Pd-Catalyzed Dehydrogenative Oxidation of Alcohols to Functionalized Molecules

Article abstract of DOI:10.1021/acs.oprd.9b00207

A dehydrogenative oxidation reaction of primary alcohols to aldehydes catalyzed by a simple Pd/Xantphos catalytic system was developed under an argon or nitrogen atmosphere without oxidizing agents or hydrogen acceptors. The reaction product could be easily changed: under aerobic conditions, esters were obtained in aprotic solvents, whereas the corresponding carboxylic acids were produced in aqueous media. These oxidizing processes were applicable to the efficient synthesis of useful nitrogen-containing heterocyclic compounds such as indole, quinazoline, and benzimidazole via intramolecular versions of this reaction from amino alcohols.

Full text of DOI:10.1021/acs.oprd.9b00207

Communication
pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Pd-Catalyzed Dehydrogenative Oxidation of Alcohols to
Functionalized Molecules
Takamichi Mori,*,† Chihiro Ishii,‡ and Masanari Kimura*,‡
†Department of Applied Chemistry, Faculty of Engineering, Sanyo-Onoda City University, 1-1-1 Daigakudori, Sanyo-Onoda,
Yamaguchi 756-0884, Japan
‡Graduate School of Engineering, Nagasaki University, 1-14 Bunkyo machi, Nagasaki 852-8521, Japan
S
* Supporting Information
ABSTRACT: A dehydrogenative oxidation reaction of
primary alcohols to aldehydes catalyzed by a simple Pd/
Xantphos catalytic system was developed under an argon
or nitrogen atmosphere without oxidizing agents or
hydrogen acceptors. The reaction product could be easily
changed: under aerobic conditions, esters were obtained
in aprotic solvents, whereas the corresponding carboxylic
acids were produced in aqueous media. These oxidizing
processes were applicable to the efficient synthesis of
Figure 1. Dehydrogenation reactions of alcohols to aldehydes, esters,
and carboxylic acids.
useful nitrogen-containing heterocyclic compounds such
as indole, quinazoline, and benzimidazole via intra-
molecular versions of this reaction from amino alcohols.
formed Pd/Xantphos complex seems to achieve dehydrogen-
ation from the alkylpalladium intermediate.
KEYWORDS: oxidation, hydrogen transfer, palladium,
Herein we disclose a Pd/Xantphos catalytic system that
accelerates the transformation of primary alcohols to aldehydes
via dehydrogenative oxidation processes. A similar catalytic
system under aerobic conditions also provides an easy route to
esters and carboxylic acids (Figure 2). Furthermore, these
aldehyde, ester, carboxylic acid
INTRODUCTION
■
The selective oxidation of alcohols to the corresponding
carbonyl compounds is one of the most fundamental and
useful transformations in both organic synthesis and industrial
chemistry.1 Various classical methods for the oxidation of
alcohols have been well-developed to date, for example, the use
of stoichiometric amounts of oxidizing agents such as
chromium salts or MnO2,2 Swern oxidizing agents,3 and the
Dess−Martin reagent,4 all of which produce large amounts of
inorganic or organic toxic waste as byproducts.5 Hydrogen
transfer oxidation reactions without any oxidizing reagents are
among the most straightforward and superior protocols from a
green chemistry viewpoint.6 Although dehydrogenative
oxidations of alcohols to aldehydes,7−10 esters,11,12 and
carboxylic acids catalyzed by homogeneous transition metals
(e.g., ruthenium, rhodium, and iridium; Figure 1) are known,13
each product requires its own catalytic system. From this point
of view, it would be worthwhile to develop a new industrially
relevant catalytic system that can control the selective
oxidation of alcohols.
Figure 2. Pd/Xantphos-catalyzed selective oxidation reactions of
alcohols.
oxidizing reactions are amenable to the efficient synthesis of
useful nitrogen-containing heterocyclic compounds such as
indole, quinazoline, and benzimidazole via acceptorless
dehydrogenative condensation from the corresponding amino
alcohols.
We recently found that Pd/Xantphos catalysts can be used
for efficient dehydrogenative carbonyl−ene-type reactions of
aldehydes in the presence of conjugated dienes to provide
dienyl alcohols.14 In that case, the Pd/Xantphos catalytic
system promotes the dehydrogenative coupling reaction
between the aldehyde and the conjugated diene via β-hydride
elimination of the key oxapalladacycle intermediate. Thus, the
Special Issue: Honoring 25 Years of the Buchwald-Hartwig
Amination
Received: May 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.9b00207
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Communication
RESULTS AND DISCUSSION
Table 2. Pd/Xantphos-Catalyzed Dehydrogenation
a b
■
,
Reaction under Ar
The dehydrogenative oxidations of benzyl alcohol (1a) to
benzaldehyde (2a) using various kinds of palladium catalysts,
solvents, and ligands under argon were investigated, and the
results are shown in Table 1. Pd(OAc)2 was used as a catalyst
Table 1. Optimization of the Reaction Conditions for the
a
Oxidation of Alcohols under Ar
yield of 2a
b
entry metal catalyst
ligand (mmol)
solvent
toluene
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
none
none
none
PPh3 (0.1)
PCy3 (0.1)
(n-Bu)3P (0.1)
Xphos (0.1)
dppb (0.05)
0
6
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd2(dba)3
Pd(acac)2
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMF
13
17
52
35
74
33
90
9
42
25
13
23
12
trace
50
dppf (0.05)
DPEphos (0.05)
Xantphos (0.05)
Xantphos (0.05)
Xantphos (0.05)
Xantphos (0.05)
Xantphos (0.05)
Xantphos (0.05)
Xantphos (0.05)
Xantphos (0.05)
Xantphos (0.05)
DMA
1,4-dioxane
THF
17
c
18
a
The reaction was undertaken in the presence of alcohol 1a (1.0
mmol), transition-metal catalyst (0.05 mmol) and ligand (0.05−0.1
mmol) in solvent (3 mL) at 100 °C for 48 h under argon.
