Synthesis of dialkyl ethers from organotrifluoroborates and acetals

Article abstract of DOI:10.1021/ja906514s

(Chemical Equation Presented) The formation of ethers by C-O bond formation under harsh basic or acidic conditions is an entrenched synthetic disconnection in organic chemistry. We report a strategic alternative that involves the BF₃?OEt_2<

Full text of DOI:10.1021/ja906514s

Published on Web 11/25/2009
Synthesis of Dialkyl Ethers from Organotrifluoroborates and Acetals
T. Andrew Mitchell and Jeffrey W. Bode*
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania, Philadelphia,
PennsylVania 19104-6323
Received August 2, 2009; E-mail: bode@sas.upenn.edu
Scheme 1. General Approaches to Alkyl Ether Formation
The 1852 report of Williamson on the displacement of alkyl
halides with alkoxides established the state of the art for the
synthesis of unsymmetrical ethers.1 Its widespread adoption has
entrenched the notion that carbon-heteroatom bonds are generally
easier to form than carbon-carbon bonds. In the intervening 150
years, chemists have greatly simplified and expanded the range of
C-C bond-forming reactions, leaving the preparation of ethers
under classical conditions a relatively harsh and unsavory approach
to bond construction. As part of a program aimed at developing
modern methods for the synthesis of common functional groups,2
we now report a strategic alternative to the synthesis of dialkyl
ethers that involves the combination of stable, easily prepared
acetals and potassium aryl-, alkenyl-, or alkynyltrifluoroborate salts
(eq 1):
Table 1. Optimization of Lewis Acid-Promoted Ether Formation
with (-)-Menthol-OCH2Y 1 and Potassium Alkynyltrifluoroborate
2a
entry
Y
Lewis acid
solvent temp (°C) time (h) yield (%)a
The limitations of the Williamson ether synthesis arise from the
need for strongly basic nucleophiles and good leaving groups that
can lead to side reactions. These reactions are also sensitive to steric
hindrance and often cannot be applied to the preparation of more
substituted products. In seeking to identify a general approach to
ether construction under mild conditions from readily available
starting materials, we considered a C-C bond-forming disconnec-
tion rather than the traditional C-O bond-forming approach
(Scheme 1). Lewis acid-mediated additions of strong organometallic
reagents (e.g., alkyllithiums or Grignard reagents) or allylsilanes
to acetals are well-known but usually proceed under harsh condi-
tions or with reactants that require prior preparation.3 Despite the
improved availability and operational simplicity offered by boronic
acids4 and potassium organotrifluoroborates,5 there have been very
few reports of ether formation6 with these reagents. This contrasts
with the powerful additions of boron nucleophiles to imines pioneered
by Petasis as a mild and attractive synthesis of substituted amines.7
In developing this orthogonal approach to ether construction, we
first sought to identify a stable functional group that could be easily
introduced and would survive multistep synthesis prior to direct
conversion to the desired ether. We selected acetals of L-menthol
(1a-c) for our initial studies of the coupling with potassium
alkynyltrifluoroborate 2a in the presence of additives (Table 1).
Such starting materials are easily prepared under mildly basic or
mildly acid conditions,8 obviating the need for strong bases at any
stage of the ether synthesis. Although we initially believed that
electronic differentiation of the acetal would be essential for
regiocontrolled coupling (entries 1 and 2), our studies demonstrated
that simple methoxymethyl (MOM) protecting groups were excel-
lent, highly regioselective substrates with acetonitrile as the solvent
(entry 3).9 Toluene gave inferior results (entry 6), but dichlo-
romethane was a viable solvent (entry 7). Under these conditions,
other fluorophilic Lewis acids gave no reaction (entry 8) or effected
1
2
3
4
5
6
7
8
9
SMe (1a)
BF3 ·OEt2 CH3CN
0
0
0
1
1
1
2
6
1
2
6
2
2
45
84
OCH2CH2OMe (1b) BF3 ·OEt2 CH3CN
OMe (1c)
OMe (1c)
OMe (1c)
OMe (1c)
OMe (1c)
OMe (1c)
OMe (1c)
BF3 ·OEt2 CH3CN
91
BF3 ·OEt2 CH3CN -78
NRc
69
BF3 ·OEt2 CH3CN -40
BF3 ·OEt2 toluene
BF3 ·OEt2 CH2Cl2
0
0
40
0
18b
85
TMSCl
SiCl4
SiCl4
CH2Cl2
THF
CH3CN
NRc
d
-
10 OMe (1c)
0
87
a Isolated yield after chromatography. b Percent conversion including
a significant quantity of L-menthol detected by 1H NMR analysis (500
MHz). c No reaction. d MOM deprotection was observed; no desired
product was detected by 1H NMR analysis (500 MHz) of the unpurified
reaction mixture.
deprotection (entry 9); however, SiCl4 in acetonitrile provided the
desired product in 87% yield (entry 10). The major side product in
these reactions was L-menthol, which arose from competing removal
of the acetal and constituted the mass balance.
(-)-Menthol-MOM 1c was treated with a variety of potassium
organotrifluoroborates 2 to provide the desired ethers 3 in moderate
to good yields (Table 2). Potassium alkynyltrifluoroborate (2b)
proceeded in good yield under the optimized conditions (entry 1).
Because of the reduced reactivity of sp2-hybridized potassium
organotrifluoroborates, we found it necessary to premix excess
potassium organotrifluoroborate and BF3 ·OEt2 in dichloromethane
prior to addition of the acetal.10 Potassium allyl- (2c) and
alkenyltrifluoroborates (2d-f) proceeded in good yield under these
modified conditions (entries 2-5). Simple potassium aryltrifluo-
roborates delivered the desired ethers in good yield (entries 6-8),
but less reactive halogenated potassium aryltrifluoroborates gave
lower yields and regioselectivities (entries 9-11).11 Preliminary
9
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J. AM. CHEM. SOC. 2009, 131, 18057–18059 18057

