Metal-, Photocatalyst-, and Light-Free Minisci C-H Alkylation of N-Heteroarenes with Oxalates

Article abstract of DOI:10.1021/acs.joc.9b00972

Herein, we report a mild protocol for metal-, photocatalyst-, and light-free Minisci C-H alkylation reactions of N-heteroarenes with alkyl oxalates derived from primary, secondary, and tertiary alcohols. The protocol uses environmentally benign persulfate

Full text of DOI:10.1021/acs.joc.9b00972

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Note
Metal-, Photocatalyst-, and Light-Free Minisci C–
H Alkylation of N-Heteroarenes with Oxalates
Jianyang Dong, Zhen Wang, Xiaochen Wang, Hongjian Song, Yuxiu Liu, and Qingmin Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00972 • Publication Date (Web): 15 May 2019
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The Journal of Organic Chemistry
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Metal-, Photocatalyst-, and Light-Free Minisci C–H Alkylation
of N-Heteroarenes with Oxalates
Jianyang Dong,† Zhen Wang,† Xiaochen Wang,† Hongjian Song,† Yuxiu Liu† and Qingmin Wang*†‡
†State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, College of
Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, People’s Republic of
China
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Supporting Information Placeholder
R
R
OH
ABSTRACT: Herein, we report a mild protocol for
metal-, photocatalyst-, and light-free Minisci C–H
alkylation reactions of N-heteroarenes with alkyl oxalates
derived from primary, secondary, and tertiary alcohols.
The protocol uses environmentally benign persulfate as a
stoichiometric oxidant and does not require high
temperatures or large excesses of either of the substrates,
making the procedure suitable for late-stage C–H
alkylation of complex molecules. Notably, several
pharmaceuticals and natural products could be
functionalized or prepared with this protocol, thus
demonstrating its utility.
1o, 2o, 3o
N
O
N
N
2-
S2O8
N
HO
N
O
O
O
N
Het
N
Het
N
R
R
+
O
O
N
H
N
53 examples
up to 92% yield
O
R
OH
caffeine
milrinone
N
R
commercially available radical precursors.
no metal, photocatalyst or light
broad scope
quinine
F
mild reaction conditions
O
Cl
O
O
N
S O
O
O
Cl
O
HN
N
O
N
O
R
N
O
N
O
N
R
N
Cl
N
R
R
etofibrate
fasudil
quinoxyfen
pentoxifylline
Heteroaryl motifs are present in a wide variety of natural
products, functional materials, small-molecule drugs, and ligands
for metal catalysts.1 Therefore, rapid, mild, and selective methods
for direct C–H functionalization of these motifs are highly sought-
after for late-stage modification of pharmaceuticals and other
molecules.2 One useful tool for this purpose is the Minisci
reaction, in which a protonated N-heteroarene is attacked by an
alkyl radical under oxidative conditions.3 Minisci C–H alkylation
reactions of N-heteroarenes with alkyl peroxides, sulfonates,
aliphatic carboxylic acids, activated esters, boronic acids,
alkyltrifluoroborates, alkyl halides, and 1,4-dihydropyridines as
the alkyl radical sources have been reported (Scheme 1A).4
However, most of the previously reported protocols require high
temperatures, (sub)stoichiometric amounts of expensive metal
salts, excesses of the radical precursors, expensive photocatalysts,
or high-energy UV light for good yields, or they are limited in
scope with respect to the alkyl source; therefore, their utility for
late-stage functionalization of complex molecules is limited.
Moreover, few structurally complex radical precursors (e.g.,
trifluoroborates and boronic acids) are commercially available or
cost-effective.
heterocycles and the oxalic acid monoesters, which narrows the
functional group tolerance and thus limits the substrate scope.
Furthermore, the yields are low, especially for primary alcohols
(<20%). MacMillan’s group reported a method for photoredox-
catalyzed C–H alkylation of heteroarenes with excess alcohol as
the radical source,8 but this method is limited to primary alcohols.
Therefore, the development of a practical, mild protocol for C–H
alkylation of heteroarenes with primary, secondary, and tertiary
alcohols with broad functional group tolerance would be a
significant advance.
Scheme 1. Methods for Minisci C–H Alkylation of N-
Heteroarenes.
A) C-H alkylation of heteroarenes
tBu
R
SO2M
BF3K
R
R
R
R
COOH
Br/I
COX
DHP
AcOO
R
R
B(OH)2
Het
N
R
Het
N
metal or photocatalyst
cost-prohibitive radical precursors
limited alkyl scope
high-energy UV light
B) Challenge: C-O bond activation
OH
96 kcal/mol
high energetic barrier
to cleavage
Alcohols are among the most widely occurring, naturally
abundant organic compounds, and they are often used as
feedstock chemicals.5 Because alcohols, from the simple to the
complex, are inexpensive, abundant, stable, nontoxic, and readily
available, the prospect of using them as alkyl radical sources is
appealing. However, few Minisci C–H alkylation reactions using
alcohols as the alkyl radical sources have been reported, because
such reactions require cleavage of the relatively strong C–O bonds
of the alcohols (∼96 kcal/mol) (Scheme 1B).6 Yokoyama’s group
achieved the first alkylation of heterocycles with alcohols by
generating half esters of oxalic acid with strongly oxidizing
hypervalent iodine(III) reagents.7 However, this reaction is
performed under refluxing benzene with a large excesses of the N-
C) This work
R
OH
1o, 2o, 3o
(NH4)2S2O8 (2.0 equiv)
5:1 DMSO/H2O (0.05 M)
50 o
O
O
O
Het
+
N
Het
N
R
R
OH
C
53 examples
up to 92% yield
add oxalyl chloride,
without purification
broad scope
commercially available radical precursors.
no metal, photocatalyst or light
mild reaction conditions
We speculated that alkyl oxalates could be used for this
purpose. Reaction of alcohols with oxalyl chloride results in the
generation of activated alcohols that can be used for radical
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Page 2 of 10
generation.9 Recently, Macmillan’s group reported that the
obtained in 84% yield in DMSO (entry 4). In fact, DMSO was the
1
2
3
4
5
6
7
8
relatively strong C–O bonds of alkyl oxalates can generally be
cleaved to form sp3 carbon radical fragments for the construction
of C–C bonds.10 Very recently, Overman's group describes the use
of tert-alkyl oxalate salts, derived from tertiary alcohols, to
introduce tertiary substituents into a variety of heterocyclic
substrates.11 Our group is interested in Minisci reactions, and we
recently reported C–H alkylation reactions of heteroarenes with
alkyl halides.12 On the basis of recent successful examples of C–H
alkylation reactions of N-heteroarenes with alkylcarboxylic
acids,13 we envisioned that a simple, mild protocol for metal-,
photocatalyst-, and light-free C–H alkylation of heteroarenes
could be achieved by using alkyl oxalates as alcohol-activating
groups. In addition, we wanted to use an environmentally benign
oxidant and avoid the need for high temperatures and large
excesses of the N-heteroarenes and alkyl oxalates. Herein, we
report a protocol for Minisci C–H alkylation of N-heteroarenes
with alkyl oxalates derived from primary, secondary, and tertiary
alcohols (Scheme 1C). The high efficiency, broad substrate scope,
excellent functional group tolerance, and mildness of this protocol
make it particularly suitable for late-stage functionalization of
complex nitrogen-containing natural products and drugs.
only solvent in which the reaction proceeded; none of the typical
Minisci solvents worked. The use of a different persulfate
(sodium persulfate or potassium persulfate) had a deleterious
effect on the yield (entries 5 and 6). Although strongly oxidizing
hypervalent iodine(III) reagents are often used in classical Minisci
reactions,4d,7,14 we obtained poor yields of 3 with these reagents,
and the reactions gave mainly the quinoline-4-carbaldehyde by-
product (entries 7 and 8). We tried adding various amounts of
H2O as a co-solvent to increase the solubility of (NH4)2S2O8 in the
solvent, and these experiments revealed that 5:1 (v/v) DMSO/H2O
was optimal (entries 9–11). Finally, performing the reaction at
room temperature rather than at 50 °C decreased the yield to 39%
(entry 12). It should be noted that the absence of exogenous
strong acid (e.g., H2SO4, TFA, or HCl which is often employed in
traditional Minisci conditions) enabled the reaction to proceed
under such mild conditions.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Scope of the Reaction with Respect to the N-
Heteroarene.[a]
R1
CO2Me
N
Boc
N
CO2Me
, R2 = Me, 87%
N
6
N
7, R2 = Ph, 62%
8, R2 = Cl, 46%
Table 1. Optimization of Reaction Conditions[a]
NBoc
3, R1 = Me, 90% (1.1 g, 85 %)
4, R1 = Cl, 39%
5, R1 = Br, 41%
N
R2
N
O
N
Boc
Boc
OH
O
10, 43%
9, 42%
Boc
Boc
N
oxidant (2.0 equiv)
N
NBoc
O
N
N
Cl
+
Ph
N
solvent (0.05 M)
50 oC, 24 h
N
N
N
N
Boc
NBoc
Boc
O
N
N
1
1.0 equiv
2
2.0 equiv
3
O
O
O
N
14, 51%
13, 46%
Boc
12, 41%
11, 36%
yield (%)[b]
Boc
N
Boc
N
entry
oxidant
solvent
R3
S
NBoc
1
2
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
Na2S2O8
toluene
<5%
NR
NR
84
N
N
N
N
N
N
NBoc
18, R3 = H, 49%
19, R3 = Br, 41%
NBoc
16, 68%
CH3CN
DCE
17, 41%
15, 40%
N
Boc
3
O
Cl
N
Cl
Cl
BocN
O
O
NH
N
N
N
N
4
DMSO
N
N
N
Cl
NBoc
Br
NBoc
NBoc
Br
20, 82%
21, 66%
22, 43%
23, 53%
5
DMSO
52
BocN
NBoc
O
NBoc
6
K2S2O8
DMSO
28
N
N
N
N
O
7
PhI(CH3CO2)2
PhI(CF3CO2)2
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8F6
DMSO
<5
BocN
NBoc
24, 32%
25, 63%
26, 70%
[a]Reactions were performed on a 0.3 mmol scale. Isolated yields
are given. See Supplementary Information for
experimental details.
