Palladium-catalyzed external-CO-free reductive carbonylation of aryl sulfonates

Article abstract of DOI:10.1016/j.tet.2020.131639

Pd-catalyzed reductive carbonylation of aryl sulfonates using N-formylsaccharin as a carbon monoxide (CO) surrogate was developed. This external-CO-free carbonylation provides a safe and practical access to aldehydes from phenol derivatives. The reaction has a broad substrate scope, rendering it an attractive method for synthesizing aldehydes.

Full text of DOI:10.1016/j.tet.2020.131639

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalyzed external-CO-free reductive carbonylation of aryl
sulfonates
Hideyuki Konishi, Minoru Kumon, Miyuki Yamaguchi, Kei Manabe*
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Pd-catalyzed reductive carbonylation of aryl sulfonates using N-formylsaccharin as a carbon monoxide
(CO) surrogate was developed. This external-CO-free carbonylation provides a safe and practical access to
aldehydes from phenol derivatives. The reaction has a broad substrate scope, rendering it an attractive
method for synthesizing aldehydes.
Received 5 August 2020
Received in revised form
15 September 2020
Accepted 16 September 2020
Available online xxx
© 2020 Elsevier Ltd. All rights reserved.
Keywords:
Reductive carbonylation
N-Formylsaccharin
Aryl sulfonate
Carbon monoxide surrogate
Aldehyde
1. Introduction
containing gas, the use of CO surrogates which can generate CO
by chemical reaction has gained its utility and practicality in the
Aldehydes are one of the most ubiquitous and abundant com-
pounds in nature. Due to their easy availability and appropriate
reactivity, they are extensively used as fundamental and useful
building blocks in both industry and academia. Therefore, a bunch
of synthetic methods for aldehydes have been reported to date
[1e6], and undoubtedly, novel ones will be continuously
developed.
Transition metal-catalyzed reductive carbonylation using car-
bon monoxide (CO) and a reductant has been established as a useful
and direct method to introduce a formyl group into haloarenes. Use
of CO in the industries enables mass production of synthetically
important aldehydes [7]. Synthetic gas is easily available and can be
used in the reaction as both carbonyl and hydride sources [8]. The
combined use of CO gas and hydrosilanes is also an effective
strategy for the synthesis of aldehydes from haloarenes [9e11].
Despite the utility of these synthetic methods, tedious reaction
procedures involving the use of pressurized and toxic CO gas cause
inconvenience and hamper their practical applications, especially
in laboratory-scale experiments.
synthetic community [12e17]. Among the various CO surrogates
developed, we have found N-formylsaccharin as a stable crystalline
CO surrogate that could produce CO under extremely mild condi-
tions and have demonstrated the reductive carbonylation of bro-
moarenes in the presence of triethylsilane (Et3SiH) as a reductant
using this CO surrogate [18]. We have also shown one example of
the reaction of phenyl trifluoromethanesulfonate (triflate) using N-
formylsaccharin, although the yield of the desired benzaldehyde
was low [18].
There is an increasing demand that versatile substrates can be
applied for accessing aldehydes either as the final target products
or as synthetic intermediates. Furthermore, development of novel
transformations using aldehydes as substrates has become a pop-
ular research area [19e24]. Nonetheless, there are surprisingly
fewer reports on the reductive carbonylation of aryl sulfonates
using CO gas [25,26] or CO surrogates [27,28] compared with that of
haloarenes. This prompted us to develop a general and convenient
method for introducing aldehyde moieties into aryl sulfonates us-
ing CO surrogates. The method would provide a safe and practical
access to aldehydes, since aryl sulfonates are easily prepared from
the corresponding phenols. We report herein the external-CO-free
Pd-catalyzed reductive carbonylation of aryl sulfonates using N-
formylsaccharin as our unique CO surrogate (Scheme 1). Successful
scale-up experiments and reaction using ordinary glassware clearly
Different from the conventional methods using CO or CO-
* Corresponding author.
