Triflimide: An Overlooked High-Performance Catalyst of the Mukaiyama Aldol Reaction of Silyl Ketene Acetals with Ketones

Article abstract of DOI:10.1002/chem.201803142

The Mukaiyama aldol reaction is a widely applied carbon–carbon bond forming reaction. However, despite numerous well-established methods using aldehydes as acceptors, only few examples exist with ketones. Here we report a highly practical catalytic approach to this transformation, namely, the triflimide catalyzed Mukaiyama aldol reaction of silyl ketene acetals with ketones. This method exhibits a broad substrate scope, is very rapid, tolerates functionalized substrates, and requires only parts-per-million catalyst loadings with preparative scale reactions up to hundreds of grams in excellent purity (>99 %).

Full text of DOI:10.1002/chem.201803142

A Journal of
Accepted Article
Title: Triflimide: An Overlooked High-Performance Catalyst of the
Mukaiyama Aldol Reaction of Silyl Ketene Acetals with Ketones
Authors: Benjamin List and Han Yong Bae
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Triflimide: An Overlooked High-Performance Catalyst of the
Mukaiyama Aldol Reaction of Silyl Ketene Acetals with Ketones
Han Yong Bae and Benjamin List*
Abstract: The Mukaiyama aldol reaction is a widely applied carbon–
carbon bond forming reaction. However, despite numerous well-
established methods using aldehydes as acceptors, only few
examples exist with ketones. Herein we report a highly practical
catalytic approach to this transformation, namely, the triflimide
catalyzed Mukaiyama aldol reaction of silyl ketene acetals with
ketones. This method exhibits a broad substrate scope, is very rapid,
tolerates functionalized substrates, and requires only parts-per-
million catalyst loadings with preparative scale reactions up to
hundreds of grams in excellent purity (>99%).
The catalytic aldol reaction of ester enolates is an
important and versatile carbon–carbon bond forming reaction.
While a number of useful versions of this reaction with
aldehydes have previously been established.[1] The utilization of
ketones as electrophiles to afford tertiary β-hydroxy esters is
rare. A key challenge in this disconnection is the propensity of
tertiary aldols to undergo the thermodynamically favoured retro-
aldolization (Scheme 1A).[2] This is in sharp contrast to the
Mukaiyama aldol reaction of ketones with silyl ketene acetals
(SKAs) which is thermodynamically favoured, possibly due to
the absence of the enol to ketone tautomerization (Scheme 1B).
Since Mukaiyama’s seminal studies,[3a] an extension of this
methodology to the reaction of SKAs with ketones has been
highly sought-after.[3b,c] After the first approach by Denmark and
co-workers on an asymmetric variant using enantiopure bis-N-
oxides as a Lewis base catalyst,[4a] few studies on novel
enantioselective, catalytic methods have followed.[4b−e] Our
group
very
recently
disclosed
an
enantiopure
imidodiphosphorimidate catalyzed variant, which gives high
enantioselectivities (up to >99:1 e.r.) in the presence of parts-
per-million (ppm) levels of catalyst loadings.[5]
Regarding non-asymmetric Mukaiyama aldol reactions of
SKAs
with
ketones,
a
metal-catalyzed
method
(CuF·3PPh3·2EtOH with (EtO)3SiF)[6] and
a
Lewis base
catalyzed method (sodium phenoxide−phosphine oxide)[7] have
been reported (Scheme 1C). Alternatively, organocatalytic
systems such as C–H acids,[8a,b] a hydrogen-bond-assisted
disulfonimide catalyst[8c] and Schreiner’s thiourea catalyst in
combination with nitro compounds[8d] have previously been
investigated with some success. Despite these advances,
Scheme 1. Catalytic methods toward the aldol reaction of esters with ketones;
(A) The direct catalytic aldol reaction of esters with ketones is
thermodynamically disfavored; (B) Catalytic Mukaiyama aldol reaction of SKA
with ketones; (C) Previous examples of catalytic Mukaiyama aldol reaction of
SKA to ketone; (D) This work: large-scale, PPM level catalyst enabled general
Mukaiyama aldol reaction of SKA to Ketone
however,
a catalytic method that is convenient, broadly
applicable, practical, and scalable remains desirable.
