Green and Scalable Palladium-on-Carbon-Catalyzed Tsuji–Trost Coupling Reaction Using an Efficient and Continuous Flow System

Article abstract of DOI:10.1002/ejoc.201601311

The first continuous flow Tsuji–Trost coupling reaction between allylic compounds and various nucleophiles has been successfully achieved within only around 40 s during a single pass through a cartridge filled with palladium on carbon (Pd/C). Two methods have been designed by using the H-cube ThalesNano technology that enable the efficient production of added-value compounds on the gram scale with high productivity. Under the optimized conditions, the cartridge catalyst can be used for 60 min of continuous processing without a decrease in reactivity. A large range of substrates and nucleophiles have successfully been submitted to the standard methods, giving good-to-excellent yields and productivity.

Full text of DOI:10.1002/ejoc.201601311

A Journal of
Accepted Article
Title: Green and Scalable Palladium on Carbon-Catalyzed Tsuji-
Trost Coupling Reaction Using an Efficient and Continuous Flow
System
Authors: Christophe Len, Clement Cazorla, Muriel Billamboz, Herve
Bricout, and Eric Monflier
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using the Digital Object Identifier (DOI) given below. The VoR will be
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601311
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601311
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10.1002/ejoc.201601311
European Journal of Organic Chemistry
Green and Scalable Palladium on Carbon-Catalyzed Tsuji-Trost Coupling Reaction
Using an Efficient and Continuous Flow System
Clément Cazorla,[a] Muriel Billamboz,[b] Hervé Bricout,[c] Eric Monflier[c] and Christophe
Len*[a]
[a] Sorbonne Universités, Université de Technologie de Compiègne, Centre de
Recherche Royallieu, CS 60 319, F-60203 Compiègne cedex, France. Fax: +33 (0)3 44
97 15 91; Tel: +33 (0)3 44 23 88 28; E-mail: christophe.len@utc.fr
[b] Ecole Supérieure de Chimie Organique et Minérale, 1 allée du Réseau Jean-Marie
Buckmaster, F-60200 Compiègne, France.
[c] Univ. Artois, CNRS, Centrale Lille, ENSCL, Univ. Lille, UMR 8181, Unité de
Catalyse et de Chimie du Solide (UCCS), F-62300 Lens, France
Keywords: Tsuji-Trost coupling / Continuous flow / Allylic compound / Green chemistry
Abstract: The first continuous flow Tsuji-Trost coupling reaction between allylic compounds
and various nucleophiles was successfully achieved within only ca. 40 s during the single-
pass through a cartridge filled with palladium on carbon (Pd/C). Two methods have been
designed using the H-cube ThalesNano technology and enable the efficient production of add-
valued compounds in the gram-scale with high productivity. Under optimized conditions, the
cartridge catalyst can be used for 60 minutes of continuous processing without a decrease in
reactivity. A large diversity of substrates and nucleophiles were successfully submitted to the
standard methods, with good to excellent yields and productivity.
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Introduction
In the frame of green chemistry principles, the ability to conduct complex and routine
transformations in a clean, sustainable and scalable way is highly desirable. In the past
few years, the use of flow reactors with immobilized reagents in synthetic organic
chemistry has been widely explored.[1] Systems use a device for delivering a substrate
solution flowing through a cartridge filled with an heterogeneous catalyst. Among
many advantages, this technology allows very efficient heat transfer compared with
classical methodologies, good monitoring of temperature and enhanced mass transfer.
