, J = 3.2 Hz, 2H), 7.72 (t, J =
7.4 Hz, 1H), 7.44ꢀ7.40 (m, 1H), 7.34ꢀ7.30 (m, 4H), 7.23ꢀ7.18 (m, 4H), 7.14(m, 1H), 5.02 (t, J = 7.2 Hz,
1H), 2.26 (m, 2H), 1.23 (m, 2H), 0.79 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.0, 158.2,
144.8, 138.6, 136.3, 129.0, 127.8, 127.6, 127.0, 126.8, 126.3, 124.4, 122.0,43.8, 34.7, 19.7, 12.8; FTIR
(film) 3061.3, 2959.1, 2931.4, 2872.4, 1681.1, 1556.1, 1330.9 cmꢀ1; ESIꢀMS (m/z, relative intensity):
331.2 [(M+H)+, 100]，176.6 (5)，165.6 (3); HRMS (ESI) m/e calcd for C22H23N2O (M+H)+ 331.1805,
found 331.1805.
Benzoyl(2ꢀ(cyclopropyl(phenyl)methyl)pyridiniumꢀ1ꢀyl)amide (3i). (71 mg, 72%); Rf
=
0.3
(CH2Cl2:MeOH = 20:1), brown oil. 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 5.6 Hz, 1H), 8.07 (d, J =
7.2 Hz, 2H), 7.90 (m, 2H), 7.44ꢀ7.38 (m, 4H), 7.36ꢀ7.26(m, 5H), 4.35 (d, J = 9.6 Hz, 1H), 0.87 (m, 1H),
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0.76ꢀ0.64 (m, 2H), 0.52ꢀ0.40 m, 2H); C NMR (100 MHz, CDCl3) δ 175.1,159.0,145.8,140.2, 137.0,
130.0, 128.6, 128.2, 128.0, 127.7, 127.4, 127.1, 126.3, 123.3, 50.0, 15.7, 5.8; FTIR (film) 3065.6,
2988.1, 2935.4, 2872.0, 1680.1, 1556.1, 1330.8 cmꢀ1; ESIꢀMS (m/z, relative intensity): 329.2 [(M+H)+,
100], 165.6 (3); HRMS (ESI) m/e calcd for C22H21N2O (M+H)+ 329.1654, found 329.1655.
(2ꢀBenzhydrylpyridiniumꢀ1ꢀyl)(benzoyl)amide (3j).6b (72 mg, 66%); Rf = 0.35 (CH2Cl2:MeOH = 20:1),
brown oil. 1H NMR (300 MHz, CDCl3,) δ 8.79 (d, J = 5.2 Hz, 1H), 7.99 (d, J = 6.8 Hz, 1H), 7.81 (t, J =
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7.2 Hz, 1H), 7.54 (d, J = 6.0 Hz, 1H), 7.39ꢀ7.28 (m, 10H), 7.11ꢀ7.10 (m, 4H), 6.42 (s, 1H). C NMR
(75 MHz, CDCl3) δ 169.3, 157.5, 145.8, 139.2, 137.1, 136.5, 129.9, 129.2, 128.7, 127.9, 127.6, 127.6,
127.3, 123.5, 52.1.
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Benzoyl(2ꢀ(pentanꢀ2ꢀyl)pyridiniumꢀ1ꢀyl)amide (3k). (45 mg, 56%); Rf = 0.3 (CH2Cl2:MeOH = 30:1),
brown oil. 1H NMR (400 MHz, CDCl3) δ 8.55 (br, 1H), 8.19 (br, 2H), 7.88 (br, 1H), 7.58 (m, 1H), 7.52ꢀ
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7.30 (m, 4H), 3.88 (m, 1H), 1.73ꢀ1.54 (m, 2H), 1.30 (m, 5H), 0.89 (t, J = 7.0 Hz, 3H); C NMR (100
MHz, CDCl3) δ 170.0, 161.7, 145.8, 137.9, 137.2, 130.0, 128.0, 127.8, 124.1, 122.9, 37.7, 33.8, 20.3,
19.0, 13.9; FTIR (film) 2950.0, 2916.6, 2800.0, 1593.4, 1553.2, 1490.3, 1334.8 cmꢀ1; ESIꢀMS (m/z,
relative intensity): 269.2 [(M+H)+, 100]，221.2 (15)，134.6 (7)，105.0 (5); HRMS (ESI) m/e calcd for
C17H21N2O (M+H)+ 269.1648, found 269.1649.
