Palladium-Catalyzed Difunctionalization of 1,3-Diene with Amine and Disilane under a Mild Re-oxidation System

Article abstract of DOI:10.1002/chem.202100043

A highly regioselective and stereoselective difunctionalization reaction of 1,3-diene with amine and disilane to form C?N and C?Si bonds via a one-step Pd/Cu/O₂ system is disclosed. The difunctionalization reaction affords allylic silanes, including the allylic amine moiety, in up to 92 % yield in the absence of any acid, base, or external ligand. The developed synthetic methodology can be scaled to 100 g in high yield with high Z-selectivity, which demonstrates the feasibility of the reaction for industrial applications.

Full text of DOI:10.1002/chem.202100043

Communication
doi.org/10.1002/chem.202100043
Chemistry—A European Journal
&
Homogeneous Catalysis
Palladium-Catalyzed Difunctionalization of 1,3-Diene with Amine
and Disilane under a Mild Re-oxidation System
Kazuyuki Torii,[a] Atsushi Kawakubo,[a] Xianjin Lin,[a] Tetsuaki Fujihara,[b] Tatsuo Yajima,[a] and
Yasushi Obora*[a]
Abstract: A highly regioselective and stereoselective di-
functionalization reaction of 1,3-diene with amine and dis-
ilane to form CÀN and CÀSi bonds via a one-step Pd/Cu/
O2 system is disclosed. The difunctionalization reaction af-
fords allylic silanes, including the allylic amine moiety, in
up to 92% yield in the absence of any acid, base, or exter-
nal ligand. The developed synthetic methodology can be
scaled to 100 g in high yield with high Z-selectivity, which
demonstrates the feasibility of the reaction for industrial
applications.
Catalytic bond formation reactions have been the subject of a
wealth of interdependent research as one of the most useful
strategies in the development of organic chemistry, as well as
for global industrial growth. Importantly, a wide variety of
methods to form CÀC bonds, such as classical cross-coupling
reactions, have been developed over many decades. These re-
actions have been designed to produce desired products
along with stoichiometric amounts of by-products. In addition,
environmentally friendly reactions are desirable to suppress
excess energy losses and to reduce waste emissions.
Alternatively, difunctionalization reactions with 1,3-dienes
have received significant attention over recent decades be-
Scheme 1. A) Difunctionalization reaction examples with 1,3-dienes. B) Previ-
cause 1,3-dienes are regarded as chemical feedstocks, and 1,3-
ous reports. C) Difunctionalization of 1,3-diene to form CÀSi and CÀN bonds.
butadiene in particular is produced on a global scale that ex-
ceeds 10 million tons per annum.[1–7] These difunctionalization
reactions allow 1,3-dienes to form two chemical bonds in one
step, which increases the molecular complexity. Thus, difunc-
tionalization reactions of 1,3-dienes are effective methods for
organic transformation reactions in terms of atom economy
and step economy. Huang and co-workers reported palladium-
catalyzed aminomethylamination of 1,3-dienes to form CÀC
and CÀN bonds (Scheme 1A-I).[8] Terao and Kambe developed
a titanium-catalyzed carbosilylation of 1,3-diene using alkyl ha-
lides and chlorosilanes to form CÀC and CÀSi bonds
(Scheme 1A-II).[9] Recently, iron-catalyzed difunctionalization of
olefins using hydrosilane and amine to form CÀN and CÀSi
bonds was reported by Song, Li, Luo, and co-workers.[10] How-
ever, difunctionalization reactions of 1,3-dienes to form CÀN
and CÀSi bonds, to the best of our knowledge, have not been
published.[11] Our group previously reported Pd-catalyzed de-
carbonylative coupling of 1,3-diene with acyl chloride and disi-
lane to form CÀC and CÀSi bonds in one step.[12] However,
emission of a stoichiometric amount of Me3SiCl and carbon
monoxide remains a significant problem because of the utiliza-
tion of acylchloride for alkylation into the allyl silane moiety.