8
DMSO
<5
9
100:1 DMSO/H2O
10:1 DMSO/H2O
5:1 DMSO/H2O
5:1 DMSO/H2O
88
10
11
12[d]
91
With the optimized conditions in hand, we investigated the
scope of the reaction with respect to the N-heteroarene (Scheme
2). Various electron-deficient heteroarenes were readily alkylated
at the most electrophilic position with N-Boc-4-hydroxypiperidine
monooxalate (2), giving the desired products in fair to excellent
yields. Quinoline substrates with electron-withdrawing or
electron-donating substituents underwent selective alkylation at
C2 and C4, respectively (giving 3–8 in 39–90% yields). Reactions
of 2 with 3-methoxycarbonyl- and 4-methoxycarbonyl-substituted
isoquinolines afforded products of selective alkylation at C1 (9
and 10, respectively, in 42% and 43% yields). Notably, pyridine
derivatives also participated in this reaction, giving moderate
yields of products 11–13. The protocol could also be used for N-
heterocycles containing two nitrogen atoms: 2-chloroquinoxaline
(14, 51%), quinazoline (15, 40%), and phthalazine (16, 68%).
Phenanthridine (17, 41%), benzothiazoles (18, 49%; 19, 41%), 4-
93 (90)[c]
39
[a]General conditions, unless otherwise noted: 1 (0.3 mmol), 2 (0.6 mmol),
oxidant (0.6 mmol), and DMSO (6 mL) under air atmosphere. [b]Determined by
1H NMR spectroscopy using dibromomethane as an internal standard. NR = no
reaction. [c]Isolated yields are given. [d]Reaction performed at room
temperature.
We began by investigating the alkylation reaction between
lepidine (1) and N-Boc-4-hydroxypiperidine monooxalate (2;
formed in situ from N-Boc-4-hydroxypiperidine, oxalyl chloride,
and water) in the presence of (NH4)2S2O8 in toluene at 50 °C for
24 h (Table 1). Unfortunately, the yield of desired product 3 under
these conditions was poor (entry 1). However, when we tested
various other solvents (entries 2–4), we found that 3 could be
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The Journal of Organic Chemistry
yields. Because alcohols are readily available and inexpensive,
hydroxyquinazoline (20, 82%), pyrimidine (21, 66%), 3,6-
1
2
3
4
5
6
7
8
this new Minisci protocol may prove highly useful in drug
dichloropyridazine (22, 43%), chloroimidazo[1,2-b]pyridazine (23,
53%), and 1,4-naphthoquinone (24, 32%) were also acceptable
substrates. Notably, the reaction could be used to modify
commercially available phenanthroline ligands, as demonstrated
by the bialkylation with 2 to afford fair to good yields of 25–26.
The selective bialkylation of these phenanthroline ligands
suggests that this protocol may find applications in the synthesis
of ligands for catalysis. The reaction between 1 and 2 could be
carried out on a gram scale with no decrease in the yield of 3.
Next, we explored the scope of the alkylation reaction with
respect to the alcohol by using lepidine (1) as the heteroarene
(Scheme 3). To our delight, both cyclic and acyclic primary,
secondary, and tertiary alcohols were found to be amenable to the
standard reaction conditions, affording fair to excellent yields of
functionalized lepidine derivatives. For example, linear primary
alcohols afforded corresponding alkylated heteroarenes 27–29 in
34–48% yields. Alkylation reactions of secondary and tertiary
alcohols also proceeded under the standard conditions to afford
corresponding alkylated heteroarenes 30–42 in moderate to
excellent yields. Notably, fluorine heteroatoms were tolerated,
which is typically not the case for Minisci reactions.15 The
relatively low yields of compounds 41 and 42 compared to 40
may be due to the addition of alkyl radicals to carbonyl group and
relatively large steric hindrance, respectively.
discovery research.17
Scheme 4. Use of the Minisci C–H Alkylation Protocol for
Functionalization of Natural Products and Drug Molecules.[a]
F
Cl
O
N
N
Cl
O
N
O
O
O
O
N
O
N
9
H
Cl
from etofibrate
from milrinone
43
44
, 72%
from quinoxyfen
, 52%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
45
, 65%
O
N
S O
HN
O
O
N
N
HO
N
N
N
NBoc
O
O
N
N
N
from pentoxifylline
48
from fasudil
47
Boc
from quinine
46
, 36%
, 57%
, 60%
O
N
N
N
H
NBoc
N
H
N
O
N
H
from caffeine
49
from menthol
50
from steride
51
, 30%
, 94%
, 65%
[a]Reactions were performed on a 0.3 mmol scale. Isolated yields
are given. See Supplementary Information for
experimental details.
Scheme 3. Scope of the Reaction with Respect to the Alcohol.[a]
Having explored the substrate scope and utility of the reaction,
we turned our attention to the mechanism. When a radical
scavenger, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or
butylated hydroxytoluene (BHT), was present in a reaction
mixture containing 1 and 2, the formation of 3 was completely
inhibited; and instead the corresponding product of radical
Ph
Ph
N
N
N
N
27
28
29
30
, 83%
, 48%
, 42%
, 34%
trapping,
tert-butyl
4-(3,5-di-tert-butyl-4-
N
N
N
N
F
hydroxybenzyl)piperidine-1-carboxylate (52), was isolated in
18% yield (Scheme 5a). To gain additional information about the
mechanism, we carried out radical clock experiments (Scheme
5b).12 Alkylation of 1 with 2-(hex-5-en-1-yloxy)-2-oxoacetic acid
(53) resulted in 5-exo-trig cyclization prior to heteroarene
addition and afforded a 22:1 mixture of 54a and
54b. Alkylation of 1 with 2-(cyclopropylmethoxy)-2-oxoacetic
acid (55) under the standard conditions gave ring-opened product
56 in 14% yield. In the reaction of 1 with 2-(cyclobutylmethoxy)-
2-oxoacetic acid 57, the cyclobutane ring remained partly
unopened, and 58a and 58b were obtained in a 3:2 ratio. When we
use acridine (59) as N-heteroarene and 2-ethoxy-2-oxoacetic acid
(60) as as radical sources, a 9:1 mixture of acyl radical
addition product (61a) and alkyl radical addition product (61b)
was afforded in 25% yield. These experiments clearly point to a
radical pathway.
F
31
32
33
34
, 65%
, 87%
, 81%
, 75%
Ph
N
N
N
N
35
36
37
38
, 85%
, 65%
, 61%
, 60%
N
N
N
N
O
39
40
41
42
, 35%
, 90%
, 81%
, 39%
[a]Reactions were performed on a 0.3 mmol scale. Isolated yields
are given. See Supplementary Information for experimental
details.
As shown in Scheme 4, our Minisci C–H alkylation protocol
could be readily used to functionalize complex natural products
and drug molecules.4,16 For instance, milrinone,
a
Scheme 5. Mechanistic Experiments.
phosphodiesterase 3 inhibitor and vasodilator, could be alkylated
to afford a moderate yield of 43. Etofibrate, which contains
clofibrate and niacin moieties, was selectively alkylated on the
pyridine ring to give 44 in 72% yield. The fungicide
quinoxyfen was alkylated at C2 of the
quinoline ring to give 45 in good yield.
Quinine, an alkaloid with a free OH group as well as amine and
vinyl groups, could be selectively alkylated at the C2 position
(46). Fasudil, a potent vasodilator, was selectively alkylated at C1
to give a fair yield of 47. Notably, the analgesic pentoxifylline
was transformed into alkylated analogue 48 in 36% yield.
Caffeine, a challenging substrate for previously reported Minisci
protocols, could be selectively alkylated at C2 to afford 49.
Naturally occurring alcohols L-menthol and steride were
successfully alkylated to afford 50 and 51, respectively, in good
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OH
O
Nuclear Magnetic Resonance (NMR) spectra were recorded on
Bruker Avance 400 Ultrashield NMR spectrometers. Chemical
a
radical inhabitor
TEMPO
yield
NR
OH
O
N
1
2
3
4
5
6
7
8
(NH4)2S2O8 (2.0 equiv)
O
+
+
N
5:1 DMSO/H2O (0.05 M)
50 oC, 24 h
BHT
Boc
NR
shifts (δ) were given in parts per million (ppm) and were
measured downfield from internal tetramethylsilane. High-
resolution mass spectrometry (HRMS) data were obtained on an
FTICR-MS instrument (Ionspec 7.0 T). The melting points were
determined on an X-4 microscope melting point apparatus and are
uncorrected. Conversion was monitored by thin layer
chromatography (TLC). Flash column chromatography was
performed over silica gel (100-200 mesh).