E-mail address: manabe@u-shizuoka-ken.ac.jp (K. Manabe).
https://doi.org/10.1016/j.tet.2020.131639
0040-4020/© 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: H. Konishi, M. Kumon, M. Yamaguchi et al., Palladium-catalyzed external-CO-free reductive carbonylation of aryl
sulfonates, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131639

H. Konishi, M. Kumon, M. Yamaguchi et al.
Tetrahedron xxx (xxxx) xxx
Table 2
Effect of ligands and bases.
Scheme 1. Pd-catalyzed reductive carbonylation of aryl sulfonates using N-
formylsaccharin.
Entry
Liganda
Base
Isolated yield of 5 (%)
demonstrate the high-safety aspect and practicality of this reaction.
1
2
3
4
5
6
7
8
PPh3
PCy3
P(t-Bu)3‧HBF4
DPPE
DPPP
DPPB
DPPPe
DPPF
Xantphos
DCyPB
DPEPhos
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
DPPF
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
KOAc
K2CO3
Cs2CO3
K3PO4
NEt3
DBU
48
5
3
2. Results and discussion
trace
26
77
77
84
18
12
67
10
54
47
59
29
40
96
We began our investigation by examining suitable conditions
for the reductive carbonylation, using biphenyl-4-yl triflate (1a) as
a model substrate in the presence of a Pd catalyst and N-for-
mylsaccharin (2) (Table 1). Solvent screening revealed the forma-
tion of an unexpected compound, 4-phenylbenzoic acid (4), which
was derived from the actual target product, 4-phenylbenzaldehyde
(3a). Compound 4 could not be detected in the 1H NMR spectrum of
the crude reaction mixture; thus, 4 was probably formed via the
aerobic oxidation of 3a during the chromatographic purification on
silica gel. Nonetheless, it was revealed that MeCN was the solvent
based on the combined yield of aldehyde 3a and carboxylic acid 4
(entry 4).
For an accurate evaluation of the effect of ligands and bases,
product 3a was converted into 4-phenylbenzyl alcohol (5) through
one-pot treatment with NaBH4 for every reaction (Table 2). Con-
version to product 5 was higher in the presence of bidentate
bisphosphines than in the presence of monodentate phosphines;
DPPB, DPPPe, and DPPF were found to be the most effective ligands
(entries 1e11). Na2CO3 was the optimal base, which was similar to
that observed for our previously developed reductive carbonylation
of bromoarenes (entries 8, 12e17) [18]. While stronger or organic
9
10
11
12
13
14
15
16
17
18b
Na2CO3
a
DPPE: 1,2-bis(diphenylphosphino)ethane, DPPP: 1,3-bis(diphenylphosphino)
DPPB: 1,4-bis(diphenylphosphino)butane, DPPPe: 1,5-
bis(diphenylphosphino)pentane, DPPF: 1,10-bis(diphenylphosphino)ferrocene,
Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, DCyPB: 1,4-
2,20-bis(diphenylphosphino)
propane,
bis(dicyclohexylphosphino)butane,
diphenyl ether.
DPEPhos:
b
Et3SiH (1.5 eq.) was used.
bases could facilitate smooth CO generation from 2, a fast CO supply
was not always effective for Pd-catalyzed carbonylation [29]. In-
crease in the amount of Et3SiH was beneficial in promoting the
reaction (entry 18).
Table 1
Solvent screening.a
With the optimal reaction conditions in hand, we investigated
the substrate scope of the reaction (Table 3). To obtain the
target aldehydes, all the reactions were conducted without NaBH4
treatment. Since some aldehydes are highly volatile, their yields
were determined based on both 1H NMR analysis of the crude
mixture and the yield after chromatographic separation, with the
least possible contact time with SiO2 (for details, see Experimental
section). Phenyl triflate (1b) and substrates with electron-donating
groups such as 1c and 1d afforded the corresponding aldehydes
3bed in high yields. Methylthio, fluoro, and chloro groups were
also compatible with this reaction to generate aldehydes 3eeg.
