Insights into Substrate Self-Assisted Activation of Allylic Alcohols Guiding to Mild Allylic Substitution of Tautomerizable Heteroarenes

Article abstract of DOI:10.1021/acs.joc.0c00094

A substrate self-assisted activation of allylic alcohols by tautomerizable heteroarenes via hydrogen bonding was disclosed by various NMR techniques, including variable-temperature ¹H NMR, Job plot, and ¹H NMR titration. Guided by th

Full text of DOI:10.1021/acs.joc.0c00094

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Insights into Substrate Self-Assisted Activation of Allylic Alcohols
Guiding to Mild Allylic Substitution of Tautomerizable Heteroarenes
Qiuju Zhou, Lingyun Zheng, Bing Ma, Lijun Huang, Aoqi Liu, Xinhua Cao, Jing Yu, and Xiantao Ma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00094 • Publication Date (Web): 09 Mar 2020
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The Journal of Organic Chemistry
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Insights into Substrate Self-Assisted Activation of Allylic Alcohols
Guiding to Mild Allylic Substitution of Tautomerizable Heteroarenes
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Qiuju Zhou,† Lingyun Zheng,† Bing Ma,† Lijun Huang,† Aoqi Liu,† Xinhua Cao† Jing Yu† Xiantao
Ma†,*
† College of Chemistry and Chemical Engineering, Green Catalysis & Synthesis Key Laboratory of Xinyang City,
Xinyang Normal University, Xinyang, Henan 464000, China.
Email: xiantaoma@126.com
Supporting Information Placeholder
H
O
O
R
H
R1
N
- H2O
[Pd]
O
N
R1
R
ABSTRACT: A substrate self-assisted activation of allylic alcohols by tautomerizable heteroarenes via hydrogen bond was
disclosed by various NMR techniques including variable-temperature 1H NMR, Job’s Plot and 1H NMR titration. Guided by
these finding, a much milder allylic substitution of tautomerizable heteroarenes with allylic alcohols was developed,
affording the target products in high yields.
The successful generation of the л-allylic palladium
species is usually crucial for a Tsuji–Trost reaction.1 The
reactive allylic halides and esters which are liable to
undergo oxidative addition with a palladium catalyst
traditionally served as precursors of л-allylic fragments.1
From the viewpoint of environmental issues and atom-
/step-economy, much attention has recently been paid to
the direct use of simple allylic alcohols as preferable
alternates, because such kind of transformation with
allylic alcohols only gives water as by-product and
moreover, the common allylic partners in Tsuji–Trost
reactions are generally prepared from the corresponding
alcohols.2 However, owing to the poor leaving character
of hydroxy group, an extra activator such as As2O3, B2O3,
BEt3, or Ti(O-iPr)4 is generally required to promote the
smooth cleavage of C-O bond in allylic alcohols.2
Therefore, developing efficient activation of allylic
alcohols becomes one of the research hotspots in this area.
In recent years, some extra activator-free Tsuji–Trost
reactions of allylic alcohols have been developed.3-5
However, the activation mechanisms of allylic alcohols
were investigated only in rare reports but mainly based on
theoretical calculations.3 Therefore, it is still highly
desirable to illuminate the activation mechanism of
activator-free Tsuji–Trost reaction especially by simple
and facile experimental methods.4
We have been interested in activation of alcohols for a
long time.6 We have recently disclosed a substrate self-
assisted secondary bond activation of allylic alcohol via a
six-membered ring complex by various NMR techniques
(Scheme 1A).6b It can be hypothesized that the substrate
bearing both a hydrogen bond donor site and an acceptor
site may interact with allylic alcohols, thus leading to the
activation of C-O bonds in allylic alcohols via hydrogen
bond (Scheme 1B).7 2-Hydroxypyridines, one of the typical
tautomerizable heteroarenes, are readily tautomerized to
2-pyridones with both hydrogen bond donor site and
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acceptor site in a molecule,8 therefore, a direct, activator-
free and substrate self-assisted allylic substitution of
tautomerizable heteroarenes with allylic alcohols is
anticipated.
Page 2 of 7
1, the tautomeric equilibrium of 2-hydroxypyridine (2a-H)
and 2-pyridone (2a-P) is susceptible to various reaction
conditions and generally 2-pyridone (2a-P) is the main
existing species in a neutral liquid medium.8 As shown in
Figure 2, the chemical shift of the free OH group in
cinnamyl alcohol (1a) is 1.598 ppm and by extra adding ca.
1.0 equiv. of 2-hydroxypyridine (2a-H), the chemical shift
could moves downfield to 1.839 ppm, revealing the
possible formation of intermolecular hydrogen bond
between cinnamyl alcohol (1a) and 2-hydroxypyridine
1
2
3
4
5
6
7
8
In 2015, Cook and coworkers achieved the activator-free
allylic substitution of tautomerizable heteroarenes with
allylic alcohols at 100 oC in a solvent of dimethyl
carbonate (DMC), however, the initial activation of allylic
alcohols which led to the smooth oxidative addition with
a palladium catalyst to give the key л-allylic palladium
species was underappreciated and not mentioned
(Scheme 1C).5d,9 It is also interestingly noticed that the
reaction could be conducted in almost all common
organic solvents including both protic and aprotic ones
(such as MeOH, EtOH, PhMe, PhH and DCE) in their
conditions screening, affording the target product in
moderate yields.5d It is still difficult to explain these
phenomena reasonably, especially why the reactions
could be carried out even in a nonpolar and aprotic
solvent which cannot activate allylic alcohols. Therefore,
an interesting activation mechanism may be involved in
these reactions. Hereon, we wish to report our results on
the possible activation mechanism of allylic alcohols by
various NMR techniques including variable-temperature
1H NMR, Job’s Plot and 1H NMR titration. The
experimental results suggested that a substrate self-
assisted activation of allylic alcohols by tautomerizable
heteroarenes via hydrogen bond might be involved
(Scheme 1D). Guided by these findings, a substrate self-
assisted and much milder allylic substitution of
tautomerizable heteroarenes with allylic alcohols was also
developed.