Furthermore, our group has reported the oxidative amination
reaction of simple olefins via a Pd/molybdovanadophosphate
salt (NPMoV)/O2 system for introduction of an amino group
(Scheme 1B-I).[13] Our research has also established oxidative si-
lylation of simple olefins via a Pd/O2 system for introduction of
[a] K. Torii, A. Kawakubo, Dr. X. Lin, Prof. Dr. T. Yajima, Prof. Dr. Y. Obora
Department of Chemistry and Materials Engineering
Faculty of Chemistry, Materials and Bioengineering
Kansai University, Suita, Osaka 564-8680 (Japan)
E-mail: obora@kansai-u.ac.jp
[b] Prof. Dr. T. Fujihara
Department of Energy and Hydrocarbon Chemistry
Graduate School of Engineering, Kyoto University
Nishikyo-ku, Kyoto 615-8510 (Japan)
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.202100043.
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a silyl group (Scheme 1B-II).[14] These reactions proceed under
halogen-free conditions using molecular oxygen as the termi-
nal re-oxidant.
zoquinone (1 equiv) to the reaction system under Ar gave no
reaction (entry 8). These results suggest that molecular oxygen
plays a crucial role except in the re-oxidation of the catalytic
species. Alternative copper salts were also tested. The use of
CuBr improved the yield of 4a (entry 9). Conversely, CuCl and
CuOAc were not efficient re-oxidants (entries 10 and 11) and
CuI was superior to any other copper salt. Among the solvents
employed in the difunctionalization reaction, amide solvents
such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide
(DMA), and N-methylpyrrolidone (NMP) were extremely effec-
tive in yielding 4a (entries 5, 12 and 13). The reaction in the
presence of acetonitrile or toluene barely proceeded (en-
tries 14 and 15). The yield of 4a was also significantly influ-
enced by the substrate ratio (entries 16–18).
Next, our group envisioned a one-step Pd-catalyzed difunc-
tionalization of 1,3-diene with amine and disilane to form CÀN
and CÀSi bonds (Scheme 1C). This reaction provided allylic
silane, including the allylic amine framework, in high yield with
high chemo-, regio-, and stereoselectivity. Furthermore, the re-
action system demonstrates significant advantages as a green
reaction procedure and a mild re-oxidation system because a
stoichiometric amount of the re-oxidant and halogen reagent
are not required.
First, the difunctionalization reaction conditions were opti-
mized (Table 1). The use of 2,3-dimethyl-1,3-butadiene (1a), N-
methylaniline (2a), and hexamethyldisilane (3a) in the pres-
ence of PdCl2 (0.05 mmol, 5 mol%) and CuI (0.1 mmol,
10 mol%) as re-oxidant under an oxygen atmosphere (1 atm,
balloon) afforded the desired nitrogen-containing allylic silane
