A high yield procedure for the Me3SiNTf2-induced carbon-carbon bond-forming reactions of silyl nucleophiles with carbonyl compounds: The importance of addition order and solvent effects

Article abstract of DOI:10.1055/s-2001-18761

We demonstrate the efficiency of Me₃SiNTf₂ (0.3-1.0 mol%) as a strong Lewis acid catalyst for the Mukaiyama aldol and Sakurai-Hosomi allylation reactions, and that the slow addition of carbonyl compounds to a solution of acid catalys

Full text of DOI:10.1055/s-2001-18761

LETTER
1851
A High Yield Procedure for the Me3SiNTf2-Induced Carbon-Carbon Bond-
Forming Reactions of Silyl Nucleophiles with Carbonyl Compounds:
The Importance of Addition Order and Solvent Effects
High
Y
ield Proced
a
ure for Car
z
bon-Carbon
u
Bond-Form
a
ing Reactio
k
ns i Ishihara, Yukihiro Hiraiwa, Hisashi Yamamoto*
Graduate School of Engineering, Nagoya University, CREST, Japan Science of Technology Corporation (JST), Furo-cho, Chikusa, Nagoya
464-8603, Japan
Fax +81(52)7893222; E-mail: yamamoto@cc.nagoya-u.ac.jp
Received 20 August 2001
Table 1 Me3SiNTf-Catalyzed Mukaiyama Aldol Reaction of 1
Abstract: We demonstrate the efficiency of Me3SiNTf2 (0.3–1.0
with Benzaldehyde
mol%) as a strong Lewis acid catalyst for the Mukaiyama aldol and
1. cat. HNTf2
–78 °C, 15 min
Sakurai–Hosomi allylation reactions, and that the slow addition of
carbonyl compounds to a solution of acid catalyst and Me3Si-Nu is
very important for suppressing side products; this may be widely
accepted as a common and reasonable general procedure for the
Lewis acid-induced reaction of Me3Si-Nu with carbonyl com-
pounds.
OSiMe3
Ph
OH
O
+
PhCHO
Ph
Ph
Ph
2. 1 M HCl–THF (1:1)
(1.0 equiv) 1 (1.1 equiv)
2
Ph
Ph
O
O
Key words: Lewis acid, catalyst, Mukaiyama aldol reaction, Saku-
rai–Hosomi allylation reaction, green chemistry
O
O
Ph
O
O
+
+
PhCH
+
O
PhMeC
Ph
Ph
Ph
Ph
2
2
3
4
5
Lewis acid-induced carbon-carbon bond-forming reac-
tions of silyl nucleophiles (R3Si-Nu) with carbonyl com-
pounds are some of the most powerful and versatile
synthetic methods.1 Ghosez2i and Mikami2j have indepen-
dently introduced an extremely powerful carbonyl-acti-
Isolated yield (%)
Entry HNTf2
(mol %)
Procedure
(solvent)a
2
3
4
5
vating
reagent,
N-(trimethylsilyl)triflylimide
1
2
3
4
5
0.5
0.5
0.3
0.3
0.5
A (CH2Cl2)
A (Et2O)
46
54
0
0
0
0
(Me3SiNTf2).2 In many cases, however, it is difficult to
control the catalytic activity of Me3SiNTf2 to induce only
the desired reaction. For example, its catalytic use for the
reaction of allyltrimethylsilane with benzaldehyde in
dichloromethane at room temperature gives the bis-allyla-
tion adduct (49%) in place of the desired homoallyl alco-
hol (<1%).2j Nevertheless, its strong Lewis acidity is very
attractive as an ideal common catalyst for the versatile re-
actions of Me3Si-Nu with carbonyl compounds, if its cat-
alytic activity can be controlled by the reaction
conditions. We describe here a general solution to solve
this problem by using the proper solvent choice as well as
addition order. A high turnover frequency of Me3SiNTf2
(0.3–1.0 mol%) without any significant side products was
now achieved for the Mukaiyama aldol and Sakurai–Ho-
somi allylation reactions.
66 34
B (CH2Cl2)
B (Et2O)
81
0
0
0
17
<2
0
2
>96
92
<2
0
C (Et2O)
a Procedure A: Slow addition of 1 to a solution of HNTf2 and benzal-
dehyde over 2 h at –78 °C; Procedure B: Usual addition of HNTf2 to
a solution of 1 and benzaldehyde; Procedure C: Slow addition of ben-
zaldehyde to a solution of HNTf2 and 1 over 2 h at –78 °C.