Benzoyl(2ꢀ(3,3ꢀdimethylbutanꢀ2ꢀyl)pyridiniumꢀ1ꢀyl)amide (3l). (69 mg, 82%); Rf = 0.3 (CH2Cl2:MeOH
1
= 20:1), brown oil. H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 5.2 Hz, 1H), 8.20 (d, J = 4.0 Hz, 2H),
7.85 (t, J = 7.6 Hz, 1H), 7.58 (m, 1H), 7.50ꢀ7.42 (m, 4H), 4.18 (q, J = 7.2 Hz, 1H), 1.28 (d, J = 7.2 Hz,
3H), 0.96 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 169.7, 160.3, 145.7, 137.6, 136.4, 129.9, 127.9, 127.8,
125.9, 122.7, 41.4, 35.2, 27.5, 15.6; FTIR (film) 3062.6, 2965.7, 2871.2, 1594.3, 1556.0, 1488.9, 1329.1
cmꢀ1; ESIꢀMS (m/z, relative intensity): 283.2 [(M+H)+, 100)，195.8 (8)，141.6 (5)，99.3 (3); HRMS
(ESI) m/e calcd for C18H23N2O (M+H)+ 283.1805, found 283.1806.
Benzoyl(2ꢀ(4ꢀmethoxybenzyl)pyridiniumꢀ1ꢀyl)amide (3m).6b (81 mg, 85%); Rf = 0.4 (CH2Cl2:MeOH =
20:1), brown oil. 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 6.0 Hz, 1H), 8.22 (dd, J = 1.6 Hz, 7.2 Hz,
2H), 7.79 (t, J = 4.04 Hz, 1H), 7.53ꢀ7.49 (m, 2H), 7.45ꢀ7.43 (m, 3H), 7.19ꢀ7.17 (m, 2H), 6.91ꢀ6.89 (m,
2H), 4.39 (s, 2H), 3.81 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 169.9, 158.9, 156.6, 144.9, 137.2, 137.0,
130.9, 130.0, 127.9, 127.8, 126.9, 126.6, 123.3, 114.4, 55.2, 36.7.
Benzoyl(2ꢀneopentylpyridiniumꢀ1ꢀyl)amide (3n). (73 mg, 91%); Rf = 0.3 (CH2Cl2:MeOH = 20:1), brown
oil.1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 6.0 Hz, 1H), 8.24ꢀ8.19 (m, 2H), 7.81 (t, J = 7.6 Hz, 1H),
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7.53ꢀ7.47 (m, 2H), 7.44ꢀ7.42 (m, 3H), 3.15 (s, 2H), 1.03 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 169.6,
154.6, 146.2, 137.5, 136.0, 129.9, 128.8, 128.0, 127.8, 123.2, 43.9, 33.9, 29.8; FTIR (film) 3058.6,
2975.7, 2881.2, 1596.3, 1558.0, 1488.9, 1329.1 cmꢀ1; ESIꢀMS (m/z, relative intensity): 269.2 [(M+H)+,
100], 169.6 (8); HRMS (ESI) m/e calcd for C17H21N2O (M+H)+ 269.1648, found 269.1652.