N
N
N
3
N
1
1
Boc
2
Boc
52, 18%
b
O
OH
(NH4)2S2O8 (2.0 equiv)
O
+
O
N
53
5:1 DMSO/H2O (0.05 M)
50 oC, 24 h
N
54b
22:1
15%
54a
O
(NH4)2S2O8 (2.0 equiv)
+
O
N
N
55
O
OH
5:1 DMSO/H2O (0.05 M)
50 oC, 24 h
1
56, 14%
O
(NH4)2S2O8 (2.0 equiv)
+
O
+
N
57
OH
OH
N
58a
5:1 DMSO/H2O (0.05 M)
50 oC, 24 h
N
58b
9
1
3:2
12%
O
Preparation of Oxalates from Alcohols. The
oxalate was synthesized according to literature report.7,10,11 The
spectral data of the oxalate is consistent with the literature data. A
round-bottom flaskwas charged with alcohol (10 g, 49.7 mmol 1.0
equiv) followed by the addition of Et2O (250 mL) and
dichloromethane (80 mL). The solution was cooled to 0 oC. Next,
oxalyl chloride (8.41 mL, 99.0 mmol, 2.0 equiv) was added
dropwise. The homogeneous reaction mixture was allowed to
warm to ambient temperature and stir for 18 h. The reaction was
c
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
(NH4)2S2O8 (2.0 equiv)
+
+
O
5:1 DMSO/H2O (0.05 M)
50 oC, 24 h
N
N
O
N
61a
60
59
9:1
25%
61b
On the basis of these observations and literature reports,11 we
propose the mechanism depicted in Scheme 6. The standard
Minisci reaction is thought to commence with decomposition of
persulfate S2O8 to sulfate radical anion (SO4−•), traditionally
2−
under metal mediation or photolysis.3,13a However, we believe that
in our case, the decomposition under mild conditions without
catalysis is achievable because the rate of decomposition is
o
cooled to 0 C and quenched by slow addition of H2O (100 mL).
After stirring for 1 h at ambient temperature, the resulting mixture
was transferred to a separatory funnel, and the aqueous layer
mixture was extracted with three portions of Et2O. The combined
organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure affording the
title compound. All the oxalates were used without further
purification.
2−
solvent-dependent, and S2O8 has in fact been reported to
decompose much more readily in DMSO than in other solvents.18
The sulfate radical anion can then oxidize N-Boc-4-
hydroxypiperidine monooxalate anion (A) to form alkyl radical B
and extrude two equiv of CO2. Radical B then adds to the
protonated electron-deficient heteroarene via a Minisci-type
pathway to afford radical cation C. Product 3 can form either via
H radical abstraction by sulfate radical anion or via a single
electron transfer (SET) reaction with persulfate.
Experimental
Procedures
and
Product
Characterization
General Procedure for the alkylation of N-heteroarenes. To
a 15 mL glass vial was added heteroarene (0.3 mmol, 1.0 equiv),
oxalate (0.6 mmol, 2.0 equiv), (NH4)2S2O8 (137 mg, 0.6 mmol,
2.0 equiv), 5.0 mL of DMSO and 1.0 mL of H2O. The reaction
mixture was sealed with PTFE cap and then stirred rapidly at 50
oC for 24 h (heating mantle). The mixture was diluted with 20 mL
of aqueous 1 M NaHCO3 solution, and extracted with DCM (3 ×
20 mL). The combined organic extracts were washed with brine
(40 mL), dried over Na2SO4, and concentrated in vacuo.
Purification of the crude product by flash chromatography on
silica gel using the indicated solvent system afforded the desired
product.
Scheme 6. Proposed Mechanism for Direct C–H Alkylation of N-
Heteroarenes.
2-
S2O8
50oC
O
O
O
O
O
OH
O
N
O
N
N
O
N
1
SO4
O
O
O
2
SO4
+
A
2
Boc
Boc
Boc
2CO2
+
SO4
2-
HSO4
SET
S2O8
N
Product Characterization
H
N
H
N
H
H
tert-butyl
4-(4-methylquinolin-2-yl)piperidine-1-carboxylate
N
Boc
B
NBoc
NBoc
product
C
(3). According to the general procedure. The spectral Data is
consistent with the literature data.12 White solid (88.0 mg, 90%).
M.p. = 59 – 60 °C. Rf 0.50 (Petroleum ether/EtOAc, 5/1). 1H
NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.4 Hz, 1H), 7.92 (d, J =
8.0 Hz, 1H), 7.70 – 7.62 (m, 1H), 7.56 – 7.43 (m, 1H), 7.13 (s,
1H), 4.30 (s, 2H), 3.00 (tt, J = 12.0, 3.6 Hz, 1H), 2.94 – 2.79 (m,
2H), 2.66 (s, 3H), 2.00 – 1.91 (m, 2H), 1.84 (ddd, J = 25.2, 12.4,
4.4 Hz, 2H), 1.49 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ
164.2, 154.8, 147.6, 144.6, 129.5, 129.1, 127.1, 125.7, 123.6,
120.0, 79.3, 45.4, 44.1, 31.6, 28.5, 18.8. HRMS (ESI) calcd for
C20H27N2O2 [M + H]+ 327.2067, found 327.2069.
tert-butyl 4-(4-chloroquinolin-2-yl)piperidine-1-carboxylate (4).
According to the general procedure. Colorless oil (40.5 mg, 39%).
Rf 0.40 (Petroleum ether/EtOAc, 10/1). 1H NMR (400 MHz,
CDCl3) δ 8.18 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.74
(t, J = 7.6 Hz, 1H), 7.66 – 7.55 (m, 1H), 7.41 (s, 1H), 4.31 (s, 2H),
3.15 – 2.78 (m, 3H), 1.99 (d, J = 12.4 Hz, 2H), 1.91 – 1.76 (m,
2H), 1.50 (s, 9H). 13C NMR{1H} (100 MHz, CDCl3) δ 164.7,
154.9, 148.8, 143.0, 130.5, 129.5, 127.0, 125.3, 124.0, 119.7, 79.6,
45.4, 43.9, 31.6, 28.6. HRMS (ESI) calcd for C19H24ClN2O2 [M +
H]+ 347.1521, found 347.1520.
HAT
abstraction by SO4
H
In conclusion, we have developed a mild protocol for Minisci
C–H alkylation of N-heteroarenes with readily available,
inexpensive alcohols as the alkyl radical sources without the need
for a metal, a photocatalyst, or light. A broad range of cyclic and
acyclic primary, secondary, and tertiary alkyl groups can be
efficiently incorporated into various N-heteroarenes, and the
protocol is scalable to the gram level. The high efficiency and
broad substrate scope of the reaction, and the fact that neither high
temperatures nor large excesses of the alkyl oxalates are required,
make the procedure suitable for late-stage C–H alkylation of
complex molecules, as demonstrated by the functionalization of
various nitrogen-containing natural products and drugs.
EXPERIMENTAL SECTION
General Method and Materials. Reagents were purchased
from commercial sources and were used as received. 1H and 13C
ACS Paragon Plus Environment

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The Journal of Organic Chemistry
tert-butyl 4-(4-bromoquinolin-2-yl)piperidine-1-carboxylate (5).
tert-butyl 4-(2,6-diacetylpyridin-4-yl)piperidine-1-carboxylate
(11). According to the general procedure. Colorless oil (37.4 mg,
36%). Rf 0.25 (Petroleum ether/EtOAc, 10/1). 1H NMR (400
MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H),
4.27 (s, 2H), 3.73 – 3.65 (m, 1H), 2.86 (s, 2H), 2.79 (s, 3H), 2.75
(s, 3H), 1.83 (d, J = 12.8 Hz, 2H), 1.67 – 1.56 (m, 2H), 1.49 (s,
9H). 13C{1H} NMR (100 MHz, CDCl3) δ 202.1, 199.2, 154.8,
151.1, 150.3, 145.4, 136.6, 124.0, 79.7, 44.3, 41.3, 37.1, 32.7,
28.8, 28.6, 28.5, 25.6. HRMS (ESI) calcd for C19H26N2NaO4 [M
+ Na]+ 369.1785, found 369.1781.
1
2
3
4
5
6
7
According to the general procedure. Colorless oil (48.0 mg, 41%).
Rf 0.20 (Petroleum ether/EtOAc, 10/1). 1H NMR (400 MHz,
CDCl3) δ 8.14 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.74
(t, J = 7.2 Hz, 1H), 7.64 – 7.52 (m, 2H), 4.29 (s, 2H), 3.02 (tt, J =
12.0, 3.6 Hz, 1H), 2.89 (s, 2H), 2.06 – 1.93 (m, 2H), 1.90 – 1.76
(m, 2H), 1.49 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.7,
154.9, 148.6, 134.6, 130.5, 129.6, 127.3, 126.7, 123.6, 79.6, 45.3,
44.0, 31.6, 28.6. HRMS (ESI) calcd for C19H24BrN2O2 [M + H]+
391.1016, found 391.1012.
8
9
tert-butyl 4-(2-methylquinolin-4-yl)piperidine-1-carboxylate (6).
According to the general procedure. White solid (85.1 mg, 87%).
M.p. = 108 – 109 °C. Rf 0.30 (Petroleum ether/EtOAc, 5/1). H
methyl
4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-
methylpicolinate (12). According to the general procedure. White
solid (41.1 mg, 41%). M.p. = 95 – 96 °C. Rf 0.25 (Petroleum
ether/EtOAc, 10/1). H NMR (400 MHz, CDCl3) δ 8.01 (d, J =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1
NMR (400 MHz, CDCl3) δ 8.03 (dd, J = 11.6, 8.4 Hz, 2H), 7.66
(t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.14 (s, 1H), 4.34 (s,
2H), 3.44 (ddd, J = 12.0, 9.2, 3.2 Hz, 1H), 2.95 (s, 2H), 2.72 (s,
3H), 1.95 (d, J = 12.8 Hz, 2H), 1.85 – 1.68 (m, 2H), 1.50 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3) δ 158.9, 154.8, 151.0, 148.3,
129.8, 129.0, 125.6, 124.9, 122.4, 118.5, 79.7, 44.3, 37.2, 32.4,
28.5, 25.6. HRMS (ESI) calcd for C20H27N2O2 [M + H]+
327.2067, found 327.2069.