4a in 36% GC yield (entry 1). Pd(PPh3)4 was not an effective
catalyst in this reaction (entry 2). Compared with these cata-
lysts, Pd(OAc)2 and Pd(TFA)2 exhibited high catalytic activity
(entries 3 and 4). Furthermore, the use of Pd(dba)2 gave 4a in
the highest yield (92% GC yield) with high stereoselectivity
(92:8, Z/E) (entry 5).[15] Surprisingly, this reaction proceeded
only oxygen atmosphere (entries 5–7). The addition of 1,4-ben-
Thereafter, various amines, dienes, and disilanes were stud-
ied for the difunctionalization reaction (Table 2). In the pres-
ence of amines, N-methylaniline derivatives bearing electron-
withdrawing groups such as ÀCl or ÀCF3 were applicable to
this reaction and gave corresponding products in good to ex-
cellent yields with high Z-selectivity (4b–4e). The reaction with
Table 2. Variation of amines, dienes, and disilanes.[a]
Table 1. Optimization of reaction conditions.[a]
69% (88:12)
85% (87:14)
83% (84:16)
4b
4c
4d
Entry
Pd/Cu
Solvent
X, Y
Yield [%][b]
1
2
3
4
PdCl2/CuI
Pd(PPh3)4/CuI
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
NMP
MeCN
toluene
DMF
DMF
DMF
3, 2
3, 2
3, 2
3, 2
3, 2
3, 2
3, 2
3, 2
3, 2
3, 2
3, 2
3, 2
3, 2
3, 2
3, 2
1, 1
3, 1
3, 3
36(90:10)
34(92:8)
72(92:8)
63(94:6)
92[87][c] (92:8)
<1
Pd(OAc) /CuI
2
Pd(TFA) 2/CuI
Pd(dba)2/CuI
Pd(dba)2/CuI
Pd(dba)2/CuI
Pd(dba)2/CuI
Pd(dba)2/CuBr
Pd(dba)2/CuCl
Pd(dba)2/CuOAc
Pd(dba)2/CuI
Pd(dba)2/CuI
Pd(dba)2/CuI
Pd(dba)2/CuI
Pd(dba)2/CuI
Pd(dba)2/CuI
Pd(dba)2/CuI
69% (90:10)
79% (93:7)
85% (86:14)
5
4e
4 f
4g
6[d]
7[e]
8[g]
9
n.d.[f]
n.d.[f]
81(91:9)
28(94:6)
34(92:8)
88(92:8)
72(94:6)
<1
10
11
12
13
14
15
16
17
18
77% (92:8)
60% (>99:-)[b,c]
CCDC 2044491[18]
4h
4j
<1
44(94:6)
46(94:6)
93(92:8)
[a] Reaction conditions: 1a (3 mmol), 2a (1 mmol), 3a (2 mmol), Pd cata-
lyst (0.05 mmol, 5 mol%) and additive (0.1 mmol, 10 mol%) were stirred
at 708C for 16 h under O2. Yield was determined by GC based on 2a
used (n-decane as internal standard). [b] The numbers in parentheses
show the Z/E ratio determined by GC. [c] Number in brackets shows iso-
lated yield. [d] Under air. [e] Under Ar. [f] n.d. = not detected. [g] Benzo-
quinone (1 equiv) was used under Ar. Pd(TFA)2 = palladium bis(2,2,2-tri-
fluoroacetate); DMF = N,N-dimethylformamide; DMA = N,N-dimethylace-
tamide; NMP = N-methyl-2-pyrrolidone.
92% (94:6)[b]
51% (11:89)[c,d]
65% (95:5)[e]
4i
4k
4l
[a] Reaction conditions: 1 (3 mmol), 2 (1 mmol), 3 (2 mmol), Pd(dba)2
(0.05 mmol, 5 mol%) and CuI (0.1 mmol, 10 mol%) were stirred at 708C
for 16 h under O2. The numbers in parentheses show Z/E ratio deter-
mined by GC. [b] Reaction time was 48 h. [c] Disilane (5 mmol) and CuI
(0.3 mmol, 30 mol%) were used. [d] DMF (8 mL) was used. [e] CuI
(0.3 mmol, 30 mol%) was used.