b
Determined by NMR analysis using ferrocene as an internal
c
standard. The reaction temperature was 60 °C.
in the absence of a ligand or in the presence of a wide variety of
ligands. In the presence of monodentate phosphine ligands
such as PPh3, PCy3, (n-Bu)3P, and Xphos, low to moderate
catalytic formation of benzaldehyde occurred (3−52% yield;
Table 1, entries 3−6). Bidentate phosphine ligands such as
dppp, dppf, DPEphos, and Xantphos tended to show higher
reactivity than the monodentate phosphine ligands (Table 1,
entries 7−10). In the presence of 0.05 mmol of Pd(OAc)2 with
0.05 mmol of Xantphos under an argon atmosphere,
benzaldehyde was obtained in 90% yield (Table 1, entry 10).
Next, we examined the reactions with various kinds of
palladium catalysts under argon at atmospheric pressure
(Table 1, entries 11−14). It became clear that a combination
of Pd(OAc)2 and a Xantphos ligand was the most effective
catalytic system for these dehydrogenative oxidation processes.
Various solvents such as toluene, DMF, DMA, 1,4-dioxane,
and THF were used, and it was found that toluene at 100 °C
provided the most efficient dehydrogenative oxidation of
benzyl alcohol to benzaldehyde (Table 1, entries 15−18).
Using these optimized catalytic conditions, we studied the
dehydrogenative oxidation reactions of different benzyl alcohol
derivatives 1 to give the corresponding aldehydes 2, and these
results are summarized in Table 2. As the oxidation of 1a in the
a
The reactions were undertaken in the presence of alcohols 1 (1.0
mmol), Pd(OAc)2 catalyst (0.05 mmol), and Xantphos (0.05 mmol)
in toluene (3 mL) at 100 °C for 48 h under argon. Yields were
determined by NMR analysis using ferrocene as an internal standard.
b
presence of Pd/Xantphos in toluene afforded 2a in 90% yield
(Table 2, entry 1), we also performed experiments with benzyl
alcohol derivatives bearing electron-donating and electron-
withdrawing groups. The reaction of the sterically demanding
alcohol 2-methylbenzyl alcohol (1b) proceeded to give the
corresponding aldehyde 2b in 76% yield (Table 2, entry 2).
The reactions of 2-pyridinemethanol (1i), furfuryl alcohol (1j),
and 3-thiophenemethanol (1k) proceeded to afford 2i, 2j, and
B
DOI: 10.1021/acs.oprd.9b00207
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Communication
2k, respectively, in high yields (Table 2, entries 9−11). The
oxidation of cinnamyl alcohol (1l) and 3-methyl-2-buten-1-ol
(1m) also provided the corresponding α,β-unsaturated
aldehydes 2l and 2m, respectively (Table 2, entries 12 and
13). Moreover, aliphatic primary alcohols were tolerated and
provided the expected aldehydes, albeit in modest yields
(Table 2, entries 14−17). A sec-alkyl alcohol, 1-methylbenzyl
alcohol, afforded the desired ketone in quantitative yield
(Table 2, entry 18). Furthermore, we succeeded in extending
the reaction to a multigram scale for the efficient synthesis of
aldehydes from alcohols (Scheme 1).
Table 3. Pd/Xantphos-Catalyzed Oxidation Reactions under
Aerobic Conditions
a b
,
a
Scheme 1. Multigram-Scale Synthesis of Aldehyde 2a
a
The reaction was undertaken in the presence of alcohol 1a (2.16 g,
20.0 mmol), Pd(OAc)2 catalyst (0.05 mmol), and Xantphos (0.05
mmol) at reflux for 48 h under an argon atmosphere without solvent.
Aldehyde 2a was isolated in 84% yield (1.78 g, 16.8 mmol), and
distilled using a Kugelrohr apparatus (bp 80 °C, 30 mmHg).
The products of the oxidation of alcohols promoted by Pd/
Xantphos could be changed to favor the formation of esters by
performing the reaction under aerobic conditions instead of an
argon atmosphere (Table 3). Esters were obtained as the main
products with 2 equiv of the alcohols. The esterification
reactions of benzyl alcohol, cyclohexylmethanol, and 3,5,5-
trimethyl-1-hexanol gave the corresponding esters in good
yields (Table 3, entries 1−3). The oxidation reactions of 1,4-
butanediol and 1,2-benzenedimethanol under aerobic con-
ditions proceeded to provide the expected lactones via
intramolecular oxidative cyclization (Table 3, entries 4 and
5). When water was used as the solvent instead of an aprotic
solvent, carboxylic acids were readily produced exclusively.
