Palladium-Catalyzed Solvent-Dependent Divergent Synthesis of Benzylformamides

Article abstract of DOI:10.1002/adsc.201800674

A palladium-catalyzed carbonylative cascade procedure for the synthesis of benzylformamides from aryl halides has been developed. The properties of the solvent chosen play a decisive role on the selectivity of the outcomes. Non-coordinative solvent facilitates the coordination and insertion of CO to the amino-palladium intermediate which then provides the formamides products. While the use of coordinative solvent leads to the formation of amines. A series of functional groups, including ester, ketone, nitro and cyano, were well tolerated under our conditions. The corresponding benzylformamides products were prepared in moderate to good yields without further optimization. (Figure presented.).

Full text of DOI:10.1002/adsc.201800674

Title: Palladium-Catalyzed Solvent-Dependent Divergent Synthesis of
Benzylformamides
Authors: Xiao-Feng Wu, fu-peng wu, jin-bao peng, xinxin qi, and jun
Ying
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800674
Link to VoR: http://dx.doi.org/10.1002/adsc.201800674

10.1002/adsc.201800674
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.2018
Palladium-Catalyzed Solvent-Dependent Divergent Synthesis of
Benzylformamides
Fu-Peng Wu,a Jin-Bao Peng,*a Xinxin Qi,a Jun Ying,a and Xiao-Feng Wu*a,b
a
Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, People’s Republic of China
E-mail: pengjb_05@zstu.edu.cn; xiao-feng.wu@catalysis.de
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Straße 29a, Rostock 18059, Germany
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.2018
Abstract. A palladium-catalyzed carbonylative cascade A series of functional groups, including ester, ketone, nitro
procedure for the synthesis of benzylformamides from aryl and cyano, were well tolerated under our conditions. The
halides has been developed. The properties of the solvent corresponding benzylformamides products were prepared in
chosen play a decisive role on the selectivity of the moderate to good yields without further optimization.
outcomes. Non-coordinative solvent facilitates the
coordination and insertion of CO to the amino-palladium
intermediate which then provides the formamides products.
While the use of coordinative solvent leads to the formation
of amines.
Keywords: Carbonylation; Aryl halides; Palladium;
Cascade reaction; Benzyl amine
carbonyl group is a potent structure unit in organic
chemistry, carbonylation reactions have been widely
explored during the last few decades (Scheme 1, a).
Some cascade procedures for the carbonylative
homologations were developed as well. For example,
Mankad and co-worker reported a copper catalyzed
reductive carbonylation of alkyl iodides to provide
Introduction
Developing new and efficient catalytic procedure for
selective synthesis is one of the key goals in modern
organic chemistry. It’s even more interesting that
different types of products can be divergently
prepared from the same substrates with slightly
difference in reaction conditions. Such type of
methodologies not only increase the diversity of the
products obtained, but also enrich the knowledge in
reactivity tuning and new catalysts design. In
transition metal-catalyzed transformations, it is
generally accepted that the electronic and steric
environment of the metal center can control the
outcome of the reaction which mainly refers to
reactivity and selectivity. Thus, fine-tuning of the
catalyst system can provide opportunities for the
divergent synthesis and several highly selective
catalytic transformations have been reported during
the last half century.[1]
one-carbon-extended
alcohols
using
diethoxymethylsilane as the reductant (Scheme 1,
b).[4] The hydroaminomethylation reaction of alkenes
had been developed as early as in 1950s by Reppe’s
group at BASF.[5] Rhodium and more recently
ruthenium based catalysts have been widely used to
catalyze this transformation (Scheme 1, c).[6]
Additionally, our group recently developed an
efficient and convenient palladium-catalyzed
carbonylative procedure for the synthesis of
bis(indolyl)methanes from aryl iodides and indoles.
