Stereocontrolled cyanohydrin ether synthesis through chiral Bronsted acid-mediated vinyl ether hydrocyanation

Article abstract of DOI:10.1021/jo4016002

Vinyl ethers can be protonated to generate oxocarbenium ions that react with Me₃SiCN to form cyanohydrin alkyl ethers. Reactions that form racemic products proceed efficiently upon conversion of the vinyl ether to an α-chloro ether prior to cya

Full text of DOI:10.1021/jo4016002

Article
pubs.acs.org/joc
Stereocontrolled Cyanohydrin Ether Synthesis through Chiral
Brønsted Acid-Mediated Vinyl Ether Hydrocyanation
Chunliang Lu, Xiaoge Su, and Paul E. Floreancig*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
S
* Supporting Information
ABSTRACT: Vinyl ethers can be protonated to generate oxocarbe-
nium ions that react with Me3SiCN to form cyanohydrin alkyl ethers.
Reactions that form racemic products proceed efficiently upon
conversion of the vinyl ether to an α-chloro ether prior to cyanide
addition in a pathway that proceeds through Brønsted acid-mediated
chloride ionization. Enantiomerically enriched products can be
accessed by directly protonating the vinyl ether with a chiral Brønsted
acid to form a chiral ion pair. Me3SiCN acts as the nucleophile and
PhOH serves as a stoichiometric proton source in a rare example of
asymmetric bimolecular nucleophilic addition into an oxocarbenium
ion. Computational studies have provided a model for the interaction
between the catalyst and the oxocarbenium ion.
applications in target-,11 diversity-,12 and function-oriented13
INTRODUCTION
■
synthesis led us to explore the potential of directly preparing
enantiomerically enriched cyanohydrin alkyl ethers through a
catalytic, asymmetric pathway. This article describes a protocol
for synthesizing these structures through Brønsted acid-
mediated enol ether hydrocyanation that proceeds through
alkene protonation followed by cyanide addition. A general
protocol for accessing racemic structures is presented, followed
by a description of an asymmetric variant in which asymmetric
Brønsted acids serve to generate chiral ion pairs that engage in
stereoselective cyanide addition reactions. These reactions,
where Me3SiCN serves as the nucleophile and phenol is used as
a proton source, are rare illustrations of asymmetric bimolecular
Brønsted acid-catalyzed asymmetric additions to oxocarbenium
ions and are the first examples in which a silylated nucleophile
couples with readily accessible enol ether substrates. The results
of these studies are analyzed through a computationally based
model that defines the interactions between the catalyst and
the oxocarbenium ion, explains the observed stereochemical
outcomes, and defines the current scope of the process.
Nitriles are remarkably versatile entities that can serve as
precursors to diverse functional groups such as carboxylic acids,
amides, amines, ketones, and aldehydes.1 Moreover, the cyano
group is proving to be an effective subunit for applications in
medicinal chemistry2 and is present in numerous natural
products.3 The broad utility of nitriles has led to efforts to
develop methods for their enantioselective synthesis. These
studies have largely focused on asymmetric cyanohydrin
formation,4 and several successful preparations from silyl
ketene imine reactions have also been reported.5 Asymmetric
cyanohydrin synthesis generally commences with the addi-
tion of cyanide to an aldehyde or ketone and concludes with
trapping of the resulting hydroxyl group as an ester or a silyl
ether, though a few examples of direct asymmetric cyanohydrin
formation are known.6 The direct formation of enantiomeri-
cally enriched cyanohydrin alkyl ethers has not been reported,
despite their synthetic utility. Cyanohydrins are unstable under
basic conditions and are weak nucleophiles, rendering their
direct alkylation implausible. Cyanohydrin alkyl ethers are
available as racemic mixtures through Lewis acid-mediated
acetal ionization reactions followed by quenching of the
resulting oxocarbenium ions with Me3SiCN.7 Stereocontrol in
these reactions is rare for acyclic substrates, though a good
level of diastereocontrol was observed in the addition into an
α-(trimethylsilyl)benzyl-substituted oxocarbenium ion.8 Diffi-
culties in controlling the stereochemical outcomes in additions
of cyanide to oxocarbenium ions result from the high reactivity
and minimal steric demands of the nucleophile and the high
reactivity of the electrophile.9
RESULTS AND DISCUSSION
■
Our initial objective was to develop a route for cyanohydrin
alkyl ether formation through alkyl enol ether protonation. Enol
ethers are attractive oxocarbenium ion precursors in comparison
with more commonly employed acetals, particularly for
substrates that contain structurally complex or valuable alkoxy
groups. These substrates are readily accessed through cross-
coupling14 or vinyl transfer15 reactions and do not require that
an equivalent of the alkoxy group be lost through cyanation.
Cyanohydrin alkyl ethers have proven to be particularly
effective substrates for amide formation through nitrile hydro-
zirconation, acylation, and nucleophilic addition.10 Multiple
Received: July 23, 2013
Published: August 22, 2013
© 2013 American Chemical Society
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a
Despite these benefits, examples of enol ethers as precursors to
cyanohydrin ethers are quite rare.16 Our initial approach to the
problem (Scheme 1) illustrated a significant obstacle to their use
Table 1. Scope of the Enol Ether Hydrocyanation Reaction
Scheme 1. Cyanohydrin Ether Formation through Enol
Ether Hydrocyanation
in these reactions. Adding a catalytic quantity of anhydrous HCl
to a mixture of benzyl vinyl ether (1) and Me3SiCN provided
cyanohydrin ether 2 in only 18% yield. The remainder of the
material resulted from oligomerization through nucleophilic
enol ether addition into oxocarbenium ion intermediates. This
problem was solved by quantitatively converting the enol ether
to an electrophile prior to the addition of Me3SiCN through the
formation of α-chloro ether 3 from 1 and HCl (1.1 equiv). The
addition of Me3SiCN (2 equiv) to the crude chloro ether led to
the formation of 2 in 81% yield for the one-pot transformation.
