Rapid Amination of Methoxy Pyridines with Aliphatic Amines

Article abstract of DOI:10.1021/acs.oprd.9b00235

A n-BuLi triggered practical amination protocol of methoxy pyridine derivatives with aliphatic amines was developed. The reaction could finish in 30 min for primary amines and 10 min for secondary amines. The amination is further highlighted by its excell

Full text of DOI:10.1021/acs.oprd.9b00235

Article
pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Rapid Amination of Methoxy Pyridines with Aliphatic Amines
Xia Wang, Cheng-Yu Long, Min-Hui Su, Yi-Xin Qu, Shen-Huan Li, Xiao-Jing Zhang, Si-Jie Huang,
and Xue-Qiang Wang*
Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of
Chemistry and Chemical Engineering, and Aptamer Engineering Center of Hunan Province, Hunan Provincial Key Laboratory of
Biomacromolecular Chemical Biology, Hunan University, 2 Lushan Nan Road, Changsha, Hunan 410082, P. R. China
S
* Supporting Information
ABSTRACT: A n-BuLi triggered practical amination protocol of methoxy pyridine derivatives with aliphatic amines was
developed. The reaction could finish in 30 min for primary amines and 10 min for secondary amines. The amination is further
highlighted by its excellent reactivity and substrate scope.
KEYWORDS: amination, methoxy pyridines, n-BuLi, transition-metal-free
Verkade’s,5 Nolan’s,6 Beller’s,7 Zhang’s,8 Yin’s,9 Dommisse’s,10
INTRODUCTION
The transition-metal-catalyzed synthesis of heteroaryl amines
(Scheme 1) had been one of the most challenging research
■
Cao’s,11 and Tu’s,12 also made their great efforts on the
amination of heteroaryl halides. Except Pd-catalysis, Ni, Cu,
and Zn were also utilized as catalysts to prepare heteroaryl
amines.13 Notably, these methods often use heteroaryl halides
Scheme 1. Approaches for the Synthesis of Heteroaryl
Amines
as starting material; the aminations of heteroaryl alkyl ethers
with amines have gained much less attention, which could be
rationalized by the high dissociation energy of the C−O
bond.14
Apart from transition-metal-catalysis, the transition-metal-
free amination of heteroaryl halides is a powerful alternative to
provide heteroaryl amines.15 In particular, the amination via
the nucleophilic aromatic substitution pathway could serve as
an attractive supplement to the ones that need transition-metal
catalysts.16 However, this transformation is largely limited to
highly activated substrates, for instance heteroaryl fluorides or
nitro substituted aryl halides. Our and Zhao’s groups recently
developed a base triggered amination of nitrile substituted aryl
alkyl thioethers with weak nucleophilic aromatic amines.17 The
preliminary mechanistic studies showed that this trans-
formation might undergo thorough nucleophilic aromatic
substitution. Promoted by this protocol, we envisioned that
the amination of methoxy pyridines with aliphatic amines
would occur owing to the electron-deficient nature of the
heteroarenes and the strong nucleophilicity of aliphatic amines.
topics in the C−N bond formation research area because the
RESULTS AND DISCUSSION
coordinating ability of the heteroatom can cause catalyst
deactivation.1 In the past few decades, extensive efforts have
been dedicated to the development of efficient catalytic
systems to couple a wide range of heteroaryl halides with
amines.2 Buchwald−Hartwig amination, the Pd-catalyzed C−
N cross-coupling of aryl (pseudo)halides with amines, has
become a principal technique for production of heteroaromatic
amines. For instance, Buchwald and co-workers developed a
series of bulky monodentate phosphine ligands, applied them
in the Pd-catalyzed amination of heteroaryl halides, and
achieved marvelous outcomes.3 Hartwig’s research group also
developed highly efficient catalytic protocols to access the
desired heteroaryl amines, significantly promoting the develop-
ment of this research field.4 Many other groups, such as
■
To test our hypothesis, we chose 4-methoxy pyridine (1a) as
modeling substrate to study its amination with diethyl amine
(2a). We first examined different bases, potassium carbonate,
lithium tert-butoxide, sodium tert-butoxide, potassium tert-
butoxide, and even potassium hexamethyldisilazane did not
give any desired amination product (Table 1, entries 1−5).