C O M M U N I C A T I O N S
Table 2. Variation of Potassium Organotrifluoroborate 2 in the
Lewis Acid-Promoted Dialkyl Ether Formation with Acetal 1ca
Table 3. Variation of Acetal 1 in the Lewis Acid-Promoted Dialkyl
Ether Formation with Potassium Alkynyltrifluoroborate 2aa
a Premixing of BF3 ·OEt2 and R3-BF3K 2 in CH2Cl2 followed by
addition of 1c (0.5 mmol) in CH2Cl2 provided superior results. b Isolated
yield after chromatography. c Reaction performed at 0 °C in CH3CN (cf.
Table 1).
a All reactions were carried out on a 0.5 mmol scale. b Isolated yield
attempts to employ potassium alkyl- and heteroaryltrifluoroborates
gave primarily acetal deprotection.12
after chromatography. c dr
)
1.5:1.0, as determined by 1H NMR
analysis (500 MHz) of the unpurified product. d Reaction allowed to
Primary, secondary, and tertiary MOM-protected alcohols all
gave the desired products under these conditions (Table 3, entries
1-6). More substituted acetals were excellent substrates and
afforded the expected ethers in good to excellent yield (entries
7-12). These experiments demonstrated that this process tolerates
functional groups, including esters and alkyl halides (entries 11
and 12). Several of these products, such as the sterically demanding
products prepared in entries 3-6 and the bromo-substituted
compound in entry 12, would be particularly challenging to prepare
by Williamson ether synthesis. With the more reactive potassium
alkynyltrifluoroborates (cf. Table 3 vs Table 2), fewer equivalents
of the nucleophile were required; in many cases, only 1.2 equiv
was sufficient (i.e., Table 3, entries 7-10).
warm to 23 °C over 4 h.
(-)-menthol-MOM 1c, demonstrating the intermediacy of phe-
nyldifluoroborane. Secondary kinetic isotope effects indicative of
sp3-to-sp2 hybridization (i.e., oxocarbenium formation) as the rate-
determining step were observed between 1c and isotopically labeled
1c′ regardless of the potassium organotrifluoroborate employed
(Scheme 2).15 Crossover studies utilizing isotopically labeled
derivatives of 1c gave the expected ethers 3a/3a′ and all possible
isotopically labeled isomers of 1c, as observed by electrospray
ionization mass spectrometry, suggesting that the rate-limiting
formation of the oxocarbenium intermediate was reversible (Scheme
3).
On the basis of these experiments, a plausible reaction pathway
is proposed (Scheme 4). Upon interaction of the potassium
organotrifluoroborate II with BF3 ·OEt2, organodifluoroborane IV
and its corresponding etherate (not shown) are produced and
presumably serve as the active Lewis acids. The less encumbered
In accord with prior studies,13 11B NMR spectroscopy revealed
the activation of potassium phenyltrifluoroborate 2g by BF3 ·OEt2
to provide phenyldifluoroborane (21.88 ppm)14 and its correspond-
ing etherate with consumption of BF3 ·OEt2.10 In addition, benzyl
ether 3g was observed by 1H NMR spectroscopy upon addition of
9
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C O M M U N I C A T I O N S
Scheme 2. Normal Secondary Kinetic Isotope Effects Demonstrate
That the Proposed Oxocarbenium Intermediate Is Formed in the
Rate-Determining Step
known ability of transition-metal catalysts to accelerate similar
processes18 offers a pathway for future developments to enhance
the chemical yield, substrate scope, and stereochemical outcome.
Acknowledgment. We are grateful to the National Institutes
of Health (GM-079339) and Bristol Myers Squibb for support of
this research. We thank Gary Molander, Noel Ellis, Deidre
Sandrock, and Belgin Canturk for generous donation of potassium
organotrifluoroborates and helpful discussions. We thank George
Furst and Pinguan Zheng for helpful discussions regarding the 11
NMR and KIE studies.
B
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Scheme 3. Crossover Experiments Demonstrate the Reversibility
of the Formation of the Proposed Oxocarbenium Intermediate
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