Since the flow channel in the cartridge is sufficiently narrow, the reaction efficiency is
expected to be enhanced due to the intimate contact of the catalyst with the substrate
and reagents in comparison to a batch-type reaction using vessels or flasks. The
immobilized catalyst – commonly a transistion-metal one – which often indicates a risk
of ignition under atmospheric conditions, is enclosed in a sealed cartridge, allowing to
secure the reaction. Moreover, flow process allows to avoid the problems associated
with highly exothermic reactions and dangerous or moisture- and air-sensitive
substrates. As a consequence, the reactions could be carried out in a safe manner. This
innovative approach also permits the integration of several steps into one single
streamlined process, thus shortening the time from research to pilot-scale and
production.[2]
Coupling flow process with heterogeneous catalysis produces a synergistic effect. In
fact, when the catalyst is immobilized in a cartridge, its recovery and reuse is
simplified.[3] In addition, typical packed-bed reactors provide a high ratio of catalyst
vs. substrate during the course of the reaction, an advantage that significantly increases
the rate of reaction and simplifies the purification of the final products. However, some
problems, such as leaching of Pd species, swelling of polymer supports, deposition of
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10.1002/ejoc.201601311
European Journal of Organic Chemistry
products/by-products and poor catalyst cartridge life cycles can complicate their use in
continuous flow systems.[4]
Metal-catalyzed cross-coupling chemistry has been widely used and studied during the last
decades and showed a great impact both on the academic and industrial fields.[5] Lots of
examples can be given covering the pharmaceutical,[6] material and polymer areas.[7] Many
examples of metal-promoted continuous flow processes have been reported,[8] such as Suzuki-
Miyaura cross-coupling aryl halides and boronic derivatives,[9] Negishi cross-coupling,[10]
Heck coupling[11] or Sonogashira reaction.[12] Among all palladium mediated cross coupling
reactions, Pd-catalyzed allylic substitution reactions are widely employed for constructing C-
C, C-N, C-S and C-O bonds with high chemo-, regio- and stereoselectivities.[13] Indeed the so-
called Tsuji-Trost reaction is very useful to introduce functional groups on the allylic position
with a high regioselectivity on the less hindered carbon atom. Recently, we focused on this
particular reaction for the bis-allylic substitution of DiVinylGlycol[14] and we also reported
allylic substitution in a photochromic micellar medium.[15] Surprisingly the development of
the Tsuji-Trost reaction in continuous flow systems was not yet described. Herein we report
the design, scope and limitations of an efficient continuous flow allylic substitution protocol.
Results and Discussion
The flow-system used consisted of a ThalesNano H-cube®, a commercial packed bed
flow hydrogenator. In our particular case, it was used only to work at high pressures
and temperatures without any production of H2. The reactants were dissolved in the
adequate solvent and injected using integrated HPLC-type pump, and flowed into a
cartridge packed with a predefined catalyst. The operating temperature was accurately
controlled by the system during the process (Figure 1).[16] This system was used for
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10.1002/ejoc.201601311
European Journal of Organic Chemistry
convenience but any set-up consisting of a pump, the cartridge, a way to heat the
cartridge and a back pressure regulator could be used as well.
Figure 1. Experimental set-up of the flow system.
At first, we focused on the Tsuji-Trost reaction between cinnamyl acetate (1) and
dibenzylamine (2 eq) in ethanol while using palladium on carbon (Pd/C) 10 w% as catalyst
and triphenylphosphine. Among the supported catalytic systems available, Pd/C 10 w% is
probably the most frequently used agent for industrial processes due to its low price, high
catalytic activity and easy removal after completion of the reaction. It is also compatible with
a wide range of solvents, including water.[17] As a consequence, the solution was passed
through the catalyst cartridge (ca. 0.7 mL inside volume, loaded with 340 mg Pd/C 10w%)
using the H-Cube ThalesNano apparatus. A first attempt was realized at 80°C with a flow rate
of 1 mL min-1 leading to a conversion of 75% and 72% yield (Table 1, entry 1). Decreasing
the flow rate to 0.5 mL min-1 allowed a significant improvement of the yield up to 90% (Table
1, entry 2). The same trend was observed when the reaction media was diluted to reach an
excellent yield of 98% at 0.05 mol L-1 (Table 1, entries 3-5). Decreasing or increasing the
temperature is deleterious for this reaction. In fact, at 60°C the conversion dropped to 21%
(Table 1, entry 6) while working at 100°C promote the formation of by-products (Table 1,
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10.1002/ejoc.201601311
European Journal of Organic Chemistry
entry 7). As expected, the conversion fell, to 21%, when the residence time is shortened
(Table 1, entry 8). This result could be attributed to shorter contact time between substrates
and catalyst. Besides, the use of triphenylphosphine is required for this reaction to achieved
good results (Table 1, entry 9). According to the optimization results, two sets of conditions
were compared. The first one, where the medium is diluted but affording excellent yield and
conversion (Method A, Table 1, entry 5) and the second one leading to a better productivity
(Method B, Table 1, entry 2).
Table 1. Optimization of the reaction conditions for the Pd/C catalyzed Tsuji-Trost coupling
in flow.
[1]
PPh3
Flow rate Residence time Conv.[a] Yield [a]
Entry T (°C)
(mol L-1) (mol%) (mL min-1)
(s)
42
84
42
42
42
42
42
21
42
(%)
75
91
92
94
98
21
96
21
15
(%)
72
90
91
94
98
16
81
15
4
1
2
3
4
5
6
7
8
9
80
80
80
80
80
60
100
80
80
0.5
0.5
10
10
10
10
10
10
10
10
0
1
0.5
1
0.2
0.1
1
0.05
0.05
0.05
0.05
0.05
1
1
1
2
1
[a] Determined by GC using dodecane as internal standard.