However, a low yield of product 3h was obtained with cyano-
containing substrate 1h, primarily due to the undesirable forma-
tion of benzonitrile as a reduced byproduct. Although using DPPPe
as a ligand and reducing the amount of Et3SiH improved the situ-
ation, the formation of benzonitrile was still observed. While 1i
bearing a 2-methyl group was well-tolerated in this reaction to
form aldehyde 3i, 1j with a 2-phenyl group resulted in low con-
version to product 3j, indicating that the reaction was strongly
influenced by the steric effect of the substrates. Substrates with
indane structure, 1k, and catechol-derived acetal 1l were also well-
tolerated and gave aldehydes 3k and 3l in high yields. Surprisingly,
naphth-1-yl triflate (1m) did not show the expected reactivity,
probably due to the rapid reduction to form naphthalene. More
flexible ligands such as DPPPe could possibly improve the yield of
Entry
Solvent
Isolated yield (%)
3a
4
1
2
3
4
5
6
toluene
1,2-dichloroethane
THF
MeCN
DMF
NMP
trace
trace
35
77
27
e
e
15
0
20
34
12
a
DPPB: 1,4-bis(diphenylphosphino)butane.
2

Table 3
perfluorobutanesulfonate (biphenyl-4-yl nonaflate, 6), which can
be obtained directly from the reaction of 4-phenylphenol and
perfluorobutanesulfonyl fluoride, was found to be a good substrate
as a triflate.
Substrate scope of the reductive carbonylation.a
It is noteworthy that the reaction could be conducted at a 1-
mmol scale in a closed test tube with a catalyst loading as low as
1 mol% (Table 4, entries 1 and 2). Furthermore, the 5-mmol scale
reaction could also be successfully conducted in a normal two-
necked round-bottomed flask with an empty balloon to maintain
the atmospheric pressure inside the flask. This clearly indicates the
high-safety aspect and potential scalability of this reaction (entry
3).
We have mentioned the reactivity of the reductive carbonyla-
tion of aryl sulfonates was influenced by solvents, among which
MeCN worked the best (Table 1). This showed a sharp contrast with
the reactions of bromoarenes where DMF was the optimal solvent
[18]. Therefore, some control experiments were performed under
atmospheric CO (Table 5). It was confirmed that the reaction pro-
ceeded smoothly under CO gas both in MeCN and DMF, indicating
that both solvents were inherently effective for the reductive
carbonylation (entries 1 and 2). Considering that sodium saccha-
rinate was gradually generated as the reaction of aryl sulfonates
using N-formylsaccharin proceeded, we next conducted the
Table 4
Scale-up experiments and reduction of catalyst loading.
Entry
X (mmol)
Y (mol%)
Isolated yield (%)
1a
2a
3b
1.0
1.0
5.0
5
1
5
93
58
74
a
A screw-capped test tube was used as the reaction vessel.
A two-necked, round-bottomed flask with an empty balloon was used as the
b
reaction vessel.
Table 5
Reactions under atmospheric CO with and without saccharin.
aldehyde 3m. Some heteroaromatic substrates were also examined.
Indol-4-yl triflate (1n) was smoothly converted into the desired
aldehyde 3n in a high yield. A sharp contrast in the yields of 3m and
3n indicated that subtle differences in the steric environments
around the reactive sites could strongly influence the substrate
reactivity. Electron-deficient quinolin-8-yl triflate (1o) failed to
afford the corresponding aldehyde 3o. Similar to the case with
cyano-containing 1h, this substrate mainly afforded quinoline as a
reduced byproduct. We were also pleased to find that complex
triflates 1p and 1q derived from estrone and protected tyrosine
successfully afforded the desired aldehydes 3p and 3q, respectively.
Entry
Solvent
X (eq.)
Isolated yield (%)
1
2
3
4
MeCN
DMF
MeCN
DMF
0
0
1.5
1.5
70
64
66
11
Furthermore,
the
reaction
of
biphenyl-4-yl
3

H. Konishi, M. Kumon, M. Yamaguchi et al.
Tetrahedron xxx (xxxx) xxx
reactions in the presence of saccharin. In MeCN, the desired alde-
hyde was obtained regardless of the presence of saccharin (entry 1
vs. 3). However, an addition of saccharin caused substantial
decrease of the yield of the product when DMF was used as a sol-
vent (entry 2 vs. 4). While further studies are needed to clarify the
precise mechanism, these results indicate that the formation of
sodium saccharinate under the basic conditions have detrimental
effects in DMF, thereby resulting in low yield of the product.