The reactions of the benzyl alcohol derivatives proceeded to
give the corresponding benzoic acids (Table 3, entries 6 and
7). Oxidation of cinnamyl alcohol provided cinnamic acid (4l)
in 59% yield, and aliphatic primary alcohols also participated in
a similar oxidation process to afford the corresponding
aliphatic carboxylic acids 4n and 4p in 88% and 47% yield,
respectively (Table 3, entries 8−10).
a
The reactions were undertaken in the presence of alcohols 1 (1.0
mmol), Pd(OAc)2 catalyst (0.05 mmol), and Xantphos (0.05 mmol)
in the solvent (3 mL) at 100 °C for 48 h under aerobic conditions.
b
Yields were determined by NMR analysis using ferrocene as an
c
internal standard. The reaction was performed at reflux temperature.
Table 4. Synthesis of Indoles via Oxidation of Alcohols
Catalyzed by Pd/Xantphos
a b
,
A series of these oxidation reactions were applicable to the
synthesis of nitrogen-containing heterocycles such as indoles
and quinazolines via acceptorless dehydrogenative condensa-
tion of amino alcohols (Tables 4 and 5).15 When 2-(2-
aminophenyl)ethanol (5a) was treated with Pd/Xantphos
under argon at atmospheric pressure, indole (6a) was obtained
via an intramolecular cyclization in high yield. We examined
the scope of the reaction with various 2-(2-aminophenyl)-
ethanol derivatives under similar catalytic conditions, and
substrates bearing an electron-donating or electron-with-
drawing group were also tolerated (Table 4). Furthermore,
when 2-aminobenzylamine and benzyl alcohols were treated
under similar catalytic conditions, quinazoline frameworks
were constructed via intermolecular oxidative condensation in
a single operation. Some representative examples of the
oxidative coupling reactions of substituted benzyl alcohols
and 2-aminobenzylamine are summarized in Table 5.
Irrespective of the electronic nature of the benzyl alcohol,
substituted benzyl alcohols such as 4-methoxybenzyl alcohol
a
The reactions were undertaken in the presence of amino alcohols 5
(1.0 mmol), Pd(OAc)2 catalyst (0.05 mmol), and Xantphos (0.05
mmol) in CH3CN (3 mL) at 80 °C for 48 h under argon. Isolated
yields are shown.
b
and 4-nitrobenzyl alcohol provided the desired heterocyclic
compounds 8b and 8c (Table 5). Although 4-trifluoromethyl-
substituted benzyl alcohol did not give the corresponding
product in high yield, this procedure is clearly useful for the
simple synthesis of fluorinated nitrogen-containing hetero-
cyclic compounds.
The dehydrogenative coupling reaction of 1,2-phenylenedi-
amine with benzyl alcohol is also a straightforward synthetic
route to benzimidazole (Scheme 2). This coupling reaction
proceeds via three-steps: dehydrogenation of the alcohol,
C
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Table 5. Synthesis of Quinazolines via Oxidation of
Alcohols Catalyzed by Pd/Xantphos
Scheme 3. Plausible Mechanism for the Oxidation of Benzyl
Alcohol Catalyzed by Pd/Xantphos
a b
,
a
The reactions were undertaken in the presence of 7 (1.0 mmol),
alcohols 1 (2.5 mmol), Pd(OAc)2 catalyst (0.05 mmol), and
Xantphos (0.05 mmol) in anisole (3 mL) at 100 °C for 48 h under
b
argon. Isolated yields are shown.
Scheme 2. Synthesis of Benzimidazole 10a via Oxidation of
a b
,
Alcohol 1a Catalyzed by Pd/Xantphos
a
The reaction was undertaken in the presence of 9 (1.0 mmol), 1a
(4.0 mmol), Pd(OAc)2 catalyst (0.05 mmol), and Xantphos (0.05
b
mmol) in CH3CN (3 mL) at 80 °C for 48 h under argon. The
isolated yield is shown.
promoted by Pd/Xantphos catalytic system under an argon or
nitrogen atmosphere without oxidizing agents. Under aerobic
conditions, esters are obtained in aprotic solvents, whereas the
corresponding carboxylic acids are produced in aqueous media.
These oxidizing processes can be applied to the efficient
synthesis of useful nitrogen-containing heterocyclic com-
pounds such as indoles, quinazolines, and benzimidazoles via
intramolecular acceptorless dehydrogenative condensation
from amino alcohols. All of the methods described herein
would be convenient and straightforward synthetic method-
ologies toward the synthesis of physiologically active molecules
and medicinal compounds.
condensation of the diamine with the aldehyde, and
dehydrogenation of the hemiaminal. It is noteworthy that the
Pd/Xantphos catalytic system promotes the consecutive
dehydrogenation and dehydration processes to provide
important nitrogen-containing heterocycles such as quinazo-
lines and benzimidazoles in a single manipulation (Table 5 and
Scheme 2).
A plausible reaction mechanism for the dehydrogenative
oxidation of benzyl alcohol to benzaldehyde is shown in
Scheme 3. The Pd(OAc)2/Xantphos complex might add to
benzyl alcohol to provide coordinated benzyloxypalladium
acetate III via σ-bond metathesis with the liberation of AcOH.