The mechanism of this transformation could proceed through
chloride ionization by a Brønsted acid or by Me3SiCN. The
cyanation step was suppressed by the addition of 2,6-di-tert-
butylpyridine, suggesting that oxocarbenium ion 4 arises from
Brønsted acid-mediated ionization in accord with observations
by the Jacobsen group.17 The addition of chloride to Me3SiCN
creates the highly reactive nucleophile 5, which adds to 4 to
form the product.18
a
Representative procedure: HCl (1.1 equiv) was added to the vinyl
ether in CH2Cl2 at −40 °C. Me3SiCN (2 equiv) was added upon
complete consumption of the starting material, and the reaction was
stirred at −40 °C until product formation was complete.
Scheme 2. Chiral Brønsted Acid-Initiated Chloride
Ionization and Cyanation
The scope of the process is illustrated through the examples
shown in Table 1. Substrates with longer alkoxy groups react
smoothly (entry 1), and functional groups such as alkenes, silyl
ethers, and sulfides are tolerated (entries 2−4). Ethers with
branched alkoxy groups react efficiently, though little stereo-
control was observed (entry 5). The vinyl group can be
lengthened (entries 6 and 7), and cyclic enol ethers react well
(entry 8). These transformations illustrate the generality of
cyanohydrin ether formation through Brønsted acid-mediated
enol ether hydrocyanation and provide an entry into the develop-
ment of an asymmetric variant.
These results led us to explore the potential of replacing HCl
with a chiral Brønsted acid19 to form asymmetric ion pair
intermediates20 (Scheme 2). Thus, we prepared chloro ether 3
and added Me3SiCN at 0 °C in the presence of thiophosphoryl
triflimide 2221 (3 mol %). This reaction provided 2 with an
enantiomeric ratio (er) of 57.5:42.5, thereby successfully
demonstrating that a modest degree of asymmetric induction
is possible for this process, although the results are not pre-
paratively useful. Success in this protocol requires that the
HCl liberated by oxocarbenium ion generation engage in an
exchange reaction with the silylated catalyst that is formed in
the cyanation step to regenerate the chiral Brønsted acid and
form Me3SiCl. However, if this process is not rapid or is not
thermodynamically viable, then the potential for a nonselective
HCl-catalyzed background reaction is high.
The capacity for a nonselective background reaction led us to
re-examine vinyl ethers as substrates. Chiral Brønsted acids
have been used to generate oxocarbenium ion intermediates
for reactions in which a proton is lost from a nucleophile, such
as an alcohol or active methylene compound, to regenerate
the acid directly.22 Silylated nucleophiles can be utilized when
a silyl group scavenger is formed upon oxocarbenium ion
generation.17a,23 All reported cases of bimolecular additions
into oxocarbenium ions utilize either sterically hindered nucleo-
philes22a or highly specific electrophiles.17a,22g,23 The asymmetric
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a
Brønsted acid-catalyzed addition of silylated nucleophiles to vinyl
ether-derived oxocarbenium ions is an unexplored process. The
obstacle to this reaction lies in the need to regenerate the
Brønsted acid when a silyl cation acts as the electrofuge. Alcohols
have been added to quench silyl electrofuges and regenerate
Brønsted acids in enantioselective enolsilane24 and silyl ketene
imine25 protonation reactions. These results inspired the
proposed catalytic cycle for the transformation that is shown in
Scheme 3. Enol ether protonation generates a chiral ion pair.
Table 2. Catalyst Screening
b
entry
catalyst
er
1
2
22: R = 2,4,6-triisopropylphenyl, X = S, Y = NHTf
65:35
23: R = 3,5-di(trifluoromethyl)phenyl, X = S,
Y = NHTf
51.5:48.5
Scheme 3. Direct Enol Ether Hydrocyanation with Catalyst
Regeneration (HA* = Chiral Brønsted Acid)
3
4
24: R = triphenylsilyl, X = S, Y = NHTf
52:48
68:32
25: R = 2,6-diisopropyl-4-adamantylphenyl, X = S,
Y = NHTf
5
26: R = 2,6-diisopropyl-4-(2,4,6-triisopropylphenyl)
phenyl, X = S, Y = NHTf
71.5:28.5
6
7
8
9
27: R = 2,4,6-triisopropylphenyl, X = O, Y = SH
28: R = 2,4,6-triisopropylphenyl, X = O, Y = NHTf
26, −40 °C
−
−
83.3:16.7
26, PhCF3 solvent, −25 °C
85:15, 85%
yield
10
26, PhCF3 solvent, −25 °C, 0.5 mol % catalyst
85:15, 84%
yield
a
Representative procedure: A solution of phenol (1.0 equiv) was
added dropwise over 20 h to a solution of the vinyl ether (1.0 equiv),
the catalyst (0.03 equiv), and Me3SiCN (2.0 equiv). The reactions
were complete shortly after the phenol addition was complete.
Enantiomeric ratios were determined by HPLC with a Lux Cellulose
3 column.
We postulate that Me3SiCN is activated by complexation with an
alcohol to form a pentavalent silyl isocyanide nucleophile, in
accord with Woerpel’s studies8 on the reactive intermediates in
the addition of silyl cyanides to oxocarbenium ions. Cyanide
transfer yields the cyanohydrin ether and an ion pair consisting
of the protonated silyl ether and the conjugate base of the
catalyst. Proton transfer regenerates the catalyst and yields a
silyl ether.
b
improved by adding PhOH slowly in an effort to minimize the
background reaction28 and side reactions such as mixed acetal
formation. Lowering the temperature to −40 °C resulted in
higher selectivity, providing 2 with an 83.3:16.7 er (entry 8). A
limited solvent screen was conducted, with the best result being
observed with PhCF3, consistent with other results from addition
reactions to chiral ion pairs.26 The minimum temperature for this
reaction is −25 °C because of the freezing point of PhCF3, yet
the process provided 2 in 85% chemical yield with an er of 85:15
(entry 9). The stereocontrol was not improved by increasing the
catalyst loading to 10 mol % (data not shown). Nearly identical
results were obtained when the catalyst loading was reduced to
0.5 mol %, however (entry 10). Lowering the catalyst loading to
0.1 mol % resulted in a reaction that was unacceptably slow.
The identification of optimal conditions allowed us to explore
the scope of the process (Table 3). The process proved to be
relatively insensitive to changes in the alkoxy group, with longer
chains and branching being tolerated (entries 1, 2, and 4).
