Direct Allylation of Active Methylene Compounds with Allylic Alcohols by Use of Palladium/Phosphine-Borane Catalyst System

Article abstract of DOI:10.1002/adsc.201800187

The C?C bond formation between active methylene compounds and allylic alcohols has been newly developed by using a palladium complex as a catalyst together with a phosphine-borane ligand. The best phosphine-borane ligand for this direct allylation has bee

Full text of DOI:10.1002/adsc.201800187

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DOI: 10.1002/adsc.201800187
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Direct Allylation of Active Methylene Compounds with Allylic
Alcohols by Use of Palladium/Phosphine-Borane Catalyst System
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Aika Shimizu,a Goki Hirata,b Gen Onodera,a,* and Masanari Kimuraa,*
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Division of Chemistry and Materials Science, Graduate School of Engineering, Nagasaki University, 1–14 Bunkyo-machi,
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Nagasaki 852-8521, Japan
phone: (+81)-95-819-2679
Fax: (+81)-95-819-2677
E-mail: onodera@nagasaki-u.ac.jp; masanari@nagasaki-u.ac.jp
b
Department of Applied Chemistry, College of Life Sciences, Ritsumeikan University, Kusatsu 525-8577, Japan
Received: February 5, 2018; Revised: March 16, 2018; Published online: &&&, &&&&
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201800187
such as Ir,[8] Pd,[9] Ni,[10] and MoÀPd cluster.[11] Many
Abstract: The CÀC bond formation between active
other direct allylations of monoketone, aldehyde and
methylene compounds and allylic alcohols has been
so on, have also been reported.[12]
newly developed by using a palladium complex as a
In our laboratory, we have so far developed the
catalyst together with a phosphine-borane ligand.
direct allylation of a variety of nucleophiles using a
The best phosphine-borane ligand for this direct
combination of a palladium catalyst and BEt3.[13] In
allylation has been revealed to be Ph2P(CH2)4(9-
these reactions, allylic alcohols were activated by
BBN) to produce a variety of desirable allylated
Lewis acidic BEt3 to form a p-allylpalladium species
as an electrophile, which was attacked by a nucleo-
phile to give the desirable product together with a sole
co-product, water. We considered that this allylic
substitution could be accelerated by linking the
palladium salt with a borane moiety. To produce this
type of palladium catalyst, we paid an attention to
products in high yields.
Keywords: palladium; phosphine-borane; allyla-
tion; allylic alcohol; active methylene
35 Allylic alcohols often show a low reactivity due to the phosphine-borane ligands. Some useful phosphine-
36 strong CÀO bond and the poor leaving ability of the borane ligands have so far been developed by several
37 OH moiety. Still, the study on the usage of allylic groups for the transition-metal-catalyzed organic re-
38 alcohols as a direct allylating agent has been devel- actions.[14–17] Based on these pioneering works, we
39 oped for many years.[1] One of the effective strategies studied on the direct allylation of amines with allylic
40 for the direct allylic substitution is to utilize Lewis alcohols in the presence of a palladium catalyst and a
41 acid to activate the hydroxy group. Synthetically phosphine-borane ligand. After the screening of many
42 important CÀC bond formation reactions between types of phosphine-borane ligands, we found that the
43 allylic alcohols and active methylene compounds by Ph2PCH2CH2(9-BBN) (L1) accelerated this reaction
44 using Lewis acid, such as BEt3,[1a,d] InCl3,[2] Yb(OTf)3,[3] quite well (Scheme 1).[18] The Pd/L1 catalyst system
45 and MoO2(acac)2,[4] have been reported by many was much better than the Pd/EtPPh2/B-n-hexyl-9-
46 groups including us. Here, InCl3, Yb(OTf)3, and MoO2 BBN system. These results show that the linking
47 (acac)2 could be used as a catalyst under the neutral between the phosphine and borane is highly effective
48 condition, while BEt3 was used together with a for the direct allylic substitution. Through this study,
49 palladium catalyst and some base, such as NaH, to
50 deprotonate the pronucleophile. The effect of carbox-
51 ylic acid and sulfonic acid as an activator was also
52 noted in the direct allylic alkylation catalyzed by
53 palladium[5] and platinum.[6] Furthermore, the study on
54 the activation of allylic alcohols by using an amide
55 acetal was recently reported.[7] The acid-free allylation
56 of 1,3-dicarbonyl compounds with allylic alcohols is
57 also possible by using the transition-metal complexes
Scheme 1. Palladium-catalyzed direct allylation of amines
with allyl alcohol.