This benzyloxypalladium acetate would readily undergo β-
hydride elimination to form benzaldehyde along with
palladium hydride complex IV.11g Bidentate phosphine ligands
with a large bite angle, such as Xantphos, seem to prefer the β-
hydride elimination to the reductive elimination.16 Thus, the
formed palladium hydride complex IV would undergo the
exchange reaction with benzyl alcohol followed by a second σ-
bond metathesis from intermediate V to afford dihydropalla-
dium complex VII with the formation of benzaldehyde. The
reductive elimination of hydrogen gas from dihydropalladium
complex VII might proceed to give rise to Pd(0)/
Xantphos.11h,17 Oxidative addition of the generated AcOH to
the Pd(0) species seems to provide palladium hydride complex
IV as an active catalyst.18
EXPERIMENTAL SECTION
■
Reactions employed oven-dried glassware unless otherwise
noted. Distillations were carried out in a Kugelrohr apparatus
(SIBATA GTO-350RG glass tube oven). Boiling points are
meant to refer to the oven temperature ( 1 °C). Micro-
analyses were performed by the Instrumental Analysis Center
of Nagasaki University. Thin-layer chromatography employed
glass 0.25 mm silica gel plates with UV indicator (silica gel 60
F
254, Merck). Flash chromatography columns were packed with
230−400 mesh silica gel as a slurry in hexane. Gradient flash
chromatography was conducted by elution with a continuous
gradient from hexane to the indicated solvent. H and 13C
1
NMR data were obtained with a JEOL GX400 NMR
spectrometer using tetramethylsilane as an internal standard.
Chemical shift values are given in parts per million downfield
from the internal standard.
General Procedure 1: Pd/Xantphos-Catalyzed Oxida-
tion of Alcohols to Aldehydes under Argon (Table 1,
entry 10). To a solution of Pd(OAc)2 (11.2 mg, 0.05 mmol)
CONCLUSION
We have developed a simple hydrogen transfer oxidation
reaction that oxidizes primary alcohols to aldehydes and is
■
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and Xantphos (28.9 mg, 0.05 mmol) in dry toluene (3 mL)
was added benzyl alcohol (1a) (108.1 mg, 1.0 mmol) via
syringe under an argon atmosphere. The mixture was stirred at
100 °C for 48 h, and the reaction was monitored by gas
chromatography. The mixture was then dried (MgSO4) and
concentrated in vacuo. The NMR yield of benzaldehyde (2a)
(90%) was determined using ferrocene as an internal standard.
120.9, 148.0, 1530, 177.9; MS (EI) m/z (relative intensity) 96
(M+, 100), 95 (87), 39 (63), 29 (20).
3-Thiophenecarbaldehyde (2k). 1H NMR (400 MHz,
CDCl3) δ 7.38 (m, 1H), 7.55 (dd, J = 5.0, 1.4 Hz, 1H),
8.13 (dd, J = 3.0, 1.4 Hz, 1H), 9.94 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 125.3, 127.4, 136.7, 143.0, 184.9; MS (EI) m/
z (relative intensity) 112 (M+, 97), 111 (100), 83 (38), 45
(36).
1
Benzaldehyde (2a). H NMR (400 MHz, CDCl3) δ 7.53
1
(td, J = 6.8, 1.6 Hz, 2H), 7.63 (tt, J = 6.8, 1.6 Hz, 1H), 7.88
(dt, J = 6.8, 1.6 Hz, 2H), 10.02 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 128.9, 129.6, 134.4, 136.3, 192.3; MS (EI) m/z
(relative intensity) 106 (M+, 82), 105 (80), 77 (100), 51 (61).
2-Methylbenzaldehyde (2b). 1H NMR (400 MHz, CDCl3)
δ 2.66 (s, 3H), 7.25 (dd, J = 7.6, 1.4 Hz, 1H), 7.35 (td, J = 7.6,
1.4 Hz, 1H), 7.47 (td, J = 7.6, 1.4 Hz, 1H), 7.79 (dd, J = 7.6,
1.4 Hz, 1H), 10.26 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
19.5, 126.3, 131.7, 132.0, 133.6, 134.1, 140.5, 192.7; MS (EI)
m/z (relative intensity) 120 (M+, 70), 119 (75), 91 (100), 65
(28).
trans-Cinnamaldehyde (2l). H NMR (400 MHz, CDCl3)
δ 6.72 (dd, J = 16.0, 7.6 Hz, 1H), 7.42−7.49 (m, 4H), 7.55−
7.57 (m, 2H), 9.71 (dd, J = 7.6, 0.8 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 128.4, 128.5, 129.0, 131.2, 133.9, 152.7,
193.6; MS (EI) m/z (relative intensity) 132 (M+, 72), 131
(100), 103 (48), 77 (55), 51 (60).
1
3-Methyl-2-butenal (2m). H NMR (400 MHz, CDCl3) δ
1.99 (d, J = 0.8 Hz, 3H), 2.18 (d, J = 0.8 Hz, 3H), 5.89 (dqq, J
= 8.4, 0.8, 0.8 Hz, 1H), 9.96 (d, J = 8.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 18.6, 26.9, 127.8, 160.3, 190.8; MS (EI)
m/z (relative intensity) 84 (M+, 100), 55 (76), 41 (43), 29
(37).
1
3-Methylbenzaldehyde (2c). H NMR (400 MHz, CDCl3)
Cyclohexanecarbaldehyde (2n). 1H NMR (400 MHz,
CDCl3) δ 1.20−1.43 (m, 5H), 1.65−1.82 (m, 3H), 1.85−1.91
(m, 2H), 2.21−2.26 (m, 1H), 9.62 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 25.0, 25.9, 49.9, 205.0; MS (EI) m/z (relative
intensity) 112 (M+, 10), 83 (27), 68 (25), 55 (100), 41 (50).