Substrates with larger aromatic groups such as naphthalenes
(entry 7) also reacted smoothly. Functional groups such as
alkenes (entry 3), esters (entry 5) and sulfides (entry 6) are
compatible with the reaction conditions. One limitation to this
method is that alkoxy groups that can fragment to form a stable
carbocation following oxocarbenium ion formation, such as tert-
butyl ethers, do not yield the cyanohydrin ether product (data
not shown).
Initial catalyst screening was conducted with 1 as the
substrate in CH2Cl2 at rt. The Brønsted acid loading was set at
3 mol %, and phenol was used as the stoichiometric proton
source. The results are shown in Table 2. The absolute stereo-
chemistry of the major isomer was determined through
comparison to authentic material that was prepared from methyl
lactate. Thiophosphoryl triflimide 22 provided an enantiomeric
ratio of 65:35 (entry 1), indicating that this protocol is superior
to oxocarbenium ion formation through chloro ether ionization.
Changing the substitution pattern of the aryl groups (23;
entry 2) and introducing a triphenylsilyl group onto the
binaphthyl core (24; entry 3) led to significantly diminished
stereocontrol. Adamantyl-substituted catalyst 25 provided an
increase in selectivity (entry 4). The selectivity was further
improved by employing biaryl-substituted catalyst 26 (entry 5).
The triflimide group proved to be essential for the reaction, as
27 proved to be an ineffective catalyst (entry 6). Phosphoryl
triflimide 28 was also ineffective (entry 7), demonstrating the
importance of the sulfide group in this process. Thus, acid 26
was selected as the lead catalyst for this process. Changing the
cyanide source to HCN with no incorporation of phenol resulted
in low conversion and diminished enantioselectivity (data
not shown). This suggests that Me3SiCN and phenol interact
to form the relevant nucleophile in this reaction and that
this nucleophile is not HCN. 13C NMR studies confirmed
that PhOH and Me3SiCN interact in solution,26 as has been
described previously.27 The generation of a more reactive
nucleophile through this interaction is consistent with the higher
yield of these reactions in comparison with the studies involving
catalytic activation by HCl. The stereocontrol was modestly
Extending the alkenyl group caused a reduction in efficiency
that was more pronounced at greater chain lengths (entries 8
and 9). (Z)-Enol ethers proved to be superior substrates
relative to the corresponding (E)-enol ethers, though identical
levels of stereocontrol were observed regardless of the substrate
alkene geometry (entries 9 and 10). This suggests that the same
reactive intermediate is formed from either isomer but that
the Z isomer is protonated more rapidly than the E isomer.
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a
Table 3. Substrate Scope for the Asymmetric Reaction
Scheme 4. Application to Acetal Substrates
since the reaction outcomes are negligibly different. Acetals,
however, are clearly superior substrates to poorly reactive
(E)-vinyl ethers in these processes. The similarities between the
outcomes of the reactions with acetals and enol ethers suggest
that they proceed through the same intermediates and that
the acetals do not react through a pathway in which one of the
enantiotopic alkoxy groups is preferentially activated by the
catalyst to generate a tight ion pair between the oxocarbenium
ion and the departing alcohol.29 NMR studies showed that
phosphoryl triflimides are silylated by Me3SiCN in the absence of
phenol25 to form a Lewis acid that most likely serves as the active
catalyst in these processes. Trimethylsilyl ethers are observed as
products in these reactions, in accord with this hypothesis.
Oxocarbenium ions do not possess obvious sites for
hydrogen bonding to the catalyst, in contrast to carbonyl and
imine groups, obscuring the development of a predictive model
for ion pairing. Thus, we initiated computational studies using
density functional theory (DFT) to gain insight into the origins of
the asymmetric induction and to explain the substrate scope.
These studies were conducted with Gaussian 0930 using B3LYP31
as the exchange−correlation functional. The interaction between
the oxocarbenium ion of ethyl vinyl ether and the conjugate
base of catalyst 22 was utilized to develop a model for these
transformations. Peripheral atoms were treated with the 3-21G
basis set,32 while contact atoms were treated with the 6-311G
basis set.33 The phosphorus and sulfur atoms were described by
the 6-311G(3df,3pd) basis set.34 Energy minima were determined
by optimizing structures from several starting geometries. Minima
were confirmed by frequency calculations.
The lowest-energy structure for the ion pair is shown in
Figure 1. This structure shows interactions between the sulfur
of the catalyst and the carbon of the oxocarbenium ion.
Additionally, the nitrogen of the triflimide group in the catalyst
interacts with the hydrogen on the electrophilic carbon of the
oxocarbenium ion. Corey has postulated that this type of
interaction can be important in structures between aldehydes
and Lewis acids,35 and recent work has postulated that these
interactions are relevant for chiral phosphoric acid-catalyzed
additions to aldehydes.36 The Mulliken charge on the indicated
hydrogen was calculated to be +0.22, supporting the postulated
electrostatic attraction. Additionally, the fluorine atoms of the
trifluoromethyl group in the catalyst are proximal to the electron-
deficient hydrogens of the alkoxy group. Although the existence
of defined C−H···F−C hydrogen bonds is controversial,37
electrostatic and van der Waals attractions between organo-
fluorine compounds and electron-deficient hydrogens are well-
established38 and could contribute to defining the orientation of
the substrate in the catalyst. The Mulliken charges on these
hydrogens were calculated to be +0.2, again supporting the
possibility of an electrostatic interaction. Thus, the Si face of the
oxocarbenium ion is blocked and the Re face is open for
a
See the Supporting Information for precise experimental details.
Chiral substrates can show matched or mismatched selectivity
in these reactions, as evidenced by the reaction of the phenethyl
vinyl ether enantiomers in entries 11 and 12. Reactions with
these compounds under HCl-mediated conditions showed little
stereocontrol. The reaction of R enantiomer 42 in the presence
of 26, however, proved to be highly diastereoselective. The
reaction of S enantiomer 14 showed little diastereoselectivity,
similar to the HCl-mediated process.
Chiral Brønsted acid catalysis can also be used to prepare
enantiomerically enriched cyanohydrin ethers from conven-
tional acetal precursors (Scheme 4). Dibenzyl acetal 45 reacts
with Me3SiCN in the presence of 26 to provide (S)-2 in 85%
yield with an er of 82.5:17.5. These numbers are comparable to
the values that were observed with the corresponding vinyl
ether substrate. Dimethyl acetal 46 reacts under these
conditions to yield (S)-17 in 91% yield with an er of 73:27.