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Benzoyl(2ꢀ(3ꢀphenylpropyl)pyridiniumꢀ1ꢀyl)amide (3o). (66 mg, 70%); Rf = 0.3 (CH2Cl2:MeOH = 30:1),
brown oil. 1H NMR (400 MHz, CDCl3) δ 8.57 (br, 1H), 8.17 (m, 2H), 7.73 (br, 1H), 7.42ꢀ7.22 (br, 5H),
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7.20ꢀ7.11 (m, 5H), 3.06 (t, J = 6.8 Hz, 2H), 2.70ꢀ2.66 (m, 2H), 2.07 (t, J = 6 Hz, 2H); C NMR (100
MHz, CDCl3) δ 170.0, 156.5, 145.7, 141.0, 137.4, 137.3, 130.0, 128.5, 128.4, 128.1, 127.9, 126.5,
126.1, 123.4, 35.5, 31.8, 28.6; FTIR (film) 3070.0, 3030.0, 2925.6, 2830, 1593.8, 1554.8, 1492.1,
1330.8 cmꢀ1; ESIꢀMS (m/z, relative intensity): 317.2 [(M+H)+, 100]，158.6 (8); HRMS (ESI) m/e calcd
for C21H21N2O (M+H)+ 317.1648, found 317.1649.
Benzoyl(2ꢀ(3ꢀ(4ꢀtertꢀbutylphenyl)ꢀ2ꢀmethylpropyl)pyridiniumꢀ1ꢀyl)amide (3p). (94 mg, 81%); Rf = 0.25
(CH2Cl2:MeOH = 40:1), brown oil. 1H NMR (400 MHz, CDCl3) δ 8.59 (br, 1H), 8.20 (br, 2H), 7.72 (br,
1H), 7.44 (m, 5H), 7.16 (m, 2H), 7.00(m, 2H) 4.10 (m, 1H), 2.81ꢀ2.76 (m, 2H), 2.57ꢀ2.54 (m, 2H), 1.26
(s, 9H), 0.89 (d, J = 4.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.0, 155.9, 148.8, 145.0, 137.4,
136.7, 130.0, 128.8, 128.1, 128.0, 127.8, 125.1, 123.3, 43.4, 39.8, 34.3, 33.1, 31.4, 19.8; FTIR (film)
2962.5, 2929.8, 2902.9, 2212.8, 1594.2, 1552.9, 1340.1 cmꢀ1; ESIꢀMS (m/z, relative intensity): 387.2
[(M+H)+, 100], 193.6 (5), 141.6 (8); HRMS (ESI) m/e calcd for C26H31N2O (M+H)+ 387.2431, found
387.2434.
Benzoyl(2ꢀ(4ꢀtertꢀbutylcyclohexyl)pyridiniumꢀ1ꢀyl)amide (3q). (71 mg, 71%); Rf = 0.3 (CH2Cl2:MeOH =
1
20:1), brown oil. H NMR (400 MHz, CDCl3) δ 8.60 (br, 1H), 8.20 (br, 2H), 7.89 (t, J = 6.8 Hz, 1H),
7.55 (m, 1H), 7.48ꢀ7.44 (m, 4H), 3.62ꢀ3.45 (m, 1H), 2,19 (m, 2H). 1.91 (m, 2H), 1.49 (m, 2H), 1.21ꢀ
1.02 (m, 9H), 0.86 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.2, 160.8, 146.1, 137.6, 137.5, 130.0,
128.0, 127.9, 123.9, 122.8, 47.8, 39.2, 32.5, 31.8, 27.5, 27.1; FTIR (film) 2951.4, 2857.7, 1593.5,
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1551.8, 1490.8, 1334.2 cmꢀ1; ESIꢀMS (m/z, relative intensity): 339.2 (26), 337.2 (M+H, 100), 336.2
(18); HRMS (ESI) m/e calcd for C22H29N2O (M+H)+ 337.2280, found 337.2273.
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Benzoyl(2ꢀmethylꢀ6ꢀneopentylpyridiniumꢀ1ꢀyl)amide (3r). (56 mg, 66%); Rf = 0.3 (CH2Cl2:MeOH =
1
40:1), brown oil. H NMR (400 MHz, CDCl3) δ 8.61ꢀ8.53 (m, 1H), 8.19 (m, 2H), 7.87ꢀ7.27 (m, 3H),
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2.65 (s, 3H), 2.17 (s, 2H), 1.04 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 168.6, 153.7, 136.2, 130.0,
129.8, 128.0, 127.8, 126.6, 125.5, 123.2, 44.6, 30.0, 28.9, 20.5; FTIR (film) 3062.2, 2957.1, 2916.0,
2860.1, 1631.7, 1595.2, 1555.5, 1330.9 cmꢀ1; ESIꢀMS (m/z, relative intensity): 283.2 [(M+H)+, 100]，
219.1 (5), 141.6(8); HRMS (ESI) m/e calcd for C18H23N2O (M+H)+ 283.1805, found 283.1805.