δ 2.44 (s, 3H), 7.40−7.44 (m, 2H), 7.67−7.69 (m, 2H), 9.99
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.2, 127.2, 128.9,
130.0, 135.3, 136.5, 138.9, 192.6; MS (EI) m/z (relative
intensity) 120 (M+, 75), 119 (85), 91 (100), 65 (32).
m-Formylbenzonitrile (2d). 1H NMR (400 MHz, CDCl3) δ
7.70 (t, J = 7.8 Hz, 1H), 7.92 (dt, J = 7.8, 1.4 Hz, 1H), 8.13
(dt, J = 7.8, 1.4 Hz, 1H), 8.18 (t, J = 1.4 Hz, 1H), 10.05 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 113.8, 117.5, 130.1,
133.2, 133.3, 136.9, 137.2, 189.9; MS (EI) m/z (relative
intensity) 131 (M+, 70), 130 (100), 102 (58), 76 (30), 50
(25).
1
Octanal (2o). H NMR (400 MHz, CDCl3) δ 0.88 (m,
3H), 1.30 (m, 8H), 1.63 (m, 2H), 2.42 (m, 2H), 9.77 (t, J =
2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.0, 22.1, 22.6,
29.0, 29.1, 31.6, 43.9, 202.9; MS (EI) m/z (relative intensity)
128 (M+, 1), 110 (10), 84 (50), 69 (25), 56 (55), 43 (100).
3,5,5-Trimethylhexanal (2p). 1H NMR (400 MHz, CDCl3)
δ 0.92 (s, 9H), 1.02 (d, J = 7.2 Hz, 3H), 1.16−1.27 (m, 2H),
2.13−2.21 (m, 1H), 2.23−2.30 (m, 1H), 2.37−2.41 (m, 1H),
9.74 (t, J = 2.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 22.9,
24.7, 29.9, 31.2, 50.8, 53.2, 203.1; MS (EI) m/z (relative
intensity) 142 (M+, 1), 109 (15), 98 (23), 83 (40), 57 (100),
41 (25).
m-Chlorobenzaldehyde (2e). 1H NMR (400 MHz, CDCl3)
δ 7.49 (t, J = 7.8 Hz, 1H), 7.59 (dt, J = 7.8, 1.2 Hz, 1H), 7.76
(dt, J = 7.8, 1.2 Hz, 1H), 7.85 (t, J = 1.2 Hz, 1H), 9.98 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 127.9, 129.2, 130.3, 134.3,
135.4, 137.7, 190.8; MS (EI) m/z (relative intensity) 140 (M+,
82), 139 (100), 111 (70), 75 (40), 50 (42).
1
p-Anisaldehyde (2f). H NMR (400 MHz, CDCl3) δ 3.87
1
Pivaldehyde (2q). H NMR (400 MHz, CDCl3) δ 1.08 (s,
(s, 3H), 7.00 (dd, J = 7.8, 1.8 Hz, 2H), 7.84 (dd, J = 7.8, 1.8
Hz, 2H), 9.88 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 55.5,
114.2, 129.8, 131.9, 164.5, 190.7; MS (EI) m/z (relative
intensity) 136 (M+, 78), 135 (100), 107 (25), 92 (25), 77
(48).
9H), 9.48 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 23.4, 42.5,
206.1; MS (EI) m/z (relative intensity) 86 (M+, 32), 57 (100),
41 (80).
Acetophenone (2r). 1H NMR (400 MHz, CDCl3) δ 2.59 (s,
3H), 7.44 (td, J = 7.8, 0.8 Hz, 2H), 7.55 (tt, J = 7.8, 0.8 Hz,
1H), 7.94 (dt, J = 7.8, 0.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 26.5, 128.2, 128.4, 133.0, 137.0, 198.0; MS (EI) m/z
(relative intensity) 120 (M+, 46), 105 (100), 77 (90), 51 (50),
43 (25).
p-Nitrobenzaldehyde (2g). 1H NMR (400 MHz, CDCl3) δ
8.10 (dd, J = 7.5, 2.0 Hz, 2H), 8.41 (dd, J = 7.5, 2.0 Hz, 2H),
10.18 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 124.2, 130.4,
140.0, 151.0, 190.3; MS (EI) m/z (relative intensity) 151 (M+,
100), 150 (86), 105 (25), 77 (76), 51 (98).
4-(Trifluoromethyl)benzaldehyde (2h). 1H NMR (400
MHz, CDCl3) δ 7.81 (dd, J = 7.2, 1.6 Hz, 2H), 8.02 (dd, J
= 7.2, 1.6 Hz, 2H), 10.11 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 122.1, 126.1, 129.9, 135.6, 138.6, 191.1; MS (EI) m/
z (relative intensity) 174 (M+, 73), 145 (100), 125 (20), 95
(25), 75 (25), 50 (35).
General Procedure 2: Pd/Xantphos-Catalyzed Oxida-
tion of Alcohols to Esters/Carboxylic Acids under
Aerobic Conditions (Table 3, entry 1). To a solution of
Pd(OAc)2 (11.2 mg, 0.05 mmol) and Xantphos (28.9 mg, 0.05
mmol) in dry toluene (3 mL) was added 1a (108.1 mg, 1.0
mmol) via syringe under aerobic conditions. The mixture was
stirred at 100 °C for 48 h, and the reaction was monitored by
gas chromatography. The reaction mixture was dried (MgSO4)
and concentrated in vacuo, and the residual oil was subjected
to column chromatography over silica gel (hexane/EtOAc = 4/
1 v/v) to give 3a (90.3 mg, 85% yield, Rf = 0.8).