Again, these values are similar to the results in the vinyl ether
series, indicating that the choice of a vinyl ether or acetal
substrate should generally be dictated by synthetic accessibility
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Figure 1. Modeled structure of the ion pair from the reaction of ethyl
vinyl ether with catalyst 22 (top) and illustrations of the relevant
interactions and nucleophilic approach trajectory (bottom). Hydro-
gens have been removed for clarity. Green = carbon, red = oxygen,
gold = sulfur, light blue = fluorine, dark blue = nitrogen.
nucleophilic attack. This correlates with the observation that
the S stereoisomer is the major product in these reactions.
Lengthening the alkyl group of the electrophilic arm of the
oxocarbenium ion results in a steric clash with a triisopropyl-
phenyl group of the catalyst, while the other arm of the
electrophile can be extended without impediment. This explains
the diminished stereocontrol that is observed when the alkenyl
group of the substrate is extended.
The substantial difference in the matched and mismatched
outcomes from the α-methylbenzyl ether substrates was not
expected on the basis of the minimal diastereocontrol that
was observed through the HCl-mediated pathway but can be
rationalized through molecular modeling based on the ion
pair structure.26 The methyl group of the R substrate 42 fills
a pocket of the catalyst (Figure 2, top image), thereby placing
the sterically undemanding benzylic hydrogen across from
the trajectory of the nucleophile. Placing the corresponding
methyl group of the S substrate 14 in the same orientation
creates steric interactions between the phenyl group and
the catalyst. Therefore, the benzylic hydrogen rotates into
that position (Figure 2, bottom image), leading to a
conformation in which the methyl and phenyl groups block
the trajectory of the nucleophile into the Re face. Therefore,
neither face of the oxocarbenium ion is open for nucleophilic
attack, and the reaction most likely proceeds through an
intermediate that is not intimately associated with the chiral
counterion.
Figure 2. Modeled structures of the ion pairs derived from 42 (top)
and 14 (bottom) with catalyst 22. Hydrogens have been deleted for
clarity.
ion that reacts with Me3SiCN. Useful levels of enantioselectivity
can be achieved by forming the oxocarbenium ion directly
through protonation of the vinyl ether with a chiral Brønsted
acid, in which catalyst regeneration is effected by the addition of
phenol. Acetals are also suitable substrates for this process,
yielding products with similar levels of enantiocontrol. These
processes represent the first examples of asymmetric Brønsted
acid-mediated addition reactions of silylated nucleophiles with
vinyl ethers and acetals and are rare cases17a,22a,g,23 in which
enantioselectivity has been observed in bimolecular reactions
into oxocarbenium ions. Computational studies have suggest
that the attraction in the ion pair arises from associations of the
conjugate base of the catalyst with the electrophilic carbon and
its attached hydrogen in the oxocarbenium ion. This model
accurately explains several experimental observations in this
study. The protocols that were developed for asymmetric
additions of silylated nucleophiles into oxocarbenium ions
coupled with the model for ion pair association will be beneficial
for broadening the scope of this useful reaction class to include
other silyl-containing nucleophiles.
CONCLUSIONS
■
We have demonstrated that vinyl ethers undergo smooth acid-
mediated hydrocyanation reactions to yield cyanohydrin ethers.
Racemic product formation proceeds most efficiently when the
vinyl ether is quantitatively converted to a chloro ether followed
by Brønsted acid-mediated ionization to form an oxocarbenium
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(390 mg, 2.3 mmol), and Hg(OAc)2 (73 mg, 0.23 mmol). The crude
product was purified by flash chromatography (15% CH2Cl2 in hexane) to
give 12 as a colorless oil (347 mg, 78%). 1H NMR (400 MHz, CDCl3) δ
7.35−7.25 (m, 5H), 6.46 (dd, 1H, J = 14.0, 6.8 Hz), 4.19 (dd, 1H, J = 14.0,
2.0 Hz), 4.04 (dd, 1H, J = 6.8, 2.0 Hz), 3.82 (t, 2H, J = 6.8 Hz), 3.80 (s,
2H), 2.71 (t, 2H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 151.6,
138.3, 129.1, 128.7, 127.2, 87.1, 67.7, 36.8, 30.1; IR (neat) 3114, 3062,
3028, 2921, 2870, 1616, 1454, 1320, 1194, 1070, 819, 702 cm−1; HRMS
(EI) m/z calcd for C11H14OS [M]+ 194.0765, found 194.0794.
(S)-(1-(Vinyloxy)ethyl)benzene (14).
EXPERIMENTAL SECTION
■
General Protocols. Chemical shifts for proton (1H) and carbon
(13C) NMR spectra are reported in parts per million (ppm) on the
delta (δ) scale. Solvent peaks were used as a reference values: CDCl3 =
1
7.27 ppm and CD2Cl2 = 5.32 ppm for H NMR and CDCl3 = 77.23
ppm for 13C NMR. Data are reported as follows: (s = singlet; d =
doublet; t = triplet; q = quartet; quin = quintet; dd = doublet of
doublets; ddd = doublet of doublets of doublets; td = triplet of
doublets). High-resolution mass spectrometry (HRMS) was per-
formed with a time-of-flight (TOF) detector. Samples for IR were
prepared as thin films on NaCl plates by dissolving the compounds in
CH2Cl2 and then evaporating the CH2Cl2. High-performance liquid
chromatography (HPLC) was performed with a refractive index
detector using chiral stationary columns (0.46 cm × 25 cm). Optical
rotations were recorded on a digital polarimeter with a sodium lamp at
ambient temperature as follows: [α]λ (c, g/100 mL). Tetrahydrofuran
and diethyl ether were distilled from sodium and benzophenone.
Methylene chloride was distilled under N2 from CaH2. α,α,α-
Trifluorotoluene, HCl solution (2.0 M in diethyl ether), ethyl acetate,
diethyl ether, toluene, and hexanes were used as purchased.
Trimethylsilyl cyanide was freshly fractionally distilled prior to use
and used under an Ar atmosphere. Analytical TLC was performed on
precoated (25 mm) silica gel 60F-254 plates. Visualization was done
under UV (254 nm). Flash chromatography was performed with 32-63
60 Å silica gel. All of the reactions were performed in oven- or flame-
dried glassware under argon with magnetic stirring, unless otherwise
noted. Substrates 1,39 8,40 29,41 31,42 and 4243 were prepared
according to reported protocols.