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o-, m-, and p-chloro-N-methylaniline proceeded with yields of
69%–85% (4b–4d). The use of N-methylaniline substituted
with an electron-donating group (ÀCH3) yielded 4 f in excellent
yields. The reaction in the presence of sterically hindered
amines, N-ethylaniline and diphenylamine, yielded 4g and 4h
in excellent yields. The highest yield was obtained in the pres-
ence of the diphenylamine derivative (4i). Significantly, the het-
erocyclic amine, carbazole, also participated in this reaction
and a conformation of 4j was determined by X-ray crystallo-
graphic analysis. However, the reaction with N-methylbenzyl-
amine or aniline did not afford the corresponding product
under these conditions. Next, the scope of dienes and disilanes
was investigated. The reaction with 1,3-butadiene proceeded
by employing 8 mL of DMF, and, because of the low boiling
point of 1,3-butadiene, the reaction furnished 4k in moderate
yield. In this case, the E-isomer was principally obtained be-
cause of the smaller steric hindrance compared with 1a. The
reaction to generate 4k was sluggish under typical reaction
conditions. The reaction with 2,3-diphenyl-1,3-butadiene or
1,3-cyclohexadiene was sluggish under these conditions. Other
1,3-dienes such as isoprene or myrcene were tolerable to this
reaction; however, the generation of regioisomers increased
the difficulty of purifying the reaction mixture. The use of
PhMe2SiSiMe2Ph as the disilane reagent was successful and
gave 4l in good yield. Unfortunately, other disilanes such as
Ph2MeSiSiMePh2 and Ph3SiSiPh3 were not suitable in this reac-
tion as a result of their poor solubility in DMF.
To evaluate the utility and scalability of this protocol, scale-
up experiments for the synthesis of 4a were performed (Fig-
ure 1A).[16]
The use of 1a (29.8 mmol), 2a (9.9 mmol), and 3a
(19.8 mmol) in the presence of Pd(dba)2 (0.5 mmol, 5 mol%)
and CuI (1.0 mmol, 10 mol%) under an oxygen atmosphere
(1 atm, balloon) afforded 4a in a satisfactory yield (87%) with
excellent regioselectivity (94:6, Z/E). Next, the difunctionaliza-
tion reaction was scaled to 10 g in the presence of 1 mol%
(0.5 mmol) of Pd(dba)2 and 2 mol% of Cu (1.0 mmol) using 1a
(151 mmol), 2a (49 mmol), and 3a (99 mmol). Product 4a was
obtained in excellent yield (89%) and with high Z-selectivity
(94:6, Z/E). Further scale-up achieved the synthesis of more
than 150 g of 4a with excellent Z-selectivity based on the reac-
tion of 2.22 mol of 1a, 0.74 mol of 2a, and 1.50 mol of 3a in
the presence of Pd(dba)2 (7.5 mmol, 1 mol%) and CuI
(15 mmol, 2 mol%). These results demonstrate the feasibility of
this reaction strategy for industrial application.
We envisioned four plausible reaction pathways (A–D)
(Scheme S1). In path A, 1,3-dienes reacted with amine via oxi-
dative amination, followed by silylation with disilane. Path B
Figure 1. A) Scale-up experiment for multi-gram, 10 g, and 100 g scale synthesis of 4a. B) Deuterated labeling experiment using 2a-d. C) Mechanistic studies.
(D) A plausible catalytic cycle for the difunctionalization reaction.
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sees hydroamination of 1,3-diene via 1,2- or 1,4-addition and
then silylation occurs. In the third possible mechanism de-
scribed as path C, a silyl group is introduced to 1,3-diene
before the oxidative amination process. Alternatively, oxidative
amination takes place after introduction of the silyl group to
1,3-diene in path D. To gain insight into the reaction mecha-
nism, a deuterated labeling experiment was performed substi-
tuting 2a with 2a-d under standard conditions (Figure 1B).
Deuterated 4a was not observed from this experiment, which
rules out the hydroamination path (Path B and C). Further in-
vestigation was performed by using possible reaction inter-
mediates (Figure 1C).[16] The oxidative amination product 5,
which is the intermediate of path A was reacted with hexame-
thyldisilane in the presence of Pd(dba)2 and CuI in DMF at
708C for 48 h, furnishing the desired product 4k in 20% yield
as determined by GC (Figure 1C-I). Compound 5 was not
formed when the reaction was performed without disilane.