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To explore further the scope of the allylic substitution reaction in continuous flow,
different allylic acetates bearing aromatic or alkyl chain were submitted to the defined
methods (methods A and B) with a variety of nucleophiles. At first, aromatic allylic acetates
were selected as substrates. Excellent yields were achieved with cinnamyl acetate (1) using
either nitrogen or sulfur nucleophiles (Table 2, entries 1-3). It is notable that the use of an
additional base is required to deal with carbon and oxygen nucleophiles. Inorganic bases were
first investigated such as K2CO3 or Na2CO3. As they are low soluble in ethanol, it appeared
necessary to add water to solubilize them. In such conditions, a drop of the conversion and
competitive saponification reaction of the substrate were observed. Furthermore, organic base
were screened and tetramethylguanidine shown satisfactory results without any saponification
(Table 2, entries 4-7). With Meldrum’s acid, only the product 1d resulting of the double
alkenylation was isolated (Table 2, entry 4). Using the diketone derivative having only one
hydrogen atom yielded to the desired product 1e with 85% yield (Table 2, entry 5). While
phenol could afford the corresponding ether 1f in 71% yield under standard Method A (Table
2, entry 6), the more electro-enriched but much hindered 2-methoxy-4-methylphenol appears
less reactive (Table 2, entry 7). As expected nitrophenol is totally inert in this process (Table
2, entry 8). The result for phenol is of particular interest as phenol, a weak nucleophile, is
known for its low reactivity. In our standard conditions, to our satisfaction, this substrate
reacted smoothly.
As expected, the branched aromatic allylic acetate derivative 2 was found to be less
reactive, due to higher steric hindrance. Even with reduced flow rate, the conversion did not
exceed 5 % (Table 2, entry 9). However, the racemic branched regioisomer of cinnamyl
acetate 3 rearranges to the linear allylic products with all nucleophiles tested and gave good
yields up to 98% (entries 10-13), comparable to those of linear cinnamyl acetate 1 (Table 2,
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10.1002/ejoc.201601311
European Journal of Organic Chemistry
entries 1, 3, 5 and 7). This proved that, under standard Method A, the formation of the pi-allyl
intermediate is not compromised.
In a second time, some aliphatic allylic acetates were submitted to the optimized
conditions. The reaction between allyl acetate 4 and dibenzylamine was achieved with a
moderate yield (Table 2, entry 14). The modification of the nucleophile vs allyl acetate 4 ratio
(2/1 instead of 1/2) permit an improvement of the result to 67% yield. The length of the alkyl
chain plays an important role in this process. In fact, the hexenyl acetate 5 afforded the amine
5a in 41% yield while the nonadienyl acetate 6 reach an excellent yield of 91% (Table 2,
entries 18 and 19). Interestingly, the reaction between the nonadienyl acetate 6 and phenol or
tolylsulfinate salt afforded two compounds corresponding to the linear and the branched
products with a ratio of 1/1 (Table 2, entries 20 and 21). In those particular cases, the
regioselectivity of the reaction is not total and, surprisingly, more sterically hindered branched
compounds are obtained. This could be due to interactions between the electron-rich double
bound of the substrate and the aromatic ring of the nucleophile.[18] As expected, the diketone
derivative reacted smoothly to give selectively the linear product 6f in 82% yield (Table 2,
entry 22). The disubstituted allyl acetate 7 derived from geraniol seems to be unreactive with
this procedure. Only trace of the target compound 7a has been detected (< 5%). This could be
due to the presence of the branched methyl group on the double bound, hindering the
formation or reactivity of the palladium intermediate.