With TFBen (benzene-1,3,5-triyl triformate) as the
solid
CO
source,
the
corresponding
bis(indolyl)methane derivatives were produced in
moderate to excellent yields.[7a] However, due to the
preference of amide formation, the direct
carbonylation based aminomethylation of aryl halides
has been scarcely reported. Recently, we have
On the other hand, transition metal-catalyzed
carbonylative transformations have experienced
impressive progresses during the last decades. It’s
already become one of the most powerful platforms
for
the
synthesis
of
carbonyl-containing
developed
a
palladium-catalyzed carbonylative
compounds.[2,3] Numerous synthetically valuable
structures can be prepared easily and atom-
aminohomologation reaction of aryl halides for the
direct synthesis of benzylic amine derivatives
economically by carbonylation procedures. In general, (Scheme 1, d).[7b] The reaction proceeded via a
carbonylation of organic halide proceeds through
acyl-metal complex as the key intermediate which
will produce the carbonyl-containing compound after
reacted with a suitable nucleophile. Since the
tandem palladium catalyzed formylation followed by
a reductive amination reaction processes with formic
acid as a cheap and efficient reductant. During the
screening of the reaction conditions, we found the
1
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10.1002/adsc.201800674
Advanced Synthesis & Catalysis
corresponding formamide can be obtained in some
reactions. However, increasing the amount of formic
acid and prolonging the reaction time all failed to
increase the yield of formamide. Hence, we
hypothesized that the formamide formation is
proceed in a different reaction pathway instead of
simple N-formylation of the in-situ generated amine.
Thus, we investigated the reaction systematically and
found that the selection of solvent plays a decisive
role on the selectivity of this reaction. Herein, we
present our new result on the solvent-directed
divergent carbonylative aminohomologation reaction
of aryl halides for the direct synthesis of
benzylformamide derivatives. The coordination
property of the solvent to palladium plays a key role
in the reaction outcomes.
formamide 4hb was isolated as the major product.
For examples, formamide 4hb was produced in 43%
yield when cyclohexane was used as the solvent.
Only trace amount of amine 3hb was detected (Table
1, entry 5). The yield was slightly improved to 54%
when the reaction was performed in toluene (Table 1,
entry 7). It has been well demonstrated that ligand
effect plays significant role on the transition metal
catalyzed carbonylation reactions.[8] A series of
phosphine ligands were investigated subsequently
(Table
1,
entries
8-11).
Substituted
triphenylphosphine ligands were effective to catalyze
this reaction but with decreased yields (details in SI).
Other palladium precursor such as Pd(CF3COO)2 was
effective as well and able to deliver the desired
formaimde 4hb product in 51% yield (Table 1, entry
12). Since higher conversion can be achieved with
MeCN as the solvent, we then examined mixed
solvents for this reaction. To our delight, when the
reaction was performed in a mixed solvent of MeCN
and toluene (1:9), a slightly higher yield can be
obtained (Table 1, entry 13). The best result was
obtained in a 1:1 mixture of MeCN and toluene, the
desired formamide 4hb was generated in 81% yield
(Table 1, entry 14). Further increasing the ratio of
MeCN resulted in poor selectivity (Table 1, entry 15,
see details in SI). This phenomenon is mainly due to
the coordinative property of MeCN. Such a property
can stabilize the palladium center during the reaction.
However, the excess of MeCN can also disturb the
coordinating of CO with palladium and subsequently
inhibit the desired formamide product 4hb formation.
Table 1. Optimization of the Reaction Conditions.a
Scheme 1. Synthesis of Aminomethyl Motif.
3hb
(%)
72
0
35
4hb
(%)
13
0
36
0
43
43
54
29
9
31
28
51
Entry Ligand
Solvent
Results and Discussion
1
P(o-tolyl)3
CH3CN
DMSO
THF
2
3
4
5
6
7
8
P(o-tolyl)3
P(o-tolyl)3
P(o-tolyl)3
P(o-tolyl)3
P(o-tolyl)3
P(o-tolyl)3
P(p-anisyl)3
We began our study with 4-chloro-iodobenzene 1h
and cyclohexylamine 2b as the model substrates
under 2 bar of CO. Under our previous reaction
conditions with Pd(OAc)2 as the catalyst and P(o-
tolyl)3 as the ligand, formamide 4hb was produced in
13% yield in MeCN. The amine 3hb was obtained as
the major product in 72% yield (Table 1, entry 1).
The screening of the reaction conditions revealed that
solvent played a crucial role in the reaction selectivity.