These results can be explained by the fact that the bases we
Special Issue: Honoring 25 Years of the Buchwald-Hartwig
Amination
Received: May 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.9b00235
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Table 1. Reaction Condition Optimization of Amination
Table 2. Substrate Scope of Secondary Amines and Methoxy
Heteroarenes
entry
base
solvent
THF
time (h)
yield (%)
1
2
3
4
5
6
7
8
K2CO3
LiOt-Bu
NaOt-Bu
KOt-Bu
KHMDS
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
16
16
16
16
16
16
16
16
16
16
16
8
0
0
0
0
THF
THF
THF
THF
THF
THF
THF
Et2O
DME
1,4-dioxane
THF
THF
THF
THF
0
99
b
94
c
59
9
98
10
11
12
13
14
15
trace
trace
99
99
99
1
30 min
10 min
96
a
Reaction conditions: 1a (1.0 equiv, 0.5 mmol), 2a (2.0 equiv, 1.0
b
mmol), base (2.0 equiv), THF (0.5 mL), 60 °C, 16 h. 1a (1.0 equiv,
0.5 mmol), 2a (1.4 equiv, 0.7 mmol), n-BuLi (1.54 equiv, 0.77 mmol,
0.3 mL, 2.5 M in hexane), THF (0.5 mL), 60 °C, 16 h. 1a (1.0 equiv,
c
0.5 mmol), 2a (1.2 equiv, 0.6 mmol), n-BuLi (1.32 equiv, 0.66 mmol,
0.26 mL, 2.5 M in hexane), THF (0.5 mL), 60 °C, 16 h.
a
Reaction conditions: 1 (1.0 equiv, 0.5 mmol), 2 (1.6 equiv, 0.8
mmol), n-BuLi (1.76 equiv, 0.88 mmol, 0.35 mL, 2.5 M in hexane),
THF (0.5 mL), 60 °C, 10 min. 1 (1.0 equiv, 0.5 mmol), 2 (3.2 equiv,
b
1.6 mmol), n-BuLi (3.52 equiv, 1.76 mmol, 0.7 mL, 2.5 M in hexane),
THF (0.5 mL), 60 °C, 10 min.
applied are not basic enough to deprotonate the proton of 2a
to generate a more nucleophilic lithium diethylamide. Next, we
moved our attention to n-BuLi that is commonly used to
prepare lithium diisopropylamide (LDA) through the depro-
tonation of diisopropylamine process. To our delight, the
aimed heteroaryl amine 3a was observed in 99% NMR yield
while the reaction was conducted in the presence of 2
equivalents of n-BuLi in THF at 60 °C for 16 h (entry 6).18
Increasing or decreasing the amount of n-BuLi led to inferior
yields (entries 7 and 8). We also found that this transformation
was sensitive to solvent; while the use of diethyl ether gave
comparable yield, 1,2-dimethoxyethane and 1,4-dioxane
delivered trace amount of targeted amine 3a (entries 9−11).
The optimization of reaction time allowed us to identify the
optimal reaction time for this reaction, the reaction was
completed in 30 min for the secondary amines, and almost
quantitative yield was obtained (entries 12−14). The yield
slightly decreased to 96% while the reaction time was
shortened to 10 min (entry 15).
After establishing the optimized reaction conditions, we then
decided to investigate the representative examples of our newly
developed rapid amination protocol. As shown in Table 2,
other acyclic secondary amines such as dibutyl amine, dibenzyl
amine, and N-methyl-1-phenylmethanamine were suited to this
amination, delivering the corresponding products in excellent
yields (Table 2, 3b, 3c, 3d). Moreover, we found that cyclic
secondary amines could also participate in this transformation.
The use of (R)-2-methylpyrrolidine gave the final product in
99% yield. This technique could also be extended to piperazine
derivatives; the products 3f, and 3g were respectively produced
in 99%, and 96% yield. Furthermore, we chose dibutyl amine
as the amino source to exame the generality of N-heteroarenes
of our newly developed amination protocol. To our surprise,
the introduction of a methyl group on the pyridine ring
significantly affected the amination efficiency; the yields
dramatically decreased to 69% (3j) and 58% (3k). Intriguingly,
excellent site-selectivity was observed for the 2,3-dimethoxy
substituted pyridine, the amination proceeded exclusively at
the ortho-position of pyridine, whereas the methoxy group at
the meta-position of pyridine remained untouched (3l). We
also witnessed the difference in terms of reactivity between
dimethoxy substituted pyridine and pyrimidine. As pictured,
the use of 2,6-dimethoxypyridine offered a monoamination
product 3m while double amination took place for dimethoxy
substituted pyrimidine (3n).
We next moved to study the substrate scope of primary
amines (Table 3). Gladly, the amination rate was at the same
level as secondary amines; all the reactions that we carried out
were finished within 30 min. As presented, the employment of
1-aminobutane gave the final product 5a in 80% isolated yield.
1-Amino hexane could participate in the amination in high
efficiency, giving 5b in almost quantitative yield. The presence
of the ether group did not influence reactivity of amine, 5c was
obtained in slightly lower yield of 94%. Unexpectedly, the
utilization of 3-phenylpropan-1-amine resulted in much
lowered isolated yield (5d). In addition, sterically bulky
amines such as 2,3-dihydro-1H-inden-1-amine and adamantan-
2-amine could take part in this amination, producing the
corresponding products 5e, and 5f in 90% and 56% yield,
respectively. A heterocycle such as thiophene was well
tolerated as demonstrated by 5g. We also found that chiral
B
DOI: 10.1021/acs.oprd.9b00235
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Article
pyridine with primary amines could finish in half an hour, and
the reaction with secondary amines completed in 10 min. It is
noteworthy that this reaction could be scaled up to 200 mmol
with almost the same efficiency.