2-Pyridinecarbaldehyde (2i). 1H NMR (400 MHz, CDCl3)
δ 7.54 (m, 1H), 7.89 (td, J = 5.2, 0.8 Hz, 1H), 7.98 (dd, J =
8.0, 0.8 Hz, 1H), 8.81 (dd, J = 5.2, 0.8 Hz, 1H), 10.09 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 121.6, 127.8, 137.0, 150.1,
152.6, 193.3; MS (EI) m/z (relative intensity) 107 (M+, 25),
79 (100), 78 (47), 52 (83), 51 (77).
Benzyl Benzoate (3a). 1H NMR (400 MHz, CDCl3) δ 5.37
(s, 2H), 7.26−7.57 (m, 8H), 8.08 (dd, J = 6.6, 1.2 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 66.8, 128.2, 128.3, 128.5,
128.7, 129.8, 130.0, 133.1, 136.1, 166.5; MS (EI) m/z (relative
1
Furfural (2j). H NMR (400 MHz, CDCl3) δ 6.61 (dd, J =
3.4, 1.2 Hz, 1H), 7.26 (dd, J = 3.4, 0.8 Hz, 1H), 7.70 (d, J = 1.2
Hz, 1H), 9.68 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 112.6,
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intensity) 212 (M+, 23), 194 (11), 105 (100), 91 (50), 77
(27), 65 (13), 51 (20).
intensity) 158 (M+, 1), 125 (7), 103 (10), 83 (25), 57 (100),
41 (33).
Cyclohexylmethyl Cyclohexanecarboxylate (3n). 1H NMR
(400 MHz, CDCl3) δ 0.90−1.03 (m, 2H), 1.11−1.34 (m, 6H),
1.40−1.49 (m, 2H), 1.58−1.78 (m, 9H), 1.84−1.92 (m, 2H),
2.26−2.32 (m, 1H), 3.87 (d, J = 6.4 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 25.5, 25.7, 26.4, 29.1, 29.7, 37.2, 43.3, 69.3,
176.2; MS (EI) m/z (relative intensity) 224 (M+, 1), 129 (13),
111 (15), 96 (100), 81 (76), 67 (25), 55 (90).
General Procedure 3: Pd/Xantphos-Catalyzed Oxida-
tion Reaction for the Synthesis of Nitrogen-Containing
Heterocycles under Argon (Table 4, entry 1). To a
solution of Pd(OAc)2 (11.2 mg, 0.05 mmol) and Xantphos
(28.9 mg, 0.05 mmol) in dry CH3CN (3 mL) was added
amino alcohol 5a (137.2 mg, 1.0 mmol) via syringe under
argon. The mixture was stirred at 80 °C for 48 h, and the
reaction was monitored by gas chromatography. The reaction
mixture was dried (MgSO4) and concentrated in vacuo, and
the residual oil was subjected to column chromatography over
silica gel (hexane/EtOAc = 4/1 v/v) to give 6a (99.6 mg, 85%
yield, Rf = 0.3).
3,5,5-Trimethylhexyl 3,5,5-Trimethylhexanoate (3p). Dia-
stereomeric mixture, 3p/3p′ = 60/40 as estimated by 1H NMR
analysis. 1H NMR (400 MHz, CDCl3, major isomer) δ 0.89 (s,
9H), 0.91 (s, 9H), 0.95 (d, J = 6.4 Hz, 3H), 0.98 (d, J = 6.4
Hz, 3H), 1.01−1.12 (m, 2H), 1.21 (t, J = 4.0 Hz, 2H), 1.42−
1.48 (m, 1H), 1.56−1.68 (m, 2H), 2.01−2.15 (m, 2H), 2.27−
2.29 (m, 1H), 4.03−4.11 (m, 2H); 13C NMR (100 MHz,
CDCl3, major isomer) δ 22.4, 22.7, 26.2, 26.6, 27.0, 29.9, 31.0,
31.1, 37.9, 44.1, 50.5, 62.7, 173.3; 1H NMR (400 MHz,
CDCl3, minor isomer) δ 0.89 (s, 9H), 0.91 (s, 9H), 0.95 (d, J
= 6.4 Hz, 3H), 0.98 (d, J = 6.4 Hz, 3H), 1.01−1.12 (m, 2H),
1.25 (t, J = 4.0 Hz, 2H), 1.42−1.48 (m, 1H), 1.56−1.68 (m,
2H), 2.01−2.15 (m, 2H), 2.30−2.32 (m, 1H), 4.03−4.11 (m,
2H); 13C NMR (100 MHz, CDCl3, minor isomer) δ 22.5,
22.7, 26.2, 26.6, 27.0, 29.9, 31.0, 31.1, 37.9, 44.1, 51.0, 62.7,
173.3; MS (EI) m/z (relative intensity) 284 (M+, 1), 269 (5),
159 (23), 141 (25), 126 (32), 115 (42), 70 (83), 57 (100).
Indole (6a). 1H NMR (400 MHz, CDCl3) δ 6.55 (d, J = 1.2
Hz, 1H), 7.12−7.22 (m, 3H), 7.36 (d, J = 8.2 Hz, 1H), 7.66
(d, J = 8.2 Hz, 1H), 8.01 (br s, 1H); 13C NMR (100 MHz,
CDCl3) δ 111.0, 119.8, 120.7, 121.9, 124.1, 127.8, 135.7; MS
(EI) m/z (relative intensity) 117 (M+, 100), 90 (50), 89 (41),
58 (28).