Triflimide (HNTf2: bis(trifluoromethanesulfonyl)imide) is a
useful strong acid catalyst (pKa = 0.3 in MeCN)[9] for various
transformations, including aldol reactions, cycloadditions,
allylations, Friedel–Crafts reactions, Nazarov cyclizations,
Michael additions, Mannich reactions,[10a,b] [3,3]-sigmatropic
rearrangements[10c] and others.[10d] The Yamamoto group has
investigated ketone-derived trialkyl-silyl enol ethers,[11] or
aldehyde-derived tris(trimethylsilyl)silyl “super silyl” enol ethers[12]
[*]
Dr. Han Yong Bae, Prof. Dr. Benjamin List
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
E-mail: list@kofo.mpg.de
Supporting information for this article is given via a link at the end
of the document.
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for the synthesis of β-siloxy aldehydes via Mukaiyama aldol
reaction. Aldehydes were utilized as electrophiles and a general
method using ketones as electrophiles remained elusive.[13]
Herein we report a general, in situ generated silyl-triflimide
catalyzed Mukaiyama aldol reactions of silyl ketene acetals with
ketones (Scheme 1D). The developed scalable methodology
provides a wide variety of silicon protected tertiary aldols within
short reaction times (30 min) using only ppm level catalyst
loadings.
reactive silyl Lewis acid,[14] provided only 16% conversion to the
aldol adduct (entry 5). BF3·OEt showed no activity under
identical conditions (entry 6), however, increasing the acid
loading to 5.0 mol% enabled full conversion (entry 7). Instead of
diethyl ether, solvents such as toluene and dichloromethane
were also successful media (entries 8 and 9). However, it is
noteworthy that performing the reaction at elevated temperature
(20 °C, entry 10) led total decomposition. Gratifyingly, lowering
the catalyst loading to 50 ppm (= 0.005 mol%, 0.007 mg) still
gave full conversion to the desired product. Notably, the purity of
SKA A played an important role for the successful outcome of
the reaction, i.e. no reaction occurred in the presence of impure
SKA A. It is likely that trace amounts of an amine base from the
preparation of the SKA inhibits the acid catalyst (for a general
procedure for the preparation of SKA, see Ref. 15).[5]
Table 1. Development of suitable reaction conditions.
With optimized reaction conditions in hand, the scope of
ketone electrophiles in the Mukaiyama aldol reaction was
studied (Table 2). To our delight, a variety of alkyl-alkyl ketones
(entries 1–12), an alkynyl-alkyl ketone (entry 13) and
(hetero)aryl-alkyl ketones (entries 16–36) successfully provided
the desired products with excellent yields (up to 99%).[16] Cyclic
ketones, from simple cyclopentanone to cyclododecanone, all
afforded the desired products with excellent yields (entries 37–
43). Interestingly, 5α-cholestan-3-one was smoothly converted
to product 45 (entry 44, 89%, d.r. = 84:16).
Entry
Variation from the standard conditions
Conv. (%)[a]
1
2
3
4
5
6
7
8
9
10
None
>99[b]
5 mol% HNTf2, <10 s
without HNTf2, 24 h
>99 [impure][b,c]
0
Next, different types of SKAs were investigated (Table 3).
Propionate-derived SKA B (E/Z = 5:1) reacted with a variety of
ketones to provide products 46–48 (entries 1 to 3, 99% yields,
[Erythro:Threo] = 83:17 to 85:15). The corresponding Z-enriched
SKA B (Z/E >20:1) gave the same major diastereomer of
product 46 (d.r. = 89:11), albeit with relatively lower reactivity
(entry 4, no reaction occurred at –20 °C; 99% yield at 0 °C). The
established catalytic system also readily enabled vinylogous
aldol reactions of ketones,[17] not only with TBS (SiMe2t-Bu: C
and D, entries 5 and 6), but also with TMS (SiMe3: E, entry 7)
protecting groups. Other silyl group variants of SKA A, such as
TMS (F), TES (SiEt3, G) and TIPS (Sii-Pr3, H) incorporated
SKAs also afforded the desired tertiary aldol products (52–54).
p-TsOH instead of HNTf2, 24 h
HOTf instead of HNTf2, 24 h
BF3·Et2O instead of HNTf2, 24 h
5 mol% BF3·Et2O instead of HNTf2, 24 h
PhMe instead of Et2O
CH2Cl2 instead of Et2O
at 20 °C
0
16
<1
99[b]
99[b]
99[b]
>90 [decomposition][b,c]
Standard conditions: reactions were performed with 2-octanone (0.5 mmol,
1.0 equiv., 64 mg), SKA A (0.6 mmol, 1.2 equiv., 113 mg), and HNTf2 (500
ppm = 0.05 mol%, 0.07 mg) in Et2O (1.0 mL, 0.5 M) at –20 °C. [a] Conversion
was determined by 1H NMR integration. [b] Isolated yield after
chromatographic purification. p-Ts = 4-Me-C6H4SO2. [c] Partial decomposition
occurs.