Table 3. Substrate Scope of Primary Amine
EXPERIMENTAL SECTION
■
General Information. All reactions were conducted in
Schlenck tubes under dinitrogen atmosphere. n-BuLi and THF
were purchased from Energy Chemical and used as received.
All the amine derivatives were purchased from Energy, Bide.
Typical Procedure I: N,N-Dibutylpyridin-4-amine (3b).
An oven-dried flask reaction tube (10 mL) was equipped with
a magnetic stir bar, and the reaction tube was vacuumed and
refilled with N2 three times at −78 °C. Then the aliphatic
amine 2b (0.8 mmol, 103.2 mg) was added under N2
atmosphere, followed THF (0.5 mL) and n-BuLi (0.88
mmol, 0.35 mL, 2.5 M in hexane) by syringe at −78 °C.
The tube was capped and stirred at room temperature for 10
min, and then the tube was opened under N2 and 4-
methoxypyridine 1a was added by microsyringe. The tube was
capped and stirred in a 60 °C oil bath for 10 min. The reaction
mixture was then allowed to cool to room temperature,
quenched by water (3 mL), and then extracted with DCM (5
mL × 3). The solvent layer was dried with dried Na2SO4. The
crude mixture was concentrated in vacuo and purified by flash
column chromatography eluting with EtOAc (1% Et3N) to
a
Reaction conditions: 1 (1.0 equiv, 0.5 mmol), 4 (1.6 equiv, 0.8
mmol), n-BuLi (2.08 equiv, 1.04 mmol, 0.42 mL, 2.5 M in hexane),
THF (0.5 mL), 60 °C, 30 min.
amine (S)-1-phenylpropan-1-amine exhibited excellent reac-
tivity.
We additionally examined the possibility of using other
pyridyl ether as material. Likewise, 4-phenoxypyridine could be
utilized to perform the amination with morpholine derivative 7
to afford the targeted heteroaryl amine in 99% yield. To
demonstrate the potential utility in industrial application of our
newly developed amination protocol, we carried out a large-
scale reaction of 200 mmol. The reaction was finished in 10
min, generating the desired product in 98% isolated yield
(Scheme 2).
1
give compound 3b as a yellow oil (102 mg, 99% yield). H
NMR (400 MHz, DCCl3) δ 8.13 (d, J = 5.1 Hz, 2H), 6.39 (d, J
= 5.1 Hz, 2H), 3.23 (t, J = 6 Hz, 4H), 1.57−1.50 (m, 4H),
1.38−1.28 (m, 4H), 0.93 (t, J = 8 Hz, 6H) ppm. 13C NMR
(101 MHz, DCCl3) δ 152.51, 149.85, 106.40, 49.96, 29.16,
20.28, 13.97 ppm.
Scheme 2. Other Etheric Substrate and Large-Scale
Reaction
N,N-Dibenzylpyridin-4-amine (3c). Following Typical
Procedure I, the reaction of 1a (0.5 mmol, 54.5 mg), 2c (0.8
mmol, 157.6 mg), and n-BuLi (0.88 mmol, 0.35 mL, 2.5 M in
hexane in THF (0.5 mL) for 10 min at 60 °C afforded 3c
(109.6 mg, 80%) as a yellow solid (eluent: EtOAc (1% Et3N)).
Melting point: 85.5 °C. HRMS (ESI) calculated for C19H18N2:
1
[M + H+]: 275.1543, found: 275.1556. H NMR (400 MHz,
DCCl3) δ 8.24 (d, J = 6.5 Hz, 2H), 7.42−7.38 (m, 4H), 7.36−
7.31 (m, 2H), 7.25 (d, J = 4 Hz, 4H), 6.63 (d, J = 4 Hz, 2H),
4.72 (s, 4H) ppm. 13C NMR (101 MHz, DCCl3) δ 154.01,
150.27, 136.97, 129.02, 127.53, 126.58, 107.23, 53.32 ppm.
N-Benzyl-N-methylpyridin-2-amine (3d). Following
Typical Procedure I, the reaction of 1d (0.5 mmol, 54.5
mg), 2d (0.8 mmol, 96.8 mg), and n-BuLi (0.88 mmol, 0.35
mL, 2.5 M in hexane in THF (0.5 mL) for 10 min at 60 °C
afforded 3d (92.1 mg, 93%) as a yellow oil (eluent: petroleum
1
ether (1% Et3N)). H NMR (400 MHz, DCCl3) δ 8.16 (s,
1H), 7.40 (t, J = 7.6 Hz, 1H), 7.29−7.26 (m, 2H), 7.20 (d, J =
8 Hz, 3H), 6.53 (s, 1H), 6.48 (d, J = 8.4 Hz, 1H), 4.77 (s, 2H),
3.04 (s, 3H) ppm. 13C NMR (101 MHz, DCCl3) δ 158.97,
148.06, 138.79, 137.42, 128.62, 127.08, 126.98, 111.91, 105.80,
53.32, 36.29 ppm.