The general procedure for vinyl ether formation was followed with
ethyl vinyl ether (8.0 mL, 83 mmol), (S)-phenylethanol (1.00 mL,
8.3 mmol), and Hg(OAc)2 (262 mg, 0.83 mmol). The crude product
was purified by flash chromatography (15% CH2Cl2 in hexane) to give
1
14 as a colorless oil (763 mg, 62%). H NMR (400 MHz, CDCl3) δ
7.38−7.29 (m, 5H), 6.33 (dd, 1H, J = 14.0, 6.4 Hz), 4.91 (q, 1H, J =
6.4 Hz), 4.27 (d, 1H, J = 14.4 Hz), 4.00 (d, 1H, J = 6.8 Hz), 1.54 (d,
3H, J = 6.4 Hz); 13C NMR (100 MHz, CDCl3) δ 150.7, 143.1, 128.7,
127.7, 125.9, 89.4, 77.5, 23.8; IR (neat) 3030, 2980, 2931, 1637, 1188,
1085, 759, 699 cm−1; HRMS (EI) m/z calcd for C10H12O [M]+
148.0888, found 148.0898; [α]2D5 = −71.1 (c 1.0, CHCl3).
(E)-(3-Methoxyallyl)benzene (16) and (Z)-(3-Methoxyallyl)-
benzene (41).
General Procedure for Preparing Vinyl Ether Substrates.17
To a solution of the alcohol (1.0 equiv) in ethyl vinyl ether (10 equiv)
was added Hg(OAc)2 (0.1 equiv). The reaction mixture was stirred at
reflux under N2 for 24 h, and then the excess ethyl vinyl ether was
removed under vacuum. The crude product was purified by flash
chromatography using CH2Cl2 and hexanes as the eluent.
Compounds 16 and 41 were prepared following Negishi’s protocol,44 with
the crude product being purified by medium-pressure liquid chromato-
graphy (MPLC) (100% hexane to 10% CH2Cl2 in hexane) three times.
The faster-eluting product was the minor isomer 41: 1H NMR (400
MHz, CD2Cl2) δ 7.28−7.24 (m, 2H), 7.21−7.19 (m, 2H), 7.17−7.14
(m, 1H), 6.02 (d, 1H, J = 6.0 Hz), 4.55 (q, 1H, J = 7.6 Hz), 3.62 (s,
3H), 3.38 (d, 2H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 146.9,
141.9, 128.5, 128.5, 125.9, 105.7, 59.8, 30.3.
(3-(Vinyloxy)propyl)benzene (6).
The general procedure for vinyl ether formation was followed with
ethyl vinyl ether (10.8 mL, 110 mmol), 3-phenylpropan-1-ol (1.5 mL,
11 mmol), and Hg(OAc)2 (176 mg, 0.55 mmol). The crude product
was purified by flash chromatography (20% CH2Cl2 in hexane) to give
1
The slower-eluting product was the major isomer 16: H NMR
(300 MHz, CDCl3) δ 7.33−7.28 (m, 2H), 7.24−7.18 (m, 3H), 6.43
(d, 1H, J = 12.6 Hz), 4.91 (dt, 1H, J = 12.6, 7.5 Hz), 3.55 (s, 3H), 3.28
(d, 2H, J = 7.5 Hz); 13C NMR (100 MHz, CDCl3) δ 148.3, 141.9,
128.6, 128.5, 126.2, 102.1, 56.1, 34.2.
1
6 as a colorless oil (1.04 g, 58%). H NMR (400 MHz, CDCl3) δ
7.33−7.29 (m, 2H), 7.22−7.20 (m, 3H), 6.50 (dd, 1H, J = 14.4, 6.8
Hz), 4.19 (dd, 1H, J = 14.4, 2.0 Hz), 4.00 (dd, 1H, J = 6.8, 2.0 Hz),
3.71 (t, 2H, J = 6.4 Hz), 2.75 (t, 2H, J = 7.2 Hz), 2.04−1.97 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 152.0, 141.7, 128.6, 128.6, 126.1,
86.6, 67.1, 32.3, 30.9; IR (neat) 3116, 3027, 2946, 2870, 1614, 1319,
1203, 1083, 815, 747, 699 cm−1; HRMS (ESI) m/z calcd for C11H15O
[M + H]+ 163.1117, found 163.1109.
(E)-(Dec-1-en-1-yloxy)cyclohexane (18).45
To a solution of (E)-1-iododec-1-ene (798 mg, 3 mmol) and
cyclohexanol (632 μL, 6 mmol) in toluene (1.5 mL) were added CuI
(57 mg, 0.3 mmol), Cs2CO3 (1.46 g, 4.5 mmol), and tetramethyl-1,10-
phenanthroline (141 mg, 0.6 mmol). The reaction tube was sealed
with a screw cap and stirred at 85 °C for 20 h. The resulting suspension
was cooled to room temperature and passed through a short pad of
silica gel, eluting with Et2O. The filtrate was concentrated under
vacuum, and the crude product was purified by flash chromatography
(100% hexane to 5% Et2O in hexane) to give 18 as a colorless oil (385
tert-Butyldiphenyl((5-(vinyloxy)pentyl)oxy)silane (10).
The general procedure for vinyl ether formation was followed with
ethyl vinyl ether (6.9 mL, 72 mmol), 5-((tert-butyldiphenylsilyl)oxy)-
pentan-1-ol (2.5 g, 7.2 mmol), and Hg(OAc)2 (115 mg, 0.375 mmol).
The crude product was purified by flash chromatography (20% to 40%
CH2Cl2 in hexane) to give 10 as a colorless oil (1.67 g, 63%). 1H NMR
(500 MHz, CDCl3) δ 7.69−7.67 (m, 4H), 7.45−7.37 (m, 6H), 6.47
(dd, 1H, J = 14.0, 6.5 Hz), 4.18 (dd, 1H, J = 14.5, 2.0 Hz), 3.98 (dd,
1H, J = 6.5, 2.0 Hz), 3.69 (t, 2H, J = 6.5 Hz), 3.67 (t, 2H, J = 6.5 Hz),
1.69−1.64 (m, 2H), 1.63−1.58 (m, 2H), 1.50−1.44 (m, 2H), 1.06 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 152.2, 135.8, 134.3, 129.7, 127.8,
86.4, 68.1, 63.9, 32.4, 29.0, 27.1, 22.5, 19.4; IR (neat) 3071, 3049, 2934,
2859, 1612, 1428, 1203, 1111, 822, 703 cm−1; HRMS (ESI) m/z calcd
for C23H33O2Si [M + H]+ 369.2244, found 369.2232.