8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 4.24 (s, 2H), 3.90 (s, 3H),
3.76 – 3.64 (m, 1H), 2.85 (s, 2H), 2.55 (s, 3H), 1.93 (dt, J = 21.2,
10.4 Hz, 2H), 1.75 (d, J = 12.4 Hz, 2H), 1.48 (s, 9H). 13C{1H}
NMR (100 MHz, CDCl3) δ 167.4, 164.8, 161.6, 154.9, 138.6,
121.9, 120.4, 79.2, 52.2, 44.3, 40.8, 31.4, 28.6, 24.9. HRMS
(ESI) calcd for C18H27N2O4 [M + H]+ 335.1965, found 335.1963.
di-tert-butyl 4,4'-(4-phenylpyridine-2,6-diyl)bis(piperidine-1-
carboxylate) (13). According to the general procedure.
Heteroarene (0.3 mmol, 1.0 equiv), oxalate (0.9 mmol, 3.0 equiv),
(NH4)2S2O8 (205 mg, 0.9 mmol, 3.0 equiv), 5.0 mL of DMSO and
1.0 mL of H2O. White solid (71.9 mg, 46%). M.p. = 115 – 116 °C.
Rf 0.40 (Petroleum ether/EtOAc, 3/1). 1H NMR (400 MHz,
CDCl3) δ 7.63 – 7.57 (m, 2H), 7.52 – 7.38 (m, 3H), 7.19 (s, 2H),
4.26 (s, 4H), 3.01 – 2.76 (m, 6H), 1.96 (d, J = 12.4 Hz, 4H), 1.84
– 1.70 (m, 4H), 1.49 (s, 18H). 13C{1H} NMR (100 MHz, CDCl3) δ
164.5, 155.0, 149.6, 139.1, 129.1, 128.9, 127.2, 116.8, 79.5, 44.7,
44.2, 31.9, 28.6. HRMS (ESI) calcd for C31H44N3O4 [M + H]+
522.3326, found 522.3331.
tert-butyl 4-(3-chloroquinoxalin-2-yl)piperidine-1-carboxylate
(14). According to the general procedure. Yellow solid (53.1 mg,
51%). M.p. = 126 – 127 °C. Rf 0.60 (Petroleum ether/EtOAc, 5/1).
1H NMR (400 MHz, CDCl3) δ 8.07 – 8.02 (m, 1H), 8.01 – 7.95
(m, 1H), 7.79 – 7.70 (m, 2H), 4.33 (s, 2H), 3.50 (ddd, J = 15.2,
11.2, 4.0 Hz, 1H), 2.94 (s, 2H), 2.04 – 1.86 (m, 4H), 1.50 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3) δ 157.2, 154.8, 147.1, 141.1,
140.8, 130.3, 130.2, 128.9, 128.2, 79.6, 43.7, 40.8, 30.2, 28.6.
HRMS (ESI) calcd for C18H23ClN3O2 [M + H]+ 348.1473, found
348.1472.
tert-butyl 4-(2-phenylquinolin-4-yl)piperidine-1-carboxylate (7).
According to the general procedure. White solid (72.2 mg, 62%).
1
M.p. = 124 – 125 °C Rf 0.35 (Petroleum ether/EtOAc, 10/1). H
NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.4 Hz, 1H), 8.13 (d, J =
7.2 Hz, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.75 – 7.67 (m, 2H), 7.58 –
7.49 (m, 3H), 7.45 (t, J = 7.2 Hz, 1H), 4.37 (s, 2H), 3.50 (ddd, J =
12.0, 9.2, 3.2 Hz, 1H), 2.97 (s, 2H), 2.01 (d, J = 12.8 Hz, 2H),
1.92 – 1.74 (m, 2H), 1.51 (s, 9H). 13C{1H} NMR (100 MHz,
CDCl3) δ 157.4, 154.8, 151.6, 148.7, 140.0, 130.9, 129.3, 129.3,
128.9, 127.6, 126.2, 125.6, 122.5, 115.6, 79.8, 44.4, 37.5, 32.5,
28.6. HRMS (ESI) calcd for C25H29N2O2 [M + H]+ 389.2224,
found 389.2221.
tert-butyl 4-(2-chloroquinolin-4-yl)piperidine-1-carboxylate (8).
According to the general procedure. White solid (47.7 mg, 46%).
1
M.p. = 92 – 93 °C. Rf 0.20 (Petroleum ether/EtOAc, 10/1). H
NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.0 Hz, 2H), 7.73 (t, J =
7.6 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.24 (s, 1H), 4.35 (s, 2H),
3.45 (t, J = 11.6 Hz, 1H), 2.95 (s, 2H), 1.97 (d, J = 12.4 Hz, 2H),
1.73 (ddd, J = 15.6, 12.4, 3.2 Hz, 2H), 1.50 (s, 9H). 13C{1H}
NMR (100 MHz, CDCl3) δ 154.8, 154.6, 151.1, 148.3, 130.3,
129.8, 126.9, 125.4, 122.8, 118.9, 79.9, 44.4, 37.5, 32.2, 28.6.
HRMS (ESI) calcd for C19H24ClN2O2 [M + H]+ 347.1521, found
347.1520.
di-tert-butyl
4,4'-(quinazoline-2,4-diyl)bis(piperidine-1-
carboxylate) (15). According to the general procedure.
Heteroarene (0.3 mmol, 1.0 equiv), oxalate (0.9 mmol, 3.0 equiv),
(NH4)2S2O8 (205 mg, 0.9 mmol, 3.0 equiv), 5.0 mL of DMSO and
1.0 mL of H2O. White solid (59.5 mg, 40%). M.p. = 76 – 77 °C.
Rf 0.20 (Petroleum ether/EtOAc, 3/1). 1H NMR (400 MHz,
CDCl3) δ 8.18 (d, J = 8.4 Hz, 2H), 7.95 (t, J = 7.6 Hz, 1H), 7.67 (t,
J = 7.6 Hz, 1H), 4.31 (s, 4H), 3.71 (t, J = 10.8 Hz, 1H), 3.32 (t, J
= 10.4 Hz, 1H), 3.08 – 2.86 (m, 4H), 2.12 – 1.82 (m, 8H), 1.50 (d,
J = 5.6 Hz, 18H). 13C{1H} NMR (100 MHz, CDCl3) δ 172.9,
168.4, 155.1, 154.9, 150.7, 133.4, 129.2, 126.8, 123.7, 121.5, 79.7,
79.4, 45.8, 44.3, 39.4, 30.9, 28.6. HRMS (ESI) calcd for
C28H41N4O4 [M + H]+ 497.3122, found 497.3116.
methyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)isoquinoline-3-
carboxylate (9). According to the general procedure. The spectral
Data is consistent with the literature data.4d White solid (46.6 mg,
42%). M.p. = 127 – 128 °C. Rf 0.60 (Petroleum ether/EtOAc, 3/1).
1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 8.29 – 8.21 (m, 1H),
8.00 – 7.94 (m, 1H), 7.74 (p, J = 6.8 Hz, 2H), 4.33 (s, 2H), 4.03 (s,
3H), 3.79 – 3.63 (m, 1H), 3.00 (t, J = 11.6 Hz, 2H), 2.16 (s, 2H),
1.96 (d, J = 12.8 Hz, 2H), 1.50 (s, 9H). 13C{1H} NMR (100 MHz,
CDCl3) δ 166.8, 164.0, 154.8, 140.8, 136.2, 130.4, 129.4, 129.3,
127.7, 124.6, 122.9, 79.5, 52.8, 44.1, 40.2, 31.2, 28.6.
HRMS (ESI) calcd for C21H27N2O4 [M + H]+ 371.1965, found
371.1960
di-tert-butyl
4,4'-(phthalazine-1,4-diyl)bis(piperidine-1-
methyl 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)isoquinoline-4-
carboxylate (10). According to the general procedure. White
solid (47.7 mg, 43%). M.p. = 110 – 111 °C. Rf 0.60 (Petroleum
carboxylate) (16). According to the general procedure.
Heteroarene (0.3 mmol, 1.0 equiv), oxalate (0.9 mmol, 3.0 equiv),
(NH4)2S2O8 (205 mg, 0.9 mmol, 3.0 equiv), 5.0 mL of DMSO and
1.0 mL of H2O. Yellow sollid (101.2 mg, 68%). M.p. = 55 –
56 °C. Rf 0.20 (Petroleum ether/EtOAc, 3/1). 1H NMR (400 MHz,
CDCl3) δ 8.20 (dd, J = 6.4, 3.2 Hz, 2H), 7.92 (dd, J = 6.4, 3.2 Hz,
2H), 4.33 (s, 4H), 3.92 – 3.82 (m, 1H), 3.73 (dd, J = 12.8, 6.4 Hz,
1H), 3.06 – 2.93 (m, 4H), 2.27 – 1.96 (m, 8H), 1.50 (d, J = 3.2 Hz,
18H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.5, 154.8, 131.7,
124.8, 124.0, 79.5, 43.9, 38.7, 30.9, 28.5. HRMS (ESI) calcd for
C28H41N4O4 [M + H]+ 497.3122, found 497.3119.
1
ether/EtOAc, 3/1). H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H),
8.99 (d, J = 8.4 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.80 (t, J = 7.6
Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 4.33 (s, 2H), 4.01 (s, 3H), 3.75
(dd, J = 15.6, 8.4 Hz, 1H), 2.98 (s, 2H), 2.04 (s, 2H), 1.92 (d, J =
10.0 Hz, 2H), 1.50 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ
168.4, 167.1, 154.7, 145.8, 134.3, 131.3, 127.4, 125.9, 125.8,
124.5, 119.0, 79.4, 52.2, 44.3, 40.2, 31.3, 28.5. HRMS (ESI)
calcd for C21H27N2O4 [M + H]+ 371.1965, found 371.1964.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 10
tert-butyl 4-(phenanthridin-6-yl)piperidine-1-carboxylate (17).
138.4, 133.8, 115.2, 101.6, 79.9, 43.7, 36.8, 30.9, 28.6. HRMS
1
According to the general procedure. White solid (44.5 mg, 41%).