(R)-4-(2-Methylpyrrolidin-1-yl)pyridine (3e). Following
Typical Procedure I, the reaction of 1a (0.5 mmol, 54.5 mg),
CONCLUSIONS
■
In summary, we reported practical amination protocols that are
capable of efficiently incorporating both primary and
secondary aliphatic amines into pyridine, generating the
corresponding amines in good to excellent yields. This strategy
is distinguished by its high reactivity; the amination of methoxy
C
DOI: 10.1021/acs.oprd.9b00235
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
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2e (0.8 mmol, 68 mg), and n-BuLi (0.88 mmol, 0.35 mL, 2.5
M in hexane in THF (0.5 mL) for 10 min at 60 °C afforded 3e
(81 mg, 99%) as a yellow oil (eluent: EtOAc (1% Et3N)).
HRMS (ESI) calculated for C10H14N2: [M + H+]: 163.1230,
MHz, DCCl3) δ 158.47, 147.87, 147.67, 112.48, 105.91, 48.52,
30.05, 21.65, 20.51, 14.20 ppm.
N,N-Dibutyl-6-methylpyridin-2-amine (3b). Following
Typical Procedure I, the reaction of 1k (0.5 mmol, 61.5 mg),
2b (0.8 mmol, 103.2 mg), and n-BuLi (0.88 mmol, 0.35 mL,
2.5 M in hexane) in THF (0.5 mL) for 10 min at 60 °C
afforded 3k (63.8 mg, 58%) as a yellow oil (eluent: petroleum
ether (1% Et3N)). HRMS (ESI) calculated for C14H24N2: [M
1
found: 163.1228. H NMR (400 MHz, DCCl3) δ 8.14 (d, J =
5.3 Hz, 2H), 6.36 (d, J = 4.8 Hz, 2H), 4.04−3.80 (m, 1H),
3.45−3.34 (m, 1H), 3.18 (d, J = 8.8 Hz, 1H), 2.61 (s, 1H),
2.09−2.00 (m, 2H), 1.72 (s, 1H), 1.15 (d, J = 6.2 Hz, 3H)
ppm. 13C NMR (101 MHz, DCCl3) δ 151.19, 149.43, 107.17,
53.27, 47.42, 33.02, 32.96, 18.95 ppm.
1
+ H+]: 221.2012, found: 221.2010. H NMR (400 MHz,
DCCl3) δ 7.29 (t, J = 7.4 Hz, 1H), 6.34 (d, J = 7.2 Hz, 1H),
6.24 (d, J = 8 Hz, 1H), 3.47−3.43 (m, 4H), 2.38 (s, 3H),
1.62−1.55 (m, 4H), 1.39−1.34 (m, 4H), 0.97 (t, J = 7.3 Hz,
6H) ppm. 13C NMR (101 MHz, DCCl3) δ 157.69, 156.85,
137.17, 109.82, 102.17, 48.18, 29.97, 24.84, 20.45, 14.16 ppm.
N,N-Dibutyl-3-methoxypyridin-2-amine (3l). Following
Typical Procedure I, the reaction of 1l (0.5 mmol, 69.5 mg),
2b (0.8 mmol, 103.2 mg) and n-BuLi (0.88 mmol, 0.35 mL,
2.5 M in hexane) in THF (0.5 mL) for 10 min at 60 °C
afforded 3l (99.1 mg, 84%) as a yellow oil (eluent: petroleum
ether/EtOAc = 100/1 (1% Et3N)). HRMS (ESI) calculated
1-Cyclopropyl-4-(pyridin-4-yl)piperazine (3f). Follow-
ing Typical Procedure I, the reaction of 1a (0.5 mmol, 54.5
mg), 2f (0.8 mmol, 100.8 mg), and n-BuLi (0.88 mmol, 0.35
mL, 2.5 M in hexane) in THF (0.5 mL) for 10 min at 60 °C
afforded 3f (100.5 mg, 99%) as a yellow solid (eluent: EtOAc
(1% Et3N)). Melting point: 51.8 °C. HRMS (ESI) calculated
1
for C12H17N3: [M + H+]: 204.1495, found: 204.1492. H
NMR (400 MHz, DCCl3) δ 8.25 (d, J = 5.8 Hz, 2H), 6.66 (d, J
= 8 Hz, 2H), 3.29 (t, J = 4 Hz, 4H), 2.72 (t, J = 6 Hz, 4H),
1.65 (m, 1H), 0.52−0.43 (m, 4H). 13C NMR (101 MHz,
DCCl3) δ 155.13, 150.30, 108.59, 52.63, 46.08, 38.54, 5.99.