HNTf2 (0.5 mol%) in dichloromethane at –78 °C over a
period of 2 h (Entry 1, Procedure A). After acidic work-
up, the desired aldol 2 was obtained in 46% yield along
with 3 (54% yield). The chemical yield of 2 increased to
66% yield by using diethyl ether, but the undesired dimer-
ic ether 3 was still produced in 34% yield (Entry 2). It was
ascertained that no dimerization of trimethylsilyl ether of
2 occurred in the presence of Me3SiNTf2 at –78 °C by a
control experiment. Therefore, the dimeric ether 3 would
be formed by aldol reaction of 1 with acetal 6 (Figure 1),
which is generated from trimethylsilyl ether of 2 and ben-
zaldehyde. Next, HNTf2 (0.3 mol%) was added to a solu-
tion of silyl enol ether 1 (1.1 equiv) and benzaldehyde (1
equiv) in dichloromethane at –78 °C to suppress the gen-
eration of 3 (Entry 3, Procedure B). As expected, 3 was
not formed at all: the desired aldol 2, its benzaldehyde ac-
The efficiency of Me3SiNTf2 as a catalyst for the Mu-
kaiyama aldol reaction was examined in the reaction of 1-
phenyl-1-(trimethylsiloxy)ethylene (1) with benzalde-
hyde (Table 1). Me3SiNTf2 was generated in situ by pro-
todesilylation of
1
with commercially available
triflylimide (HNTf2).2i,3 First, silyl enol ether 1 (1.1 equiv)
was added to a solution of benzaldehyde (1 equiv) and
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1851,1854,ftx,en;G18101ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1852
K. Ishihara et al.
LETTER
etal 4, and its acetophenone acetal 5 were obtained in a and HNTf2 at room temperature.2i,3 The reaction of ben-
molar ratio of 81:17:2. Unexpectedly, the use of diethyl zaldehyde proceeded smoothly at –78 °C in dichlo-
ether almost completely suppressed byproducts 4 and 5 romethane, and after acidic work-up, the desired
(Entry 4, yield of 2: >96%). To suppress the formation of homoallyl alcohol 12 was obtained in 89% yield along
dimeric ether 3 and acetals 4 and 5 more reasonably, ben- with dimeric ether 13 (8% yield), which would be formed
zaldehyde was added dropwise over a period of 2 h at –78 via intermediate 15 (Figure 2) which is analogous to 6
°C to a solution of silyl enol ether 1 and HNTf2 in diethyl (Entry 1). The reaction proceeded cleanly in diethyl ether
ether (Entry 5, Procedure C). The reaction proceeded very at room temperature and gave 12 in 98% yield after acidic
cleanly to give 2 almost exclusively in 92% yield.
work-up (Entry 2).4 The reaction of an aliphatic aldehyde
such as cyclohexanecarboxaldehyde proceeded cleanly in
dichloromethane (Entry 3), while the reaction in diethyl
ether surprisingly gave only the cyclic trimer of an alde-
hyde such as 14 (Entry 5).5 Allylation of hydrocinnamal-
dehyde, 2-octanone, and cyclohexanone in dichloro-
methane also gave the desired homoallyl alcohols 12 in
high yields. It is noteworthy that chlorobenzene could be
used as a less toxic solvent, but the reactivity was a little
lower than with dichloromethane.
OSiMe3
Ph
O
O
Ph
Ph
6
Figure 1
Other examples using this new procedure (C) in diethyl
ether are shown in Scheme 1. The reaction of 1 with an al-
iphatic aldehyde such as cyclohexanecarboxaldehyde also
proceeded smoothly to give the desired aldol 7 in 87%
yield. Syn aldols were obtained as major diastereomers in-
dependent of the stereochemistry of silyl enol ethers
(products 8 and 9). It is noteworthy that the aldol reaction
of 1 with ketones also gave the desired aldols in high
yields (products 10 and 11).
Table 2 Solvent Effect on the Sakurai–Hosomi Allylation of Car-
bonyl Compounds (Procedure C)
1. HNTf2 (0.5 mol%), solvent, rt, 0.5 h
2. Addition of R1R2C=O (1 equiv)
at –78 °C over 2 h
SiMe3
3. Stirred at –78 °C, 15 min
(1.5 equiv)
4. 1 M HCl–THF (1:1)
R2
R1
R1 R2
1. HNTf2 (1.0 mol%)
Et2O, –78 °C, 15 min
2. Addition of R1R2C=O
OH
R2
O
+
+
O
O
R1
R2
R1
OSiMe3
R4
OH
R2
O
R1
R1
(1 equiv) at –78 °C over 2 h
O
R2
R2
R3
R1
R4
12
13
14
3. Stirred at –78 °C, 15 min
R3
(1.1 equiv)
4. 1 M HCl–THF (1:1) or Bu4NF/THF
Isolated yield (%)
13 14
8 (13a)
Products [Isolated yield (Unless otherwise noted, reactions were
performed according to the conditions indicated in the above equation.)]