Finally, with continuous interest for our research group, some biobased diallyl acetate
substrate 8 was evaluated. In our hands, the allyl acetate 8 affords only the corresponding
product 8a in medium yield (Table 2, entries 24). Reducing the flow rate (0.3 mL min-1 vs 1
mL min-1) gave no variation in the productivity of compound 8a. This selectivity for the di-
allylated product was previously noticed.[14]
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Table 2. Scope of the reaction with optimized methods A and B.[a]
Yield[e] (%)
Entry
Substrates
Nucleophiles
Products
Method Method
A
B
1
2
94
83
1a
1b
97
82
93
3
ND
1c
4[b]
63
47
1d
1
5[b]
6[b]
7[b]
8[b]
85
71
58
0
71
ND
48
1e
1f
1g
1h
ND
9
<5
92
ND
ND
2a
1a
2
10
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3 +/-
11
81
98
65
ND
ND
ND
1c
1e
1g
4a
4b
4c
4d
5a
12[b]
13[b]
14
52
ND
67[c]
95[c]
15
71[c]
44[c]
50[c]
41
ND
4
16[b]
48[c]
76[c]
ND
17[b]
18
5
19
91
ND
ND
6a
6b
80
20
L:B 1:1
6c
6
61
6d
21[b]
L:B
1.3:1
ND
6e
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22[b]
82
<5
ND
ND
6f
23
7a
7
53
24
ND
8a
54[d]
8
(Z/E 85 :15)
[a] Method A: Substrate (1 mmol), Nucleophile (2 mmol), PPh3 (0.1 mmol), EtOH (20 mL),
flow rate 1 mL min-1. Method B: Substrate (5 mmol), Nucleophile (10 mmol), PPh3 (0.5
mmol), EtOH (10 mL), flow rate 0.5 mL min-1. [b] Addition of tetramethylguanidine (2
mmol for Method A or 10 mmol for Method B) as base. [c] Ratio Substrate/Nucleophile 2/1.
[d] Flow rate 0.3 mL min-1. [e] Isolated yield.
To gain in productivity a second set of conditions was evaluated, referred as Method B
(Table 1, entry 2). The concentration is tenfold higher than in Method A. In consequence, the
flow rate should be decreased to reach high yield. The cinnamyl acetate (1) gave good yield
lower to those obtained with the method A (Table 3, entries 1-6). With a nucleophile vs
substrate ratio of 2/1, the allylic substitution of allyl acetate 4 with various nucleophiles was
more efficient than in Method A (Table 3, entries 7-9).
Finally, the stability of the supported catalyst was investigated. At first, the same cartridge
was reemployed for the Tsuji-trost reaction between cinnamyl acetate (1) and dibenzylamine.
It was found that after 6 consecutive runs the yield dropped to 91% and decreased gradually
to 70% after 17 runs. The calculated turnover number (TON) was higher than 40 for the
method A and close to 30 for the method B. Then the behavior over the time of the catalyst
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European Journal of Organic Chemistry
for both methods on the standard reaction has been studied. A long run was performed, 6h for
method A and 3h for method B (Figure 2). For method A, the yield became to drop smoothly
after 60 minutes of reaction. For method B the activity of the catalyst dropped dramatically
after 30 minutes and then decreased gradually to 40% after 3h of reaction. Leaching of
palladium was determined using ICP with a standard curve for the coupling reaction at less
than 60 ppb after 1 hour of reaction for Method A. These results demonstrate the low level of
leaching of metal catalyst from the support.
Conclusions
In present study, a clean, mild, reproductible and scalable continuous flow process for Tsuji-
Trost cross-coupling reaction using a Pd/C 10 w% supported catalyst has been developed. A
wide scope of different substrates has been successfully submitted to the optimized protocols,
leading to the target products with good to excellent yields. Except for 2 examples, a total
selectivity for the linear products has been observed. The stability of the catalyst over 60
minutes of continuous run is worth noting. The affordable price of the supported catalyst and
the efficiency of the reaction make this procedure a practical alternative to perform allylic
substitutions.
Figure 2. Tsuji-Trost reaction between cinnamyl acetate and dibenzylamine (Method A in
blue, Method B in pink).
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Experimental Section
General: All commercially available products and solvents were used without further
purification. Reactions were monitored by TLC (Kieselgel 60F254 aluminum sheet) with
detection by UV light or phosphomolybic acid solution. Column chromatography was
performed on silica gel 40−60 μm. Flash column chromatography was performed on an
1
13
automatic apparatus, using silica gel cartridges. H and C NMR spectra were recorded on a
400 MHz/54 mm ultralong hold. Chemical shifts (δ) are quoted in parts per million (ppm) and
are referenced to TMS as an internal standard. Coupling constants (J) are quoted in hertz.
Synthesis
General flow procedure (Method A) for Preparation of 1a-g, 4a-d, 5ab6a-f and 8a. A
solution containing the allylic acetate (1 mmol), the nucleophile (2 mmol),
triphenylphosphine (0.1 mmol, 25mg) and tetramethylguanidine (2 mmol, 230 mg)
when required, in technical ethanol (20 mL) were pumped at 1 mL min-1 using the H-
cube ThalesNano system. The solution was passed through a cartridge filled with Pd/C
10w% (ca 340 mg) at 80°C, giving a residence time of 0.7 min. The outlet solution was
evaporated to dryness and submitted to flash chromatography on silica
(cyclohexane/EtOAc) to afford compounds 1a-g
,
4a-d
,
5ab6a-f
,
8a and 9a
.