1-Isopropyl-4-(pyridin-4-yl)piperazine (3g). Following
Typical Procedure I, the reaction of 1a (0.5 mmol, 54.5 mg),
2g (0.8 mmol, 102.4 mg), and n-BuLi (0.88 mmol, 0.35 mL,
2.5 M in hexane) in THF (0.5 mL) for 10 min at 60 °C
afforded 3g (98.4 mg, 96%) as a yellow solid (eluent: EtOAc
(1% Et3N)). Melting point: 120.5 °C. HRMS (ESI) calculated
1
for C14H24N2O: [M + H+]: 237.1961, found: 237.1959. H
NMR (400 MHz, DCCl3) δ 7.98 (d, J = 8 Hz, 1H), 6.12 (d, J
= 8 Hz, 1H), 5.88 (d, J = 4 Hz, 1H), 3.79 (s, 3H), 3.41 (t, J =
12 Hz, 4H), 1.61−1.53 (m, 4H), 1.39−1.30 (m, 4H), 0.94 (t, J
= 8 Hz, 6H) ppm. 13C NMR (101 MHz, DCCl3) δ167.02,
159.96, 149.37, 98.80, 90.13, 54.87, 48.66, 30.00, 20.50, 14.19
ppm.
1
for C12H19N3: [M + H+]: 206.1652, found: 206.1655. H
N,N-Dibutyl-6-methoxypyridin-2-amine (3m). Follow-
ing Typical Procedure I, the reaction of 1m (0.5 mmol, 69.5
mg), 2b (0.8 mmol, 103.2 mg), and n-BuLi (0.88 mmol, 0.35
mL, 2.5 M in hexane) in THF (0.5 mL) for 10 min at 60 °C
afforded 3m (92.1 mg, 78%) as a yellow oil (eluent: petroleum
ether (1% Et3N)). HRMS (ESI) calculated for C14H24N2O:
NMR (400 MHz, DCCl3) δ 8.18 (d, J = 6.6 Hz, 2H), 6.59 (d, J
= 6.6 Hz, 2H), 3.28 (t, J = 5.1 Hz, 4H), 2.70−2.64 (m, 1H),
2.58 (t, J = 4 Hz, 4H), 1.02 (d, J = 4 Hz, 6H) ppm. 13C NMR
(101 MHz, DCCl3) δ 155.01, 149.98, 108.26, 54.51, 48.21,
46.22, 18.48 ppm.
1
N-(2-Methoxyethyl)-N-methylpyridin-4-amine (3h).
Following Typical Procedure I, the reaction of 1a (0.5
mmol, 54.5 mg), 2h (0.8 mmol, 53.4 mg), and n-BuLi (0.88
mmol, 0.35 mL, 2.5 M in hexane) in THF (0.5 mL) for 10 min
at 60 °C afforded 3h (78.1 mg, 94%) as yellow oil (eluent:
EtOAc (1% Et3N)). 1H NMR (400 MHz, DCCl3) δ 8.14 (d, J
= 6.4 Hz, 2H), 6.46 (d, J = 6.5 Hz, 2H), 3.49 (s, 4H), 3.30 (s,
3H), 2.96 (s, 3H) ppm. 13C NMR (101 MHz, DCCl3) δ
153.48, 149.67, 106.57, 69.82, 59.12, 51.09, 38.20 ppm.
2-(Pyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline (3i).
Following Typical Procedure I, the reaction of 1a (0.5
mmol, 54.5 mg), 2i (0.8 mmol, 106.4 mg), and n-BuLi (0.88
mmol, 0.35 mL, 2.5 M in hexane) in THF (0.5 mL) for 10 min
at 60 °C afforded 3i (84.1 mg, 80%) as yellow oil (eluent:
EtOAc (1% Et3N)). 1H NMR (400 MHz, DCCl3) δ 8.26 (d, J
= 6.1 Hz, 2H), 7.26−7.18 (m, 4H), 6.67 (d, J = 4 Hz, 2H),
4.47 (s, 2H), 3.60 (t, J = 5.9 Hz, 2H), 2.97 (t, J = 5.8 Hz, 2H)
ppm. 13C NMR (101 MHz, DCCl3) δ 153.88, 149.91, 135.03,
133.35, 128.24, 126.98, 126.59, 126.55, 107.40, 47.92, 43.55,
28.92 ppm.
[M + H+]: 237.1961, found: 237.1957. H NMR (400 MHz,
DCCl3) δ 7.32 (t, J = 7.9 Hz, 1H), 5.94 (m, 7.9 Hz, 2H), 3.86
(s, 3H), 3.43−3.35 (m, 4H), 1.59 (m, 4H), 1.35 (q, J = 7.4 Hz,
4H), 0.95 (t, J = 7.4 Hz, 6H). 13C NMR (101 MHz, DCCl3) δ
163.17, 139.69, 96.68, 95.11, 52.82, 20.53, 14.19.
N2,N2,N4,N4-Tetrabutylpyrimidine-2,4-diamine (3n).
Following Typical Procedure I, the reaction of 1n (0.5
mmol, 70 mg), 2b (1.6 mmol, 103.2 mg), and n-BuLi (1.76
mmol, 0.7 mL, 2.5 M in hexane) in THF (1 mL) for 10 min at
60 °C afforded 3n (165.3 mg, 99%) as a yellow oil (eluent:
petroleum ether/EtOAc = 20/1 (1% Et3N)). HRMS (ESI)
calculated for C20H38N4: [M + H+]: 335.3169, found:
1
335.3166. H NMR (400 MHz, DCCl3) δ 7.85 (d, J = 4 Hz,
1H), 5.65 (d, J = 8 Hz, 1H), 3.48 (m, 4H), 3.35 (s, 4H), 1.62−
1.52 (m, 8H), 1.38−1.28 (m, 8H), 0.95- 0.91 (m, 12H). 13C
NMR (101 MHz, DCCl3) δ 161.51, 161.39, 155.88, 91.73,
48.03, 47.61, 30.57, 30.19, 20.60, 20.52, 14.27, 14.14.