9
1
(2a-H) (Figure 2). Then variable-temperature H NMR
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experiments were carried out.10,6b As the test temperature
is increased, the chemical shift of OH group in cinnamyl
o
alcohol (1a) moves upfield from 1.839 (25 C), to 1.771 (35
oC), 1.706 (45 C) and finally to 1.655 ppm (55 C), further
suggesting the possible formation of intermolecular
hydrogen bond (Figure 2).
o
o
tautomerization
Ph
OH
N
H
O
N
OH
1a
2a-H
2a-P
Figure 1. Test samples: 1a and 2a
Ph
OH
OH
1a (100%)
CDCl3, 25 oC
δ : 1.598
Ph
1a/2a-P (1:1)
CDCl3, 25 oC
δ : 1.839
Ph
Ph
OH
OH
1a/2a-P (1:1)
CDCl3, 35 oC
δ : 1.771
δ : 1.706
1a/2a-P (1:1)
CDCl3, 45 oC
A) Our previous work: Secondary bond activation of allylic alcohols
PdLn
Ph
OH
1a/2a-P (1:1)
CDCl3, 55 oC
H
R1
δ : 1.655
O
PdLn
O
PPh3
R2
R1
B) Our hypothsis: Activation of allylic alcohols by substrate with H-A and H-D
PdLn
Figure 2. Variable-temperature NMR analysis
Then the Job’s Plot and 1H NMR titration techniques were
employed to investigate the possible host-guest binding
interactions between cinnamyl alcohol (1a) and 2-
hydroxypyridine (2a-H) (Figures 3-4).11-14 Job’s Plot is the
most popular way of determining the stoichiometry of
complexes.12 By continuous variation of the concentration
of [1a] and [2a-H], our Job’s Plot experimental results was
shown in Figure 3 and the maximum in the curve for
cinnamyl alcohol (1a) is at X1a = 0.55 (Figure 3A), while 2-
hydroxypyridine (2a-H) serves as the host, the maximum
lies at molar fraction X2a-H = 0.38 (Figure 3B), indicating
that both 1:1 and 2:1 binding complexes were possibly
formed (Figure 5).12 Moreover, residual distribution
analysis of the fitting curve of 1H NMR titration
experiments further suggested that the possible formation
of 1:1 and 2:1 binding complex via hydrogen bond. (Figure
5).12-14 As shown in figure 5, the 1:1 binding complex can be
in a six-membered ring form (i) or linear form (ii) and
(iii), and the 2:1 binding complex can be in form (iv).
These binding complexes readily reached equilibrium in
the reaction.
H
R1
O
PdLn
H-A
S
H-D
R1
S : substrate; H-A : hydrogen bond donor site; H-D: hydrogen bond acceptor site
C) Cook's method: Allylic alkylation of tautomerizable heteroarenes in DMC
OH
O
R2
cat. [Pd]
OH
R1
N
+
N
R1
R2
DMC, 100 o
C
Y
Y
X
X
D) This work: Activation of allylic alcohols by tautomerizable heteroarenes
PdLn
H
tautomerization
R1
O
H
O
PdLn
allylic alcohol
[PdLn]
O
R
R
N
N
N
OH
R1
R
H
Scheme 1. Activation modes of allylic alcohol and the
working hypothesis.
Cinnamyl alcohol (1a) and 2-hydroxypyridine (2a-H) were
selected as the test samples (Figure 1). As shown in Figure
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Based on these experimental results, some control
1
experiments were carried out to investigate the possible
substrate self-assisted activation of allylic alcohols via
binding complex. As shown in scheme 2, The reaction of
cinnamyl alcohol (1a) and 2-hydroxypyridine (2a-H) in
toluene successfully afforded the target 3a under Cook’s
conditions (Scheme 2, eq. 1), suggesting the possible
activation of cinnamyl alcohol (1a) by 2-hydroxypyridine
(2a-H) via binding complex. However, the reaction of 4-
hydroxypyridine (2b-H) and 2-ethoxypyridine (2c) which
could not form a six-membered ring binding complex (i)
with cinnamyl alcohol (1a) via hydrogen bond failed to
give the target N-allylic alkylation products even at 120 oC.
(Scheme 2, eqs. 2-3). These experimental results revealed
the formation of the six-membered ring binding complex
is crucial for the activation of allylic alcohols, due to the
efficient activation of allylic alcohols via double hydrogen
bonds. As the reaction proceeds, binding complexes ii, iii
and iv can be transformed into the six-membered ring
complex i, thus allylic alcohols can be activated to
generate the key л-allylic palladium species.
