A Solvent-Free Reaction for Silyl Enol Ethers Synthesis

Article abstract of DOI:10.1055/s-0036-1590876

Silyl enol ethers are extremely useful nucleophilic intermediates for chemical transformations because they are synthetically versatile substrates for a wide range of C-C bond-forming reactions. Here, we present a new, mild, and solvent-free procedure for the synthesis of silyl enol ethers that employs a catalytic amount of solid-supported base and an equimolar amount of N, O -(bistrimethylsilyl)acetamide as a silylating agent.

Full text of DOI:10.1055/s-0036-1590876

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
de
C. Morozzi et al.
Letter
Synlett
A Solvent-Free Reaction for Silyl Enol Ethers Synthesis
O
Me3Si
Chiara Morozzi
O
R2
R1
R2
Ornelio Rosati
R1
Me3Si
PS-BEMP
(5–10 mol%)
1 equiv
or
O
Massimo Curini
Daniela Lanari*
SiMe3
or
+
N
SolFC
1–12 h
Me3Si
R3
O
O
1 equiv
R3
60 °C
Dipartimento di Scienze Farmaceutiche, Università degli
Studi di Perugia, via del Liceo, 1, 06123 Perugia, Italy
daniela.lanari@unipg.it
H
H
1 equiv
25 examples
yields up to 98%
catalyst recycling
R1 = aliphatic/aromatic
R2, R3 = aliphatic
PS-BEMP = polystyrene-bound 2-tert-butylimino-2-diethylamino-
1,3-dimethylperhydro-1,3,2-diazaphosphorine
SolFC = solvent-free conditions
Received: 22.05.2017
Accepted after revision: 20.07.2017
Published online: 22.08.2017
separation of the metal.3c,4,5 Moreover, complete selectivity
to form only one stereoisomer from an unsymmetrical ke-
tone is not always attained.3c,4 In 2001, Smietana and Mios-
kowski prepared silyl enol ethers by using N,O-(bistrimeth-
ylsilyl)acetamide (BSA) in ionic liquids.6,7 This method em-
ployed an excess of BSA, and the ionic liquid was not
recovered. Additionally, some methods that use catalytic
amounts of bases have appeared in the literature; for exam-
ple, in 2002 Tanabe and co-workers reported a new method
to obtain silyl enol ethers by using various silylating agents
and a catalytic amount of NaH,8 whereas in 2008, Song et al.
used N-heterocyclic carbenes as catalysts and trialkylsilyl
ketene acetals as silylating agents.9 Both procedure em-
ployed unrecoverable bases and large amounts of silylating
agents, and involved laborious anhydrous reaction condi-
tions. Therefore, despite the availability of many methods,
there is still room for an alternative environmentally
friendly method with improved efficiency and with the
possibility of recycling and reusing the catalyst.
DOI: 10.1055/s-0036-1590876; Art ID: st-2017-b0386-l
Abstract Silyl enol ethers are extremely useful nucleophilic intermedi-
ates for chemical transformations because they are synthetically versa-
tile substrates for a wide range of C–C bond-forming reactions. Here,
we present a new, mild, and solvent-free procedure for the synthesis of
silyl enol ethers that employs a catalytic amount of solid-supported
base and an equimolar amount of N,O-(bistrimethylsilyl)acetamide as a
silylating agent.
Key words silyl enol ethers, catalyst support, green chemistry, het-
erogeneous catalysis, solvent-free conditions
Sustainable chemistry is a fast-growing area of research
in which organic chemists play a critical role in finding effi-
cient and environmentally friendly protocols for organic
transformations.1 During optimization processes for the
syntheses of key molecules, great attention is devoted to
avoiding the use of toxic solvents, to the use of catalytic
protocols, to the development of easily scaled-up proce-
dures, and to the minimization of waste production. Re-
cently, our research group has successfully contributed to
this field by employing polystyrene-supported catalysts
and solvent-free conditions to promote a variety of organic
processes.2
Silyl enol ethers are common reaction intermediates
whose synthetic utility is already well established and
whose preparations have been extensively studied and re-
viewed.3 Conventional preparations of silyl enol ethers em-
ploy a silyl chloride and an equimolar amount of base to
generate an anion enolate and/or to capture HCl, and they
require careful attention during the workup of the reaction
and the isolation of products. The use of metals and the low
temperatures (–78 °C to –10 °C) required to obtain the eno-
lates from the corresponding ketones lead to difficulties in
This work is focused on a new green and easy synthesis
of silyl enol ethers to provide a sustainable alternative to
the procedures reported in the literature.