General flow procedure (Method B) for Preparation of 1a, 1b, 1d-g
,
4a, 4c and 4d.
Method B. A solution containing the allylic acetate (5 mmol), the nucleophile (10
mmol), triphenylphosphine (0.5 mmol, 125mg) and tetramethylguanidine (10 mmol,
1,15 g) when required, in technical ethanol (10 mL) were pumped at 0.5 mL min-1
using the H-cube ThalesNano system. The solution was passed through a cartridge
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10.1002/ejoc.201601311
European Journal of Organic Chemistry
filled with Pd/C 10w% (ca 340 mg) at 80°C, giving a residence time of 0.7 min. The
outlet solution was evaporated to dryness and submitted to flash chromatography on
silica (cyclohexane/EtOAc) to afford compounds 1a, 1b, 1d-g, 4a, 4c and 4d.
(E)-N,N-Dibenzyl-3-phenylprop-2-en-1-amine (1a).[19] Prepared according to Method A as
pale yellow oil; yield 295 mg (94%). Prepared according to Method B as pale yellow oil;
1
yield 1.378 g (88%). H NMR (400 MHz, CDCl3): δ = 7.57 – 7.14 (m, 15 H), 6.58 (d, J =
15.9 Hz, 1 H), 6.35 (dt, J = 15.9, 6.5 Hz, 1 H), 3.68 (s, 3 H), 3.27 (d, J = 6.3 Hz, 2 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 139.65, 137.22, 132.49, 128.82, 128.54, 128.25, 127.80,
127.33, 126.87, 126.28, 57.96, 55.79 ppm.
4-Cinnamylmorpholine (1b).[5d] Prepared according to Method A as pale yellow oil; yield
1
197 mg (97%). Prepared according to Method B as pale yellow oil; yield 950 mg (93%). H
NMR (400 MHz, CDCl3): δ = 7.44 – 7.19 (m, 5 H), 6.56 (d, J = 15.9 Hz, 1 H), 6.28 (dt, J =
15.8, 6.9 Hz, 1 H), 3.76 (dd, J = 10.9, 6.2 Hz, 4 H), 3.20 (dd, J = 6.9, 1.3 Hz, 2 H), 2.60 (d, J
= 32.7 Hz, 4 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 136.68, 133.86, 128.60, 127.68,
126.37, 125.36, 66.73, 61.28, 53.42 ppm.
trans-Cinnamyl-p-tolyl Sulfone (1c).[5d] Prepared according to Method A as white solid;
yield 224 mg (82%); m.p. 120°C. 1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 8.2 Hz, 2 H),
7.38 – 7.25 (m, 7 H), 6.41 (d, J = 15.8 Hz, 1 H), 6.23 – 6.03 (m, 1 H), 3.95 (d, J = 7.5 Hz, 2
H), 2.46 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 144.76, 139.02, 135.83, 135.52,
129.73, 128.67, 128.53, 128.49, 126.63, 115.35, 60.57, 21.66 ppm.
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European Journal of Organic Chemistry
5,5-Dicinnamyl-2,2-dimethyl-1,3-dioxane-4,6-dione (1d).[5d] Prepared according to Method
A as white solid; yield 412 mg (63%). Prepared according to Method B as white solid; yield
409 mg (47%). m.p. 130°C. 1H NMR (400 MHz, CDCl3): δ = 7.47 – 7.16 (m, 10 H), 6.57 (d,
J = 15.8 Hz, 2 H), 6.11 (dt, J = 15.7, 7.8 Hz, 2 H), 2.98 (d, J = 7.8 Hz, 2 H), 1.58 (d, J = 12.9
Hz, 6 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 168.78, 136.21, 135.99, 128.66, 127.99,
126.35, 121.72, 106.07, 56.35, 42.12, 29.79 ppm.
3-Cinnamyl-3-methylpentane-2,4-dione (1e).[20] Prepared according to Method A as a
colorless oil; yield 196 mg (85%). Prepared according to Method B as a colorless oil; yield
1
817 mg (71%). H NMR (400 MHz, CDCl3): δ = 7.38 – 7.20 (m, 5 H), 6.48 (dd, J = 14.9,
13.7 Hz, 1 H), 6.08 – 5.91 (m, 1H), 2.76 (dd, J = 7.5, 1.3 Hz, 2 H), 2.16 (s, 6 H), 1.40 (s, 3 H)
ppm. 13C NMR (101 MHz, CDCl3): δ = 206.78, 136.87, 134.04, 128.54, 127.51, 126.21,
123.96, 66.75, 38.05, 26.76, 18.29 ppm.