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(A)
O
(Pd(PPh3)4 (5 mol%)
Ph
OH
+
(1)
N
OH
Ph
N
toluene, 100 oC, N2, 12 h
1a
2a-H
3a,
70%
OH
O
(Pd(PPh3)4 (5 mol%)
Ph
Ph
OH
OH
+
Ph
N
(2)
toluene, 120 oC, N2, 12 h
N
1a
2b-H
3b,
0%
O
Pd(PPh3)4 (5 mol%)
Me
+
(3)
N
O
Ph
N
toluene, 120 oC, N2, 12 h
(B)
1a
2c
3a,
0%
Figure 3. The Job’s Plots
Scheme 2. Control experiments to show the key roles of
six-membered ring complex
Table 1. Allylic alkylation of tautomerizable heteroarenes
with allylic alcoholsa,b
[Pd(ally)Cl]2 (2.5 mol%)
dppf (10 mol%)
R1
R1
OH
N
+
cyclohexane, N2, 60 o
C
N
OH
O
1
2
3
O
O
Ph
N
Ph
N
Ph
N
S
N
O
c
c
d
c
3a
3c
3d
(1) , 90% (81%)
(2) , 94% (90% , 51% ) (3) , 94% (90%)
O
3e
(4) R = 4-MeO, , 86%
3f
(5) R = 4-F, , 90%
N
R
3g
(6) R = 4-Cl, , 92%
3h
N
(7) R = 2-MeO, , 84%
O
Figure 4. 1H NMR titration experiments
O
N
O
N
H
H
N
H
N
H
O
H
Ph
O
H
Ph
Ph
O
H
Ph
O
O
O
O
H
Ph
O
N
(10) , 82%d,e (91%)c
N
d,e
N
3k
3i
N
(8) , 82%
3j
(9) , 89%
O
H
O
N
O
O
i
( )
ii
iii
iv
)
(
)
(
)
(
N
N
Me
Ph
N
N
Figure 5. Formation of binding complexes via hydrogen
c,e,f
g
3l
(11) , 65% (E/Z = 85/15)
3m
3a
(12)
, 73%d (78%)c (13) , 93% (0.981 g)
bond
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Page 4 of 7
a
Unless otherwise noted, the mixture of 1 (0.60 mmol), 2 (0.50
bond may be the main path (path b), following by
oxidative addition with a palladium catalyst giving the
crucial π-allyl palladium intermediate. Once the key π-
mmol), [Pd(ally)Cl]2 (2.5 mol%), dppf (10 mol%) in cyclohexane (1.0
mL) was sealed under N2 in a 20 mL Schlenk tube, and stirred at 60
1
2
3
4
oC for 12 h, and monitored by TLC and/or GC-MS. Isolated yield
b
allyl palladium intermediate is generated,
a final
based on 2; reported yields in parentheses by Cook,s method, see ref.
5d for details. c 100 oC, d 80 oC. e 1 (1.5 equiv.) was used. f Hex-2-en-1-ol
nucleophilic attack by tautomerizable heteroarenes
affords the target products.
g
(E/Z = 85/15) was used. The reaction was carried out in 5.0 mmol
5
scale, 65 oC, 17 h.
6
7
8
9
[Pd]
Moreover, the variable-temperature NMR analysis
showed that the intermolecular hydrogen bond between
cinnamyl alcohol (1a) and 2-hydroxypyridine (2a-H) will
become stronger as the test temperature is decreased
(Figure 2). Therefore, a mild allylic substitution of 2-
hydroxypyridine (2a-H) with allylic alcohol is anticipated.
By screening the palladium catalysts, solvents and
reaction temperatures,13 to our delight, the reaction of
cinnamyl alcohol (1a) and 2-hydroxypyridine (2a-H)
could successfully afford the target 3a in 90% isolated
yield at 60 oC in a nonpolar and aprotic solvent of
cyclohexane (Table 1, run 1).15 The method can be easily
extended to the allylic alkylation of 4-hydroxyquinazoline
(2d-H) and benzo[d]thiazol-2-ol (2e-H), giving the target
products in a same excellent isolated yield of 94% (runs 2-
3). By contrast, these products were obtained in yields of
R1
OCO2Me
DMC
method
a
R1
[Pd]
+
Cook'spath
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R1
OH
[Pd]
[Pd]
2
H
N
O
R1
cyclohe
2
O
xane
This
method
H
path
b
R
Target product
Scheme 3. Possible activation mechanism of cinnamyl
alcohol under extra activator-free conditions
In conclusion, we disclosed a substrate self-assisted
activation of allylic alcohol by various NMR techniques
including variable-temperature 1H NMR, Job’s Plot and 1H
NMR titration. The efficient activation of allylic alcohols
may be involved in a 1:1 binding six-membered-ring
complex via hydrogen bond, thus leading to the
generation of the key л-allylic palladium species. Guided
by these finding, a much milder dehydrative substitution
of tautomerizable heteroarenes with allylic alcohols was
developed. Compared with Cook’ method, the reactions
can be carried out in milder conditions, affording the
target allylic products in high yields. Further application
of this novel substrate self-assisted activation of allylic
alcohols for the developments of mild Tsuji–Trost
reactions is under way.