When the reaction was performed in coordinative
solvents such as MeCN, THF and DCE, the amine
3hb was obtained as the main product (Table 1,
entries 2-4). Comparably, when the reaction was
conducted in non-coordinative solvents, the
DCE
37
cyclohexane
benzene
toluene
toluene
trace
trace
trace
0
0
0
9
P(m-anisyl)3 toluene
10
11
12b
P(o-anisyl)3
P(1-Nap)3
P(o-tolyl)3
toluene
toluene
toluene
CH3CN/Tol.
(1:9)
trace
0
13
P(o-tolyl)3
P(o-tolyl)3
trace
57
CH3CN/Tol.
(1:1)
14
7
81
2
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10.1002/adsc.201800674
Advanced Synthesis & Catalysis
4lb). 1-Fluoro-4-iodobenzene and 1-chloro-4-
iodobenzene were transformed into the corresponding
products in 53% and 75% yields, respectively (Table
2, 4gb and 4hb). It should be noted that some
reductant-sensitive functional groups such as nitro
and cyano groups are tolerated as well; the
corresponding products 4kb and 4lb were obtained in
58% and 73% yields, respectively. 1-Iodonaphthalene
was efficiently converted into the desired formamide
4mb in 79% yield. Moreover, heteroaryl iodides were
also tolerated in the reaction. When 3-iodopyridine
and 3-iodothiophene were subjected to the optimized
conditions, the corresponding formamide products
were synthesized in 60% and 70% yields,
respectively (Table 2, 3nb and 3ob). It’s important to
mention that the differences between conversions and
yields are due to the reduction (de-halogenation) of
the aryl iodides and also the existing of the non-N-
formylated products.
CH3CN/Tol.
(9:1)
15
P(o-tolyl)3
35
48
aReaction conditions: 4-chloroiodobenzene (0.5 mmol),
cyclohexylamine (0.75 mmol), Pd(OAc)2 (0.5 mol%),
Ligand (1 mol%), Et3N (1 mmol), HCOOH (2.0 mmol),
solvent (2 mL), CO (2 bar), 24 h. bPd(CF3COO)2 instead
of Pd(OAc)2.
With the optimized reaction conditions in hand
(Table 1, entry 14), we examined the substrates scope
of aryl iodides. As shown in Table 2, the
carbonylative formamido-homologation reaction
showed good generality. Both electron-donating
group (Table 2, 4ab-4fb) and electron-withdrawing
group (Table 2, 4gb-4lb) substituted aryl iodides
were well tolerated and afforded the target products
in 40%-75% yields under our standard conditions.
More specifically, synthetically useful functional
groups such as ether, chloride, bromide, ester, ketone,
nitro and cyano are compatible here (Table 2, 4fb-
Table 2. Synthesis of Benzylformamides.a
3
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10.1002/adsc.201800674
Advanced Synthesis & Catalysis
aReaction conditions: aryl iodide (0.5 mmol), amine (0.75 mmol), Pd(OAc)2 (0.5 mol%), P(o-tolyl)3 (1 mol%), Et3N (1
mmol), HCOOH (2.0 mmol), MeCN/toluene (1:1, 2 mL), CO (2 bar), 24 h, isolated yields.
Then, we investigated the generality of this method
with a series of amines. Cyclopentylamine and
cycloheptylamine were well tolerated and produced
the desired products in 61% and 58% yields,
respectively (4aa and 4ac). Other less-sterically
hindered primary aliphatic amines such as
benzylamine and n-butylamine were applicable as
well, and the corresponding products were obtained
successfully in acceptable yields (4ad and 4ae).
Small amounts of tertiary amines can be detected as
the by-products. However, when aniline was
subjected to the standard conditions, only trace
amount of 4af was obtained. Non-formylated amine
3af was obtained as the major product.[7]
possibility that 4 was formed from 3 via N-
formylation.
In our control experiments (Scheme 2), under our
standard
chlorobenzyl)cyclohexanamine
chlorobenzyl)-N-cyclohexylformamide
produced from 4-chlorobenzaldehyde
cyclohexanamine.
conditions,
N-(4-
N-(4-
were
and
and
N-(4-Chlorobenzyl)-N-
cyclohexylformamide was found as the major product.