N-Butylpyridin-4-amine (5a). Following Typical Proce-
dure I, the reaction of 1a (0.5 mmol, 54.5 mg), 4a (0.8 mmol,
58.4 mg), and n-BuLi (1.04 mmol, 0.42 mL, 2.5 M in hexane)
in THF (0.5 mL) for 30 min at 60 °C afforded 5a (60 mg,
80%) as yellow oil (eluent: EtOAc (1% Et3N)). 1H NMR (400
MHz, DCCl3) δ 8.13 (d, J = 4.8 Hz, 2H), 6.39 (d, J = 6.1 Hz,
2H), 4.40 (s, 1H), 3.11 (q, J = 6.8 Hz, 2H), 1.58 (m, J = 7.1
Hz, 2H), 1.40 (m, J = 7.3 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H)
ppm. 13C NMR (101 MHz, DCCl3) δ 153.65, 149.92, 107.51,
42.40, 31.27, 20.23, 13.87 ppm.
N,N-Dibutyl-4-methylpyridin-2-amine (3j). Following
Typical Procedure I, the reaction of 1j (0.5 mmol, 61.5 mg),
2b (0.8 mmol, 103.2 mg), and n-BuLi (0.88 mmol, 0.35 mL,
2.5 M in hexane) in THF (0.5 mL) for 10 min at 60 °C
afforded 3j (75.9 mg, 69%) as yellow oil (eluent: petroleum
ether (1% Et3N)). HRMS (ESI) calculated for C14H24N2: [M
1
+ H+]: 221.2012, found: 221.2024. H NMR (400 MHz,
DCCl3) δ 7.99 (d, J = 8 Hz, 1H), 6.31 (d, J = 4 Hz, 1H), 6.23
(s, 1H), 3.41 (t, J = 7.6 Hz, 4H), 2.23 (s, 3H), 1.61−1.53 (m,
4H), 1.40−1.31 (m, 4H), 0.93 (s, 6H) ppm. 13C NMR (101
N-Octylpyridin-2-amine (5b). Following Typical Proce-
dure I, the reaction of 1a (0.5 mmol, 54.5 mg), 4b (0.8 mmol,
103.2 mg), and n-BuLi (1.04 mmol, 0.42 mL, 2.5 M in hexane)
D
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in THF (0.5 mL) for 30 min at 60 °C afforded 5b (102 mg,
mg), 4g (0.8 mmol, 90.4 mg), and n-BuLi (1.04 mmol, 0.42
mL, 2.5 M in hexane) in THF (0.5 mL) for 30 min at 60 °C
afforded 5g (94.1 mg, 99%) as a yellow solid (eluent: EtOAc
(1% Et3N)). Melting point: 119.2 °C. HRMS (ESI) calculated
99%) as a yellow solid (eluent: petroleum ether (1% Et3N)).
1
Melting point: 40.1 °C. H NMR (400 MHz, DCCl3) δ 8.05
(d, J = 6.1 Hz, 1H), 7.39 (t, J = 6.8 Hz, 1H), 6.52 (t, J = 8 Hz,
1H), 6.35 (d, J = 8.4 Hz, 1H), 4.54 (s, 1H), 3.22 (q, J = 7.0 Hz,
2H), 1.64−1.56 (m, 2H), 1.39−1.26 (m, 10H), 0.87 (t, J = 6.8
Hz, 3H) ppm. 13C NMR (101 MHz, DCCl3) δ 159.09, 148.32,
137.45, 112.65, 106.36, 42.42, 31.92, 29.69, 29.47, 29.35,
27.19, 22.75, 14.19 ppm.
1
for C10H10N2S: [M + H+]: 191.2715, found: 191.0638. H
NMR (400 MHz, DCCl3) δ 8.18 (d, J = 6.4 Hz, 2H), 7.33−
7.31 (m, 1H), 7.17 (s, 1H), 7.04 (d, J = 5.0 Hz, 1H), 6.47 (d, J
= 6.5 Hz, 2H), 4.70 (s, 1H), 4.36 (d, J = 5.5 Hz, 2H) ppm. 13C
NMR (101 MHz, DCCl3) δ 153.24, 150.14, 139.03, 126.95,
126.75, 122.19, 107.82, 42.48 ppm.