We recently reported how the silylating agent BSA, in
the presence of a polymer-supported fluoride (Amberlyst
fluoride; Amb-F) was able to act as a strong base in promot-
ing the synthesis of a wide array of alkenyl nitriles from al-
dehydes and alkyl nitriles under solvent-free conditions
(SolFC).10 Inspired by this work, we initially screened the
formation of silyl enol ethers under solvent-free conditions
by using acetophenone (1) as test compound with an equi-
molar amount of BSA (2), and employing various polysty-
rene-supported bases as catalysts (Table 1). The reaction
between acetophenone (1) and BSA (2) in the absence of a
catalyst did not lead to the desired product, demonstrating
the need for catalytic activation when the silylating agent is
present in an equimolar amount (Table 1, entry 1). Amb-F
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
C. Morozzi et al.
Letter
Synlett
has been investigated for its ability to break a chemical
bond between carbon or a heteroatom and silicon and to
promote the formation of silyl enol ethers, but the reaction
in the presence of Amb-F gave a poor yield, probably be-
cause the catalyst promoted both the silylation and desil-
ylation processes (Table 1, entry 2). Polystyrene-bound 4-
(dimethylamino)pyridine (PS-DMAP), polystyrene-bound
1,5,7-triazabicyclo[4.4.0]dec-5-ene (PS-TBD), and polysty-
rene-bound 1,4-diazabicyclo[2.2.2]octane hydrochloride
(PS-DABCO) as catalysts showed moderate abilities to form
the product 3 (Table 1, entries 3–5). However, the yield of
the silyl enol ethers was increased by using polystyrene-
bound 1,8-diazabicyclo[5.4.0]undec-7-ene (PS-DBU) as a
catalyst (Table 1, entry 6), but increasing the amount of cat-
alyst from 5 mol% to 10 mol% produced a decreased prod-
uct yield (Table 1, entry 7). The best result was obtained by
using 10 mol% of polystyrene-bound 2–tert–butylimino–
2–diethylamino–1,3–dimethylperhydro-1,3,2-diazaphos-
phorine (PS-BEMP), which gave the expected product in
78% yield (Table 1, entry 9).
Table 2 Comparison of the PS-BEMP-Catalyzed Silylation Reaction of 1
with Various Silylating Agents
Entry
1
Silylating agent
Yield (%) of 3
Si
Si
78
O
N
N
2
O
2
3
Si
24
–
4
O
Si
F3C
N
5
a Determined by 1H NMR analysis.
With the optimized reaction conditions in hand, namely
PS-BEMP (10 mol%) at 60 °C, the scope of a range of aromat-
ic ketones was investigated (Table 3). Depending on the
starting material, the silylating process gave very good to
excellent yields. For instance, ketones substituted with an
electron-donating group on the aromatic moiety, such as 4-
methylacetophenone (6a) or 3-methoxyacetophenone (6b),
were less reactive, but nevertheless gave the desired prod-
ucts in good yields (Table 3, entries 1 and 2). Excellent re-
sults were obtained when the reactions were carried out
with aromatic ketones 6c–e bearing electron-withdrawing
groups (Table 3, entries 3–5). Moreover, heteroaromatic
ketones 6f and 6g were smoothly converted into the corre-
sponding silyl enol ethers (Table 3, entries 6 and 7).
Table 1 Screening of Various Supported Bases in the Formation of a
Silyl Enol Ether from Acetophenone (1)
Si
O
O
cat.