Under the same conditions started from N-(4-
chlorobenzyl)cyclohexanamine, the corresponding N-
formylated product can be obtained in 68% yield.
Scheme 3. A Plausible Mechanism.
Conclusion
In summary, we have developed a solvent-
controlled selective carbonylative procedure for the
direct synthesis of benzylformamides. Using aryl
iodides as the substrates and palladium as the
catalyst,[9] good yields of the desired products can be
obtained. A broad range of functional groups
including chloride, bromide, ester, ketone, nitro and
cyano were well tolerated in this reaction. Non-
coordinative solvent facilitates the coordination and
insertion of CO to the amino-palladium intermediate
and provides the amide products. While the use of
coordinative solvent leads to the formation of amines.
Scheme 2. Control experiments.
Based on our results and previous literatures,[7]
a
plausible mechanism of the solvent-controlled
selective carbonylative amino-homologation reaction
is proposed and shown in Scheme 3. Initially, the
reductive carbonylation of the aryl halide 1 produced
the corresponding aldehyde 5, which was converted
into the corresponding imine intermediate 6 after
condensation with amine 2. Meanwhile,
catalytically active palladium hydride
a
was
7
Experimental Section
generated in-situ from the reaction of palladium pre-
catalyst and formic acid. Palladium hydride 7 reacted
with imine 6 to form an amino-palladium complex 8.
Then, the coordination and insertion of CO to the
General Information:
Unless otherwise noted, all reactions were carried out
under a nitrogen atmosphere. All reagents were from
commercial sources and used as received without further
purification. All solvents were dried by standard
techniques, and distilled prior to use. Column
chromatography was performed on silica gel (200-300
amino-palladium complex
8
would give the
formamide 4 with 9 as the intermediate. Comparably,
if the reaction was performed in a coordinative
solvent, the coordination of solvent to the palladium
center would block the coordination of CO, thus,
produced the amine product 3 after decarboxylation
and reductive elimination. Meanwhile, the in-situ
generated Pd(0) reacted with formic acid to
regenerate palladium hydride 7 for the next cycle. It
is also important to mention that based on our control
experiments (Scheme 2), we cannot exclude the
o
meshes) using petroleum ether (bp. 60~90 C) and ethyl
1
acetate as eluent. H and 13C NMR spectra were taken on
400 MHz instruments and spectral data were reported in
ppm relative to tetramethylsilane (TMS) as internal
standard and CDCl3(1H NMR δ 7.26, 13C NMR δ 77.0) as
solvent. All coupling constants (J) are reported in Hz with
the following abbreviations: s = singlet, d = doublet, dd =
double doublet, ddd = double doublet of doublets, t =
triplet, dt = double triplet, q = quatriplet, m = multiplet, br
=
broad. Gas chromatography (GC) analyses were
4
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10.1002/adsc.201800674
Advanced Synthesis & Catalysis
performed on a Shimadzu GC-2014C chromatograph
equipped with a FID detector. Mass spectra (MS) were
measured on spectrometer by direct inlet at 70 eV.
NMR (101 MHz, CDCl3) δ 162.51, 158.59, 128.78,
128.18, 113.69, 58.35, 55.12, 44.18, 32.91, 25.81, 25.11.
N-Cyclohexyl-N-(4-fluorobenzyl)formamide (4gb), yellow
oil (62.8 mg, 53%). 1H NMR (400 MHz, CDCl3,
mixtures of rotamers, major rotamer: minor rotamer =
1:0.32) major rotamer: δ 8.37 (s, 1H), 7.26 – 7.20 (m, 2H),
7.00 (t, J = 8.7 Hz, 2H), 4.51 (s, 2H), 3.25 (tt, J = 12.0, 3.6
Hz, 1H), 1.85 – 0.91 (m, 10H). 13C NMR (101 MHz,
CDCl3) δ 162.74, 161.99 (d, J = 243 Hz) 129.20 (d, J = 8
Hz), 115.33 (d, J = 11 Hz), 58.60, 44.14, 33.00, 25.88,
25.18.