Our studies commenced when we made
a peculiar
observation in the reaction of 2-octanone with 1-(tert-
butyldimethylsilyloxy)-1-methoxyethene (SKA A). While 5 mol%
of HNTf2 very rapidly (<10 seconds, entry 2 of Table 1) and
exothermically promoted the desired Mukaiyama aldol reaction
with full conversion, partial decomposition led to inseparable
side products (see the Supporting Information for detail). In
contrast, with only 0.05 mol% (= 500 ppm) of the catalyst,
compound 1 was cleanly obtained as the sole product within 30
minutes and in quantitative yield (entry 1). In either the presence
of no catalyst or a weaker Brønsted acid (p-TsOH, pKa = 8.5 in
MeCN),[9a] the desired product was not obtained (entries 3 and
4). Triflic acid (HOTf, trifluoromethanesulfonic acid, pKa = 0.7 in
MeCN),[9] which is known to in situ generate TBS-OTf as less
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Table 2. Substrate scope of ketone electrophiles in Mukaiyama aldol reaction.
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Table 3. Substrate scope of SKA nucleophiles in Mukaiyama aldol reaction.
Reactions were performed with ketone (0.5 mmol, 1.0 equiv.), SKA B–H (0.6
mmol, 1.2 equiv.), and HNTf2 (500 ppm = 0.05 mol%, 0.07 mg) in Et2O (1.0 mL,
0.5 M) at –20 °C. Yield was determined after chromatographic purification.
TMS = SiMe3; TES = SiEt3; TIPS = Sii-Pr3. [a] Ratio of the [Erythro:Threo],
Reactions were performed with ketone (0.5 mmol, 1.0 equiv.), SKA A (0.6
mmol, 1.2 equiv., 113 mg), and HNTf2 (500 ppm = 0.05 mol%, 0.07 mg) in
Et2O (1.0 mL, 0.5 M) at –20 °C. Yield was determined after chromatographic
purification. TBDPS = SiPh2t-Bu. [a] Determined by 1H NMR analysis.
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which is determined by 1H NMR analysis. See the Supporting Information for
detail. [b] Reaction was performed at 0 °C.
To demonstrate the synthetic practicability of the method,
large scale syntheses of biologically relevant molecules were
performed (Scheme 2). Initially, starting from each 1.00 g of 2-
pentanone (11.6 mmol) and 6-methyl-5-hepten-2-one (7.92
mmol), 3-hydroxy-3-methylhexanoic acid[18] (HMHA: induces
human axillary odor) precursor 2 (96% yield, 3.05 g) and 3-
hydroxy-citronellic acid[19] (rat metabolite, mono-terpene
derivative) precursor 5 (98% yield, 2.43 g) were obtained,
respectively (Scheme 2A). Reformatsky reactions in the
presence of stoichiometric to excess amount of Zn were
previously used to obtain these tertiary aldols.[18,19] Next, 20.0 g
(129 mmol) of p-chloroacetophenone was converted to 44.2 g of
product 19 (Scheme 2B, >99% yield, >99 % purity by GC
analysis, see the Supporting Information for detail). Without
further purification, 1,2-addition of methylmagnesium iodide
(MeMgI) and subsequent TBS deprotection with tetra-N-
butylammonium fluoride (n-Bu4NF) lead to Fenpentadiol 55
(81%, over two steps), which is used as tranquillizer and
antidepressant.[20] Finally, 100 g (795 mmol) of 6-methyl-5-
hepten-2-one was successfully converted to 251 g of product 5
in excellent purity, using only 25 ppm of HNTf2 (Scheme 2C,
>99% yield, >99 % purity by GC analysis).[21]
In summary, we have developed a powerful and general
triflimide catalyzed Mukaiyama aldol reaction of silyl ketene
acetal with a large variety of ketones. The discovery of this
overlooked catalyst system was enabled by utilizing a very low
catalyst loading at low temperature and with purified SKA. The
developed method displays extreme reactivity with simple
ketones and diverse SKAs. Its robustness presumably stems
from the self-repair mechanism, compensating the very high
water sensitivity of the silylated catalyst. Additionally, the method
is very rapid and scalable, features that potentially enable its
practical application in target-oriented synthesis.