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Table 1. Reaction of diethyl methylmalonate (2a) with allyl alcohol (1a).[a]
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Entry
Pd catalyst (mol%)
Ligand (mol%)
Solvent
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
PdCl2 (2.5)
Pd2(dba)3 (1.25)
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
Pd(OAc)2 (2.5)
L1 (7.5)
L1 (7.5)
L1 (7.5)
L1 (7.5)
L1 (7.5)
L1 (5.0)
L1 (2.5)
L1 (7.5)
L1 (7.5)
L2 (7.5)
L3 (7.5)
L4 (7.5)
L5 (7.5)
L6 (7.5)
L7 (7.5)
L8 (5.0)
Toluene
THF
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15
15
5
93
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99
99
69
74
2
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
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15
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15
1
0
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25
78
0
57
98
2
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[a] A mixture of 1a (2.0 mmol), 2a (1.0 mmol), Pd catalyst, ligand, and solvent (1 mL) was stirred under N2.
[b] Determined by GLC, based on calibration curve and using cyclododecane as an internal standard.
38 we have learned that the Lewis acidity of borane proceeded in refluxing toluene to give diethyl 2-allyl-
39 moiety and the length of linkage between phosphorus 2-methylmalonate (3aa) in 93% yield after 15 h
40 and boron were important for improving the catalytic (entry 1). When THF was used as a solvent instead of
41 activity. This successful application of a Pd/phosphine- toluene, the product yield was lower (entry 2). By use
42 borane system led us to study the CÀC bond formation of 1,4-dioxane, the reaction provided 3aa in quantita-
43 using allylic alcohols. We have now found that the tive yield even after 5 h (entries 3 and 4). The ratio of
44 butylene-linked phosphine-borane Ph2P(CH2)4(9- L1 to Pd was then investigated. Although the use of
45 BBN) (L5) works much better than L1 in the direct two equivalents of L1 to Pd gave the product in a
46 allylation of active methylene compounds to afford good yield, an equimolar amount of L1 to Pd was not
47 the expected CÀC bond formation products. In effective for this reaction (entries 6 and 7). These
48 contrast, L5 was far less effective than L1 in the direct results suggest that one equivalent of L1 can be used
49 allylation of amines, and the yield of the correspond- as the reductant of Pd(OAc)2 to form Pd(0) species. In
50 ing allylamine was extremely low after the same contrast to Pd(OAc)2, PdCl2 and Pd2(dba)3 was not a
51 reaction time.[19] Herein, we report this new finding as suitable catalyst precursor for this reaction (entries 8
52 a communication form.
and 9). We next screened a variety of phosphine-
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Results of palladium-catalyzed allylation of diethyl borane ligands in this direct allylation. Ligand L2
54 methylmalonate (2a) with allyl alcohol (1a) using a bearing a dicyclohexylboryl group decreased the yield
55 variety of phosphine-borane ligands are summarized (entry 10), and ligand L3 bearing a dicyclohexylphos-
56 in Table 1. The reaction using L1 (7.5 mol%), the best phino group inhibited the reaction (entry 11). The
57 ligand for the so-far disclosed allylation of amines, propylene-linked phosphine-borane ligand L4 was less
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Table 2. Reactions of diethyl methylmalonate (2a) and diethyl benzylmalonate (2b) with g-substituted allylic alcohols 1b–
n.[a–c]
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[a] A mixture of 1, 2, Pd(OAc)2 (0.025 mmol), L5 (0.075 mmol), and 1,4-dioxane (1 mL) was stirred under N2.
[b] Isolated yield.
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[c] Regio- and stereoisomers were not separated and the ratios were determined by H NMR and GLC.
[d] L1 (0.075 mmol) was used instead of L5.