N-(4-chlorobenzyl)-N-cyclohexylformamide (4hb), yellow
oil (94.5 mg, 75%). 1H NMR (400 MHz, CDCl3,
mixtures of rotamers, major rotamer: minor rotamer =
1:0.29) major rotamer: δ 8.35 (s, 1H), 7.27 (d, J = 8.4 Hz,
2H), 7.23 – 7.15 (m, 2H), 4.49 (s, 2H), 3.25 (tt, J = 12.0,
3.5 Hz, 1H), 1.85 – 0.94 (m, 10H). 13C NMR (101 MHz,
CDCl3) δ 163.41, 162.72, 137.00, 136.80, 133.53, 132.90,
128.92, 128.86, 128.59, 128.32, 58.61, 53.12, 48.03, 44.17,
32.97, 30.66, 25.83, 25.74, 25.33, 25.14.
N-(4-Acetylbenzyl)-N-cyclohexylformamide (4ib), yellow
oil (50.7 mg, 40%). 1H NMR (400 MHz, CDCl3,
mixtures of rotamers, major rotamer: minor rotamer =
1:0.25) major rotamer: δ 8.37 (s, 1H), 7.88 (d, J = 8.2 Hz,
2H), 7.33 (d, J = 8.1 Hz, 2H), 4.55 (s, 2H), 3.28 (tt, J =
11.9, 3.4 Hz, 1H), 2.57 (s, 3H), 1.84 – 0.91 (m, 10H). 13C
NMR (101 MHz, CDCl3) δ 197.80, 162.90, 143.72,
136.12, 128.63, 127.52, 58.73, 44.53, 32.90, 26.64, 25.80,
25.11.
General procedure:
Pd(OAc)2 (0.5 mol %), ligand (1 mol% for monodentate
ligands and 0.5 mol% for bidentate ligand) were
transferred into a 15 mL tube which was filled with
nitrogen. Acetonitrile (1.0 mL), toluene (1.0 mL),
triethylamine (1 mmol), cyclohexylamine (0.75 mmol),
iodobenzene (0.5 mmol) and formic acid were added to the
reaction tube. Then the tube was purged and charged with
CO. The tube was sealed and the mixture was stirred at
120 °C for 24 h. After the reaction was completed, the
reaction mixture was filtered and concentrated under
vacuum. The crude product was purified by column
chromatography on silica gel to afford the corresponding
product.
Analytic data:
N-Benzyl-N-cyclohexylformamide (4ab), yellow oil (65.0
1
mg, 60%). H NMR (400 MHz, CDCl3, mixtures of
rotamers, major rotamer: minor rotamer = 1:0.4) major
rotamer: δ 8.39 (s, 1H), 7.36 – 7.24 (m, 5H), 4.55 (s, 2H),
3.26 (tt, J = 11.6, 3.1 Hz, 1H), 1.80 – 0.87 (m, 10H). 13C
NMR (101 MHz, CDCl3) δ 162.76, 128.48, 127.49,
126.99, 58.59, 44.85, 32.96, 25.89, 25.20.
N-Cyclohexyl-N-(2-methylbenzyl)formamide
(4bb),
1
yellow oil (69.1 mg, 60%). H NMR (400 MHz, CDCl3,
mixtures of rotamers, major rotamer: minor rotamer =
1:0.43) major rotamer: δ 8.41 (s, 1H), 7.17 – 7.07 (m, 4H),
4.52 (s, 2H), 3.21 (tt, J = 12.1, 3.3 Hz, 1H), 2.31 (s, 3H),
1.85 – 0.84 (m, 10H). 13C NMR (101 MHz, CDCl3) δ
162.44, 135.55, 135.00, 130.34, 127.62, 127.12, 126.00,
58.20, 42.91, 32.82, 25.91, 25.25, 19.30.