Si
Si
+
O
N
60 °C, 5 h
SolFC
1
2
3
Entry
Catalyst (mol%)
Yielda of 3 (%)
1
2
3
4
5
6
7
8
9
–
trace
26
Furthermore, the indanones 6h and 6i smoothly gave
the desired products (Table 3, entries 8 and 9). We further
extended this methodology to α-substituted ketones under
the optimal reaction conditions, but with the amount of cat-
alyst reduced from 10 mol% to 5 mol%. The reaction was
completely stereoselective, leading to the formation of the Z-
stereoisomers exclusively. Silyl enol ethers were formed
quantitatively when ketones 6j and 6k were employed as
substrates (Table 3, entries 10 and 11), and an excellent yield
(85%) was obtained when ketone 6l was employed (Table 3,
entry 12). The use of propiophenone (6m) as a starting ma-
terial gave very good results in terms of both the yield (70%)
and the stereoselectivity, as only the Z-isomer was detected
(Table 3, entry 13). Also the feasibility of using the protocol
on sulfone 6n and enone 6o was also tested, and very good
results were obtained (Table 3, entries 14 and 15).
A further investigation was performed to extend the
scope of the work to include aliphatic ketones and alde-
hydes (Table 4), which showed similar reactivities to the ke-
tones previously discussed. In particular, cyclohexanone
(6p) gave the corresponding silylated ketone 7p after three
hours in 84% yield (Table 4, entry 1). A very good yield of
the silyl enol ether (88%) was obtained from 4-methylcyclo-
hexanone (6q) after 12 hours (Table 4, entry 2). A lower
Amb-F (5)
PS-DMAP (5)
PS-TBD (5)
PS-DABCO (5)
PS-DBU (5)
PS-DBU (10)
PS-BEMP (5)
PS-BEMP (10)
49
41
57
68
52
55
78
a As determined by 1H NMR analysis.
Other silylating agents were examined to verify
whether BSA (2) was the best choice of silylating agent for
the case study. The PS-BEMP-catalyzed silylation reaction
of 1 to yield 3 was therefore also performed by using N-
methyl-N-(trimethylsilyl)acetamide (MTSA, 4) and N-[tert-
butyl(dimethyl)silyl]-2,2,2-trifluoroacetamide (MTBSTFA,
5), as summarized in Table 2. Reactant 4 gave a lower yield
compared with 2, and the bulkier 5 was ineffective, the un-
reacted ketone 1 being recovered after five hours at 60 °C.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
C. Morozzi et al.
Letter
Synlett
Table 3 (continued)
Entry Ketone
yield of the expected product (51%) was obtained with cy-
clohex-2-en-1-one (6r) (Table 4, entry 3). The more com-
plex heteroatom-containing ketones tetrahydro-4H-pyran-
4-one (6s) and 1-benzylpiperidin-4-one (6u) also gave
good results (Table 4, entries 4 and 6). The α,β-unsaturated
ketone 6t showed moderate reactivity (Table 4, entry 5). A
preliminary study on aldehydes showed that they could be
successfully employed as reactants, giving very good results
in short reaction times (Table 4, entries 7–9). Unfortunately
the purification step for these silylated compounds proved
to be more challenging than for those derived from aromat-
ic ketones.11 Although products 3, and 7a–o could be puri-
fied by extraction with water to eliminate the acetamide
and then, if necessary, by a flash chromatography, the si-
lylated products derived from aliphatic ketones or alde-
hydes could not isolated by following such a procedure. In-
stead, distillation worked well for products 7p–s, 7v, and 7x
with relatively low boiling points, but failed for the other
products which were distilled along with monosilylated ac-
etamides.