[e] E/Z mixture of 1n (E/Z=83/17) was used.
Scheme 2. Reactions of diethyl methylmalonate (2a) and diethyl benzylmalonate (2b) with a-substituted allylic alcohols 1o
and 1p.
42 effective than L1 (entry 12). On the other hand, the L1 was used as a ligand instead of L5, a mixture of
43 butylene-linked phosphine-borane ligand L5 was the 3ba and 3’ba was obtained in 56% yield (3ba/3’ba=
44 best ligand and the reaction was completed within 91/9) after 15 h and dicinnamyl ether was also formed
45 only 1 h (entry 13; compare with the result using L1 as as a byproduct. Other cinnamyl alcohol derivatives
46 the ligand (entry 5)). Phenylene-linked phosphine- 1c–i reacted to afford the corresponding allylated
47 borane ligands L6 and L7 gave only a trace amount of products 3ca–3ia in high yields with almost complete
48 the product (entries 14 and 15). The diphosphine- regio- and stereoselectivities. Some other 3-aryl- and
49 borane L8 was effective in some extent (entry 16).
3-heteroaryl-2-propen-1-ols 1j–m reacted with 2a to
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Various allylic alcohols 1 could be used in this give the corresponding products 3ja–3ma in good to
51 allylic alkylation. Results of the reactions of diethyl high yields. When crotyl alcohol (1n) was used in the
52 methylmalonate (2a) and diethyl benzylmalonate (2b) reaction with 2b, a mixture of the corresponding
53 with a variety of g-substituted allylic alcohols 1b–n products 3nb and 3’nb was obtained in 36% in the
54 are summarized in Table 2. Cinnamyl alcohol (1b) ratio of 90/10.
55 gave the corresponding product 3ba as a single
Next, we investigated the allylation using a-sub-
56 product in 92% after 2 h. In this reaction, we also stituted allylic alcohols 1o and 1p (Scheme 2). Ally-
57 confirmed that L5 was more effective than L1. When lated products 3ba and 3’ba (98/2) were obtained by
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the reaction of 2a with 1-phenyl-2-propen-1-ol (1o) in
high yield (Scheme 2a). The reaction of 2b with 3-
buten-2-ol (1p) gave the products as a mixture of 3nb
and 3’nb (83/17) in 39% yield (Scheme 2b), the result
of which is similar to that of the reaction of 2b with
crotyl alcohol (1n, R1 =Me) shown in Table 2. Togeth-
er with the fact that the reaction with either 1o or 1p
gave mainly the linear products 3, these results
indicated that this allylation proceeded via a p-
Table 4. Reactions of 2-substituted 1,3-dicarbonyl com-
pounds 2b–g with allyl alcohol (1a).[a,b]
10 allylpalladium intermediate.
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Furthermore, we tried the allylation using some b-
12 substituted allylic alcohols 1q–t (Table 3). The reaction
13 of 2a with b-aryl-substituted allylic alcohols 1q–s
14 provided the corresponding products in high yields. The
15 allylation of 2b with 2-methyl-2-propen-1-ol (1t) also
16 proceeded successfully. Unfortunately, a,g-, a,a- and g,g-
17 disubstituted allylic alcohols were revealed to be not
18 applicable to this reaction system.
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[a] A mixture of 1 a, 2, Pd(OAc)2 (0.025 mmol), L5
(0.075 mmol), and 1,4-dioxane (1 mL) was stirred under
N2.
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[b] Isolated yield.
Table 3. Reactions of diethyl methylmalonate (2a) and
diethyl benzylmalonate (2b) with b-substituted allylic alco-
hols 1q–t.[a,b]
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a mixture of monoallylated product 3qh (15%) and
diallylated product 4qh (76%) was obtained. When
the amount of 1q was increased to 3 equiv., diallylated
product 4qh was obtained in 89% yield as expected
together with a small amount of monoallylated
product 3qh. In contrast, when 3 equiv. of 2h to 1q
was used to avoid diallylation, only monoallylated
product 3qh was formed in 70% yield. Similarly,
allylation was also applicable to 1,3-diphenyl-1,3-
propanedione (2i) to give the corresponding products
3ai and 4ai. In the case of ethyl benzoylacetate (2j)
and 2-(phenylsulfonyl)acetophenone (2k), the mono-
allylation and diallylation were completely controlled.