(ESI) calcd for C16H21BrClN4O2 [M + H]+ 415.0531, found
415.0534.
1
M.p. = 136 – 137 °C. Rf 0.30 (Petroleum ether/EtOAc, 10/1). H
2
3
4
5
6
7
8
9
NMR (400 MHz, CDCl3) δ 8.66 (d, J = 8.4 Hz, 1H), 8.53 (d, J =
7.6 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H),
7.82 (t, J = 7.2 Hz, 1H), 7.70 (ddd, J = 11.6, 5.2, 2.4 Hz, 2H),
7.64 – 7.57 (m, 1H), 4.35 (s, 2H), 3.75 (ddd, J = 14.8, 11.2, 3.6
Hz, 1H), 3.02 (s, 2H), 2.26 – 1.92 (m, 4H), 1.51 (s, 9H). 13C{1H}
NMR (100 MHz, CDCl3) δ 163.2, 154.9, 143.8, 133.2, 130.2,
130.1, 128.7, 127.4, 126.6, 125.3, 124.6, 123.5, 122.9, 121.9, 79.5,
44.5, 40.1, 31.3, 28.7. HRMS (ESI) calcd for C23H27N2O2 [M +
H]+ 363.2067, found 363.2063.
tert-butyl 4-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)piperidine-
1-carboxylate (24). According to the general procedure. Yellow
oil (32.7 mg, 32%). Rf 0.30 (Petroleum ether/EtOAc, 10/1). H
NMR (400 MHz, CDCl3) δ 8.18 – 8.01 (m, 2H), 7.75 (dd, J = 5.6,
3.2 Hz, 2H), 6.73 (s, 1H), 4.25 (s, 2H), 3.07 (ddd, J = 12.0, 9.2,
2.8 Hz, 1H), 2.86 (s, 2H), 1.82 (d, J = 12.8 Hz, 2H), 1.52 – 1.44
(m, 11H). 13C{1H} NMR (100 MHz, CDCl3) δ 185.3, 184.7, 154.9,
154.3, 134.0, 133.9, 133.6, 132.5, 132.0, 126.9, 126.2, 79.9, 44.1,
35.3, 31.1, 28.6. HRMS (ESI) calcd for C20H23NNaO4 [M + Na]+
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
tert-butyl 4-(benzo[d]thiazol-2-yl)piperidine-1-carboxylate (18).
According to the general procedure. White solid (46.7 mg, 49%).
M.p. = 72 – 73 °C. Rf 0.20 (Petroleum ether/EtOAc, 10/1). H
364.1519, found 364.1512.
di-tert-butyl
4,4'-(2,9-dimethyl-1,10-phenanthroline-4,7-
1
diyl)bis(piperidine-1-carboxylate) (25). According to the general
procedure. Heteroarene (0.3 mmol, 1.0 equiv), oxalate (0.9 mmol,
3.0 equiv), (NH4)2S2O8 (205 mg, 0.9 mmol, 3.0 equiv), 5.0 mL of
DMSO and 1.0 mL of H2O. Yellow oil (108.5 mg, 63%). Rf 0.40
NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.0 Hz, 1H), 7.86 (d, J =
8.0Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 4.23
(s, 2H), 3.25 (t, J = 11.6 Hz, 1H), 2.92 (t, J = 11.6 Hz, 2H), 2.15
(d, J = 12.4 Hz, 2H), 1.85 (ddd, J = 15.6, 12.4, 4.0 Hz, 2H), 1.48
(s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ 175.2, 154.8, 153.2,
134.6, 126.1, 124.9, 122.8, 121.7, 79.8, 43.7, 41.6, 32.2, 28.6.
HRMS (ESI) calcd for C17H23N2O2S [M + H]+ 319.1475, found
319.1470.
1
(CH2Cl2/MeOH, 30/1). H NMR (400 MHz, CDCl3) δ 8.02 (s,
2H), 7.34 (s, 2H), 4.36 (s, 4H), 3.50 (t, J = 12.0 Hz, 2H), 3.03 –
2.87 (m, 10H), 2.01 (d, J = 11.2 Hz, 4H), 1.79 (d, J = 9.6 Hz, 4H),
1.51 (s, 18H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.4, 154.9,
150.9, 146.4, 124.4, 120.2, 120.0, 79.9, 44.4, 37.7, 32.6, 28.6,
26.4. HRMS (ESI) calcd for C34H47N4O4 [M + H]+ 575.3592,
found 575.3582.
di-tert-butyl 4,4'-(3,4,7,8-tetramethyl-1,10-phenanthroline-2,9-
diyl)bis(piperidine-1-carboxylate) (26). According to the general
procedure. Heteroarene (0.3 mmol, 1.0 equiv), oxalate (0.9 mmol,
3.0 equiv), (NH4)2S2O8 (205 mg, 0.9 mmol, 3.0 equiv), 5.0 mL of
DMSO and 1.0 mL of H2O. White solid (126.4 mg, 70%). M.p. =
tert-butyl
4-(6-bromobenzo[d]thiazol-2-yl)piperidine-1-
carboxylate (19). According to the general procedure. Yellow
solid (48.7 mg, 41%). M.p. = 83 – 84 °C. Rf 0.40 (Petroleum
1
ether/EtOAc, 40/1). H NMR (400 MHz, CDCl3) δ 7.99 (d, J =
1.2 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 8.8, 1.6 Hz,
1H), 4.23 (s, 2H), 3.23 (ddd, J = 11.6, 8.0, 3.6 Hz, 1H), 2.92 (s,
2H), 2.15 (d, J = 12.4 Hz, 2H), 1.92 – 1.76 (m, 2H), 1.48 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3) δ 175.8, 154.8, 152.1, 136.3,
129.6, 124.3, 123.9, 118.5, 79.8, 43.6, 41.6, 32.1, 28.6. HRMS
(ESI) calcd for C17H22BrN2O2S [M + H]+ 397.0580, found
397.0577.
1
82 – 83 °C. Rf 0.60 (CH2Cl2/MeOH, 20/1). H NMR (400 MHz,
CDCl3) δ 7.94 (s, 2H), 4.28 (d, J = 11.2 Hz, 4H), 3.34 (s, 2H),
3.05 (s, 4H), 2.66 (s, 6H), 2.50 (s, 6H), 2.35 – 1.94 (m, 8H), 1.50
(s, 18H). 13C{1H} NMR (100 MHz, CDCl3) δ 162.0, 155.3, 143.7,
141.3, 128.0, 125.9, 121.6, 79.2, 44.6, 41.7, 30.6, 28.7, 15.3, 15.1.
HRMS (ESI) calcd for C36H51N4O4 [M + H]+ 603.3905, found
603.3900.
tert-butyl
4-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-
yl)piperidine-1-carboxylate (20). According to the general
procedure. White solid (95.7 mg, 82%). M.p. = 199 – 200 °C. Rf
1
0.40 (EtOAc). H NMR (400 MHz, CDCl3) δ 12.16 (s, 1H), 7.59
2-ethyl-4-methylquinoline (27). According to the general
procedure. The spectral Data is consistent with the literature
data.4i Colorless oil (24.6 mg, 48%). Rf 0.50 (Petroleum
(s, 1H), 7.12 (s, 1H), 4.30 (s, 2H), 4.03 (d, J = 4.0 Hz, 6H), 3.07 –
2.80 (m, 3H), 2.13 – 1.87 (m, 4H), 1.48 (s, 9H). 13C{1H} NMR
(100 MHz, CDCl3) δ 163.7, 157.3, 155.5, 154.8, 149.0, 146.0,
113.9, 108.0, 105.1, 79.7, 56.4, 43.7, 42.2, 29.8, 28.6. HRMS
(ESI) calcd for C20H28N3O5 [M + H]+ 390.2023, found 390.2022.
1
ether/EtOAc, 20/1). H NMR (400 MHz, CDCl3) δ 8.04 (d, J =
8.4 Hz, 1H), 7.93 (dd, J = 8.4, 0.8 Hz, 1H), 7.66 (ddd, J = 8.4, 7.2,
1.2 Hz, 1H), 7.53 – 7.45 (m, 1H), 7.14 (s, 1H), 2.95 (q, J = 7.6
Hz, 2H), 2.66 (s, 3H), 1.38 (t, J = 7.6 Hz, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 163.8, 147.8, 144.4, 129.5, 129.1, 126.9,
125.5, 123.7, 121.6, 32.4, 18.8, 14.2. HRMS (ESI) calcd for
C12H14N [M + H]+ 172.1121, found 172.1120.
2-benzyl-4-methylquinoline (28). According to the general
procedure. The spectral Data is consistent with the literature
data.12
tert-butyl
4-(5-bromo-2-chloropyrimidin-4-yl)piperidine-1-
carboxylate (21). According to the general procedure. White
solid (74.3 mg, 66%). M.p. = 87 – 88 °C. Rf 0.30 (Petroleum
1
ether/EtOAc, 15/1). H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H),
4.29 (s, 2H), 3.29 – 3.15 (m, 1H), 2.84 (s, 2H), 1.82 (s, 4H), 1.48
(s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ 173.4, 160.8, 159.9,
154.6, 119.0, 79.7, 43.9, 42.4, 29.4, 28.5. HRMS (ESI) calcd for
C14H19BrClN3NaO2 [M + Na]+ 398.0241, found 398.0235.