A plausible reaction mechanism is shown in Scheme 2. N-For-
mylsaccharin (2) reacts with a base to produce CO and saccharinate.
Oxidative addition of substrate 1 to Pd(0) generates Pd(II) inter-
mediate A, which is followed by coordination and migratory
insertion of CO to form intermediate B. This intermediate seems to
react directly with Et3SiH to afford the desired product 3. Another
plausible pathway from intermediate B to product 3 could be that
via the formation of intermediate C by the ligand exchange of tri-
flate with saccharinate [18].
4. Experimental section
4.1. General
All the reactions were performed in oven-dried or flame-dried
glassware under an argon atmosphere. Reactions were monitored
by TLC on Merck silica gel 60 F254 plates by visualizing with a UV
lamp at 254 nm. Column chromatography was performed on Merck
silica gel 60, and preparative TLC was performed on Merck silica gel
60 F254 0.5 mm plates. In the 5-mmol experiment, column chro-
matography was performed on a Yamazen Smart Flash W-Prep 2XY
using Hi-Flash column. Recycling preparative HPLC was performed
on a Japan Analytical Industry LaboACE LC-5060 using a JALGEL-
2HR column (solvent: ethyl acetate, flow rate: 10 mL/min, detec-
tion: 254 nm). NMR spectra were acquired on a JEOL AL-400 NMR
spectrometer (400 MHz for 1H spectra) or a JEOL ECX-500 NMR
spectrometer (500 MHz for 1H spectra,125 MHz for 13C spectra, and
470 MHz for 19F spectra) and are quoted in ppm for measurement
against tetramethylsilane (TMS) or residual solvent peak as an in-
ternal standard. Infrared spectra were acquired on a SHIMADZU IR
Prestige-21 spectrometer (ATR). High-resolution mass spectra
(HRMS) were acquired on a Bruker MicrOTOF time-of-flight mass
spectrometer (ESI).
All the solvents and ligands, Pd(OAc)2, and Et3SiH were pur-
chased from commercial suppliers and used directly without pu-
rification. Aryl triflates [30,31] and N-formylsaccharin [32] were
synthesized from the corresponding phenol derivatives and
saccharin, respectively, according to reported procedures.
4.2. General experimental procedure for the reductive
carbonylation of aryl triflate 1 using N-formylsaccharin (2)
CAUTION! To avoid an unexpected leak of toxic CO and an in-
crease in the internal pressure of the reaction vessel, all reactions
should be conducted behind a blast shield in a well-ventilated fume
hood.
Pd(OAc)2 (2.2 mg, 10.0
mmol, 5.00 mol%), DPPF (8.3 mg,
15.0 mol, 7.50 mol%), 2 (63.4 mg, 0.300 mmol, 1.50 equiv), and
m
MeCN (1.00 mL) were added to an oven-dried, 10-mL test tube with
a septum containing a magnetic stirring bar. The tube was evacu-
ated and backfilled with Ar three times. Aryl triflate
1
(0.200 mmol), Et3SiH (47.8 L, 0.300 mmol, 1.50 equiv), and Na2CO3
m
(31.8 mg, 0.300 mmol, 1.50 equiv) were added to the mixture under
Ar flow. The tube was tightly screw-capped and heated to 80 ꢀC in
an oil bath. The mixture was stirred for 16 h. After cooling to room
temperature, the mixture was diluted with CH2Cl2 and H2O,
extracted with CH2Cl2 from aqueous layer, washed with brine, dried
over Na2SO4, filtered, and concentrated. After the 1H NMR analysis
of the crude reaction mixture with a small amount of 1,2,4,5-
tetramethylbenzene as an internal standard, the obtained residue
was purified by preparative TLC (SiO2, developed with hexane/
EtOAc mixture). The desired aldehyde was eluted just after finish-
ing the development of the preparative TLC plate to prevent un-
desirable oxidation to carboxylic acid on SiO2. Further purification
by recycling preparative HPLC afforded the analytically pure
product. The 1-mmol scale experiment was conducted in a 26-mL
test tube.
Scheme 2. Proposed reaction mechanism.