Thus, the monoallylated products (3aj and 3ak) and
the diallylated products (4aj and 4ak) were obtained
in high yields, respectively. Similarly, although allyla-
tion of malononitrile (2l) with 1q gave a mixture of
[a] A mixture of 1, 2, Pd(OAc)2 (0.025 mmol), L5
(0.075 mmol), and 1,4-dioxane (1 mL) was stirred under
N2.
[b] Isolated yield.
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Results of allylation of 2-substituted 1,3-dicarbonyl mono- and diallylated products by using 2 equiv. of 2l
42 compounds 2b–g with allyl alcohol (1a) under the to 1q, the reaction with 3 equiv. of 1q to 2l proceeded
43 optimized reaction conditions (Table 1, entry 12) are to give only diallylated product 4ql in 91% yield. In
44 summarized in Table 4. Reactions of 2-substituted these reactions, the ratio of allylic alcohols to active
45 malonic esters 2b and 2c proceeded smoothly to give methylene compounds was important for the selectiv-
46 the products 3ab and 3ac, respectively, in high yields. ity of mono- and diallylation.
47 A variety of cyclic b-ketoesters 2d–f afforded the
The remarkable effect of linking between the
48 corresponding products 3ad–3af in good yields, and phosphine and borane moiety was observed in the
49 the allylation of the cyclic diketone 2g successfully allylation of 2a. When both EtPPh2 and B-n-hexyl-9-
50 underwent to give 3ag in 86%.
BBN were used instead of L5, the reaction of 2a with
51
We next examined the scope of 2-unsubstituted 1b gave a mixture of 3ba and 3’ba in only 11% yield
52 1,3-dicarbonyl compounds 2h–l (Table 5). Both mono- (3ba/3’ba=94/6) even after 24 h (Scheme 3). These
53 and diallylated products were produced from unsub- results indicated that the linking between the
54 stituted malonic ester, because the monoallylated phosphine and borane group is critical for obtaining
55 product could be used as a pronucleophile under these the high catalytic activity.
56 reaction conditions. When 2 equiv. of 2-phenyl-2-
Plausible reaction pathway is shown in Scheme 4.
57 propene-1-ol (1q) to diethyl malonate (2h) was used, In this reaction, the borane group of the phosphine-
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Table 5. Reactions of active methylene compounds 2h–l with allyl alcohol (1a) and 2-phenyl-2-propen-1-ol (1q).[a,b]
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[a] A mixture of 1, 2, Pd(OAc)2 (0.025 mmol), L5 (0.075 mmol), and 1,4-dioxane (1 mL) was stirred under N2.
[b] Isolated yield.
Scheme 3. Reaction of diethyl methylmalonate (2a) with cinnamyl alcohol (1b) by using EtPPh2 and B-n-hexyl-9-BBN.
29 borane ligand L5 acts as a Lewis acid to activate the alcohols catalyzed by Pd/phosphine-borane. By using
30 hydroxy group of allyl alcohol. Successive intramolec- the phosphine-borane ligand L5, the corresponding
31 ular oxidative addition proceeds immediately to give a allylated products were obtained in high yields under
32 p-allylpalladium intermediate I which can be attacked base-free conditions. Further synthetic application and
33 by an active methylene compound. In this reaction investigation of mechanistic details are currently in
34 system, a hydroxide anion deprotonates the pronu- progress.