Time Product
(h)
Yiel-
da (%)
O
Si
O
N
6
5
5
3
89
87
88
N
6f
7f
O
Si
O
S
7
S
6g
7g
O
Si
O
8
6h
7h
Si
O
9
1
1
86
98
O
6i
7i
Table 3 Scope of the Silyl-Ether-Formation Reaction with PS-BEMP
O
Si
O
Si
PS-BEMP
(10 mol%)
O
O
Cl
10b
Si
Si
R
Cl
+
O
N
Ar
R
Ar
6j
60 °C, t (h)
SolFC
7j
6a–o
2
7a–o
O
Entry Ketone
Time Product
(h)
Yiel-
Si
da (%)
O
O2N
Br
11b
2
5
98
85
O2N
Br
6k
O
Si
7k
O
1
7
72
89
O
Si
Si
6a
O
7a
Br
12b
Br
6l
O
Si
7l
O
MeO
2
5
1
MeO
O2N
Br
O
6b
O
7b
13b
12
1
70
76
61
6m
7m
O
Si
O
O2N
3
92
O
O
Si
Si
O
O
O
O
S
6c
S
14
15
7c
6n
7n
O
Si
O
Br
O
4
5
5
98
92
O
4
6d
7d
6o
MeO
7o
MeO
O
Si
a Isolated yield.
b PS-BEMP (5 mol%) was used.
O
5
6e
Cl
7e
Cl
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
C. Morozzi et al.
Letter
Synlett
Table 4 Reactivity of Aliphatic Ketones and Aldehydes in Forming the
Corresponding Silyl Enol Ethers
Finally, to verify the robustness of the protocol, we re-
peated the reaction of 4-chloroacetophenone (6e) on a
gram scale by using 50 mmol of the starting material. The
yield obtained (95%) was consistent with the result ob-
tained in the reaction performed on a 1 mmol scale (entry
5). Recycling of the catalyst was also investigated in the re-
action with 4-chloroacetophenone (6e). After three runs,
the catalytic ability was not affected and the same yield was
consistently obtained.
We have developed a new protocol for the synthesis of
silyl enol ethers that employs a stoichiometric amount of
the silylating agent and a catalytic amount of a supported
base under solvent-free conditions. A wide array of ketones
and aldehydes were tested as reactants and consistently
gave good to excellent results. Furthermore, the catalyst
could be recycled up to three times, making this procedure
even more convenient from the point of view of sustain-
ability.
O
PS-BEMP
(10 mol%)
Si
O
Si
Si
R
O
N
+
R
R
t (h)
60 °C
SolFC
R
6p–x
2
7p–x
Entry
1
Ketone
Time (h)Product
Yield (%)
O
Si
O
3
12
12
81
85
48
6p
7p
O
Si
O
2
3
Studies on the incorporation of such a procedure in a
one-pot protocol in which the reactant is a silyl enol ether
derivative (i.e., Mukaiyama or Mannich reactions) are in
progress.
6q
7q
O
Si
O
Funding Information
6r
7r
The authors gratefully thank the Fondazione Cassa di Risparmio di
Perugia (Grant no. FCR 2015.0381.021) for supporting the research.
F
o
n
d
a
ozin
e
C
a
sa
d
i
Rsp
i
armo
i
d
i
P
eruga
i
2(
0
1
50.3
8
10.21)
O
O
Si
O
O
4
4
77
42
Supporting Information
6s
7s
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590876.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
O
Si
O
5a
12
n-Pent
n-Pent
6t
7t
References and Notes
Si
O
N
(1) Sheldon, R. A. Green Chem. 2007, 9, 1273.
O
N
(2) For some representative examples see: (a) Lanari, D.; Piermatti,
O.; Morozzi, C.; Santoro, S.; Vaccaro, L. Synthesis 2017, 49, 973.
(b) Strappaveccia, G.; Angelini, T.; Bianchi, L.; Santoro, S.;
Piermatti, O.; Lanari, D.; Vaccaro, L. Adv. Synth. Catal. 2016, 358,
2134. (c) Bianchi, L.; Ballerini, E.; Curini, M.; Lanari, D.;
Marrocchi, A.; Oldani, C.; Vaccaro, L. ACS Sustainable Chem. Eng.
2015, 3, 1873. (d) Ballerini, E.; Curini, M.; Gelman, D.; Lanari, D.;
Piermatti, O.; Pizzo, F.; Santoro, S.; Vaccaro, L. ACS Sustainable
Chem. Eng. 2015, 3, 1221. (e) Lanari, D.; Rosati, O.; Curini, M.