Entry R1R2C=O
solvent 12
OH
O
OH
O
OH
O
1
2
PhCHO
CH2Cl2 89 (12a)
0 (14a)
0 (14a)
Ph Ph
Ph
Ph
PhCHO
Et2Oa
98 (12a) <2 (13a)
3
c-C6H11CHO
c-C6H11CHO
c-C6H11CHO
CH2Cl2 92 (12b)
0 (13b)
0 (13b)
<1 (14b)
<7 (14b)
7 87%
8 92% (syn:anti=70:30)
9 88% (syn:anti=76:24)
(silyl enol ether, 96% cis)
4
PhCl
Et2O
82 (12b)
0 (12b)
OH
O
OH
O
5
0 (13b) <95 (14b)
0 (13c) trace (14c)
0 (13c) trace (14c)
Ph
Ph
Ph
6
PhCH2CH2CHO CH2Cl2 90 (12c)
PhCH2CH2CHO PhClb
84 (12c)
10 87%
11 92%
(step 3: –40 °C, 0.5 h)
7
c
8
n-C6H13COMe CH2Cl2 89 (12d)
n-C6H13COMe PhCld
85 (12d)
CH2Cl2 91 (12e)
PhClb
89 (12e)
0 (13d)
0 (13d)
0 (13e)
0 (13e)
0 (14d)
0 (14d)
0 (14e)
0 (14e)
Scheme 1 Examples of the Mukaiyama aldol reaction of 1 with al-
dehydes and ketones (procedure C)
9
10
11
c-C6H10O
c-C6H10O
The efficiency of Me3SiNTf2 as a catalyst for Sakurai-Ho-
somi allylation was also examined in the reaction of allyl-
trimethylsilane (1.5 equiv) with aldehydes or ketones (1.0
equiv) using the best procedure C for the Mukaiyama re-
action (Table 2). Me3SiNTf2 was prepared in situ, accord-
ing to the Ghosez’s procedure, from allyltrimethylsilane
a The reaction was carried out at room temperature for 15 min (step 3).
b The reaction was carried out at –40 °C (steps 2 and 3).
c The reaction was carried out at –20 °C (step 3).
d The reaction was carried out at –40 °C (step 2) and 0 °C (step 3).
Synlett 2001, No. 12, 1851–1854 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
High Yield Procedure for Carbon-Carbon Bond-Forming Reactions
1853
Table 3 Comparison of Catalytic Activities in the Mukaiyama Al-
dol and Sakurai–Hosomi Allylation Reactions Induced by Represen-
tative Acids
R1 R2
O
OSiMe3
R1
Yield, % (Catalyst, mol %)
R2
Aldol products
Allylation products
12a 12b
15
Catalyst, Solvent,
Procedurea
2
7
Figure 2
Me3SiNTf2, Et2O, C
92(0.5) 87(1)
98(0.5) 92(0.5)b
In light of the above experiments, a reasonable mechanis-
tic hypothesis for the Me3SiNTf2-induced reaction of
Me3Si-Nu with carbonyl compounds is shown in
Scheme 2. The presence of excess molar amounts of car-
bonyl compounds per desired adduct produced in the re-
action concurrently promotes at least three reactions: (1)
cyclic trimerization of the aldehyde (path a), (2) dimeriza-
tion of the desired adducts (path b), and (3) acetalization
of the desired adducts (path c). The slow addition of car-
bonyl compounds to a mixed solution of Me3Si-Nu and
Me3SiNTf2 (procedure C) was the best solution to give the
desired products selectively.
Me2AlNTf2, CH2Cl2,c C’
HN(SO2F)2, CH2Cl2,d,e
90(2)
–
92(2)
–
93(5)
94(5)
–
–
86(5)
–
Me3SiOTf-MABR,
94(1)
90(5)
CH2Cl2,f C’
Me3SiB(Otf)4, CH2Cl2,g B’
B(C6F5)3, CH2Cl2,h A’
–
–
–
80(1)
n.r.i
84(1)
n.r.i
96(1)
a Procedure C: Slow addition of carbonyl compounds to a solution of
catalyst and Me3Si-Nu; Procedure A’: Usual addition of Me3Si-Nu to
a solution of catalyst and carbonyl compounds; Procedure B’: Usual
addition of catalyst to a solution of carbonyl compounds and Me3Si-
Nu; Procedure C’: Usual addition of carbonyl compounds to a solution
NTf2
R
O
R
O
path a
Me3Si-NTf2
SiMe3
of catalyst and Me3Si-Nu.
bCH2Cl2 was used instead of Et2O.
c Reference 2p.