Benzoyl(4ꢀmethylꢀ2ꢀneopentylpyridiniumꢀ1ꢀyl)amide (3s). (60 mg, 71%); Rf = 0.35 (CH2Cl2:MeOH =
20:1), brown oil. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 6.0 Hz, 1H), 8.18 (d, J = 5.2 Hz, 2H), 7.42ꢀ
7.27 (m, 5H), 3.07 (s, 2H), 2.52 (s, 3H), 1.03 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 169.9, 153.9,
149.0, 145.3, 137.5, 129.9, 129.3, 128.0, 127.8, 124.2, 43.7, 33.8, 29.8, 21.3; FTIR (film) 3061.8,
2958.3, 2915.9, 2866.2, 1630.7, 1595.6, 1554.6, 1332.7 cmꢀ1; ESIꢀMS (m/z, relative intensity): 283.2
[(M+H)+, 100]，219.1 (5), 141.6 (8); HRMS (ESI) m/e calcd for C18H23N2O (M+H)+ 283.1805, found
283.1805.
Benzoyl(2ꢀneopentylꢀ4ꢀphenylpyridiniumꢀ1ꢀyl)amide (3t). (80 mg, 78%); Rf = 0.3 (CH2Cl2:MeOH =
1
30:1), brown oil. H NMR (400 MHz, CDCl3) δ 8.81ꢀ8.72 (m, 1H), 8.22 (d, J = 4.0 Hz, 2H), 7.82 (m,
1H), 7.68 (m, 3H), 7.54 (m, 3H), 7.43(m, 3H), 3.09 (s, 2H), 1.08 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
169.8, 154.3, 148.5,146.0, 135.6, 130.6, 129.9, 129.6, 128.1, 127.8, 127.3, 126.0, 123.2, 121.0, 44.1,
34.0, 29.9; FTIR (film) 2961.1, 2920.1, 1625.5, 1593.3, 1548.4, 1334.7 cmꢀ1; ESIꢀMS (m/z, relative
intensity): 345.2 [(M+H)+, 100]，275.1 (8)，253.2 (8)，229.8 (7)，207.6 (5)，172.6 (8); HRMS (ESI)
m/e calcd for C23H25N2O (M+H)+ 345.1961, found 345.1962.
Benzoyl(2ꢀneopentylquinoliniumꢀ1ꢀyl)amide (3u). (67 mg, 70%); Rf = 0.3 (CH2Cl2:MeOH = 20:1),
1
brown oil. H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 8.8 Hz, 1H), 8.33 (m, 3H), 7.97 (d, J = 7.6 Hz,
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1H), 7.81 (t, J = 7.4 Hz, 1H), 7.69ꢀ7.60 (m, 2H), 7.47(m, 3H), 2.83 (s, 2H), 1.11 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 169.4, 157.6, 140.5, 137.4, 133.3, 130.0, 128.7, 128.5, 128.4, 128.2, 127.9, 124.5,
121.4, 46.0, 34.9, 30.3; FTIR (film) 3062.7, 2959.5, 2927.0, 2868.1, 1594.3, 1555.4, 1334.8 cmꢀ1; ESIꢀ
MS (m/z, relative intensity): 319.2 [(M+H)+, 100]，317.2 (60), 159.6 (8); HRMS (ESI) m/e calcd for
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C21H23N2O (M+H)+ 319.1805, found 319.1807.
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ACKNOWLEDGMENTS
The project is supported by National Basic Research Program (973 Program, No. 2009CB825300),
Natural Science Foundation of China.
Supporting Information
Deuterium exchange experiments, copies of H and 13C spectra for all products, details of DFT
1
calculation. This material is available free of charge via the Internet at http://pubs.acs.org.
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