Experimental Section
A general procedure for hundred-gram scale Mukaiyama aldol
reaction of silyl ketene acetal with ketone. To a flame dried J. Young
Schlenk flask, HNTf2 (5.6 mg, 0.020 mmol, 0.0025 mol% = 25 ppm) and
6-methyl-5-hepten-2-one (100 g, 795 mmol, 1.00 equiv.) was added
under Ar atmosphere. Dried Et2O (99.0 mL, 8.00 M) was added via
syringe at 23 °C. The reaction mixture was cooled to –78 °C and SKA A
(157 g, 835 mmol, 1.05 equiv.) was slowly added at this temperature,
then warmed up to 23 °C and stirred for 72 h. The solvent and remaining
SKA A (boiling point = 62 °C/12 mbar) was evaporated in vacuo to afford
the desired tertiary aldol product 5 (251 g, >99%) in excellent purity
(>99% by GC analysis), without further purification. 1H NMR (500 MHz,
CDCl3) δ 5.27–4.90 (m, 1H), 3.64 (s, 3H), 2.49 (m, 2H), 2.09–1.99 (m,
2H), 1.67 (s, 3H), 1.60 (s, 3H), 1.60–1.54 (m, 2H), 1.36 (s, 3H), 0.85 (s,
9H), 0.08 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 171.66, 131.56, 124.45,
74.71, 51.40, 46.84, 42.94, 28.00, 25.89, 25.84, 23.11, 18.28, 17.71, –
1.92, –1.95; HRMS (m/z): [M + Na]+ calcd. for C17H34O3SiNa: 337.2169;
found: 337.2172.
Scheme 2. Preparative scale syntheses of biologically relevant molecules; (A)
Gram scale syntheses of HMHA precursor 2 and 3-hydroxy-citronellic acid
precursor 5; (B) Deca-gram scale synthesis of product 19 (in 50 mL RBF) and
further short total synthesis of Fenpentadiol (55); (C) Hundred-gram scale
synthesis of product 5 (in 500 mL RBF, up scheme), GC-traces of 6-methyl-5-
hepten-2-one (left) and the crude reaction mixture (right), respectively.
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[10] a) For comprehensive information regarding triflimide catalyzed
reactions, see: J. Sun, “Triflimide”, In e-EROS Encyclopedia of
reagents for organic synthesis, John Wiley & Sons, Ltd, 2010 and
references therein. b) For a short review, see: V. L. Rendina, Synlett
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Acknowledgements
Generous support from the Max Planck Society, the Deutsche
Forschungsgemeinschaft (Leibniz Award to B.L. and Cluster of
Excellence RESOLV, EXC 1069), and the European Research
Council (Advanced Grant “C–H Acids for Organic Synthesis,
CHAOS”) are gratefully acknowledged. We thank Jennifer L.
Kennemur for her suggestions during the preparation of this
manuscript, the technicians of our group, and the members of
our NMR, MS and GC departments for their excellent service.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: Mukaiyama aldol reaction • aldol reaction of ketone •
Lewis acid catalysis • parts-per-million catalyst loading • tertiary
aldols • silyl ketene acetal
[1]
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diisopropylamine (5.0 mL, 36 mmol, 1.2 equiv.) at 0 °C and stirred for
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3,4,5,6,-tetrahydro-2-(1H)-pyrimidinone (DMPU; 7.9 mL, 65.5 mmol, 1.6
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saturated aqueous copper sulfate (CuSO4; 3 × 100 mL), saturated
aqueous sodium bicarbonate solution (1 × 100 mL), and brine (1 × 100
mL). The organic layer was then dried over anhydrous sodium sulfate,
filtered, concentrated in vacuo, and distillated in the presence of CaH2
to give the SKA A in 4.5 g (58% yield). 1H NMR (500 MHz, CDCl3) δ
7.53 (m, 2H), 7.52 (m, 1H), 7.41–7.36 (m, 3H), 6.70 (d, J = 16.3 Hz, 1H),
2.37 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 198.40, 143.46, 134.47,
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adduct 16 (98%). See Ref. 5.
[9]
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[21] Compared with previous experiments, extended time (72 h) and higher
temperature (23 °C) were applied in this hundred-gram scale reaction,
due to the lower catalyst loading (25 ppm). We speculate that higher
catalyst loading may accelerate the reaction rate.
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10.1002/chem.201803142
Chemistry - A European Journal
COMMUNICATION
Table of Contents
COMMUNICATION
Han Yong Bae and Benjamin List*
Page No. – Page No.
Triflimide: An Overlooked High-
Performance Catalyst of the
Mukaiyama Aldol Reaction of Silyl
Ketene Acetals with Ketones
Text for Table of Contents
This article is protected by copyright. All rights reserved.