Yellow oil (29.4 mg, 42%). Rf 0.30 (Petroleum ether/EtOAc,
tert-butyl
4-(3,6-dichloropyridazin-4-yl)piperidine-1-
1
20/1). H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.4 Hz, 1H),
carboxylate (22). According to the general procedure. Yellow
solid (42.7 mg, 43%). M.p. = 91 – 92 °C. Rf 0.50 (Petroleum
7.95 – 7.87 (m, 1H), 7.72 – 7.63 (m, 1H), 7.56 – 7.45 (m, 1H),
7.34 – 7.26 (m, 4H), 7.25 – 7.19 (m, 1H), 7.05 (s, 1H), 4.29 (s,
2H), 2.58 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.9,
147.7, 144.7, 139.5, 129.6, 129.3, 129.3, 128.7, 127.0, 126.5,
125.8, 123.7, 122.3, 45.6, 18.8. HRMS (ESI) calcd for C17H16N
[M + H]+ 234.1277, found 234.1276.
4-methyl-2-(3-phenylpropyl)quinoline (29). According to the
general procedure. Heteroarene (0.3 mmol, 1.0 equiv), oxalate
(0.9 mmol, 3.0 equiv), (NH4)2S2O8 (205 mg, 0.9 mmol, 3.0 equiv),
5.0 mL of DMSO and 1.0 mL of H2O. Yellow oil (26.6 mg, 34%).
Rf 0.30 (Petroleum ether/EtOAc, 20/1). 1H NMR (400 MHz,
CDCl3) δ 8.04 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.67
(t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.31 – 7.27 (m, 2H),
7.24 – 7.15 (m, 3H), 7.13 (s, 1H), 3.03 – 2.91 (m, 2H), 2.74 (t, J =
1
ether/EtOAc, 3/1). H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H),
4.32 (s, 2H), 3.04 (tt, J = 12.0, 3.2 Hz, 1H), 2.86 (s, 2H), 1.94 (d,
J = 12.8 Hz, 2H), 1.55 – 1.51 (m, 2H), 1.48 (s, 9H). 13C{1H}
NMR (100 MHz, CDCl3) δ 156.5, 156.4, 154.5, 146.7, 127.3,
80.0, 43.6, 38.6, 30.6, 28.5. HRMS (ESI) calcd for
C14H20Cl2N3O2 [M + H]+ 332.0927, found 332.0923.
tert-butyl
4-(3-bromo-6-chloroimidazo[1,2-b]pyridazin-7-
yl)piperidine-1-carboxylate (23). According to the general
procedure. Yellow solid (65.8 mg, 53%). M.p. = 74 – 75 °C. Rf
1
0.60 (Petroleum ether/EtOAc, 3/1). H NMR (400 MHz, CDCl3)
δ 7.73 (s, 1H), 6.91 (s, 1H), 4.31 (s, 2H), 3.50 (tt, J = 12.4, 3.2 Hz,
1H), 2.93 (s, 2H), 2.10 – 1.98 (m, 2H), 1.78 – 1.65 (m, 2H), 1.49
(s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ 154.7, 148.5, 146.2,
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The Journal of Organic Chemistry
7.6 Hz, 2H), 2.67 (s, 3H), 2.15 (dt, J = 15.6, 7.6 Hz, 2H). 13C{1H}
3H), 1.38 (d, J = 7.2 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ
1
2
3
4
5
6
7
8
NMR (100 MHz, CDCl3) δ 162.3, 147.9, 144.4, 142.3, 129.5,
129.2, 128.6, 128.5, 126.9, 125.9, 125.6, 123.7, 122.2, 38.9, 35.9,
31.7, 18.8. HRMS (ESI) calcd for C19H20N [M + H]+ 262.1590,
found 262.1586.
167.5, 147.7, 144.4, 129.6, 129.0, 127.1, 125.5, 123.7, 119.9, 37.4,
22.7, 18.9. HRMS (ESI) calcd for C13H16N [M + H]+ 186.1277,
found 186.1276.
(R)-4-methyl-2-(5-methylhexan-2-yl)quinoline (36). According
to the general procedure. Yellow oil (44.1 mg, 61%). Rf 0.60
2-cyclopentyl-4-methylquinoline (30). According to the general
procedure. The spectral Data is consistent with the literature
data.12 Yellow oil (52.5 mg, 83%). Rf 0.40 (Petroleum
1
(Petroleum ether/EtOAc, 20/1). H NMR (400 MHz, CDCl3) δ
8.06 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.65 (t, J = 7.6
Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.13 (s, 1H), 3.07 – 2.93 (m,
1H), 2.67 (s, 3H), 1.81 (tdd, J = 12.8, 7.6, 5.2 Hz, 1H), 1.73 –
1.60 (m, 1H), 1.53 (tt, J = 13.2, 6.8 Hz, 1H), 1.35 (d, J = 6.8 Hz,
3H), 1.25 (dd, J = 12.0, 6.0 Hz, 1H), 1.13 – 1.01 (m, 1H), 0.84
(dd, J = 6.8, 3.2 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ
167.0, 147.7, 144.2, 129.7, 128.9, 127.1, 125.4, 123.6, 120.2,
43.3, 37.1, 35.0, 28.3, 22.7, 20.9, 18.9. HRMS (ESI) calcd for
C17H24N [M + H]+ 242.1903, found 242.1898.
1
ether/EtOAc, 40/1). H NMR (400 MHz, CDCl3) δ 8.04 (d, J =
8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.70 – 7.61 (m, 1H), 7.52 –
7.44 (m, 1H), 7.17 (s, 1H), 3.41 – 3.27 (m, 1H), 2.67 (s, 3H), 2.17
(ddd, J = 10.8, 9.2, 2.4 Hz, 2H), 1.97 – 1.81 (m, 4H), 1.81 – 1.66
(m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.0, 147.6, 144.2,
129.5, 129.0, 127.1, 125.4, 123.6, 120.7, 48.9, 33.7, 26.1, 18.9.
HRMS (ESI) calcd for C15H18N [M + H]+ 212.1434, found
212.1436.
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
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53
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58
59
60
2-cyclohexyl-4-methylquinoline (31). According to the general
procedure. The spectral Data is consistent with the literature
data.12 Yellow oil (58.7 mg, 87%). Rf 0.40 (Petroleum
(R)-4-methyl-2-(4-phenylbutan-2-yl)quinoline (37). According
to the general procedure. Yellow oil (49.5 mg, 60%). Rf 0.40
1
(Petroleum ether/EtOAc, 20/1). H NMR (400 MHz, CDCl3) δ
1
ether/EtOAc, 40/1). H NMR (400 MHz, CDCl3) δ 7.95 (d, J =
8.08 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.66 (t, J = 7.6
Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.29 – 7.24 (m, 2H), 7.16 – 7.11
(m, 4H), 3.16 – 3.02 (m, 1H), 2.71 – 2.63 (m, 4H), 2.58 – 2.47 (m,
1H), 2.19 (dtd, J = 10.4, 8.4, 5.6 Hz, 1H), 1.99 (ddd, J = 16.8,
12.8, 6.4 Hz, 1H), 1.40 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 166.3, 147.8, 144.4, 142.6, 129.7, 129.0, 128.5,
128.3, 127.1, 125.7, 125.5, 123.7, 120.4, 42.6, 38.8, 34.1, 21.0,
18.9. HRMS (ESI) calcd for C20H22N [M + H]+ 276.1747, found
276.1744.
8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.59 – 7.47 (m, 1H), 7.42 –
7.30 (m, 1H), 7.04 (s, 1H), 2.77 (tt, J = 12.0, 3.2 Hz, 1H), 2.54 (s,
3H), 1.97 – 1.86 (m, 2H), 1.78 (dd, J = 10.0, 2.8 Hz, 2H), 1.72 –
1.62 (m, 1H), 1.52 (ddd, J = 24.8, 12.4, 2.8 Hz, 2H), 1.42 – 1.29
(m, 2H), 1.28 – 1.19 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ
166.5, 147.7, 144.2, 129.6, 128.9, 127.1, 125.4, 123.6, 120.3,
47.7, 32.9, 26.6, 26.2, 18.9. HRMS (ESI) calcd for C16H20N [M +
H]+ 226.1590, found 226.1594.
2-cyclododecyl-4-methylquinoline (32). According to the
general procedure. White solid (75.1 mg, 81%). M.p. = 72 –
73 °C.
2-(tert-butyl)-4-methylquinoline (38). According to the general
procedure. The spectral Data is consistent with the literature
data.12 Colorless oil (50.7 mg, 85%). Rf 0.70 (Petroleum
1
Rf 0.60 (Petroleum ether/EtOAc, 20/1). 1H NMR (400 MHz,
CDCl3) δ 8.06 (d, J = 8.4 Hz, 1H), 7.92 (dd, J = 8.4, 0.8 Hz, 1H),
7.64 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H), 7.47 (ddd, J = 8.0, 7.2, 1.2
Hz, 1H), 7.12 (s, 1H), 3.09 (p, J = 6.8 Hz, 1H), 2.66 (s, 3H), 1.96
– 1.84 (m, 2H), 1.75 – 1.67 (m, 2H), 1.50 – 1.29 (m, 18H).
13C{1H} NMR (100 MHz, CDCl3) δ 166.8, 147.8, 143.8, 129.8,
128.8, 127.1, 125.4, 123.6, 121.5, 43.2, 30.3, 24.1, 24.0, 23.8,
23.5, 23.0, 18.9. HRMS (ESI) calcd for C22H32N [M + H]+
310.2529, found 310.2523.
ether/EtOAc, 40/1). H NMR (400 MHz, CDCl3) δ 8.05 (d, J =
8.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H),
7.47 (t, J = 7.6 Hz, 1H), 7.34 (s, 1H), 2.66 (s, 3H), 1.45 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3) δ 169.0, 147.5, 143.7, 130.1,
128.8, 126.7, 125.5, 123.5, 119.0, 38.0, 30.3, 19.1. HRMS (ESI)
calcd for C14H18N [M + H]+ 200.1434, found 200.1431.
4-methyl-2-(2-methyl-1-phenylpropan-2-yl)quinoline
(39).
According to the general procedure. Yellow oil (74.3 mg, 90%).