o
81% and 90% respectively at 100 C by Cook’s method
(runs 1-3).5d Besides, the allylic alkylation of 4-
hydroxyquinazoline is sensitive to the reaction
temperature by Cook’s method, and the yield of target 3c
is decreased greatly to 51% at 80 oC (run 2).5d Then various
allylic alcohols were tested to extend the scopes of the
method. As shown in table 1, like the model reaction, both
electron-rich and -deficient cinnamyl alcohols reacted
efficiently with 4-hydroxyquinazoline, affording the target
products in high yields (runs 4-7). To our delight, the
allylic alkylation of 2-hydroxypyridine (2a-H) with
aliphatic allylic alcohols can smoothly proceed, affording
the target products in high yields under mild conditions
(runs 8-9). As to 4-hydroxyquinazoline, the target
products could be obtained in comparable yields to
Cook’s method only by increasing the reaction
EXPERIMENTAL SECTION
General Information. Unless otherwise specified, all
reactions were carried out in sealed Schlenk tubes under
N2 and then monitored by TLC and/or GC-MS. Products
were purified by column chromatography on silica gel
o
temperature to 80 or 100 C (runs 10-12). Despite that no
better yields were obtained, a substrate self-assisted
activation of allylic alcohols is still possibly involved.
Finally, a larger scale (5.0 mmol) reaction of cinnamyl
alcohol (1a) and 2-hydroxypyridine (2a-H) could afford
the target products 3a in a slightly higher yield of 93%
(0.981 g), showing the practicability of this new method.
1
using petroleum ether and ethyl acetate as the eluent. H
and 13C {1H} NMR spectra were measured on a JNM-
ECZ600R/S3 (Jeol, Japan) (600 MHz and 150 MHz,
respectively) using CDCl3 as the solvent. Chemical shifts
for 1H and 13C NMR were referred to internal Me4Si (0 ppm)
as the standard. Mass spectra were measured on an
Agilent GC-MS-5890A/5975C Plus spectrometer (EI).
High resolution mass spectra (HRMS) were recorded on a
LC-TOF spectrometer (Xevo G2-XS QTof) using ESI
techniques. Melting points are uncorrected.
Based on these control experiments and the literature
[2,5d,6b,9]
reports,
a possible reaction mechanism was
depicted in scheme 43. As to this novel extra activator-
free Tsuji–Trost reaction of allylic alcohols with
tautomerizable heteroarenes, two activation paths might
be involved in the activation of allylic alcohols (Scheme 3).
General procedure for variable-temperature NMR
analysis: A mixture of cinnamyl alcohol 1a (5.6 mg, 0.418
mmol), 2-hydroxypyridine (2a-H) (4.0 mg, 0.418 mmol)
was dissolved in CDCl3 (0.50 mL). Then variable-
temperature NMR experiments (25, 35, 45 and 55 oC) were
conducted at a JNM-ECZ600R/S3 NMR spectrometer.
A
DMC-assisted activation of allylic alcohol via
transesterification may be involved in cook’s method,5d,9
leading to the generation of key π-allyl palladium
intermediate. However, when the reaction is carried out
in a nonpolar and aprotic solvent such as cyclohexane, a
substrate self-assisted activation of allylic alcohols via
formation of six-membered ring complex by hydrogen
General
procedure
for
determination
of
stoichiometry between cinnamyl alcohol (1a) and 2-
hydroxypyridine (2a-H) studied by Job’s Plot method.
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The stock solutions of Cinnamyl alcohol 1a (225mM,
3-Cinnamylbenzo[d]thiazol-2(3H)-one (3d). Colorless
solid, m.p. 46-47 oC, (EA/PE = 0 ~ 1/1, 125.5 mg, 94%). 5d 1
1
2
3
4
5
6
7
8
5.5mL) and 2-hydroxypyridine 2a-H (225mM, 5.5mL) were
prepared by directly dissolving their powers (1a, 166.4mg;
2a-H, 117.9mg) in 5.5 mL CDCl3, respectively. The
solutions of the 1a (Host) and 2a-H (Guest) were mixed to
NMR tubes according to certain proportions as
summarized in Table S1 and S2. The hydroxyl protons (–
OH) chemical shifts of both host (1a) and guest (2a-H)
were referenced to TMS. All 1H NMR spectra were
recorded at 600MHz 25K on a JNM－ECZ600R/S3 NMR
spectrometer.
General procedure for Host-guest interactions of
cinnamyl alcohol (1a) and 2-hydroxypyridine (2a-H)
by 1H NMR titration experiments. The stock solution of
Cinnamyl alcohol 1a (224mM, 800μL) was prepared by
directly dissolving 24.0 mg power in 800μL CDCl3. The
stock solution of 2-hydroxypyridine 2a-H (2.24M, 157μL)
was prepared by directly dissolving 33.5mg power in 157μL
CDCl3.
H
NMR (600 MHz, CDCl3) δ 7.47 – 7.42 (m, 1H), 7.36 – 7.31
(m, 1H), 7.31 – 7.27 (m, 2H), 7.24 – 7.21 (m, 3H), 7.16 (t, J =
7.4 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 15.9 Hz,
1H), 6.22 (dt, J = 15.9, 5.8 Hz, 1H), 4.73 (dd, J = 5.8, 1.5 Hz,
2H); 13C {1H} NMR (150 MHz, CDCl3) δ 170.0, 137.1, 136.0,
133.6, 128.7, 128.2, 126.6, 126.5, 123.3, 122.8, 122.7, 122.2, 111.2,
44.7; m/z (EI) : 267, 249, 234, 223, 212, 207, 193, 176, 165,
150, 136, 122, 117, 115, 106, 91, 78, 69, 65, 57, 54, 51.