N-(3-Butoxypropyl)pyridin-4-amine (5c). Following
Typical Procedure I, the reaction of 1a (0.5 mmol, 54.5
mg), 4c (0.8 mmol, 104.8 mg), and n-BuLi (1.04 mmol, 0.42
mL, 2.5 M in hexane) in THF (0.5 mL) for 30 min at 60 °C
afforded 5c (97.8 mg, 94%) as a yellow oil (eluent: EtOAc (1%
Et3N)). HRMS (ESI) calculated for C12H20N2O: [M + H+]:
(R)-N-(1-Phenylpropyl)pyridin-4-amine (5h). Following
Typical Procedure I, the reaction of 1a (0.5 mmol, 54.5 mg),
4h (0.8 mmol, 108 mg), and n-BuLi (1.04 mmol, 0.42 mL, 2.5
M in hexane) in THF (0.5 mL) for 30 min at 60 °C afforded
5h (96.5 mg, 91%) as a yellow solid (eluent: EtOAc (1%
Et3N)). Melting point: 103.9 °C. HRMS (ESI) calculated for
1
209.1648, found: 209.1653. H NMR (400 MHz, DCCl3) δ
1
C14H16N2: [M + H+]: 213.1386, found: 213.1390. H NMR
8.09 (d, J = 4 Hz, 2H), 6.36 (d, J = 4.8 Hz, 2H), 5.01 (s, 1H),
3.50 (q, J = 5.5 Hz, 2H), 3.48−3.36 (m, 2H), 3.22−3.20 (m,
2H), 1.86−1.82 (m, 2H), 1.55−1.52 (m, 2H), 1.36−1.33 (q, J
= 6.8, 6.1 Hz, 2H), 0.92−0.87 (m, 3H). 13C NMR (101 MHz,
DCCl3) δ 153.73, 149.74, 149.69, 107.40, 70.99, 69.38, 31.85,
28.93, 19.44, 13.94.
(400 MHz, DCCl3) δ 8.09 (d, J = 4.4 Hz, 2H), 7.34−7.26 (m,
5H), 6.35 (d, J = 4.6 Hz, 2H), 4.60 (s, 1H), 4.29−4.24 (m,
1H), 1.87−1.82 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H) ppm. 13C
NMR (101 MHz, DCCl3) δ 152.75, 149.85, 142.41, 128.84,
127.51, 126.43, 108.35, 58.92, 31.37, 10.87 ppm.
N-(3-Phenylpropyl)pyridin-2-amine (5d). Following
Typical Procedure I, the reaction of 1d (0.5 mmol, 54.5
mg), 4d (0.8 mmol, 108 mg), and n-BuLi (1.04 mmol, 0.42
mL, 2.5 M in hexane) in THF (0.5 mL) for 30 min at 60 °C
afforded 5d (72.1 mg, 68%) as a yellow oil (eluent: petroleum
ether (1% Et3N)). HRMS (ESI) calculated for C14H16N2: [M
(S)-3-Methyl-4-(pyridin-4-yl)morpholine (8). Following
Typical Procedure I, the reaction of 6 (0.5 mmol, 85.5 mg), 7
(0.8 mmol, 80.8 mg), and n-BuLi (0.88 mmol, 0.35 mL, 2.5 M
in hexane) in THF (0.5 mL) for 30 min at 60 °C afforded 8
(88.1 mg, 99%) as a yellow oil (eluent: petroleum ether (1%
Et3N)). HRMS (ESI) calculated for C10H14N2O: [M + H+]:
1
+ H+]: 213.1386, found: 213.1394. H NMR (400 MHz,
1
179.1179, found: 179.1177. H NMR (400 MHz, DCCl3) δ
DCCl3) δ 8.08 (d, J = 3.9 Hz, 1H), 7.42−7.38 (m, 1H), 7.29
(t, J = 8 Hz, 2H), 7.21−7.18 (m, 3H), 6.57−6.54 (m, 1H),
6.33 (d, J = 8.3 Hz, 1H), 4.51 (s, 1H), 3.30 (q, J = 6.8 Hz, 2H),
2.74 (t, J = 8 Hz, 2H), 2.00−1.92 (m, 2H) ppm. 13C NMR
(101 MHz, DCCl3) δ 158.97, 148.36, 141.73, 137.55, 128.57,
128.54, 126.09, 112.89, 106.52, 41.85, 33.42, 31.30 ppm.
N-(2,3-Dihydro-1H-inden-1-yl)pyridin-4-amine (5e).
Following Typical Procedure I, the reaction of 1a (0.5
mmol, 54.5 mg), 4e (0.8 mmol, 106.4 mg), and n-BuLi
(1.04 mmol, 0.42 mL, 2.5 M in hexane) in THF (0.5 mL) for
30 min at 60 °C afforded 5e (94.5 mg, 90%) as a yellow oil
(eluent: EtOAc (1% Et3N)). HRMS (ESI) calculated for
8.20 (d, J = 4.9 Hz, 2H), 6.54 (d, J = 4.9 Hz, 2H), 4.00−3.79
(m, 2H), 3.73 (d, J = 11.4 Hz, 2H), 3.62−3.49 (m, 1H), 3.28
(d, J = 12.5 Hz, 1H), 3.17−3.05 (m, 1H), 1.14 (d, J = 6.4 Hz,
3H) ppm. 13C NMR (101 MHz, DCCl3) δ 154.20, 150.52,
108.16, 71.40, 66.88, 48.56, 40.76, 12.21 ppm.