3. Conclusion
We have developed an external-CO-free method for the Pd-
catalyzed reductive carbonylation of aryl sulfonates using N-for-
mylsaccharin as a stable crystalline CO surrogate. The reaction has a
broad substrate scope and is extremely safe and practical owing to
the use of a CO surrogate instead of CO gas. Since aryl sulfonates can
be easily obtained from the corresponding phenols via a single-step
sulfonylation reaction, the combined sulfonylation and reductive
carbonylation can provide a convenient route for the conversion of
a phenolic hydroxy group into a formyl group, thereby affording
aromatic aldehydes.
4.2.1. [1,10-biphenyl]-4-carbaldehyde (3a) [33]
A colorless oil; 28.6 mg; 79% yield; 1H NMR (500 MHz, CDCl3)
d
10.06 (s, 1H), 7.95 (d, J ¼ 8.6 Hz, 2H), 7.75 (d, J ¼ 8.0 Hz, 2H), 7.64
(d, J ¼ 7.4 Hz, 2H), 7.48 (t, J ¼ 7.4 Hz, 2H), 7.42 (t, J ¼ 7.4 Hz,1H) ppm;
13C NMR (125 MHz, CDCl3)
128.5, 127.7, 127.3 ppm.
d 191.9, 147.2, 139.7, 135.1, 130.3, 129.0,
4

H. Konishi, M. Kumon, M. Yamaguchi et al.
Tetrahedron xxx (xxxx) xxx
4.2.2. Benzaldehyde (3b) [33]
d
9.96 (s, 1H), 7.73 (s, 1H), 7.65 (d, J ¼ 8.0 Hz, 1H), 7.36 (d, J ¼ 7.4 Hz,
A colorless oil; 9.7 mg; 46% yield; 1H NMR (500 MHz, CDCl3)
1H), 2.97 (t, J ¼ 7.4 Hz, 4H), 2.13 (quint, J ¼ 7.4 Hz, 2H) ppm; 13C
d
10.03 (s, 1H), 7.89 (d, J ¼ 6.9 Hz, 2H), 7.65 (t, J ¼ 7.4 Hz, 1H), 7.55 (t,
NMR (125 MHz, CDCl3) d 192.4, 152.1, 145.3, 135.2, 128.9, 125.1,
124.8, 33.1, 32.3, 25.3 ppm.
J ¼ 7.4 Hz, 2H) ppm; 13C NMR (125 MHz, CDCl3)
d
192.4,136.4,134.5,
129.8, 129.0 ppm.
4.2.12. Benzo[d][1,3]dioxole-5-carbaldehyde (3l) [39]
4.2.3. 4-Methylbenzaldehyde (3c) [34]
A colorless oil; 25.5 mg; 85% yield; 1H NMR (500 MHz, CDCl3)
A colorless oil; 17.4 mg; 73% yield; 1H NMR (500 MHz, CDCl3)
d
9.91 (s, 1H), 7.42 (dd, J ¼ 8.0, 1.1 Hz, 1H), 7.34 (d, J ¼ 1.1 Hz, 1H),
d
9.97 (s, 1H), 7.78 (d, J ¼ 8.0 Hz, 2H), 7.34 (d, J ¼ 8.0 Hz, 2H), 2.45 (s,
6.94 (d, J ¼ 7.4 Hz, 1H), 6.08 (s, 2H) ppm; 13C NMR (125 MHz, CDCl3)
3H) ppm; 13C NMR (125 MHz, CDCl3)
d 192.0, 145.6, 134.2, 129.9,
d
190.3, 153.1, 148.7, 131.8, 128.7, 108.3, 106.8, 102.1 ppm.
129.7, 21.9 ppm.