Methyl 4-((N-cyclohexylformamido)methyl)benzoate (4jb),
1
yellow oil (95.8 mg, 70%). H NMR (400 MHz, CDCl3,
mixtures of rotamers, major rotamer: minor rotamer =
1:0.26) major rotamer: δ 8.37 (s, 1H), 7.95 (d, J = 8.2 Hz,
2H), 7.30 (d, J = 8.1 Hz, 2H), 4.55 (s, 2H), 3.88 (s, 3H),
3.26 (tt, J = 12.0, 3.5 Hz, 1H), 1.82 – 0.94 (m, 10H). 13C
NMR (101 MHz, CDCl3) δ 166.79, 162.76, 143.45,
129.73, 128.97, 127.27, 58.60, 52.02, 44.41, 32.81, 25.71,
25.02.
N-Cyclohexyl-N-(4-nitrobenzyl)formamide (4kb), yellow
oil (75.0 mg, 58%). 1H NMR (400 MHz, CDCl3,
mixtures of rotamers, major rotamer: minor rotamer =
1:0.17) major rotamer: δ 8.37 (s, 1H), 7.95 (d, J = 8.2 Hz,
2H), 7.29 (t, J = 9.1 Hz, 2H), 4.55 (s, 2H), 3.32 – 3.19 (m,
1H), 1.81 – 0.76 (m, 10H). 13C NMR (101 MHz, CDCl3) δ
162.96, 145.85, 128.13, 123.76, 58.79, 44.29, 32.93, 25.75,
25.07.
N-(4-Cyanobenzyl)-N-cyclohexylformamide (4lb), yellow
oil (116.8 mg, 73%). 1H NMR (400 MHz, CDCl3,
mixtures of rotamers, major rotamer: minor rotamer =
1:0.18 ) major rotamer: δ 8.35 (s, 1H), 7.57 (d, J = 8.2 Hz,
2H), 7.34 (d, J = 8.1 Hz, 2H), 4.53 (s, 2H), 3.30 (tt, J =
11.9, 3.5 Hz, 1H), 1.81 – 0.87 (m, 10H). 13C NMR (101
MHz, CDCl3) δ 162.97, 143.81, 132.33, 127.99, 118.77,
111.01, 58.72, 44.42, 32.86, 25.73, 25.06.
N-Cyclohexyl-N-(3-methylbenzyl)formamide
(4cb),
1
yellow oil (36.7 mg, 43%). H NMR (400 MHz, CDCl3,
mixtures of rotamers, major rotamer: minor rotamer =
1:0.47) major rotamer: δ 8.37 (s, 1H), 7.07 (dd, J = 17.3,
7.8 Hz, 4H), 4.50 (s, 2H), 3.23 (t, J = 11.9 Hz, 1H), 2.33 (s,
3H), 1.86 – 0.93 (m, 10H). 13C NMR (101 MHz, CDCl3) δ
162.68, 138.12, 138.02, 128.32, 128.16, 127.89, 124.51,
58.56, 44.83, 32.97, 25.91, 25.23, 21.44.
N-Cyclohexyl-N-(4-methylbenzyl)formamide
(4db),
colorless oil (70.5 mg, 62%). 1H NMR (400 MHz, CDCl3,
mixtures of rotamers, major rotamer: minor rotamer =
1:0.5) major rotamer: δ 8.35 (s, 1H), 7.11 (q, J = 8.0 Hz,
4H), 4.48 (s, 2H), 3.21 (dd, J = 16.3, 7.7 Hz, 1H), 2.31 (s,
3H), 1.81 – 0.85 (m, 10H). 13C NMR (101 MHz, CDCl3) δ
162.64, 136.73, 135.08, 129.14, 127.52, 58.51, 44.63,
33.00, 25.91, 25.23, 21.10.
N-([1,1'-Biphenyl]-4-ylmethyl)-N-cyclohexylformamide
1
(4eb), colorless oil (102.6 mg, 70%). H NMR (400 MHz,
CDCl3, mixtures of rotamers, major rotamer: minor
rotamer = 1:0.40) major rotamer: δ 8.40 (s, 1H), 7.62 –
7.51 (m, 4H),, 7.43 (t, J = 7.4 Hz, 2H), 7.34 (dd, J = 7.8,
4.2 Hz, 3H), 4.58 (s, 2H), 3.28 (tt, J = 12.0, 3.3 Hz, 1H),
1.87 – 0.97 (m, 10H). 13C NMR (101 MHz, CDCl3) δ
162.78, 140.76, 140.03, 137.23, 128.86, 128.79, 127.95,
127.20, 127.04, 58.64, 44.60, 33.01, 25.91, 25.23.