Rf 0.50 (Petroleum ether/EtOAc, 40/1). 1H NMR (400 MHz,
CDCl3) δ 8.09 (d, J = 8.4 Hz, 1H), 7.94 – 7.89 (m, 1H), 7.68 –
7.61 (m, 1H), 7.51 – 7.44 (m, 1H), 7.18 (s, 1H), 7.10 (dd, J = 6.4,
3.6 Hz, 3H), 6.91 (dd, J = 6.4, 2.8 Hz, 2H), 3.14 (s, 2H), 2.62 (s,
3H), 1.43 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 167.6,
147.5, 143.5, 139.4, 130.6, 130.2, 128.8, 127.7, 126.7, 125.9,
125.6, 123.6, 119.7, 49.1, 42.2, 27.6, 19.0. HRMS (ESI) calcd for
C20H22N [M + H]+ 276.1747, found 276.1744.
2-(adamantan-1-yl)-4-methylquinoline (40). According to the
general procedure. The spectral Data is consistent with the
literature data.12 White solid (67.3 mg, 81%). M.p. = 105 – 106 °C.
Rf 0.65 (Petroleum ether/EtOAc, 40/1). 1H NMR (400 MHz,
CDCl3) δ 8.08 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.66
(t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.33 (s, 1H), 2.69 (s,
3H), 2.20 – 2.08 (m, 9H), 1.84 (s, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ 168.80, 147.68, 143.66, 130.11, 128.73, 126.84, 125.44,
123.53, 118.63, 41.95, 39.68, 37.05, 29.00, 19.09. HRMS (ESI)
calcd for C20H24N [M + H]+ 278.1903, found 278.1900.
2-(4,4-difluorocyclohexyl)-4-methylquinoline (33). According
to the general procedure. The spectral Data is consistent with the
literature data.13a Yellow oil (58.7 mg, 75%). Rf 0.50 (Petroleum
1
ether/EtOAc, 20/1). H NMR (400 MHz, CDCl3) δ 8.03 (d, J =
8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H),
7.51 (t, J = 7.6 Hz, 1H), 7.16 (s, 1H), 2.96 (t, J = 11.2 Hz, 1H),
2.69 (s, 3H), 2.27 (dt, J = 10.8, 7.6 Hz, 2H), 2.13 – 1.94 (m, 5H),
1.93 – 1.81 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.0,
147.7, 144.8, 129.7, 129.3, 127.2, 125.9, 123.7, 119.9, 45.2, 33.9
(dd, J = 25.1, 23.1 Hz), 28.9, 28.8, 18.9. HRMS (ESI) calcd for
C16H18F2N [M + H]+ 262.1402, found 262.1400.
2-(2,3-dihydro-1H-inden-2-yl)-4-methylquinoline
(34).
According to the general procedure. Yellow solid (50.5 mg,
65%). M.p. = 40 – 41 °C. Rf 0.50 (Petroleum ether/EtOAc, 20/1).
1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.4 Hz, 1H), 7.91 (d, J
= 8.4 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H),
7.25 (d, J = 3.2 Hz, 2H), 7.21 – 7.14 (m, 3H), 4.01 (p, J = 8.8 Hz,
1H), 3.42 (qd, J = 16.0, 8.8 Hz, 4H), 2.62 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 164.6, 147.6, 144.6, 142.9, 129.6, 129.2,
127.1, 126.6, 125.7, 124.5, 123.6, 120.6, 48.0, 39.8, 18.9. HRMS
(ESI) calcd for C19H18 N [M + H]+ 260.1434, found 260.1431.
2-isopropyl-4-methylquinoline (35). According to the general
procedure. The spectral Data is consistent with the literature
data.12 Yellow oil (36.1 mg, 65%). Rf 0.30 (Petroleum
5-(4-methylquinolin-2-yl)adamantan-2-one (41). According to
the general procedure. White solid (34.0 mg, 39%). M.p. = 130 –
1
131 °C. Rf 0.40 (Petroleum ether/EtOAc, 10/1). H NMR (400
MHz, CDCl3) δ 8.04 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H),
7.67 (t, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.29 (s, 1H),
2.77 – 2.65 (m, 5H), 2.49 – 2.38 (m, 4H), 2.33 (s, 3H), 2.17 (d, J
= 12.0 Hz, 2H), 2.08 (d, J = 12.4 Hz, 2H). 13C{1H} NMR (100
MHz, CDCl3) δ 218.2, 165.6, 147.5, 144.3, 129.9, 129.0, 126.8,
125.8, 123.5, 118.0, 46.7, 43.2, 40.8, 39.3, 38.7, 28.2, 19.0.
1
ether/EtOAc, 40/1). H NMR (400 MHz, CDCl3) δ 8.05 (d, J =
8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.69 – 7.62 (m, 1H), 7.53 –
7.44 (m, 1H), 7.17 (s, 1H), 3.21 (hept, J = 7.2 Hz, 1H), 2.68 (s,
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HRMS (ESI) calcd for C20H22NO [M + H]+ 292.1696, found
292.1694.
4-methyl-2-(2-methyladamantan-2-yl)quinoline (42). According
132.4, 132.3, 129.8, 126.9, 125.5, 116.0, 79.5, 50.8, 50.2, 47.6,
1
2
3
4
5
6
7
8
47.4, 43.9, 40.3, 31.6, 30.9, 28.5. HRMS (ESI) calcd for
C24H35N4O4S [M + H]+ 475.2374, found 475.2369.
to the general procedure. White solid (30.6 mg, 35%). M.p. = 100
tert-butyl
4-(3,7-dimethyl-2,6-dioxo-1-(5-oxohexyl)-2,3,6,7-
(48).
1
– 101 °C. Rf 0.40 (Petroleum ether/EtOAc, 10/1). H NMR (400
tetrahydro-1H-purin-8-yl)piperidine-1-carboxylate
MHz, CDCl3) δ 8.02 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H),
7.64 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.29 (s, 1H),
2.75 – 2.58 (m, 5H), 2.26 (d, J = 12.4 Hz, 2H), 1.94 (s, 1H), 1.81
(dd, J = 24.0, 12.4 Hz, 4H), 1.73 – 1.66 (m, 3H), 1.62 (d, J = 12.4
Hz, 2H), 1.30 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 169.5,
147.9, 143.7, 130.0, 128.6, 126.5, 125.4, 123.5, 119.1, 46.7, 39.0,
34.7, 34.2, 33.3, 28.4, 28.1, 27.9, 19.2. HRMS (ESI) calcd for
C21H26N [M + H]+ 292.2060, found 292.2055.
According to the general procedure. White solid (49.8 mg, 36%).
1
M.p. = 128 – 129 °C. Rf 0.60 (CH2Cl2/MeOH, 20/1). H NMR
(400 MHz, CDCl3) δ 4.21 (s, 2H), 3.97 (t, J = 6.4 Hz, 3H), 3.92 (s,
3H), 3.51 (s, 3H), 2.85 (dd, J = 12.4, 8.8 Hz, 3H), 2.47 (t, J = 6.8
Hz, 2H), 2.11 (s, 3H), 1.90 – 1.76 (m, 4H), 1.64 – 1.60 (m, 3H),
1.45 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ 208.8, 156.1,
155.4, 154.6, 151.5, 148.1, 107.4, 79.8, 43.3, 42.8, 40.7, 33.9,
31.6, 30.0, 29.9, 29.7, 28.5, 27.6, 21.1. HRMS (ESI) calcd for
C23H36N5O5 [M + H]+ 462.2711, found 462.2708.
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
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45
46
47
48
49
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56
57
58
59
60
2'-(tert-butyl)-2-methyl-6-oxo-1,6-dihydro-[3,4'-bipyridine]-5-
carbonitrile (43). According to the general procedure. White
tert-butyl 4-(1,3,7-trimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-
purin-8-yl)piperidine-1-carboxylate (49). According to the
general procedure. White solid (33.9 mg, 30%). M.p. = 208 –
209 °C.
solid (41.7 mg, 52%). M.p.
= 180 – 181 °C. Rf 0.60
1
(CH2Cl2/MeOH, 40/1). H NMR (400 MHz, MeOD) δ 8.53 (d, J
= 5.2 Hz, 1H), 8.08 (s, 1H), 7.46 (s, 1H), 7.23 (d, J = 5.2 Hz, 1H),
2.37 (s, 3H), 1.40 (s, 9H). 13C NMR{1H} (100 MHz, MeOD) δ
169.6, 161.1, 150.9, 149.6, 148.3, 145.1, 121.4, 120.0, 117.9,
115.1, 101.3, 37.1, 29.1, 17.1. HRMS (ESI) calcd for C16H18N3O
[M + H]+ 268.1444, found 268.1442.
1
Rf 0.60 (CH2Cl2/MeOH, 20/1). H NMR (400 MHz, CDCl3) δ
4.23 (s, 2H), 3.96 (s, 3H), 3.56 (s, 3H), 3.39 (s, 3H), 2.88 (td, J =
10.8, 5.2 Hz, 3H), 1.99 – 1.78 (m, 4H), 1.48 (s, 9H). 13C{1H}
NMR (100 MHz, CDCl3) δ 156.0, 155.6, 154.7, 151.8, 148.0,
107.4, 79.9, 43.4, 34.0, 31.6, 30.0, 29.8, 28.6, 27.9. HRMS (ESI)
calcd for C18H28N5O4 [M + H]+ 378.2136, found 378.2130.