4.2.13. 1-Naphthaldehyde (3m) [40]
4.2.4. 4-Methoxybenzaldehde (3d) [34]
A colorless oil; 23.8 mg; 87% yield; 1H NMR (500 MHz, CDCl3)
The reaction was performed with DPPPe instead of DPPF. A pale
yellow oil; 6.8 mg; 22% yield; 1H NMR (500 MHz, CDCl3)
d 10.40 (s,
d
9.89 (s, 1H), 7.85 (d, J ¼ 8.6 Hz, 2H), 7.01 (d, J ¼ 8.6 Hz, 2H), 3.90 (s,
3H) ppm; 13C NMR (125 MHz, CDCl3)
d 190.8, 164.6, 132.0, 129.9,
1H), 9.26 (d, J ¼ 8.6 Hz, 1H), 8.10 (d, J ¼ 8.0 Hz, 1H), 8.00 (d,
J ¼ 6.9 Hz, 1H), 7.93 (d, J ¼ 8.0 Hz, 1H), 7.70 (t, J ¼ 6.9 Hz, 1H), 7.63 (t,
J ¼ 8.0 Hz, 1H), 7.60 (t, J ¼ 6.9 Hz, 1H) ppm; 13C NMR (125 MHz,
114.3, 55.6 ppm.
CDCl3)
d 193.6, 136.7, 135.3, 133.7, 131.4, 130.5, 129.1, 128.5, 127.0,
4.2.5. 4-(Methylthio)benzaldehyde (3e) [35]
A colorless oil; 22.3 mg; 73% yield; 1H NMR (500 MHz, CDCl3)
124.9 ppm (one carbon signal is missing).
d
9.93 (s, 1H), 7.78 (d, J ¼ 8.0 Hz, 2H), 7.33 (d, J ¼ 8.6 Hz, 2H), 2.54 (s,
3H) ppm; 13C NMR (125 MHz, CDCl3)
125.2, 14.7 ppm.
d 191.3, 147.9, 132.9, 130.0,
4.2.14. 1H-Indole-4-carbaldehyde (3n) [41]
A white solid; 21.8 mg; 75% yield; 1H NMR (500 MHz, CDCl3)
d
10.26 (s, 1H), 8.70 (br s, 1H), 7.68 (d, J ¼ 7.4 Hz, 1H), 7.65 (d,
J ¼ 7.4 Hz, 1H), 7.44 (t, J ¼ 2.9 Hz, 1H), 7.38e7.32 (m, 2 H) ppm; 13
C
4.2.6. 4-Fluorobenzaldehyde (3f) [36]
A colorless oil; 13.5 mg; 54% yield; 1H NMR (500 MHz, CDCl3)
NMR (125 MHz, CDCl3)
121.3, 117.5, 103.0 ppm.
d 193.3, 136.5, 128.3, 127.7, 127.6, 125.6,
d
9.98 (s, 1H), 7.95-7.90 (m, 2H), 7.22 (t, J ¼ 8.6 Hz, 2H) ppm; 13C
NMR (125 MHz, CDCl3)
d
190.5, 166.5 (d, J ¼ 256 Hz), 132.9 (d,
J ¼ 2.5 Hz), 132.2 (d, J ¼ 10 Hz), 116.4 (d, J ¼ 21 Hz) ppm; 19F NMR
4.2.15. Quinoline-8-carbaldehyde (3o) [42]
(470 MHz, CDCl3)
d
ꢁ102.2 (m) ppm.
A white solid; 1.9 mg; 6% yield; 1H NMR (500 MHz, CDCl3)
d
11.47 (s, 1H), 9.07 (dd, J ¼ 4.3, 1.4 Hz, 1H), 8.35 (dd, J ¼ 7.4, 1.1 Hz,
4.2.7. 4-Chlorobenzaldehyde (3g) [33]
1H), 8.26 (dd, J ¼ 8.3, 1.4 Hz, 1H), 8.11 (dd, J ¼ 8.0, 1.1 Hz, 1H), 7.70 (t,
A white solid; 15.0 mg; 53% yield; 1H NMR (500 MHz, CDCl3)
J ¼ 7.4 Hz, 1H), 7.53 (dd, J ¼ 8.6, 4.0 Hz, 1H) ppm; 13C NMR
d
9.99 (s, 1H), 7.83 (d, J ¼ 8.6 Hz, 2H), 7.52 (d, J ¼ 8.6 Hz, 2H) ppm;
(125 MHz, CDCl3)
d 192.7, 151.3, 147.6, 136.3, 134.2, 131.7, 129.4,
13C NMR (125 MHz, CDCl3)
d
190.9, 141.0, 134.7, 130.9, 129.5 ppm.