O
O
O
R
H
R
H
R
Nu
d Reference 1b.
e No report.
R
R
f Reference 1c.
O
OSiMe3
Nu
g Reference 1d.
Me3Si-Nu
R
R
O
OSiMe3
path c
R
h References 1e and 1f.
i No reaction.
O
R
Nu
O
Nu
path b
Me3Si-Nu
R
R
In conclusion, we demonstrated the efficiency of
Me3SiNTf2 as an ideal common catalyst (0.3–1.0 mol%)
for addition reactions of Me3Si-Nu to carbonyl com-
pounds. The slow addition of carbonyl compounds to a so-
lution of acid catalyst and Me3Si-Nu and the choice of
solvents are very important to suppress side products.
This may be widely accepted as a general procedure for
the Lewis acid-induced reaction of Me3Si-Nu with carbo-
nyl compounds.
Nu
Nu
Scheme 2 General outline for the Me3SiNTf2-induced addition re-
action of carbonyl compounds with Me3Si-Nu
The catalytic activities in the Mukaiyama aldol and Saku-
rai–Hosomi allylation reactions induced by representative
acids are compared in Table 3. The replacement of current
chemical processes with more environmentally benign al-
ternatives is an important topic. Considering environmen-
tal benefits, the efficiency of Me3SiNTf2 as a catalyst is
striking. In particular, Me3SiNTf2 has the great advantage
of allowing the use of diethyl ether and chlorobenzene as
less-toxic solvents. In contrast, the other acids in Table 3
work in dichloromethane, which is not environmentally
friendly, and it would be difficult to effectively use their
catalytic loading in diethyl ether because of the strong af-
finity between the Lewis acidic metal atom and ethereal
oxygen atoms. Fluorosulfonylimide is also a remarkably
strong acid like HNTf2,1b,2b but is relatively unstable.6 Fur-
thermore, this Brønsted acid, which is not commercially
available, must be prepared from urea and fluorosulfonic
acid, wich is highly toxic.7
References
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rather HN(SO2F)2: Kaur, G.; Manju, K.; Trehan, S. Chem.
Commun. 1996, 581. (c) Oishi, M.; Aratake, S.; Yamamoto,
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1854
K. Ishihara et al.
LETTER
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(4) A typical procedure (C) for the reaction of
allyltrimethylsilane with benzaldehyde: Commercially
available triflylimide (556 L of 0.072 M solution in diethyl
ether, 0.04 mmol) was added at room temperature under
argon to a solution of allyltrimethylsilane (1.90 mL, 12
mmol)in diethyl ether (2 mL). After stirring the mixture for
0.5 h, benzaldehyde (8.0 mL of 1.0 M solution in diethyl
ether, 8.0 mmol)was added dropwise over a period of 2 h at
–78 °C, and the reaction mixture was allowed to warm up to
room temperature. After stirring for 0.5 h, 1 M HCl (10 mL)
and THF (10 mL) were added. The reaction mixture was
stirred for 0.5 h, poured into NaHCO3 solution, and extracted
with diethyl ether. The combined organic extracts were dried
over MgSO4 and concentrated, and the residue was purified
by column chromatography on silica gel (ethyl
Tetrahedron Lett. 1998, 39, 3215. (n) Berry, M. B.;
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Yufit, D. S. J. Chem. Soc., Perkin Trans. 1 1999, 3645.
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Tetrahedron Lett. 2000, 41, 9561.
acetatehexane, 1/10)to give 12 (1.16 g, 98% yield) as a
colorless liquid.
(3) The use of Me3SiNTf2,2c,i,l prepared from
(5) Zhu, Z.; Espenson, J. H. Synthesis 1998, 417.
(6) Appel, R.; Ruff, J. K. Chem. Ber. 1962, 95, 246.
(7) Handbook of Fine Chemicals and Laboratory Equipment;
Aldrich: U.S.A., 2000-2001.
chlorotrimethylsilane and silver triflylimide,2c for the
Mukaiyama and Sakurai–Hosomi reactions gave the same
experimental results as when HNTf2 was used.
Synlett 2001, No. 12, 1851–1854 ISSN 0936-5214 © Thieme Stuttgart · New York