1
5-Methylindole (6b). H NMR (400 MHz, CDCl3) δ 2.45
(s, 3H), 6.47 (d, J = 1.6 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H),
7.13 (d, J = 2.6 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.44 (s, 1H),
7.96 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.4, 102.0,
110.6, 120.3, 123.6, 124.2, 128.1, 129.0, 134.0; MS (EI) m/z
(relative intensity) 131 (M+, 78), 130 (100), 103 (11), 77
(22), 65 (47), 51 (18).
1
γ-Butyrolactone (3s). H NMR (400 MHz, CDCl3) δ 2.28
(dquin, 2H), 2.50 (td, 2H), 4.36 (td, J = 7.6, 8.8 Hz, 2H); 13
C
5-Chloroindole (6c). H NMR (400 MHz, CDCl3) δ 6.49
1
NMR (100 MHz, CDCl3) δ 21.9, 27.5, 68.3, 177.6; MS (EI)
(d, J = 3.6 Hz, 1H), 7.15 (dd, J = 8.8, 1.6 Hz, 1H), 7.21 (d, J =
3.6 Hz, 1H), 7.29 (dd, J = 8.8, 1.6 Hz, 1H), 7.61 (s, 1H), 8.14
(br s, 1H); 13C NMR (100 MHz, CDCl3) δ 102.4, 111.9,
120.1, 122.3, 125.5, 128.9, 134.1; MS (EI) m/z (relative
intensity) 151 (M+, 100), 124 (11), 116 (23), 89 (30), 76
(17), 58 (15).
m/z (relative intensity) 86 (M+, 50), 56 (42), 42 (100).
1
Phthalide (3t). H NMR (400 MHz, CDCl3) δ 5.33 (s,
2H), 7.51 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.70 (t,
J = 7.6 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 69.6, 122.1, 125.7, 129.0, 146.5, 171.1; MS
(EI) m/z (relative intensity) 134 (M+, 43), 105 (100), 77
(69), 51 (30).
General Procedure 4: Pd/Xantphos-Catalyzed Oxida-
tive Synthesis of Quinazolines from Diamine 7 and
Alcohols (Table 5). To a solution of Pd(OAc)2 (11.2 mg,
0.05 mmol) and Xantphos (28.9 mg, 0.05 mmol) in dry anisole
(3 mL) were successively added 1a (270.3 mg, 2.5 mmol) and
diamine 7 (122.2 mg, 1.0 mmol) via syringe under argon. The
mixture was stirred at 100 °C for 48 h, and the reaction was
monitored by gas chromatography. The reaction mixture was
dried (MgSO4) and concentrated in vacuo, and the residual oil
was subjected to column chromatography over silica gel
(hexane/EtOAc = 50/1 v/v) to give 8a (175.4 mg, 85%, Rf =
0.4).
Benzoic Acid (4a). 1H NMR (400 MHz, CDCl3) δ 7.48 (td,
J = 8.0, 2.0 Hz, 2H), 7.63 (tt, J = 8.0, 2.0 Hz, 1H), 8.13 (dt, J =
8.0, 2.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 128.5, 129.3,
130.2, 133.8, 172.4; MS (EI) m/z (relative intensity) 122 (M+,
83), 105 (100), 77 (82), 51 (60).
1
m-Chlorobenzoic Acid (4e). H NMR (400 MHz, CDCl3)
δ 7.43 (td, J = 7.6, 1.6 Hz, 1H), 7.60 (dt, J = 7.6, 1.6 Hz, 1H),
8.01 (dt, J = 7.6, 1.6 Hz, 1H), 8.10 (t, J = 1.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 128.3, 129.8, 130.3, 130.9, 133.9,
134.7, 170.9; MS (EI) m/z (relative intensity) 156 (M+, 82),
139 (100), 111 (52), 75 (35), 50 (29).
1
2-Phenylquinazoline (8a). H NMR (400 MHz, CDCl3) δ
1
trans-Cinnamic Acid (4l). H NMR (400 MHz, CDCl3) δ
7.51−7.59 (m, 4H), 7.89−7.91 (m, 2H), 8.07 (dd, J = 8.2, 0.8
Hz, 1H), 8.62 (dd, J = 8.2, 2.0 Hz, 2H), 9.45 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 123.6, 127.1, 127.2, 128.5, 128.6,
130.6, 134.0, 138.0, 150.7, 160.4, 161.0; MS (EI) m/z (relative
intensity) 206 (M+, 100), 179 (56), 103 (30), 76 (34), 50
(25).
6.47 (d, J = 16.0 Hz, 1H), 7.25−7.43 (m, 3H), 7.56 (dd, J =
7.2, 2.0 Hz, 2H), 7.81 (d, J = 16.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 117.3, 128.4, 128.9, 130.7, 134.0, 147.1,
172.5; MS (EI) m/z (relative intensity) 148 (M+, 75), 147
(100), 131 (25) 103 (47), 77 (50), 51 (62).
1
Cyclohexanecarboxylic Acid (4n). H NMR (400 MHz,
2-(4-Methoxyphenyl)quinazoline (8b). 1H NMR (400
MHz, CDCl3) δ 3.87 (s, 3H), 7.03 (dd, J = 6.8, 2.0 Hz,
2H), 7.52 (td, J = 6.8, 1.6 Hz, 1H), 7.83 (td, J = 6.8, 2.0 Hz,
2H), 8.02 (dd, J = 6.8, 2.0 Hz, 1H), 8.87 (dd, J = 6.8, 2.0 Hz,
2H), 9.38 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 55.3,
113.9, 123.2, 126.7, 127.0, 128.3, 130.1, 130.7, 133.9, 150.7,
160.3, 160.8, 161.8; MS (EI) m/z (relative intensity) 236 (M+,
100), 221 (17), 193 (13), 166 (12), 118 (14), 96 (15).