21]
(Cinnamyloxy)benzene (1f).[ Prepared according to Method A as white solid; yield 150
mg (71%). Prepared according to Method B as white solid; yield 751 mg (71%). m.p. 70°C.
1H NMR (400 MHz, CDCl3): δ = 7.30 (d, J = 7.5 Hz, 2 H), 7.26 – 7.10 (m, 5 H), 6.86 (dd, J =
7.5, 5.0 Hz, 3 H), 6.62 (d, J = 16.0 Hz, 1 H), 6.31 (dt, J = 16.0, 5.8 Hz, 1 H), 4.64 – 4.50 (m, 2
13
H) ppm. C NMR (101 MHz, CDCl3): δ = 158.71, 136.54, 133.02, 129.59, 128.68, 127.97,
126.67, 124.60, 120.98, 114.85, 68.60 ppm.
1-(Cinnamyloxy)-2-methoxy-4-methylbenzene (1g). Prepared according to Method A as
white solid; yield 148 mg (58%). Prepared according to Method B as white solid; yield 610
mg (48%). m.p. 70°C. 1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 7.7 Hz, 2 H), 7.35 (t, J =
7.5 Hz, 2 H), 7.31 – 7.23 (m, 1 H), 6.88 (d, J = 8.1 Hz, 1 H), 6.79 – 6.70 (m, 3 H), 6.49 (dt, J
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European Journal of Organic Chemistry
13
= 16.0, 5.9 Hz, 1 H), 4.77 (dd, J = 5.9, 1.1 Hz, 2 H), 3.91 (s, 3 H), 2.34 (s, 3 H) ppm. C
NMR (101 MHz, CDCl3): δ = 149.30, 145.83, 136.56, 133.07, 131.02, 128.56, 127.82,
126.62, 124.90, 120.82, 113.80, 112.79, 69.96, 55.85, 21.08 ppm. HRMS (EI) m/z: [M+H]+
Calcd for C17H19O2 255.1385, Found 255.1421.
N,N-dibenzylprop-2-en-1-amine (4a).[22] Prepared according to Method A, using allylic
acetate (2 mmol) and nucleophile (1 mmol), as a yellow oil; yield 158 mg (67%). Prepared
according to Method B, using allylic acetate (2 mmol) and nucleophile (1 mmol), as a
yellow oil; yield 1.17 g (95%). 1H NMR (400 MHz, CDCl3): δ = 7.34 (m, 10 H), 5.96 (dd, J =
13
15.1, 8.3 Hz, 1 H), 5.34 – 5.14 (m, 1 H), 3.62 (s, 4 H), 3.10 (brs, 2 H) ppm. C NMR (101
MHz, CDCl3): δ = 139.70, 136.02, 128.79, 128.21, 126.83, 117.36, 57.75, 56.35 ppm.
1-(Allylsulfonyl)-4-methylbenzene (4b).[23] Prepared according to Method A, using allylic
acetate (2 mmol) and nucleophile (1 mmol), as a yellow oil; yield 140 mg (71%). 1H NMR
(400 MHz, CDCl3): δ = 7.79 – 7.73 (m, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 5.80 (ddt, J = 17.4,
10.1, 7.4 Hz, 1 H), 5.34 (dd, J = 10.1, 0.7 Hz, 1 H), 5.16 (dq, J = 17.1, 1.1 Hz, 1 H), 3.80 (d, J
= 7.4 Hz, 1 H), 2.46 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 144.75, 135.36, 129.69,
128.51, 124.81, 124.59, 60.96, 21.65 ppm.
3-Allyl-3-methylpentane-2,4-dione (4c).[24] Prepared according to Method A, using allylic
acetate (2 mmol) and nucleophile (1 mmol), as a yellow oil; yield 68 mg (44%). Prepared
according to Method B, using allylic acetate (2 mmol) and nucleophile (1 mmol), as a
yellow oil; yield 369 mg (48%). 1H NMR (400 MHz, CDCl3): δ = 5.67 – 5.48 (m, 1 H), 5.16
– 5.03 (m, 2 H), 2.59 (d, J = 7.3 Hz, 2 H), 2.14 – 2.09 (m, 6 H), 1.33 (s, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 206.73, 132.46, 119.08, 66.42, 38.77, 26.67, 18.06 ppm.