1
mg, 54%). H NMR (300 MHz, CDCl3) δ 6.09 (d, 1H, J = 12.3 Hz),
4.89 (dt, 1H, J = 12.3, 7.2 Hz), 3.65−3.56 (m, 1H), 1.90−1.88 (m,
4H), 1.76−1.74 (m, 2H), 1.56−1.51 (m, 1H), 1.43−1.27 (m, 18H),
0.89 (t, 3H, J = 6.6 Hz); 13C NMR (125 MHz, CDCl3) δ 144.7, 106.6,
78.1, 32.3, 32.1, 30.8, 29.7, 29.5, 29.3, 27.9, 25.8, 24.0, 22.9, 14.3; IR
(neat) 2928, 2855, 1671, 1452, 1164, 922 cm−1; HRMS (ASAP) m/z
calcd for C16H31O [M + H]+ 239.2375, found 239.2377.
3-(Vinyloxy)propyl Benzoate (35).
Benzyl(2-(vinyloxy)ethyl)sulfane (12).
The general procedure for vinyl ether formation was followed
with ethyl vinyl ether (2.3 mL, 23 mmol), 2-(benzylthio)ethan-1-ol
The general procedure for vinyl ether formation was followed with
ethyl vinyl ether (12 mL, 130 mmol), 3-hydroxypropyl benzoate
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(2.27 g, 12.6 mmol), and Hg(OAc)2 (401 mg, 1.26 mmol). The crude
colorless oil (52 mg, 92%). For characterization data, see the procedure
for preparing enantioenriched material.
2-(Hex-5-en-1-yloxy)propanenitrile (9).
product was purified by flash chromatography (5% EtOAc in hexane)
1
to give 35 as a colorless oil (1.51 g, 58%). H NMR (400 MHz,
CDCl3) δ 8.05 (d, 2H, J = 6.8 Hz), 7.57 (t, 1H, J = 6.6 Hz), 7.45 (t,
2H, J = 7.6 Hz), 6.49 (dd, 1H, J = 14.0, 6.8 Hz), 4.45 (t, 2H, J = 6.4
Hz), 4.22 (dd, 1H, J = 14.4, 2.0 Hz), 4.03 (dd, 1H, J = 6.8, 2.0 Hz),
3.86 (t, 2H, J = 6.0 Hz), 2.15 (quin, 2H, J = 6.4 Hz); 13C NMR (100
MHz, CDCl3) δ 166.6, 151.8, 133.0, 130.4, 129.7, 128.5, 86.8, 64.5,
61.9, 28.6; IR (neat) 3117, 3064, 2962, 2881, 1721, 1617, 1452, 1275,
1199, 1112, 820, 712 cm−1; HRMS (EI) m/z calcd for C12H14O3 [M]+
206.0943, found 206.0937.
The general procedure for hydrocyanation was followed with 8 (38 mg,
0.3 mmol), HCl solution (165 μL, 0.33 mmol), TMSCN (75 μL,
0.6 mmol), and CH2Cl2 (3 mL). The crude product was purified by
flash chromatography (10% Et2O in pentane) to give 9 as a colorless oil
(35 mg, 76%). 1H NMR (300 MHz, CDCl3) δ 5.81 (ddt, 1H, J = 17.1,
10.2, 6.6 Hz), 5.06−4.95 (m, 2H), 4.22 (q, 1H, J = 6.9 Hz), 3.76 (dt,
1H, J = 8.7, 6.3 Hz), 3.47 (dt, 1H, J = 8.7, 6.3 Hz), 2.09 (q, 2H, J = 6.9
Hz), 1.69−1.60 (m, 2H), 1.57 (d, 3H, J = 6.6 Hz), 1.53−1.43 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 138.6, 119.3, 115.0, 70.6, 64.7, 33.5,
28.9, 25.4, 20.0; IR (neat) 3078, 2941, 2870, 1641, 1443, 1331, 1113,
1077, 997, 912 cm−1; HRMS (ESI) m/z calcd for C9H16ON [M + H]+
154.1226, found 154.1218.
2-((Vinyloxy)methyl)naphthalene (37).
The general procedure for vinyl ether formation was followed with
ethyl vinyl ether (1.9 mL, 20 mmol), 2-naphthalenemethanol (316 mg,
2.0 mmol), and Hg(OAc)2 (32 mg, 0.1 mmol). The crude product was
purified by flash chromatography (10% to 20% CH2Cl2 in hexane) to
1
2-((5-((tert-Butyldiphenylsilyl)oxy)pentyl)oxy)propanenitrile (11).
give 37 as the desired product (152 mg, 41%). H NMR (400 MHz,
CDCl3) δ 7.88−7.84 (m, 4H), 7.51−7.47 (m, 3H), 6.64 (dd, 1H, J =
14.4, 6.8 Hz), 4.95 (s, 2H), 4.38 (dd, 1H, J = 14.4, 2.0 Hz), 4.13 (dd,
1H, J = 6.8, 2.0 Hz); 13C NMR (100 MHz, CDCl3) δ 151.9, 134.6,
133.5, 133.2, 128.5, 128.1, 127.9, 126.6, 126.4, 126.3, 125.6, 87.8, 70.4;
IR (neat) 3055, 2923, 2867, 1616, 1319, 1196, 959, 816, 752 cm−1;
HRMS (EI) m/z calcd for C13H12O [M]+ 184.0888, found 184.0896.