(E)-3-(3-(4-Methoxyphenyl)allyl)quinazolin-4(3H)-
one (3e). Colorless solid, m.p. 122-124 oC, (EA/PE = 0 ~ 1/2,
125.5 mg, 86%). 16 1H NMR (600 MHz, CDCl3) δ 8.37 – 8.28
(m, 1H), 8.09 (s, 1H), 7.80 – 7.65 (m, 2H), 7.50 – 7.48 (m,
1H), 7.28 (dd, J = 9.0, 2.4 Hz, 2H), 6.81 (dd, J = 9.0, 2.4 Hz,
2H), 6.59 (d, J = 15.6 Hz, 1H), 6.18 (dt, J = 15.6, 6.6 Hz, 1H),
4.80 – 4.71 (m, 2H), 3.77 (s, 3H); 13C {1H} NMR (150 MHz,
CDCl3) δ 161.0, 159.8, 148.2, 146.3, 134.4, 134.2, 128.6, 128.0,
127.6, 127.4, 126.9, 122.2, 120.5, 114.1, 55.4, 48.4; m/z (EI) :
292, 280, 267, 261, 249, 235, 229, 207, 201, 191, 171, 147, 131,
115, 103, 91, 77, 63, 55, 51.
(E)-3-(3-(4-Fluorophenyl)allyl)quinazolin-4(3H)-one
(3f). Colorless solid, m.p. 110-111 oC, (EA/PE = 0 ~ 1/3, 126.0
mg, 90%).17 1H NMR (600 MHz, CDCl3) δ 8.33 – 8.26 (m,
1H), 8.06 (s, 1H), 7.76 – 7.64 (m, 2H), 7.47 (t, J = 7.2 Hz,
1H), 7.28 (dd, J = 8.4, 5.4 Hz, 2H), 6.95 (t, J = 8.4 Hz, 2H),
6.57 (d, J = 15.6 Hz, 1H), 6.22 (dt, J = 15.6, 6.6 Hz, 1H), 4.73
(d, J = 6.0 Hz, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 162.7
(d, J = 247.6 Hz), 161.0, 148.2, 146.2, 134.4, 133.3, 132.1 (d, J =
2.6 Hz), 128.3 (d, J = 7.8 Hz), 127.5 (d, J = 25.5 Hz), 126.8,
122.7, 122.2, 115.7 (d, J = 21.7 Hz), 48.2; m/z (EI) : 280, 265,
251, 232, 221, 207, 199, 191, 171, 165, 147, 135, 120, 115, 109, 102,
90, 83, 76, 63, 57, 50.
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500μL 1a stock solution was transferred to an NMR tube
and was titrated with 100 μL 2a-H (2.24M), added in 5μL
increments for 10 times and 10μL increments for 5 times,
and then with 32.1mg 2a-H powder, added in 10.7mg
increments for 3 times. The details were summarized in
Table S3. The chemical shift of hydroxyl protons (–OH) of
1
host (-OH of 1a) was referenced to TMS. All H NMR
spectra were recorded at 600 MHz 298 K on a JNM －
ECZ600R/S3 NMR spectrometer.
Typical Procedures for mild allylic substitution of
tautomerizable heteroarenes with allylic alcohols.
The mixture of cinnamyl alcohol 1a (80.4 mg, 0.60 mmol)
and 2-hydroxypyridine 2a-H (47.5 mg, 0.50 mmol),
[Pd(allyl)Cl]2 (4.6 mg, 2.5 mol%), dppf (13.8 mg, 10 mol%)
and cyclohexane (1.0 mL) was sealed in a Schlenk tube (20
mL) under N2, and stirred at 60 oC (oil bath) for 12 h. The
reaction was then monitored by TLC and/or GC-MS. After
completion of the reaction, the reaction mixture was
purified by flash column chromatography on silica gel
using ethyl acetate and petroleum ether (EA/PE = 0 ~ 1/1)
as the eluent, giving 3a in 90% isolated yield.
1-Cinnamylpyridin-2(1H)-one (3a). Colorless oil,
(EA/PE = 0 ~ 1/1, 95.0 mg, 90%).5d 1H NMR (600 MHz,
CDCl3) δ 7.35 (d, J = 7.4 Hz, 2H), 7.33 – 7.27 (m, 4H), 7.23
(dd, J = 8.2, 6.3 Hz, 1H), 6.65 – 6.51 (m, 2H), 6.29 (dt, J =
15.8, 6.5 Hz, 1H), 6.23 – 6.05 (m, 1H), 4.70 (dd, J = 6.3, 1.0
Hz, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 162.6, 139.6,
137.1. 136.1, 134.1, 128.7, 128.2, 126.7, 123.7, 121.2, 106.3, 50.8;
m/z (EI) : 211, 194, 182, 171, 152, 146, 133, 120, 117, 115, 102, 96,
91, 78, 65, 51.