128.3, 126.2, 121.8 ppm.
4.2.8. 4-Formylbenzonitrile (3h) [36]
4.2.16. (8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-
decahydro-6H-cyclopenta[a]phenanthrene-3-carbaldehyde (3p)
[43]
The reaction was performed with DPPPe instead of DPPF. A
white solid; 8.6 mg; 33% yield; 1H NMR (500 MHz, CDCl3)
d 10.11 (s,
1H), 8.01 (d, J ¼ 8.0 Hz, 2H), 7.87 (d, J ¼ 8.0 Hz, 2H) ppm; 13C NMR
A white solid; 41.2 mg; 73% yield; 1H NMR (500 MHz, CDCl3)
(125 MHz, CDCl3)
d 190.6, 138.7, 132.9, 129.9, 117.7, 117.6 ppm.
d
9.95 (s, 1H), 7.65 (d, J ¼ 8.0 Hz, 1H), 7.61 (s, 1H), 7.47 (d, J ¼ 8.0 Hz,
1H), 3.05-2.94 (m, 2H), 2.56-2.44 (m, 2H), 2.37 (td, J ¼ 10.9, 4.0 Hz,
4.2.9. 2-Methylbenzaldehyde (3i) [33]
1H), 2.21-1.98 (m, 4H), 1.70-1.44 (m, 6H), 0.93 (s, 3H) ppm; 13C NMR
A colorless oil; 9.6 mg; 40% yield; 1H NMR (500 MHz, CDCl3)
(125 MHz, CDCl3)
d 220.4, 192.2, 147.0, 137.5, 134.2, 130.2, 127.2,
d
10.28 (s, 1H), 7.81 (d, J ¼ 7.4 Hz, 1H), 7.49 (td, J ¼ 7.4, 1.1 Hz, 1H),
7.37 (d, J ¼ 7.4 Hz, 1H), 7.29-7.26 (m, 1H), 2.68 (s, 3H) ppm; 13C NMR
126.0, 50.4, 47.8, 44.8, 37.6, 35.7, 31.4, 29.1, 26.1, 25.5, 21.5, 13.7 ppm.
(125 MHz, CDCl3)
19.6 ppm.
d 192.8, 140.6, 134.1, 133.7, 132.1, 131.8, 126.3,
4.2.17. (S)-4-(2-acetamido-3-ethoxy-3-oxopropyl)benzoic acid
(3q)
4.2.10. [1,10-biphenyl]-2-carbaldehyde (3j) [37]
A pale yellow oil; 39.4 mg; 75% yield; 1H NMR (500 MHz, CDCl3)
A colorless oil; 2.2 mg; 6% yield; 1H NMR (500 MHz, CDCl3)
d
9.99 (s, 1H), 7.82 (d, J ¼ 8.0 Hz, 2H), 7.30 (d, J ¼ 8.0 Hz, 2H), 6.04 (d,
d
9.99 (s, 1H), 8.03 (d, J ¼ 7.4 Hz, 1H), 7.65 (td, J ¼ 7.4, 1.1 Hz, 1H),
7.53-7.43 (m, 5H), 7.41-7.37 (m, 2H) ppm; 13C NMR (125 MHz,
CDCl3) 192.5, 146.0, 137.7, 133.7, 133.6, 130.8, 130.1, 128.4, 128.1,
J ¼ 6.9 Hz, 1H), 4.94-4.88 (m, 1H), 4.23-4.14 (m, 2H), 3.25 (dd,
J ¼ 13.8, 6.3 Hz, 1H), 3.18 (dd, J ¼ 13.8, 5.2 Hz, 1H), 2.01 (s, 3H), 1.25
(t, J ¼ 6.9 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3)
d
191.8, 171.3,
d
127.8, 127.6 ppm.
169.6, 143.3, 135.3,130.0, 129.9, 61.8, 52.9, 38.2, 23.1, 14.1 ppm; IR
(ATR) 1735,1697, 1654, 1606,1535, 1375, 1213, 1170,1018, 732 cmꢁ1
;
4.2.11. 2,3-Dihydro-1H-indene-5-carbaldehyde (3k) [38]
HRMS (ESI) [MþNa]þ calcd for C14H17NNaO5: 302.0999; found:
A colorless oil; 24.0 mg; 82% yield; 1H NMR (500 MHz, CDCl3)
302.0991.