2-((1R,2R,5R)-2-isopropyl-5-methylcyclohexyl)-4-
methylquinoline (50). According to the general procedure. The
spectral Data is consistent with the literature data.13d Yellow oil
(79.2 mg, 94%). Rf 0.60 (Petroleum ether/EtOAc, 20/1). 1H NMR
(400 MHz, CDCl3) δ 8.05 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.0 Hz,
1H), 7.65 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.2 Hz, 1H), 7.12 (s, 1H),
2.86 (t, J = 11.2 Hz, 1H), 2.68 (s, 3H), 2.01 – 1.69 (m, 4H), 1.56
(s, 1H), 1.41 – 1.19 (m, 3H), 1.09 (dd, J = 24.0, 11.6 Hz, 1H),
0.91 (d, J = 6.0 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H), 0.74 (d, J = 6.4
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 166.0, 147.9, 144.1,
129.7, 128.9, 127.2, 125.4, 123.7, 120.7, 51.0, 46.6, 43.5, 35.3,
33.1, 28.3, 24.7, 22.6, 21.6, 19.0, 15.8. HRMS (ESI) calcd for
C20H28N [M + H]+ 282.2216, found 282.2213.
2-((2-(4-chlorophenoxy)-2-methylpropanoyl)oxy)ethyl 6-(tert-
butyl)nicotinate (44). According to the general procedure.
Colorless oil (90.5 mg, 72%). Rf 0.65 (Petroleum ether/EtOAc,
5/1). 1H NMR (400 MHz, CDCl3) δ 9.09 (d, J = 2.0 Hz, 1H), 8.04
(dd, J = 8.4, 2.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.14 – 7.05 (m,
2H), 6.80 – 6.73 (m, 2H), 4.53 (q, J = 5.6 Hz, 4H), 1.60 (s, 6H),
1.39 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ 174.4, 173.9
165.2, 154.0, 150.0, 137.3, 129.2, 127.3, 122.6, 120.3, 118.8, 79.4,
63.2, 62.5, 38.1, 30.1, 25.4. HRMS (ESI) calcd for C22H27ClNO5
[M + H]+ 420.1572, found 420.1575.
2-(adamantan-1-yl)-5,7-dichloro-4-(3-fluorophenoxy)quinolone
(45). According to the general procedure. Colorless oil (86.0 mg,
65%). Rf 0.40 (Petroleum ether/EtOAc, 100/1). 1H NMR (400
MHz, CDCl3) δ 7.99 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H),
7.15 (dd, J = 11.2, 6.0 Hz, 2H), 7.11 – 7.06 (m, 2H), 6.74 (s, 1H),
2.08 (s, 3H), 1.94 – 1.91 (m, 6H), 1.80 – 1.71 (m, 6H). 13C{1H}
NMR (100 MHz, CDCl3) δ 172.0, 162.1, 159.8 (d, J = 244 Hz),
151.4, 150.9, 134.6, 129.8, 128.7, 128.0, 121.7, 121.6, 117.2,
116.9, 116.9, 104.6, 41.6, 40.0, 36.8, 28.7. HRMS (ESI) calcd for
C25H23Cl2FNO [M + H]+ 442.1135, found 442.1136.
2-((3S,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-17-((R)-6-
methylheptan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-
3-yl)-4-methylquinoline (51). According to the general procedure.
The spectral Data is consistent with the literature data.12 White
solid (100.0 mg, 65%). M.p. = 167 – 168 °C. Rf 0.60 (Petroleum
1
(1S)-(2-(tert-butyl)-6-methoxyquinolin-4-yl)((1S,4S)-5-
ether/EtOAc, 40/1). H NMR (400 MHz, CDCl3) δ 8.04 (d, J =
vinylquinuclidin-2-yl)methanol (46). According to the general
procedure. Yellow solid (68.4 mg, 60%). M.p. = 120 – 121 °C. Rf
8.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H),
7.47 (t, J = 7.6 Hz, 1H), 7.17 (s, 1H), 3.01 – 2.84 (m, 1H), 2.66 (s,
3H), 1.98 (d, J = 12.4 Hz, 1H), 1.90 – 1.76 (m, 4H), 1.71 – 1.48
(m, 6H), 1.44 – 1.25 (m, 9H), 1.20 – 0.96 (m, 10H), 0.95 – 0.89
(m, 7H), 0.87 (dd, J = 6.4, 1.2 Hz, 6H), 0.67 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 166.4, 147.8, 144.3, 129.7, 129.0,
127.2, 125.5, 123.6, 120.3, 56.7, 56.5, 54.7, 48.0, 46.9, 42.7, 40.2,
39.7, 38.8, 36.3, 36.0, 35.9, 35.7, 35.1, 32.3, 29.0, 28.5, 28.4, 28.2,
24.4, 24.0, 23.0, 22.7, 21.2, 19.0, 18.8, 12.7, 12.2. HRMS (ESI)
calcd for C37H56N [M + H]+ 514.4407, found 514.4413.
1
0.30 (CH2Cl2/MeOH, 20/1). H NMR (400 MHz, CDCl3) δ 7.79
(s, 1H), 7.61 (d, J = 9.2 Hz, 1H), 6.80 (dd, J = 9.2, 2.4 Hz, 1H),
6.72 (d, J = 2.4 Hz, 1H), 6.34 (s, 1H), 6.05 (s, 1H), 5.52 (ddd, J =
17.2, 10.4, 6.8 Hz, 1H), 5.10 – 4.85 (m, 2H), 4.54 (t, J = 9.6 Hz,
1H), 3.49 (s, 3H), 3.41 (dd, J = 13.2, 10.8 Hz, 1H), 3.31 – 3.22 (m,
1H), 3.10 (td, J = 11.6, 5.6 Hz, 1H), 2.98 (dd, J = 13.2, 2.8 Hz,
1H), 2.67 (s, 1H), 2.26 (t, J = 10.8 Hz, 1H), 2.14 (dd, J = 13.2, 7.2
Hz, 1H), 2.06 (d, J = 2.4 Hz, 1H), 1.83 (t, J = 9.6 Hz, 1H), 1.47 (s,
9H), 1.33 – 1.28 (m, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ
165.7, 157.4, 143.3, 143.1, 137.4, 131.3, 123.2, 121.5, 117.3,
115.7, 99.0, 66.2, 60.3, 56.9, 54.9, 44.1, 37.9, 37.4, 30.3, 27.2,
24.4, 18.1. HRMS (ESI) calcd for C24H33N2O2 [M + H]+
381.2537, found 381.2543.
Gram-scale Reaction. To a 250 mL glass vial was added
lepidine
1
(0.8 mL,
6
mmol, 1.0 equiv), N-Boc-4-
hydroxypiperidine 2 (3.3 g, 12 mmol, 2.0 equiv), (NH4)2S2O8 (2.7
g, 12 mmol, 2.0 equiv), 100 mL of DMSO and 20 mL of H2O.
The reaction mixture was stirred rapidly at 50 oC for 24 h (heating
mantle). The mixture was diluted with 100 mL of aqueous 1 M
NaHCO3 solution, and extracted with DCM (3 × 100 mL). The
combined organic extracts were washed with brine (200 mL),
dried over Na2SO4, and concentrated in vacuo. After purification
by flash column chromatography on silica gel, the product 3 (1.1
g) was obtained in 85% yield.
tert-butyl
4-(5-((1,4-diazepan-1-yl)sulfonyl)isoquinolin-1-
yl)piperidine-1-carboxylate (47). According to the general
procedure. Yellow oil (81.1 mg, 57%). Rf 0.20 (CH2Cl2/MeOH,
20/1).
1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 6.0 Hz, 1H), 8.47 (d, J
= 8.4 Hz, 1H), 8.36 – 8.23 (m, 2H), 7.68 (t, J = 8.0 Hz, 1H), 4.32
(s, 2H), 3.72 (t, J = 10.8 Hz, 1H), 3.57 – 3.39 (m, 4H), 3.21 – 2.88
(m, 7H), 2.04 (s, 2H), 1.90 (dd, J = 14.4, 8.8 Hz, 4H), 1.49 (s, 9H).
13C{1H} NMR (100 MHz, CDCl3) δ 164.5, 154.8, 143.9, 135.5,
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compounds and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
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Active Esters with N-Heteroarenes. ACS Catal. 2017, 7, 907. (d)
Li, G.-X.; Morales-Rivera, C. A.; Wang, Y.; Gao, F.; He, G.; Liu,
P.; Chen, G. Photoredox-mediated Minisci C–H alkylation of N-
heteroarenes using boronic acids and hypervalent iodine. Chem.
Sci. 2016, 7, 6407. (e) Dong, J.; Xia, Q.; Lv, X.; Yan, C.; Song,
H.; Liu, Y.; Wang, Q. Photoredox-Mediated Direct Cross-
Dehydrogenative Coupling of Heteroarenes and Amines. Org.
Lett. 2018, 20, 5661. (f) DiRocco, D. A.; Dykstra, K.; Krska, S.;
Vachal, P.; Conway, D. V.; Tudge, M. Late‐Stage
Functionalization of Biologically Active Heterocycles Through
Photoredox Catalysis. Angew. Chem., Int. Ed. 2014, 53, 4802. (g)
Gutierrez-Bonet, A.; Remeur, C.; Matsui, J. K.; Molander, G. A.
Late-Stage C–H Alkylation of Heterocycles and 1,4-Quinones via
Oxidative Homolysis of 1,4-Dihydropyridines. J. Am. Chem. Soc.
2017, 139, 12251.
(5) Henkel, T.; Brunne, R. M.; Muller, H.; Reichel, F. Statistical
Investigation into the Structural Complementarity of Natural
Products and Synthetic Compounds. Angew. Chem., Int. Ed. 1999,
38, 643.
(6) (a) Pedley, J. B.; Naylor, R. D.; Kirby, S. P. In
Thermochemical Data of Organic Compounds, 2nd ed.; Chapman
and Hall: New York, 1986. (b) McCallum, T.; Pitre, S.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wangqm@nankai.edu.cn.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
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We are grateful to the National Key Research and Development
Program of China (2018YFD0200100) and the National Natural
Science Foundation of China (21732002, 21672117) for generous
financial support for our programs.
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