(Z)-((Prop-1-en-1-yloxy)methyl)benzene (39).46
The general procedure for hydrocyanation was followed with 10 (74 mg,
0.2 mmol), HCl solution (110 μL, 0.22 mmol), TMSCN (50 μL,
0.4 mmol), and CH2Cl2 (2 mL). The crude product was purified by flash
chromatography (3% to 5% EtOAc in hexane) to give 11 as a colorless
1
oil (76 mg, 96%). H NMR (500 MHz, CDCl3) δ 7.69−7.67 (m, 4H),
7.45−7.37 (m, 6H), 4.20 (q, 1H, J = 6.5 Hz), 3.74 (dt, 1H, J = 9.0, 6.5
Hz), 3.68 (t, 2H, J = 6.5 Hz), 3.44 (dt, 1H, J = 9.0, 6.5 Hz), 1.64−1.58
(m, 4H), 1.56 (d, 3H, J = 7.0 Hz), 1.48−1.42 (m, 2H), 1.06 (s, 9H); 13C
NMR (125 MHz, CDCl3) δ 135.8, 134.3, 129.7, 127.8, 119.3, 70.7, 64.7,
63.9, 32.4, 29.2, 27.1, 22.4, 20.0, 19.4; IR (neat) 3050, 2997, 2941, 1589,
1473, 1113, 823, 706, 613 cm−1; HRMS (ESI) m/z calcd for
C24H34O2NSi [M + H]+ 396.2353, found 396.2343.
To a solution of allyl benzyl ether (592 mg, 4.0 mmol) in DMSO (40 mL)
was added t-BuOK (1.63 g, 10 mmol) under an Ar atmosphere. The
reaction mixture was stirred at 60 °C for 2 h and then diluted with
Et2O, washed with H2O (3×), dried over Na2SO4, and concentrated
under vacuum. The crude product was purified by flash chromatog-
raphy (3% EtOAc in hexane) to give 39 as a colorless oil (460 mg, 78%,
Z:E = 97:3). 1H NMR (300 MHz, CDCl3) δ 7.41−7.29 (m, 5H), 6.05
(dq, 1H, J = 6.0, 1.5 Hz), 4.81 (s, 2H), 4.46 (app quin, 1H, J = 6.6 Hz),
1.64 (dd, 3H, J = 6.9, 1.5 Hz); 13C NMR (125 MHz, CDCl3) δ 145.4,
138.0, 128.6, 127.9, 127.4, 101.9, 73.6, 9.5. These data are consistent
with reported literature values.47
General Procedure for Vinyl Ether Hydrocyanation via
α-Chloro Ether Formation. To a solution of the vinyl ether (1.0
equiv) in freshly distilled methylene chloride (0.1 M) at −40 °C under
Ar was added a solution of HCl (1.1 equiv, 2.0 M in diethyl ether)
dropwise. After 5 min, TMSCN (2 equiv) was added to the reaction
mixture. The mixture was stirred at −40 °C for 1 h, and then the
reaction was quenched with Et3N (0.3 mL) followed by saturated
NaHCO3 solution. The reaction mixture was then warmed to room
temperature, extracted with methylene chloride (2×), dried over
Na2SO4, and concentrated under vacuum. The crude product was
purified by flash chromatography.
2-(2-(Benzylthio)ethoxy)propanenitrile (13).
The general procedure for hydrocyanation was followed with 12 (58 mg,
0.3 mmol), HCl solution (165 μL, 0.33 mmol), TMSCN (75 μL,
0.6 mmol), and CH2Cl2 (3 mL). The crude product was purified by
flash chromatography (4% EtOAc in hexane) to give 13 as a colorless
oil (60 mg, 85%). For characterization data, see the procedure for
preparing enantioenriched material.
2-((S)-1-Phenylethoxy)propanenitrile (15).
The general procedure for hydrocyanation was followed with 14
(104 mg, 0.7 mmol), HCl solution (385 μL, 0.77 mmol), TMSCN
(175 μL, 1.4 mmol), and CH2Cl2 (7 mL). The crude product was
purified by flash chromatography (3% EtOAc in hexane) to give two
diastereomers (112 mg, 91%, d.r. = 1.2:1).
2-(Benzyloxy)propanenitrile (2).
The faster-eluting product was the major diastereomer 44: 1H NMR
(400 MHz, CDCl3) δ 7.41−7.31 (m, 5H), 4.75 (q, 1H, J = 6.4 Hz),
3.97 (q, 1H, J = 6.8 Hz), 1.52 (d, 3H, J = 6.4 Hz), 1.51 (d, 3H, J = 6.8
Hz); 13C NMR (100 MHz, CDCl3) δ 141.4, 129.1, 128.6, 126.6, 119.4,
77.9, 61.7, 24.1, 20.1; IR (neat) 3032, 2982, 2887, 1453, 1057, 763,
702 cm−1; HRMS (EI) m/z calcd for C11H13NO [M]+ 175.0997,
found 175.1016; [α]2D5 = −323.3 (c 1.0, CHCl3).
The general procedure for hydrocyanation was followed with 1 (54 mg,
0.4 mmol), HCl solution (220 μL, 0.44 mmol), TMSCN (100 μL,
0.8 mmol), and CH2Cl2 (4 mL). The crude product was purified by
flash chromatography (3% EtOAc in hexane) to give 2 as a colorless
oil (52 mg, 81%). For characterization data, see the procedure for
preparing enantioenriched material.
2-(3-Phenylpropoxy)propanenitrile (7).
1
The slower-eluting product was the minor diastereomer: H NMR
(400 MHz, CDCl3) δ 7.41−7.31 (m, 5H), 4.68 (q, 1H, J = 6.8 Hz),
4.31 (q, 1H, J = 6.8 Hz), 1.58 (d, 3H, J = 6.4 Hz), 1.51 (d, 3H, J = 6.4
Hz); 13C NMR (125 MHz, CDCl3) δ 141.9, 128.8, 128.5, 126.6, 119.4,
78.2, 62.2, 22.6, 20.4; IR (neat) 3032, 2981, 2889, 1453, 1029, 762,
701 cm−1; HRMS (EI) m/z calcd for C11H13NO [M]+ 175.0997,
found 175.1018; [α]2D5 = −8.7 (c 1.0, CHCl3).
The general procedure for hydrocyanation was followed with 6
(49 mg, 0.3 mmol), HCl solution (165 μL, 0.33 mmol), TMSCN
(75 μL, 0.6 mmol), and CH2Cl2 (3 mL). The crude product was
purified by flash chromatography (4% EtOAc in hexane) to give 7 as a
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2-Methoxy-4-phenylbutanenitrile (17).
Information for the determination of the absolute stereochemistry of
the major product.