N-Cyclohexyl-N-(naphthalen-1-ylmethyl)formamide
1
(4mb), yellow oil (106.2 mg, 79%). H NMR (400 MHz,
CDCl3, mixtures of rotamers, major rotamer: minor
rotamer = 1:0.30) major rotamer: δ 8.48 (s, 1H), 8.08 (d, J
= 8.1 Hz, 1H), 7.89 (t, J = 6.1 Hz, 1H), 7.81 (d, J = 8.4 Hz,
1H), 7.59 – 7.48 (m, 2H), 7.47 – 7.41 (m, 1H), 7.36 (d, J =
7.0 Hz, 1H), 5.04 (s, 2H), 3.23 (tt, J = 12.1, 3.3 Hz, 1H),
1.84 – 0.98 (m, 10H). 13C NMR (101 MHz, CDCl3) δ
N-Cyclohexyl-N-(4-methoxybenzyl)formamide
(4fb),
1
yellow oil (87.7 mg, 70%). H NMR (400 MHz, CDCl3,
mixtures of rotamers, major rotamer: minor rotamer =
1:0.44) major rotamer: δ 8.34 (s, 1H), 7.19 (d, J = 8.5 Hz,
2H), 6.83 (d, J = 8.6 Hz, 2H), 4.47 (s, 2H), 3.79 (s, 3H),
3.21 (tt, J = 12.0, 3.3 Hz, 1H), 1.81 – 0.94 (m, 10H). 13C
5
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10.1002/adsc.201800674
Advanced Synthesis & Catalysis
References
162.29, 133.75, 132.49, 131.26, 128.76, 128.19, 126.41,
125.88, 125.77, 125.19, 123.40, 57.94, 43.25, 32.84, 25.93,
25.21.
[1] For reviews on selective reactions: a) J.
Mahatthananchai, A. M. Dumas, J. W. Bode, Angew.
Chem. Int. Ed. 2012, 51, 10954-10990; b) Y. Wei, M.
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46, 4299-4328; d) Y.-C. Lee, K. Kumar, H.
N-Cyclohexyl-N-(pyridin-3-ylmethyl)formamide
(4nb),
1
yellow oil (78.4 mg, 60%). H NMR (400 MHz, CDCl3,
mixtures of rotamers, major rotamer: minor rotamer =
1:0.20) major rotamer: δ 8.55 (d, J = 32.0 Hz, 2H), 8.35 (s,
1H), 7.63 (d, J = 7.8 Hz, 1H), 7.23 (dd, J = 7.7, 4.9 Hz,
1H), 4.52 (s, 2H), 3.28 (tt, J = 12.0, 3.5 Hz, 1H), 1.85 –
0.89 (m, 10H). 13C NMR (101 MHz, CDCl3) δ 162.84,
148.89, 148.72, 135.51, 123.58, 123.53, 58.67, 42.35,
33.01, 25.81, 25.11.
N-Cyclohexyl-N-(thiophen-3-ylmethyl)formamide (4ob),
colorless oil (78.6 mg, 70%). 1H NMR (400 MHz, CDCl3,
mixtures of rotamers, major rotamer: minor rotamer =
1:0.37) major rotamer: δ 8.27 (s, 1H), 7.22 (dd, J = 4.9, 3.0
Hz, 1H), 7.09 (d, J = 2.8 Hz, 1H), 7.00 (dd, J = 4.9, 0.9 Hz,
1H), 4.48 (s, 2H), 3.22 (tt, J = 12.1, 3.6 Hz, 1H), 1.82 –
0.94 (m, 10H). 13C NMR (101 MHz, CDCl3) δ 162.33,
138.89, 127.51, 125.75, 122.08, 58.40, 40.15, 32.78, 25.78,
25.09.
Waldmann,
Angew.
Chem.
Int.