Typical Procedure II: N,N-Diethylpyridin-4-amine
(3a). A round-bottomed flask reaction tube (1 L) was
equipped with a magnetic stir bar, and the reaction tube was
vacuumed and filled with N2 three times at −78 °C. Then the
aliphatic amine 2a (320 mmol, 23.4 g) was added under N2
atmosphere, followed by THF (200 mL) and n-BuLi (352
mmol, 140 mL, 2.5 M in hexane) by syringe at −78 °C. The
round-bottomed flask was stirred at room temperature for 10
min. Then 4-methoxypyridine 1a (200 mmol, 21.8 g) was
added quickly by syringe. The reaction mixture was stirred in a
60 °C oil bath for 10 min. The reaction mixture was then
allowed to cool to room temperature, quenched by water (100
mL), and then extracted with DCM (100 mL × 3). The
solvent layer was dried with dried Na2SO4. The crude mixture
was concentrated in vacuo and purified by flash column
chromatography eluting with EtOAc (1% Et3N) to give
1
C14H14N2: [M + H+]: 211.1230, found: 211.1228. H NMR
(400 MHz, DCCl3) δ 8.23 (d, J = 5.1 Hz, 2H), 7.38−7.26(m,
4H), 6.57 (d, J = 5.1 Hz, 2H), 5.08 (q, J = 7.0 Hz, 1H), 4.61 (s,
1H), 3.11−3.04 (m, 2H), 3.00−2.92 (m, 1H), 2.67−2.59 (m,
1H), 2.00−1.92 (m, 1H) ppm. 13C NMR (101 MHz, DCCl3)
δ152.94, 150.17, 143.62, 143.30, 128.39, 126.94, 125.13,
124.21, 107.97, 57.64, 33.59, 30.26 ppm.
N-((1r,3r,5r,7r)-Adamantan-2-yl)pyridin-2-amine (5f).
Following Typical Procedure I, the reaction of 1d (0.5 mmol,
54.5 mg), 4f (0.8 mmol, 120.8 mg), and n-BuLi (1.04 mmol,
0.42 mL, 2.5 M in hexane) in THF (0.5 mL) for 30 min at 60
°C afforded 5f (63.8 mg, 56%) as a yellow solid (eluent:
petroleum ether (1% Et3N)). Melting point: 93.4 °C. HRMS
(ESI) calculated for C15H20N2: [M + H+]: 229.1699, found:
229.1705. 1H NMR (400 MHz, DCCl3) δ 8.06 (d, J = 4.2 Hz,
1H), 7.41−7.37 (m, 1H), 6.53−6.50 (m, 1H), 6.35 (d, J = 8.4
Hz, 1H), 4.92 (s, 1H), 3.75 (d, J = 8 Hz, 1H), 2.03−1.83 (m,
10H), 1.76 (s, 2H), 1.62 (d, J = 12.0 Hz, 2H) ppm. 13C NMR
(101 MHz, DCCl3) δ 158.30, 148.50, 137.54, 112.50, 106.42,
55.64, 37.83, 37.49, 31.96, 31.79, 27.51, 27.44 ppm.
1
compound 3a as a yellow oil (29.3 g, 97.6% yield). H NMR
(400 MHz, DCCl3) δ 8.14 (d, J = 5.2 Hz, 2H), 6.43 (d, J = 5.2
Hz, 2H), 3.34 (q, J = 7.1 Hz, 4H), 1.16 (t, J = 7.1 Hz, 6H)
ppm. 13C NMR (101 MHz, DCCl3) δ 152.13, 149.89, 106.32,
43.84, 12.38 ppm.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.9b00235.
N-(Thiophen-3-ylmethyl)pyridin-4-amine (5g). Follow-
ing Typical Procedure I, the reaction of 1a (0.5 mmol, 54.5
1H and 13C NMR spectra (PDF)
E
DOI: 10.1021/acs.oprd.9b00235
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Article
Reactivity in Aryl Amination. Org. Lett. 2002, 4, 2229−2231.
(b) Marion, N.; Ecarnot, E. C.; Navarro, O.; Amoroso, D.; Bell, A.;
Nolan, S. P. (IPr)Pd(acac)Cl: An Easily Synthesized, Efficient, and
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wangxq@hnu.edu.cn.
ORCID
(7) Beller, M.; Riermeier, T. H.; Reisinger, C. P.; Herrmann, W. A.
First Palladium-Catalyzed Aminations of Aryl Chlorides. Tetrahedron
Lett. 1997, 38, 2073−2074. (b) Riermeier, T. H.; Zapf, A.; Beller, M.
Palladium-catalyzed C−C- and C−N-coupling reactions of aryl
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Xue-Qiang Wang: 0000-0003-1631-9158
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge Hunan University for the
startup funding. This paper is dedicated to Stephen L.
Buchwald on Honoring 25 Years of the Buchwald−Hartwig
Amination.
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excess amount of n-BuLi.
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