Nickel catalyzed dealkoxylative Csp2-Csp3 cross coupling reactions - Stereospecific synthesis of allylsilanes from enol ethers

Article abstract of DOI:10.1039/c4cc08187k

The application of cyclic and acyclic enol ethers as electrophiles in cross coupling reactions offers new possibilities for the preparation of functional compounds. A novel nickel catalyzed dealkoxylative cross coupling reaction allows access to structurally diverse allylsilanes and alcohol derivatives with high stereospecificity and in good yields under mild reaction conditions directly from the corresponding enol ethers.

Full text of DOI:10.1039/c4cc08187k

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Nickel catalyzed dealkoxylative Csp2–Csp3 cross
coupling reactions – stereospecific synthesis of
allylsilanes from enol ethers†
Cite this:DOI: 10.1039/c4cc08187k
Received 15th October 2014,
Accepted 11th December 2014
Lin Guo,‡ Matthias Leiendecker,‡ Chien-Chi Hsiao, Christoph Baumann and
Magnus Rueping*
DOI: 10.1039/c4cc08187k
www.rsc.org/chemcomm
The application of cyclic and acyclic enol ethers as electrophiles in
cross coupling reactions offers new possibilities for the preparation of
functional compounds. A novel nickel catalyzed dealkoxylative cross
coupling reaction allows access to structurally diverse allylsilanes and
alcohol derivatives with high stereospecificity and in good yields under
mild reaction conditions directly from the corresponding enol ethers.
The development of novel dealkoxylative cross coupling reactions
allows the replacement of aryl halides by environmentally friendly
and easily accessible anisoles as electrophiles in Caryl–C bond
forming reactions.1 So far the direct arylation with Grignard
reagents, boronic esters or organozincates which leads to biaryls,2
the methylation3 and the reduction of anisoles in the presence of
hydride donors4 have been reported. However, whereas cross
coupling with Caryl–O electrophiles is an emerging field, the
potential of enol ethers and O-containing heterocycles as easily
accessible, C–O active building blocks in coupling reactions is less
explored and limited to the arylation and methylation.5 Cyclic and
acyclic enol ethers can further undergo a wide variety of reactions
including b-carbon halogenation, metalation, alkylation, acylation
and oxidation, thermal and acid-catalyzed rearrangements, and
cycloadditions.6 Dealkoxylative methods leading to functional
building blocks, however, are only known for activated enol
phosphates and silyl enol ethers.7
However, if the existing structural variety of enol ethers and
oxygen containing heterocycles could be employed in a trans-
formation which leads to allylsilanes, this would be a powerful
synthetic tool for the construction of various molecular scaffolds
and allow versatile subsequent modifications (Scheme 1).
For the synthesis of a family of bioactive compounds we
recently needed a variable stereoselective method for the con-
struction of hydroxyl functionalized allylsilanes. Allylsilanes are
Scheme 1 Structural diversity accessible from enol ethers.
widely applied in synthetic chemistry as versatile bench-stable
allylation reagents and functional olefins.8–21 Several methods
for their synthesis are known,22 as they are important building
blocks in the syntheses of asymmetric homoallylic alcohols,8
and amines,9 ethers,10 b,g-unsaturated ketones,11 allyl fluor-
ides12 and trimethylfluorides,13 allyl azides14 and substituted
allenes15 and form prochiral precursors for TMS functionalized
scaffolds16,17 and polymers18 (Scheme 1).
In this context, we wondered if readily available enol ethers
can be precursors for the synthesis of functionalized allylsilanes
and if a metal catalyzed C–O bond cleavage and the new Csp2
–
Csp3 bond formation would proceed stereoselectively (Scheme 2).
RWTH Aachen University, Institute of Organic Chemistry, Landoltweg 1, D-52074
Aachen, Germany. E-mail: magnus.rueping@rwth-aachen.de; Fax: +49 241 8092665
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc08187k
Scheme 2 Allylsilanes and allylsilane alcohols via C–O bond activation.
‡ L.G. and M.L. contributed equally to this work.
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Table 1 Optimization of the dealkoxylating enol ether silylation reaction
Table 2 Substrate scope for enol ether substratesa
Ni(COD)2
(mol%)
Temp.