Tetrahedron Lett. 2014, 55, 1752.
6a
12
67
83
6u
7u
O
H
O
Si
7
3
(3) (a) Brownbridge, P. Synthesis 1983, 1. (b) Fleming, I.; Barbero,
A.; Walter, D. Chem. Rev. 1997, 97, 2063. (c) Ishino, Y.; Kita, Y.;
Maekawa, H.; Ohno, T.; Yamasaki, Y.; Miyata, T.; Nishiguchi, I.
Tetrahedron Lett. 1999, 40, 1349. (d) Gati, W.; Yamamoto, H. Acc.
Chem. Res. 2016, 49, 1757.
(4) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976,
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(5) (a) Cahiez, G.; Figadère, B.; Cléry, P. Tetrahedron Lett. 1994, 35,
6295. (b) Gao, R.; Yi, C. S. ACS Catal. 2011, 1, 544.
6v
7v
O
Si
O
8a
C9H19
2
3
98
54
C9H19
H
6w
7w
Si
O
O
9
H
6x
7x
(6) Smietana, M.; Mioskowski, C. Org. Lett. 2001, 3, 1037.
a Conversion values determined by 1H NMR analysis of the crude mixture.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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C. Morozzi et al.
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(7) Heaney, H.; Cui, J. In e-EROS Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, 2007, DOI:
10.1002/047084289X.rb208.pub2.
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2016, 18, 2680.
{[(Z)-2-Bromo-1-(3-nitrophenyl)vinyl]oxy}(trimethyl)silane
(7k)
Yellow oil; yield: 309 mg (98%). 1H NMR (200 MHz, CDCl3):
δ = 0.25 (s, 9 H), 6.15 (s, 1 H), 7.52 (t, J = 8 Hz, 1 H), 7.78 (t,
J = 4 Hz, 1 H), 8.16 (d, J = 12 Hz, 1 H), 8.31 (s, 1 H). 13C NMR
(400 MHz, CDCl3): δ = 1.18, 91.33, 120.76, 123.71, 129.96,
131.48, 138.92, 148.78, 151.65. GC/EIMS: m/z (%) = 315 (18)
[M+], 300 (43), 139 (43), 89 (25), 73 (100), 63 (9). Anal. calcd for
C
11H14BrNO3Si: C, 41.78; H, 4.46; N, 4.43. Found: C, 41.75; H,
(11) Silyl Enol Ethers 3 and 7a–o; General Procedure
The appropriate aromatic ketone (1.0 mmol), BSA (244 μL, 1.0
mmol), and PS-BEMP (10 mol%, 45 mg or 5 mol%, 22 mg) were
added to a vial, and the mixture was stirred at 60 °C for 5 h. The
catalyst was filtered off, the mixture was washed with H2O
(3 × 2 mL), and the aqueous phase was extracted with hexane (3
× 2 mL). The organic phases were combined, washed with brine
(2 mL), dried (Na2SO4), filtered, and concentrated in vacuo to
eliminate the acetamide byproduct. The crude mixture was
then purified by flash chromatography [silica gel, hexane–Et2O
(99:1)] to remove any residual reagent.
4.60; N, 4.32.
Silyl enol ethers 7p–s, 7v, and 7x: General Procedure
The appropriate aliphatic ketone or aldehyde (1.0 mmol), BSA
(244 μL, 1.0 mmol), and PS-BEMP (10 mol%, 45 mg) were added
to a vial, and the mixture was stirred at 60 °C for the appropri-
ate time. The products were purified by distillation under pres-
sure.
(3,6-Dihydro-2H-pyran-4-yloxy)(trimethyl)silane (7s)
Colorless oil; yield: 133 mg (77%). 1H NMR (200 MHz, CDCl3):
δ = 0.26 (s, 9 H), 2.18–2.22 (m, 2 H), 3.86 (t, J = 5.59 Hz, 2 H),
4.19 (q, J = 2.53, 5.23 Hz, 2 H), 4.87–4.90 (m, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E