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European Journal of Organic Chemistry
1-(Allyloxy)-2-methoxy-4-methylbenzene (4d). Prepared according to Method A, using
allylic acetate (2 mmol) and nucleophile (1 mmol), as a yellow oil; yield 90 mg (50%).
Prepared according to Method B, using allylic acetate (2 mmol) and nucleophile (1
mmol), as a yellow oil; yield 682 mg (76%). 1H NMR (400 MHz, CDCl3): δ = 6.81 (dd, J =
11.3, 7.2 Hz, 1 H), 6.76 – 6.66 (m, 2 H), 6.10 (ddt, J = 17.2, 10.7, 5.4 Hz, 1 H), 5.41 (ddd, J =
17.3, 3.0, 1.4 Hz, 1 H), 5.29 (ddd, J = 10.5, 2.7, 1.3 Hz, 1 H), 4.60 (dt, J = 5.4, 1.4 Hz, 2 H),
13
3.88 (s, 3 H), 2.32 (s, 3 H) ppm. C NMR (101 MHz, CDCl3): δ = 149.25, 145.77, 133.64,
130.91, 120.73, 117.78, 113.68, 112.81, 70.09, 55.83, 21.04 ppm. HRMS (EI) m/z: [M+H]+
Calcd for C11H15O2 179.1072, Found 179.0856.
(E)-N,N-dibenzylhex-2-en-1-amine (5a).[25] Prepared according to Method A as a yellow oil;
yield 116 mg (41%). 1H NMR (400 MHz, CDCl3): δ = 7.44 – 7.17 (m, 10 H), 5.71 – 5.44 (m,
2 H), 3.59 (s, 4 H), 3.03 (d, J = 5.7 Hz, 2 H), 2.04 (dd, J = 13.5, 6.8 Hz, 2 H), 1.46 – 1.36 (m,
2 H), 0.92 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 139.90, 134.01, 128.82,
128.15, 127.26, 126.73, 57.61, 55.53, 34.57, 22.54, 13.71 ppm.
(2E,6Z)-N,N-Dibenzylnona-2,6-dien-1-amine (6a).[25] Prepared according to Method A as a
yellow oil; yield 290 mg (91%). 1H NMR (400 MHz, CDCl3): δ = 7.46 – 7.19 (m, 10 H), 5.69
– 5.51 (m, 2 H), 5.48 – 5.29 (m, 2 H), 3.58 (s, 4 H), 3.03 (d, J = 5.5 Hz, 2 H), 2.18 – 1.98 (m,
6 H), 0.96 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 139.88, 133.45, 132.04,
128.81, 128.40, 128.15, 127.58, 126.73, 57.66, 55.54, 32.60, 27.00, 20.58, 14.34 ppm. HRMS
(EI) m/z: [M+H]+ Calcd for C23H30N 320.2378, Found 320.1842.
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10.1002/ejoc.201601311
European Journal of Organic Chemistry
1-Methyl-4-((2E,6Z)-nona-2,6-dien-1-ylsulfonyl)benzene (6b) and (Z)-1-methyl-4-(nona-
1,6-dien-3-ylsulfonyl)benzene (6c). Prepared according to Method A as a yellow oil; yield
1
111 mg (40%) of compound 6b and 112 mg (40%) of compound 6c. For compound 6b: H
NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 7.9 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 5.60 – 5.15
(m, 4 H), 3.74 (d, J = 7.1 Hz, 2 H), 2.46 (s, 3 H), 2.13 – 1.93 (m, 6 H), 0.95 (t, J = 7.5 Hz, 3
13
H) ppm. C NMR (101 MHz, CDCl3): δ = 144.52, 134.45, 133.57, 130.31, 129.43, 129.24,
126.61, 123.72, 69.23, 26.98, 23.88, 21.64, 20.62, 14.22 ppm. HRMS (EI) m/z: [M+H]+
1
Calcd for C16H23O2S 279.1419, Found 279.1478. For compound 6c: H NMR (400 MHz,
CDCl3): δ = 7.72 (d, J = 8.1 Hz, 2 H), 7.34 (d, J = 8.1 Hz, 2 H), 5.63 (dt, J = 17.2, 9.7 Hz, 1
H), 5.49 – 5.37 (m, 1 H), 5.33 (d, J = 10.2 Hz, 1 H), 5.29 – 5.17 (m, 1 H), 5.07 (d, J = 17.1
Hz, 1 H), 3.58 – 3.44 (m, 1 H), 2.46 (s, 3 H), 2.18 – 1.90 (m, 5 H), 1.79 – 1.65 (m, 1 H), 0.99
– 0.89 (m, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 144.52, 134.45, 133.57, 130.31,
129.43, 129.24, 126.61, 123.72, 69.23, 26.98, 23.88, 21.64, 20.62, 14.22 ppm. HRMS (EI)
m/z: [M+H]+ Calcd for C16H23O2S 279.1419, Found 279.1397.