(E)-3-(3-(4-Chlorophenyl)allyl)quinazolin-4(3H)-one
o
(3g). Colorless solid, m.p. 138-139 C, (EA/PE = 0 ~ 1/3,
1
136.1 mg, 92%). H NMR (600 MHz, CDCl3) δ 8.32 (dd, J =
8.4, 1.2 Hz, 1H), 8.07 (s, 1H), 7.78 – 7.74 (m, 1H), 7.71 (d, J =
7.8 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.28 – 7.23 (m, 4H),
6.58 (d, J = 15.6 Hz, 1H), 6.30 (dt, J = 15.6, 6.6 Hz, 1H), 4.77
13
(dd, J = 6.0, 1.2 Hz, 2H); C {1H} NMR (150 MHz, CDCl3) δ
161.0, 148.2, 146.2, 134.5, 134.3, 134.0, 133.2, 128.9, 127.9,
127.64, 127.55, 126.9, 123.6, 122.19, 48.2; m/z (EI) : 298, 297,
296, 281, 267, 253, 207, 191, 184, 176, 171, 151, 147, 125, 115, 102,
90, 76, 63, 58, 50. HRMS (ESI-TOF) m/z: (M+H)+ calcd for
C17H14ClN2O 297.0795, found 297.0807.
(E)-3-(3-(2-Methoxyphenyl)allyl)quinazolin-4(3H)-
one (3h). Colorless solid, m.p. 112-113 oC, (EA/PE = 0 ~ 1/2,
1
122.6 mg, 84%). H NMR (600 MHz, CDCl3) δ 8.31 (d, J =
7.8 Hz, 1H), 8.10 (s, 1H), 7.73 –7.68 (m, 2H), 7.47 (t, J = 7.8
Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.23 – 7.18 (m, 1H), 6.99 (d,
J = 15.6 Hz, 1H), 6.89 – 6.80 (m, 2H,), 6.35 (dt, J = 15.6, 6.6
Hz, 1H), 4.77 (d, J = 6.6 Hz, 2H), 3.80 (s, 3H); 13C {1H} NMR
(150 MHz, CDCl3) δ 161.0, 156.9, 148.2, 146.4, 134.3, 130.0,
129.4, 127.6, 127.4, 127.3, 126.9, 124.8, 123.5, 122.3, 120.7, 110.9,
55.5, 48.8; m/z (EI) : 292, 280, 273, 249, 235, 229, 207, 201,
191, 171, 147, 131, 115, 103, 91, 77, 63, 55, 51. HRMS (ESI-TOF)
m/z: (M+H)+ calcd for C18H17N2O2 293.1290, found
293.1268.
3-Cinnamylquinazolin-4(3H)-one (3c). Colorless solid,
o
5d
m.p. 108-109 C, (EA/PE = 0 ~ 1/3, 123.5 mg, 94%). 1H
NMR (600 MHz, CDCl3) δ 8.34 – 8.29 (m, 1H), 8.08 (s, 1H),
7.75 – 7.68 (m, 2H), 7.50 – 7.46 (m, 1 H), 7.36 – 7.31 (m,
2H), 7.27 (t, J = 7.5 Hz, 2H), 7.24 – 7.20 (m, 1 H), 6.63 (d, J
= 15.9 Hz, 1H), 6.31 (dt, J = 15.8, 6.4 Hz, 1H), 4.75 (dd, J =
6.8, 1.1 Hz, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 161.0,
148.2, 146.3, 135.8, 134.5, 134.4, 128.7, 128.4, 127.6, 127.5,
126.9, 126.7, 122.9, 122.2, 48.3; m/z (EI) : 262, 247, 233, 216,
201, 191, 184, 171, 147, 130, 117, 115, 102, 91, 77, 63, 51.
1-Allylpyridin-2(1H)-one (3i). Colorless oil (EA/PE = 0 ~
8a
1/1, 55.3 mg, 82%).
1H NMR (600 MHz, CDCl3) δ 7.30
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(ddd, J = 8.8, 6.6, 1.8 Hz, 1H), 7.23 (dd, J = 6.6, 1.8 Hz, 1H),
ASSOCIATED CONTENT
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7
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6.56 (d, J = 8.8 Hz, 1H), 6.28 – 6.10 (m, 1H), 6.04 – 5.84 (m,
1H), 5.23 (d, J = 10.4 Hz, 1H), 5.16 – 5.14 (m, 1H), 4.54 (d, J =
5.4 Hz, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 162.5, 139.6,
137.2, 132.6, 121.2, 118.5, 106.2, 51.1; m/z (EI) : 135, 133, 128,
120, 118, 109, 106, 96, 92, 79, 78, 67, 51.
Supporting Information
Details of the control experiments for mechanistic studies
are supplied as Supporting Information (file type, i.e., PDF)
and this material is available free of charge via the Internet at
http://pubs.acs.org.”
1-(Cyclohex-2-en-1-yl)pyridin-2(1H)-one (3j). Colorless
1
oil, (EA/PE = 0 ~ 1/1, 77.9 mg, 89%). H NMR (600 MHz,
AUTHOR INFORMATION
CDCl3) δ 7.47 – 7.29 (m, 1H), 7.29 – 7.15 (m, 1H), 6.51 –6.45
(m, 1H), 6.13 –6.08 (m, 2H), 5.59 – 5.41 (m, 2H), 2.11 –2.05
(m, 3H), 1.74 – 1.56 (m, 2H), 1.54 – 1.47 (m, 1H); 13C {1H}
NMR (150 MHz, CDCl3) δ 162.6, 139.0, 134.9, 134.1, 126.2,
120.5, 105.9, 51.2, 29.7, 24.7, 19.7; m/z (EI) : 175, 165, 161, 157,
146, 141, 127, 122, 118, 113, 109, 96, 81, 80, 79, 78, 77, 67, 66,
60, 57, 53, 52, 51. HRMS (ESI-TOF) m/z: (M+H)+ calcd for
C11H14NO 176.1075, found 176.1071.