CDCl3) δ 1.22−1.34 (m, 3H), 1.41−1.48 (m, 2H), 1.63−1.66
(m, 1H), 1.75−1.77 (m, 2H), 1.92−1.96 (m, 2H), 2.30−2.36
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 25.3, 25.7, 28.8,
42.9, 182.5; MS (EI) m/z (relative intensity) 128 (M+, 22), 83
(50), 73 (62), 55 (100), 41 (70).
1
3,5,5-Trimethylhexanoic Acid (4p). H NMR (400 MHz,
CDCl3) δ 0.87 (s, 9H), 1.02 (d, J = 6.4 Hz, 3H), 1.12−1.34
(m, 2H), 2.06−2.40 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
22.6, 26.8, 29.9, 31.0, 43.7, 50.5, 179.4; MS (EI) m/z (relative
1
2-(4-Nitrophenyl)quinazoline (8c). H NMR (400 MHz,
CDCl3) δ 7.73 (t, J = 7.6 Hz, 1H), 8.00 (t, J = 7.6 Hz, 2H),
F
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8.13 (dd, J = 7.6, 1.2 Hz, 1H), 8.37 (dd, J = 7.2, 2.0 Hz, 2H),
8.82 (dd, J = 7.2, 2.0 Hz, 2H), 9.51 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 123.7, 123.9, 127.2, 128.3, 128.8, 129.4, 134.6,
143.8, 149.2, 150.6, 158.8, 160.7; MS (EI) m/z (relative
intensity) 251 (M+, 70), 221 (30), 207 (52), 194 (100), 77
(25), 44 (32).
ABBREVIATIONS
■
dppb, 1,4-bis(diphenylphosphino)butane; dppf, 1,1′-bis-
(diphenylphosphino)ferrocene; Xantphos, 4,5-bis-
(diphenylphosphino)-9,9-dimethylxanthene; DMF, N,N-dime-
thylformamide; DMA, N,N-dimethylacetamide; THF, tetrahy-
drofuran
2-(4-Trifluoromethylphenyl)quinazoline (8d). 1H NMR
(400 MHz, CDCl3) δ 7.69 (t, J = 8.0 Hz, 1H), 7.79 (d, J =
8.0 Hz, 2H), 7.95−7.98 (m, 2H), 8.13 (dd, J = 8.4, 1.2 Hz,
1H), 8.76 (dd, J = 8.4, 1.2 Hz, 2H), 9.50 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 123.9, 125.4, 125.5, 127.2, 127.9, 128.8,
128.8, 132.0, 134.4, 141.3, 150.7, 159.7, 160.7; MS (EI) m/z
(relative intensity) 274 (M+, 100), 247 (32), 76 (31), 50 (26).
General Procedure 5: Pd/Xantphos-Catalyzed Oxida-
tive Synthesis of Benzimidazoles from Diamine 9 and
Alcohols (Scheme 2). To a solution of Pd(OAc)2 (11.2 mg,
0.05 mmol) and Xantphos (28.9 mg, 0.05 mmol) in dry
CH2CN (3 mL) were successively added 1a (432.5 mg, 4.0
mmol) and diamine 9 (108.1 mg, 1.0 mmol) via syringe under
argon. The mixture was stirred at 80 °C for 48 h, and the
reaction was monitored by gas chromatography. The reaction
mixture was dried (MgSO4) and concentrated in vacuo, and
the residual oil was subjected to column chromatography over
silica gel (hexane/EtOAc = 10/1 v/v) to give 10a (184.9 mg,
65%, Rf = 0.3).
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.9b00207.
Experimental procedures, plausible mechanism for
oxidation of alcohols, and H and 13C NMR spectra of
1
products (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: tmori@rs.socu.ac.jp (T. Mori).
*E-mail: masanari@nagasaki-u.ac.jp (M. Kimura).
ORCID
Masanari Kimura: 0000-0003-2900-9554
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research (B) (JP18H01981) from JSPS and partly by a Grant-
in-Aid for Scientific Research on Innovative Areas “Precise
Formation of a Catalyst Having a Specified Field for Use in
Extremly Difficult Substrate Conversion Reactions“
(JP18H04266) from MEXT.
(8) For a review of the oxidative transformation of organic substrates
catalyzed by iridium complexes, see: Fujita, K.-i.; Yamaguchi, R.
Catalytic Activity of Cp* Iridium Complexes in Hydrogen Transfer
Reactions. In Iridium Complexes in Organic Synthesis; Oro, L. A.,
Claver, C., Eds.; Wiley-VCH: Weinheim, Germany, 2009; Chapter 5,
pp 107−143.
G
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H
DOI: 10.1021/acs.oprd.9b00207
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
Intermolecular Addition of Formamides to Alkynes. J. Am. Chem. Soc.
2010, 132, 2094−2098.
(17) The evolution of hydrogen gas was observed by GC analysis
(see the Supporting Information). Although it is premature to
rationalize the mechanism by qualitative analysis, a dehydrogenative
oxidation mechanism seems to be probable.
(18) A possible mechanism involving the generation of hydrogen
peroxide with a palladium hydride complex under aerobic conditions
is proposed in Scheme SI-1.
I
DOI: 10.1021/acs.oprd.9b00207
Org. Process Res. Dev. XXXX, XXX, XXX−XXX