1-((2E,6Z)-Nona-2,6-dienyloxy)benzene (6d) and 1-((Z)-nona-1,6-dien-3-yloxy) benzene
(6e). Prepared according to Method A as a yellow oil; yield 132 mg (61%) of a mixture of 6d
1
and 6e (1.3:1). H NMR (400 MHz, CDCl3): δ = 7.32 (m, 4H, HAr), 6.99 – 6.92 (m, 6 H,
HAr), 5.93 – 5.73 (m, 3H, CH=CH), 5.45 – 5.35 (m, 4H, CH=CH), 5.31 – 5.20 (m, 2H,
CH=CH2 branched), 4.63 (qapp, J = 5.7 Hz, CH-O branched), 4.51 (d, J = 5.8 Hz, 2H, CH2-O linear),
2.25 – 1.58 (m, 12H, CH2), 0.99 (t, J = 7.5 Hz, 3H, CH3 linear), 0.94 (t, J = 7.5 Hz, 3H, CH3
branched) ppm. 13C NMR (101 MHz, CDCl3): δ = 158.73, 158.43, 138.07, 134.95, 132.65,
132.31, 129.42, 129.29, 128.07, 127.98, 125.23, 120.70, 120.67, 116.44, 116.02, 114.75,
78.16, 68.67, 35.63, 32.48, 26.62, 22.99, 20.60, 20.54, 14.35, 14.28 ppm. HRMS (EI) m/z:
[M+H]+ Calcd for C15H21O 217.1592, Found 217.1608.
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10.1002/ejoc.201601311
European Journal of Organic Chemistry
3-Methyl-3-((2E,6Z)-nona-2,6-dien-1-yl)pentane-2,4-dione (6f). Prepared according to
Method A as a yellow oil; yield 195 mg (82%). 1H NMR (400 MHz, CDCl3): δ = 5.57 – 5.47
(m, 1 H), 5.42 – 5.34 (m, 1 H), 5.32 – 5.15 (m, 2 H), 2.55 (dd, J = 7.1, 6.5 Hz, 2 H), 2.15 –
1.98 (m, 12 H), 1.31 (s, 3H), 0.96 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
207.03, 134.81, 132.14, 128.14, 123.91, 66.64, 37.62, 32.65, 26.89, 26.74, 20.55, 18.09, 14.31
ppm. HRMS (EI) m/z: [M+H]+ Calcd for C15H25O2 237.1855, Found 237.1795.
(Z)- and (E)-N1,N1,N4,N4-Tetrabenzylbut-2-ene-1,4-diamine (8a). Prepared according to
Method A as a white solid; yield 244 mg (53%) of a mixture of (Z)-isomer and (E)-isomer in
1
ration 85:15; m.p. 111°C. For the (Z) isomer: H NMR (400 MHz, CDCl3): δ = 7.48 – 7.23
13
(m, 20 H), 5.78 (s, 2 H), 3.63 (s, 8 H), 3.12 (s, 4 H) ppm. C NMR (101 MHz, CDCl3): δ =
139.71, 130.75, 128.81, 128.23, 126.86, 57.81, 55.25 ppm. For the (E) isomer: 1H NMR (400
MHz, CDCl3): δ = 7.48 – 7.23 (m, 20 H), 5.78 (s, 2 H), 3.57 (s, 8 H), 3.06 (d, J = 3.8 Hz, 1 H)
ppm. 13C NMR (101 MHz, CDCl3): δ = 139.71, 130.20, 128.81, 128.23, 126.86, 58.09, 57.81
ppm. HRMS (EI) m/z: [M+H]+ Calcd for C32H35N2 447.2800, Found 447.2351.
Acknowledgments
This work was performed, in partnership with the SAS PIVERT, within the frame of the
French Institute for the Energy Transition (Institut pour la Transition Energétique (ITE)
P.I.V.E.R.T. (www.institut-pivert.com) selected as an Investment for the Future
(“Investissements d’Avenir”). This work was supported, as part of the Investments for the
Future, by the French Government under the reference ANR-001-01.
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