3-Allylquinazolin-4(3H)-one (3k). Colorless solid, m.p.
63-64 oC, (EA/PE = 0 ~ 1/3, 76.2 mg, 82%). 5d 1H NMR (600
MHz, CDCl3) δ 8.29 (dd, J = 7.8, 1.2 Hz, 1H), 8.00 (s, 1H),
7.75 – 7.68 (m, 2H), 7.50 – 7.47 (m, 1H), 6.00 – 5.94 (m,
1H), 5.35 – 5.20 (m, 2H), 4.62 (dt, J = 6.0, 1.2 Hz, 2H); 13C
{1H} NMR (150 MHz, CDCl3) δ 160.9, 148.2, 146.3, 134.4,
131.9, 127.6, 127.4, 126.9, 122.2, 119.0, 48.4; m/z (EI) : 186, 185,
171, 169, 157, 145, 143, 132, 130, 118, 102, 92, 91, 89, 78, 76, 75,
65, 63, 56, 54, 52, 50.
Corresponding Author
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* xiantaoma@126.com
ORCID
Xiantao Ma: 0000-0002-0012-6944
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the Foundation of Key Scientific and
Technological Project of Henan Province (192102310031 ，
182400410166)，the Key Research Programs in Universities of
Henan Province (19B150018, 18A150049), the National Natural
Science Foundation of China (No. 21804117), the Nanhu
Scholars Program for Young Scholars of XYNU, the Young
Core Instructor Program of XYNU (2018GGJS—05) and
Research and innovation projects for college students
(2019-DXS-026). We also thank Prof. Filip Ulatowski and
Prof. Janusz Jurczak at Polish Academy of Sciences for their
(E)-3-(Hex-2-en-1-yl)quinazolin-4(3H)-one
(3l).
1
Colorless oil (EA/PE = 0 ~ 1/3, 74.1 mg, 65%). H NMR
(600 MHz, CDCl3) δ 8.30 (dd, J = 8.4, 1.2 Hz, 1H), 8.02 (s,
1H), 7.74 – 7.74 (m, 1H), 7.49 – 7.47 (m, 2H), 5.83 – 5.68 (m,
1H), 5.66 – 5.56 (m, 1H), 4.56 (d, J = 6.0 Hz, 2H), 2.02 (q, J
= 7.2 Hz, 2H), 1.41 – 1.35 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H);
13C {1H} NMR (150 MHz, CDCl3) δ 161.0, 148.2, 146.3, 136.5,
134.3, 127.5, 127.3, 126.9, 123.7, 122.2, 48.0, 34.3, 22.1, 13.7;
m/z (EI) : 228, 211, 2017, 199, 197, 185, 171, 147, 129, 127, 118,
102, 99, 94, 91, 90, 82, 76, 67, 63, 65, 53, 50. HRMS (ESI-
TOF) m/z: (M+H)+ calcd for C14H17N2O 229.1341, found
229.1322.
1
kindly help on the data analysis of Job’s Plot and HNMR
titration experiments.
REFERENCES
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3-(Cyclohex-2-en-1-yl)quinazolin-4(3H)-one
(3m).
Colorless oil (EA/PE = 0 ~ 1/3, 82.5 mg, 73%). 5d 1H NMR
(600 MHz, CDCl3) δ 8.30 (dd, J = 8.4, 1.2 Hz, 1H), 8.15 (s,
1H), 7.77 – 7.71 (m, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.49 – 7.47
(m, 1H), 6.23 – 6.20 (m, 1H), 5.64 – 5.62 (m, 1H), 5.56 – 5.53
(m, 1H), 2.27 – 2.08 (m, 3H), 1.80 – 1.72 (m, 2H), 1.72 – 1.62
(m, 1H); 13C {1H} NMR (150 MHz, CDCl3) δ 161.0, 148.0,
144.9, 134.7, 134.3, 127.4, 127.2, 126.9, 125.3, 122.0, 50.0, 29.9,
24.7, 19.7; m/z (EI) : 226, 197, 185, 171, 147, 130, 118, 102, 90,
80, 77, 63, 55, 53.
Typical Procedures for mild allylic substitution of 2-
hydroxypyridine 2a-H with cinnamyl alcohol 1a on a
large scale. The mixture of cinnamyl alcohol 1a (804.9
mg, 6.0 mmol) and 2-hydroxypyridine 2a-H (475.0 mg,
5.0 mmol), [Pd(allyl)Cl]2 (46.6 mg, 2.5 mol%), dppf (138.0
mg, 10 mol%) and cyclohexane (5.0 mL) was sealed in a
Catalyzed
Allylic
Substitution
Reaction
of
o
Schlenk tube (20 mL) under N2, and stirred at 65 C (oil
Benzothiazolylacetamide with Allylic Alcohols in Water, J. Org.
Chem. 2019, 84, 10111-10119. (g) Yan, P.; Pan, S.; Hu, J.; Lu, L.; Zeng,
X.; Zhong, G.; Palladium Catalyzed Controllable Mono‐ or Di‐
Allylic Substitution Reaction of Benzothiazolylacetate with
Allylic Alcohols, Adv. Synth. Catal. 2019, 361, 1322-1334. (h) Xie, P.;
Fu, W.; Cai, X.; Sun, Z.; Wu, Y.; Li, S.; Gao, C.; Yang, X.; Loh, T.-
P.; A Ba/Pd Catalytic System Enables Dehydrative Cross-
bath) for 17 h. The reaction was then monitored by TLC
and/or GC-MS. After completion of the reaction, the
reaction mixture was purified by flash column
chromatography on silica gel using ethyl acetate and
petroleum ether (EA/PE = 0~ 1/1) as the eluent, giving 3a
in 93% isolated yield (0.981 g).