35 cleophile. Then, a boryl enolate species II might be
36 formed and the intramolecular nucleophilic attack
37 proceeds smoothly to give the allylated product along
Experimental Section
38 with 1 equiv. of water. The length and the flexibility of Preparation of 4-(9-Borabicyclo[3.3.1]Nonanyl)
39 butylene linker in L5 might be well matched for this Butyldiphenylphosphine (L5)
40 large-membered ring transition state II. On the other
The ligand L5 was synthesized by a similar method as
41 hand, in the case of ethylene-linked phosphine-borane
42 ligand L1, the transition state might be an unstable
43 medium-membered ring which causes the reaction to
44 be slow, although the details are not yet known.
described in the literature (Scheme 5).[18,20,21] To a two-necked
200 mL round bottom flask fitted with a septum and reflux
condenser under a nitrogen atmosphere were added magne-
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Scheme 4. Plausible reaction pathway of the direct allylation with allyl alcohol catalyzed by Pd/L5.
sium turnings (1.8 g, 75 mmol, 2.5 equiv.). Dry diethyl ether
(60 mL) was added to the flask, and 4-bromobutene (3.1 mL,
In summary, we have developed the direct allyla-
57 tion of active methylene compounds with allylic
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30 mmol, 1.0 equiv.) was then added dropwise. The solution,
refluxed gently during addition, was stirred for 1 h at 408C.
The resulting solution was allowed to cool to room temper-
ature. Chlorodiphenylphosphine (3.6 mL, 20 mmol) was
added slowly at 08C. The reaction mixture was allowed to
warm to room temperature and stirred for overnight. The
solvent was removed under vacuum. To this residue was
added hexane and the mixture was filtered. The filtrate was
concentrated under vacuum to afford 3-butenyldiphenyl-
phosphine. As a next step, to a THF (50 mL) solution of 3-
butenyldiphenylphosphine (4.8 g, 20 mmol) was added 0.5 M
9-BBN in THF solution (40 mL, 20 mmol) at room temper-
ature and the mixture was stirred at 608C for overnight. The
5 v/v) to give 3aa as a colorless oil (211.4 mg, 98%, Rf =0.7;
hexane/ AcOEt=80/20 v/v).
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Acknowledgements
This research was supported by JSPS KAKENHI Grant No.
JP17K14486 (to G.O.).
References
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13 solvent was removed under vacuum to afford a white solid.
The solid was washed with hexane and methanol and dried
under vacuum, affording 4-(9-borabicyclo[3.3.1]nonanyl)bu-
tyldiphenylphosphine (L5) as a white solid in 35% yield
14
15
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(2.5 g, 7.0 mmol, 2 steps); H NMR (400 MHz, CDCl3) d 0.9–
1.0 (m, 2H), 1.3 (s, 4H), 1.6–1.9 (m, 14H), 2.3–2.4 (m, 2H),
7.3–7.4 (m, 6H), 7.5–7.6 (m, 4H); 13C NMR (100 MHz,
CDCl3) d 21.9, 22.1, 23.9, 24.0 (br), 24.9, 25.0 (d, J=2.2 Hz),
32.3, 128.6 (d, J=6.0 Hz), 130.1, 133.0 (d, J=6.8 Hz), 133.6
(d, J=26.5 Hz); 31P NMR (162 MHz, CDCl3) d À3.3; 11B
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calcd for C24H32PB: 362.2335, Found: m/z 362.2336 (M+).
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Scheme 5. Synthesis of L5.
General Procedure for Allylation of Active
Methylene Compound with Allylic Alcohol (Table 1,
E-
nt-
r-
y
1-
2)
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Phosphine-borane ligand L5 (28.4 mg, 0.078 mmol) and
Pd(OAc)2 (5.8 mg, 0.026 mmol) were dissolved in 1,4-
dioxane (1.0 mL) under nitrogen. The mixture was stirred at
room temperature for 1 h during which period it changed to
a yellow solution. To the solution were added allyl alcohol
(1a, 120.2 mg, 2.1 mmol) and diethyl methylmalonate (2a,
174.7 mg, 1.0 mmol). The mixture was stirred under reflux.
The progress of the reaction was monitored by TLC. After
1 h, the resulting solution was concentrated and purified with
column chromatography over silica gel (hexane/AcOEt=95/
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by using Pd(OAC)2/L1 system provided the correspond-
ing allylamine in quantitative yield after 1 h. On the
other hand, when L5 was used instead of L1 in the same
reaction, only a trace amount of the corresponding
product was obtained after 1 h.
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Direct Allylation of Active Methylene Compounds with
Allylic Alcohols by Use of Palladium/Phosphine-Borane
Catalyst System
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