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N-Benzyl-N-cyclopentylformamide (4aa), yellow oil (62.0
1
mg, 61%). H NMR (400 MHz, CDCl3, mixtures of
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rotamers, major rotamer: minor rotamer = 1:0.40) δ
8.38 (s, 1H), 7.37 – 7.27 (m, 2H), 7.27 – 7.20 (m, 3H),
4.54 (s, 2H), 3.85 – 3.75 (m, 1H), 1.91 – 1.45 (m, 8H). 13
C
NMR (101 MHz, CDCl3) δ 162.59, 137.80, 128.50,
127.26, 127.12, 59.71, 45.00, 30.95, 23.43.
N-Benzyl-N-cycloheptylformamide (4ac), yellow oil (67.3
1
mg, 58%). H NMR (400 MHz, CDCl3, mixtures of
rotamers, major rotamer: minor rotamer = 1:0.44) δ
8.30 (s, 1H), 7.33 – 7.13 (m, 4H), 4.45 (s, 2H), 3.36 – 3.26
(m, 1H), 1.79 – 1.18 (m, 12H). 13C NMR (101 MHz,
CDCl3) δ 162.68, 137.88, 128.40, 127.61, 127.10, 60.77,
45.32, 35.09, 27.18, 24.90.
N,N-Dibenzylformamide (4ad), yellow oil (63.0 mg, 58%).
1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.4 Hz, 6H),
7.32 (t, J = 7.5 Hz, 6H), 7.23 (t, J = 7.3 Hz, 3H), 3.56 (s,
6H). 13C NMR (101 MHz, CDCl3) δ 139.68, 128.76,
128.25, 126.88, 57.93. 13C NMR (101 MHz, CDCl3) δ
162.86, 136.01, 135.63, 128.96, 128.73, 128.55, 128.18,
127.74, 127.70, 50.26, 44.63.
N-Benzyl-N-butylformamide (4ae), yellow oil (60.0 mg,
63%). 1H NMR (400 MHz, CDCl3, mixtures of rotamers,
major rotamer: minor rotamer = 1:0.80) major rotamer:
δ 8.21 (s, 1H), 7.41 – 7.31 (m, 3H), 7.30 – 7.19 (m, 2H),
4.55 (s, 2H), 3.14 (t, J = 7.1 Hz, 2H), 1.56 – 1.41 (m, 2H),
1.36 – 1.22 (m, 2H), 0.90 (td, J = 7.3, 4.4 Hz, 3H). 13C
NMR (101 MHz, CDCl3, mixtures of rotamers) δ 162.92,
136.52, 136.22, 128.87, 128.66, 128.17, 128.06, 127.56,
127.46, 51.23, 46.49, 45.12, 41.67, 30.15, 28.95, 20.08,
19.60, 13.79, 13.63.
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Acknowledgements
The authors thank the financial supports from NSFC (21472174,
21772177), education department of Zhejiang Province
(Y201636555), Zhejiang Sci-Tech University (16062095-Y) and
Zhejiang Natural Science Fund for Distinguished Young Scholars
(LR16B020002).
[7]a) X. Qi, H. Ai, N. Zhang, J. Peng, J. Ying, X. F. Wu, J.
Catal. 2018, 362, 74-77; b) J.-B. Peng, F.-P. Wu, C.
Xu, X. Qi, J. Ying, X.-F. Wu, Communications
6
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10.1002/adsc.201800674
Advanced Synthesis & Catalysis
Chemistry, 2018, 1, 29 (doi:10.1038/s42004-018-
0029-8).
[9] For a review on carbonylative multi-component
reactions and references there cited in, see: C. Shen,
X.-F. Wu, Chem. Eur. J. 2017, 23, 2973-2987.
[8] For a review on ligand controlled divergent
carbonylation reactions, see: J.-B. Peng, X.-F. Wu,
Angew. Chem. Int. Ed. 2018, 57, 1152-1160.
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800674
Advanced Synthesis & Catalysis
UPDATE
Palladium-Catalyzed Solvent-Dependent Divergent
Synthesis of Benzylformamides
Adv. Synth. Catal. Year, Volume, Page – Page
Fu-Peng Wu, Jin-Bao Peng,* Xinxin Qi, Jun Ying,
and Xiao-Feng Wu*
8
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