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Coupling and Excellent E-Selective Wittig Reactions, Org. Lett.
2019, 21, 7055-7059.
Heteroaryl Chloride, Sodium Thiosulfate Pentahydrate, and
Alcohol, J. Org. Chem. 2019, 84, 11294-11300.
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[3] For selected examples based on theoretical calculations, see:
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direct use of allyl alcohol for Tsuji-Trost reaction without
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Thoumazet, C.; Jean, Y.; le Floch, P.; DFT study on the
palladium-catalyzed allylation of primary amines by allylic
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unsaturated γ-lactams by stereoselective amination of α-tertiary
allylic alcohols, Angew. Chem. Int. Ed. 2018, 57, 16727-16731. and
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[7] Jiang and coworkers hypothesized a substrate self-activation
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elusory character of hydrogen bond, no theoretical calculations
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[8] (a) Feng, B.; Li, Y.; Li, H.; Zhang, X.; Xie, H.; Cao, H.; Yu, L.;
Xu, Q.; Specific N-Alkylation of Hydroxypyridines Achieved by a
Catalyst- and Base-Free Reaction with Organohalides, J. Org.
Chem. 2018, 83, 6769-6775. (b) Tsuchida, N.; Yamabe, S.;
Reaction Paths of Tautomerization between Hydroxypyridines
and Pyridones, J. Phys. Chem. A, 2005, 109, 1974-1980.
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[4] For rare examples based on experimental approaches, see: (a)
Ozawa, F.; Okamoto, H.; Kawagishi, S.; Yamamoto, S.; Minami,
[9] Allylic alcohols might be activated by DMC via
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direct benzylation/allylation of malonates with alcohols – in situ
C–O bond activation, Green Chem., 2016, 18, 2638-2641.
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mechanistic study,
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Jagadeesh, R.V.; Junge, K.; Junge, H.; Beller, M.; Efficient and
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Palladium catalyzed direct allylation of azlactones with simple
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25596-25599. (d) Kumar, D.; Vemula, S. R.; Cook, G. R.; Highly
chemo-
and
regioselective
allylic
substitution
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allylic alkylation of β-ketoesters with allylic alcohols by a
nickel/diphosphine catalyst, Angew. Chem. Int. Ed. 2016, 55,
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Achard, M., Access to 3-oxindoles from allylic alcohols and
indoles, Chem. Eur. J. 2018, 24, 7964-7969. (g) Sweeney, J. B.; Ball,
A. K.; Smith, L. J.; Catalytic C-C bond formation using a simple
nickel precatalyst system: base- and activator-free direct C-
allylation by alcohols and amines, Chem. Eur. J. 2018, 24, 7354-
7357. (h) Shimizu, A.; Hirata, G.; Onodera, G.; Kimura, M.; Direct
allylation of active methylene compounds with allylic alcohols
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Synth. Catal. 2018, 360, 1954-1960.
[6] (a) Ma, X.; Yu, J.; Han, C.; Zhou, Q.; Ren, M.; Li, L.; Tang, L.;
Dehydrative synthesis of functionalized skipped dienes from
stabilized phosphonium ylides and allylic alcohols in water, Adv.
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R.; Zheng, L.; Wang, L.; Substrate Self-Assisted Secondary Bond
Activation of Allylic Alcohol in Tsuji–Trost Reaction Revealed by
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J.; Ma, R.; Yan, R.; Zhang, Z.; Palladium-catalyzed dehydrative
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Yan, R.; Yan, M.; Xu, Q.; Promoting Effect of Crystal Water
Leading to Catalyst-Free Synthesis of Heteroaryl Thioether from
[12] Thanks for one of the reviewers’ kind suggestions, the job’s
plot experiments was carried at a very high concentration (ca.
225 mM) to obtain the reliable stoichiometry between cinnamyl
alcohol (1a) and 2-hydroxypyridine (2a-H). For reference, see: F.
Ulatowski, K. Da˛browa, T. Bałakier, J. Jurczak, Recognizing the
limited applicability of Job’s plots in studying host-guest
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[13] See SI for details.
[14] The data of 1HNMR titration experiments and residual
distribution analysis was dealt with Thordarson’s free program at
http://supramolecular.org/. For reference, see: P. Thordarson,
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[15] The synergistically activation of allylic alcohols by substrate-
assisted intermolecular hydrogen bond and Pd catalyst led to the
efficient cleavage of C-O bonds, therefore, the reaction can only
occur in an appropriate reaction temperature.
[16] Lu, C.-J.; Chen, D.-K.; Chen, H.; Wang, H.; Jin, H.;Huang, X.;
Gao, J.; Palladium-catalyzed allylation of tautomerizable
heterocycles with alkynes, Org. Biomol. Chem. 2017, 15, 5756-
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[17] Vemula, S. R.; Kumar, D.; Cook, G. R.; Palladium-Catalyzed
Allylic Amidation with N-Heterocycles via sp3 C–H Oxidation,
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