(1C)
Time
(h)
Yielda
(%)
Entry
Solvent
E : Zb
1
2
3
4
5
6
7
8
9
5c
5
2.5
—
5
5
5
5
5
Toluene
Toluene
Toluene
Toluene
THF
60
60
60
60
60
30
30
r.t.
60
2
2
2
2
2
2
2
2
82
99
97
—
—
98
—
95
90
420 : 1
420 : 1
420 : 1
—
—
420 : 1
—
Et2O
CH2Cl2
Toluene
Toluene
420 : 1
420 : 1
0.5
a
c
Yield of isolated products. b E:Z ratio determined by 1H NMR. Reaction
was performed with 5 mol% NiCl2(PPh3)2.
We here report the development of a novel metal catalyzed
dealkoxylative Csp2–Csp3 cross coupling reaction for the stereo-
selective preparation of functionalized allylsilanes.23 These are
important intermediates in the synthesis of various chiral
heterocycles including substituted oxanes, tetrahydrofuranes,
azetidines, pyrrolidines, piperidines and the more complex
natural products isoretronecanol and epilupinine.24
a
Reaction conditions: 0.25 mmol substrate, 5 mol% Ni(COD)2, 1.3 equiv.
LiCH2SiMe3 in 1.5 mL toluene at 60 1C for 2 h; yields of isolated products
are indicated. Room temperature, 0.5 h.
b
We started investigating the dealkoxylative cross coupling of
enol ethers by reacting (E)-2-(2-methoxyvinyl)naphthalene (1a)
with LiCH2SiMe3 as the nucleophile in the presence of different phenyl (1w–bb) silylenol ethers reacted smoothly and even allyl-
catalysts. To our delight, the corresponding E-allyltrimethyl- silylpyrrole 3u and furan 3v were obtained in good yields. To
silane 3a was formed with good selectivity (E : Z 4 20 : 1) in 82% show the applicability, we conducted a scale-up experiment with
yield when NiCl2(PPh3)2 was applied as the catalyst (Table 1, decreased catalyst loading (1 mol%) and transformed 4.1 mmol
entry 1). With retaining stereospecificity the yield could be even of substrate 1m into 0.97 g (98%) of the corresponding product
increased to 99% when Ni(COD)2 (5 mol%) was used as the 3m. This demonstrates the potential of this methodology.
catalyst (entry 2). Applying 2.5 mol% catalyst led to a slightly
Given the broad natural availability and structural diversity
lower yield, while no reaction was observed in the absence of a of heterocycles containing a Csp2–O bond, a ring opening
nickel catalyst (entries 3 and 4). Similar good results were functionalization method with LiCH2SiMe3 as the nucleophile
obtained in diethyl ether (entry 6), whereas reactions in THF would allow the preparation of various hydroxyl substituted
or CH2Cl2 did not lead to conversion of starting material allylsilanes and phenols, respectively. Due to the structural
(entries 5 and 7). The product was obtained with lower yield, relation to enol ethers, we chose benzofuran (4a) as the first
when the reactions were performed at room temperature or substrate to test our dealkoxylative allysilane formation proto-
with shorter reaction times (entries 8 and 9).
col and obtained 72% of the corresponding phenol substituted
A series of enol ethers was employed to determine the scope product (5a) (Table 4, entry 1).
of the cross coupling reaction. As shown in Table 2, a wide
In order to improve the yield and the stereoselectivity,
variety of substrates could be transformed leading to corres- we examined the influence of different ligands on the reaction
ponding allyltrimethylsilanes in high yields. The scope includes outcome. Various phosphine ligands (entries 2–8) gave moderate
aromatic (3a–g) and aliphatic (3h–3l) enol ethers and the to good yields, with low Z-selectivity at room temperature.
reaction proceeded well for double (3b, 3c, 3e–l) and single E-Selectivity was only achieved with 40% yield in the presence of
substituted double bonds with both retained E and retained Z traces of THF and PEt3 as the ligand. However, the more electron
configurations (3a, 3d). In addition, enol ethers with nitrogen rich NHC ligand SIPrÁHCl led to 99% yield and 8 : 1 Z-selectivity at
(3j), oxygen (3g), and sulfur (3i) containing heterocycles reacted room temperature. At À10 1C the stereospecificity was increased
under the coupling conditions. Silylenol ethers can be prepared to Z:E = 14:1 while a slightly lower yield of 93% was obtained
in a simple one-step procedure from ketones and aldehydes25 (entry 11). Since the yield dropped to 77% with only slightly
and are, therefore, interesting starting materials for the synthesis improved Z-selectivity when the temperature was lowered to
of allylsilanes.7 The reaction with silylenol ethers proceeded with À25 1C (entry 12), we decided to investigate the scope of the ring
similar good yields allowing an extension of the scope to ketone opening allylsilylation reaction with the following conditions:
and aldehyde scaffolds (Table 3). Various naphthyl (1m–n) and Ni(COD)2 and SIPrÁHCl at À10 1C with toluene as solvent.