5

H. Konishi, M. Kumon, M. Yamaguchi et al.
Tetrahedron xxx (xxxx) xxx
4.2.18. [1,10-biphenyl]-4-carboxylic acid (4) [44]
over Na2SO4, filtered, and concentrated. The obtained residue was
purified by column chromatography (performed by Smart Flash W-
Prep 2XY using Hi-Flash column, hexane/AcOEt ¼ 100/0 to 85/15)
to afford [1,10-biphenyl]-4-carbaldehyde (3a, 677 mg, 3.71 mmol,
74%).
This compound was obtained during the purification process of
the 3a in the reaction of 1a (Table 1, entries 3, 5, 6). A white solid; 1H
NMR (500 MHz, DMSO‑d6)
d
8.02 (d, J ¼ 8.6 Hz, 2H), 7.80 (d,
J ¼ 8.0 Hz, 2H), 7.73 (d, J ¼ 7.4 Hz, 2H), 7.50 (t, J ¼ 6.9 Hz, 2H), 7.42 (t,
J ¼ 7.5 Hz, 1H) ppm (carboxy proton signal is missing); 13C NMR
(125 MHz, DMSO‑d6)
d 167.2, 144.4, 139.1, 130.0, 129.7, 129.2, 128.4,
Declaration of competing interest
127.0, 126.9 ppm.
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
4.2.19. [1,10-biphenyl]-4-ylmethanol (5) [45]
This compound was obtained after the treatment of the crude
reaction mixture with NaBH4 (37.8 mg, 5.0 equiv) in MeOH at rt for
30 min, which was followed by the same purification process as
that of aldehyde 3a (Table 2). A white solid; 1H NMR (500 MHz,
Acknowledgments
CDCl3)
d
7.61-7.57 (m, 4H), 7.46-7.42 (m, 4H), 7.35 (t, J ¼ 7.5 Hz, 1H),
This study was partly supported by JSPS KAKENHI Grant
Numbers 20H03368 and 18K06584, and the Platform Project for
Supporting in Drug Discovery and Life Science Research (Platform
for Drug Discovery, Informatics, and Structural Life Science) from
the Ministry of Education, Culture, Sports, Science and Technology
(MEXT) and Japan Agency for Medical Research and Development
(AMED).
4.74 (s, 2H), 1.79 (br s, 1H) ppm; 13C NMR (125 MHz, CDCl3)
d
140.8,
140.6, 139.8, 128.8, 127.4, 127.3, 127.1, 65.1 ppm (one carbon signal is
missing) ppm.
4.3. Five-mmol experiment for the synthesis of [1,10-biphenyl]-4-
carbaldehyde (3a)
Appendix A. Supplementary data
Pd(OAc)2 (56.1 mg, 0.250 mmol, 5.00 mol%), DPPF (208 mg,
0.375 mmol, 7.50 mol%), 2 (1.85 g, 7.50 mmol, 1.50 equiv), and
MeCN (25.0 mL) were added to an oven-dried, 100-mL round-
bottomed flask with a reflux condenser, Ar balloon, and a septum
containing a magnetic stirring bar. The flask was evacuated and
backfilled with Ar three times. Biphenyl-4-y triflate 1a (1.51 g,
5.00 mmol), triethylsilane (1.20 mL, 7.50 mmol, 1.50 equiv), and
Na2CO3 (795 mg, 7.50 mmol, 1.50 equiv) were added to the mixture
under the flow of Ar. The Ar balloon and the septum were replaced
to an empty balloon (Fig. 1 (a)) and a glass stopcock, respectively,
and the flask was warmed to 80 ꢀC in an oil bath. The mixture was
stirred for 16 h. A balloon was inflated due to CO generation and
evaporation of MeCN on the course of the reaction (Fig. 1). After
cooling to rt, the mixture was diluted with CH2Cl2 and H2O,
extracted with CH2Cl2 from aqueous layer, washed with brine, dried
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131639.
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