When intermediates of hydroamination of 1,3-diene (6 and 7)
reacted with 3a under standard conditions, desired product
4a was not observed (Figure 1C-II and III). An intermediate of
silylation of 1,3-diene 8 of path D did not react with 2a (Fig-
ure 1C-IV). These results suggest that 5 is the intermediate of
this difunctionalization reaction via oxidative amination fol-
lowed by silylation.
ic Chemistry, AIST, for carrying out 100 g scale experiment and
for helpful discussions.
Conflict of interest
The authors declare no conflict of interest.
Keywords: difunctionalization · molecular oxygen · oxidative
amination · palladium · regio- and stereoselective
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From the results of mechanistic studies and previous reports,
a plausible catalytic cycle for the difunctionalization reaction is
shown in Figure 1D.[14,17] First, PdII (I) coordinates with 1,3-
diene (1a) to afford intermediate II. Thereafter, nucleophilic
amine (2a) undergoes an intermolecular nucleophilic attack to
form intermediate III. b-hydride elimination of intermediate III
leads to intermediates IV, followed by the production of inter-
mediate V by coordination of PdII. Finally, p-allyl intermediate
VI is formed from V and reacts with disilane (3a) to give de-
sired product (4a) along with metallic Pd, which is oxidized to
PdII by Cu and O2. Previously, our group reported that Pd/p-
allyl intermediate could react with disilanes.[14] Therefore, the
mechanism involves oxidative amination, leading to Pd/p-allyl
formation, followed by silane functionalization and reoxidation.
In conclusion, a highly regioselective and stereoselective di-
functionalization reaction of 1,3-dienes with amine and disilane
was developed using molecular oxygen as the terminal re-oxi-
dant. The reaction produces allylic silanes, including the allylic
amine moiety, in up to 92% yield and scale-up has been dem-
onstrated for more than 150 g. Further investigations of the
detailed reaction mechanism and applications of this method-
ology in medicinal or biological chemistry are in progress.
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2018.
Acknowledgements
This work was supported by the “Development of Innovative
Catalytic Process for Organosilicon Functional Materials” proj-
ect (PL: Kazuhiko Sato, AIST) from the New Energy and Indus-
trial Technology Development Organization (NEDO). High-reso-
lution mass spectra were performed at Global Facility Center,
Hokkaido University. We thank Dr. Kazuhiro Matsumoto and Dr.
Norihisa Fukaya of Interdisciplinary Research Center for Catalyt-
[12] Y. Obora, Y. Tsuji, T. Kawamura, J. Am. Chem. Soc. 1993, 115, 10414–
10415.
[13] Y. Shimizu, Y. Obora, Y. Ishii, Org. Lett. 2010, 12, 1372–1374.
[14] S. Nakai, M. Matsui, Y. Shimizu, Y. Adachi, Y. Obora, J. Org. Chem. 2015,
80, 7317–7320.
[15] We conducted computational calculations of the Gibbs free energy
(kcalmolÀ1) between Z and E isomers of 4a at the M06-2X/6–311+
G(d,p)//B3LYP/6–31+G(d,p) level of theory with Gaussian 16. All calcu-
lated data involve Gibbs energy using thermal corrections at 343 K with
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CPCM model (DMF solvent). The results showed that Z isomer is ther-
modynamically more stable than E isomer (see the Supporting Informa-
tion).
tionszentrum Karlsruhe Access Structures service www.ccdc.cam.ac.uk/
structures.
[16] For detailed reaction conditions, see the Supporting Information.
[17] V. Kotov, C. C. Scarborough, S. S. Stahl, Inorg. Chem. 2007, 46, 1910–
1923.
[18] Deposition Number 2044491 contains the supplementary crystallo-
graphic data for this paper. These data are provided free of charge by
the joint Cambridge Crystallographic Data Centre and Fachinforma-
Manuscript received: January 5, 2021
Revised manuscript received: January 19, 2021
Accepted manuscript online: January 20, 2021
Version of record online: February 15, 2021
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