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Table 3 Substrate scope for silylenol ether substratesa
Table 5 Substrate scope of the enol ethers ring opening reactiona
Entry Substrate
1
Product
Yield (%) Z : E
5a, 97
5b, 98
5c, 96
5d, 91
5e, 77
13 : 1
2
420 : 1
420 : 1
420 : 1
12 : 1
3
4b
5c
6c
7c
8d
5f, 82
5g, 65
5h, 65
11 : 1
10 : 1
a
Reaction conditions: 0.25 mmol substrate, 5 mol% Ni(COD)2, 1.3 equiv.
LiCH2SiMe3 in 1.5 mL toluene at 60 1C for 2 h; yields of isolated products
are indicated. Scale-up experiment transforming 4.1 mmol 1m in
20 mL of toluene, 1 mol% Ni(COD)2. 10 mol% Ni(COD)2, 10 mol%
SIPrÁHCl. 10 mol% Ni(COD)2, 10 mol% SIPrÁHCl, 100 1C.
b
c
d
420 : 1
Table 4 Optimization of the benzofuran ring opening silylation
9c
5i, 78
5j, 83
9 : 1
10
11
420 : 1
Entry
Ligand (x mol%)
Temp. (1C)
Yielda (%)
Z : Eb
1
2
3
4
5
6
7
8
—
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
À10
À25
72
93
91
79
82
73
48
53
40
99
97
77
2.7 : 1
2.7 : 1
5 : 1
PCy3 (10)
PPh3 (10)
dppe (5)
dppp (5)
XANTPHOS (5)
TTMPP (10)
P(n-Bu)3 (10)
PEt3 (10, 1 M in THF)
SIPrÁHCl (5)
SIPrÁHCl (5)
SIPrÁHCl (5)
5k, 88
5l, 63
420 : 1
420 : 1
3 : 1
2.7 : 1
1.2 : 1
1 : 1.3
1.8 : 1
1 : 16
8 : 1
12e
a
Reaction conditions: 0.25 mmol substrate, 5 mol% Ni(COD)2, and
9
1.3 equiv. LiCH2SiMe3 in 1.5 mL toluene at À10 1C for 16 h; yields of
10
11
12
b
c
isolated products are indicated. 2.5 equiv. LiCH2SiMe3. 60 1C, 2 h.
13 : 1
15 : 1
d
e
10 mol% Ni(COD)2, 10 mol% SIPrÁHCl, 80 1C, 2 h. 10 mol% Ni(COD)2,
10 mol% SIPrÁHCl.
a
b
Yield of isolated products. Z : E ratio determined by 1H NMR.
In addition to aromatic substituted allylsilanes, we were able
Various substituted benzofurans, dihydrofurans and dihydro- to synthesize primary and secondary alcohols via opening of
pyrans were then applied successfully and the desired products substituted and unsubstituted furan and pyran ring systems.
(5a–l) were isolated with good yields and high Z-selectivities The cleavage of 2-phenyl-2,3-dihydrofuran (4j) led to the homo-
(Table 5). In the presence of 2.5 equiv. of LiCH2SiMe3, both the allylic alcohol (5j). In addition, alcohol 5k was obtained by the
C(sp2)–Br and the C(sp2)–O bonds in 5-bromobenzofuran 4d Ni-catalyzed allylsilylation of 3,4-dihydro-2H-pyran with high
were cleaved leading to product 5d which contains both nucleo- stereoselectivity (Z : E 4 20 : 1). Tolerating TBDPS protecting
philic allylsilyl functionality and a ArCH2SiMe3 moiety suitable groups our method is further suitable to synthesize monopro-
for Peterson olefination reactions.26
tected diols with allylsilyl functionality (5l).
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C
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