(S)-2-Phenethoxypropanenitrile (30).
The general procedure for hydrocyanation was followed with 16
(30 mg, 0.2 mmol), HCl solution (110 μL, 0.22 mmol), TMSCN
(50 μL, 0.4 mmol), and CH2Cl2 (2 mL) at 0 °C. The crude product
was purified by flash chromatography (4% EtOAc in hexane) to give
17 as a colorless oil (29 mg, 83%). For characterization data, see the
procedure for preparing enantioenriched material.
The general asymmetric hydrocyanation procedure was followed with
29 (45 mg, 0.3 mmol), catalyst 26 (11 mg, 0.0009 mmol), TMSCN
(76 μL, 0.6 mmol), phenol (28 mg, 0.3 mmol), and trifluorotoluene
(3 mL). The crude product was purified by flash chromatography (4%
EtOAc in hexane) to give 30 as a colorless oil (41 mg, 78%). 1H NMR
(300 MHz, CDCl3) δ 7.35−7.22 (m, 5H), 4.22 (q, 1H, J = 6.9 Hz),
4.00 (dt, 1H, J = 8.7, 6.9 Hz), 3.67 (dt, 1H, J = 8.7, 6.9 Hz), 2.94 (t,
2H, J = 6.9 Hz), 1.56 (d, 3H, J = 6.9 Hz); 13C NMR (100 MHz,
CDCl3) δ 138.2, 129.1, 128.7, 126.7, 119.1, 71.4, 64.8, 36.1, 20.0; IR
(neat) 3029, 2995, 2871, 1497, 1475, 1330, 1115, 750, 700 cm−1;
HRMS (EI) m/z calcd for C11H13NO [M]+ 175.0997, found 175.1014;
2-(Cyclohexyloxy)undecanenitrile (19).
The general procedure for hydrocyanation was followed with 18 (72 mg,
0.3 mmol), HCl solution (165 μL, 0.33 mmol), TMSCN (75 μL,
0.6 mmol), and CH2Cl2 (3 mL). The crude product was purified by
flash chromatography (4% EtOAc in hexane) to give 19 as a colorless oil
(75 mg, 94%). 1H NMR (400 MHz, CDCl3) δ 4.21 (t, 1H, J = 6.8 Hz),
3.58−3.52 (m, 1H), 1.96−1.71(m, 6H), 1.55−1.38 (m, 4H), 1.30−1.27
(m, 16H), 0.89 (t, 3H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ
119.6, 77.9, 66.0, 34.2, 32.8, 32.0, 31.1, 29.6, 29.5, 29.4, 29.2, 25.7, 25.1,
24.0, 23.9, 22.9, 14.3; IR (neat) 2930, 2857, 1453, 1337, 1099 cm−1;
HRMS (ASAP) m/z calcd for C17H31NO [M]+ 265.2406, found
265.2394.
HPLC (Lux cellulose-3), 90:10 hexane/i-PrOH, 1 mL/min, tmajor
=
10.0 min, tminor = 13.6 min, er = 87.5:12.5; [α]2D5 = −61.3 (c 1.0,
CHCl3). Racemic material was prepared through cyanation of the
α-chloro ether.
(S)-2-(3-Phenylpropoxy)propanenitrile ((S)-7).
The general asymmetric hydrocyanation procedure was followed with
6 (49 mg, 0.3 mmol), catalyst 26 (11 mg, 0.0009 mmol), TMSCN
(76 μL, 0.6 mmol), phenol (28 mg, 0.3 mmol), and trifluorotoluene
(3 mL). The crude product was purified by flash chromatography
(4% EtOAc in hexane) to give (S)-7 as a colorless oil (51 mg, 90%).
1H NMR (300 MHz, CDCl3) δ 7.33−7.28 (m, 2H), 7.23−7.19 (m,
3H), 4.20 (q, 1H, J = 6.9 Hz), 3.77 (dt, 1H, J = 9.3, 6.3 Hz), 3.46 (dt,
1H, J = 9.0, 6.3 Hz), 2.72 (t, 2H, J = 7.5 Hz), 2.00−1.91 (m, 2H), 1.58
(d, 3H, J = 6.9 Hz); 13C NMR (100 MHz, CDCl3) δ 141.5, 128.7,
128.6, 126.2, 119.3, 69.9, 64.8, 32.3, 31.1, 20.1; IR (neat) 3027, 2941,
2870, 1453, 1329, 1116, 748, 701 cm−1; HRMS (ASAP) m/z calcd for
C12H15NO [M]+ 189.1154, found 189.1147; HPLC (Lux cellulose-3),
90:10 hexane/i-PrOH, 1 mL/min, tmajor = 8.8 min, tminor = 10.2 min,
er = 86:14; [α]2D5 = −46.6 (c 1.0, CHCl3).
Tetrahydro-2H-pyran-2-carbonitrile (21).
The general procedure for hydrocyanation was followed with 20 (72 mg,
0.8 mmol), HCl solution (440 μL, 0.88 mmol), TMSCN (200 μL,
1.6 mmol), and CH2Cl2 (8 mL). The crude product was purified by
flash chromatography (6% EtOAc in hexane) to give 21 as a colorless
oil (58 mg, 65%). 1H NMR (300 MHz, CDCl3) δ 4.64 (t, 1H, J = 4.5
Hz), 3.94−3.86 (m, 1H), 3.81−3.74 (m, 1H), 1.96−1.80 (m, 3H),
1.78−1.74 (m, 1H), 1.68−1.63 (m, 2H). These data are consistent with
reported literature values.48
General Procedure for Asymmetric Cyanide Addition to
Vinyl Ethers. To a solution of catalyst 26 (0.03 equiv) in anhydrous
PhCF3 at room temperature under Ar was added TMSCN. The
reaction mixture was stirred at rt for 10 min and then was cooled to
−25 °C. A solution of vinyl ether (1.0 equiv) in PhCF3 (0.3 mL) was
added to the reaction mixture dropwise. The vial containing vinyl ether
was rinsed with PhCF3 (0.3 mL), and the rinses were also transferred
to the reaction mixture to give a 0.1 M solution. After 5 min, phenol
(1.0 equiv) in PhCF3 (0.6 mL) was added via a syringe pump using
a 3 mL syringe at a rate of 0.03 mL/h over 20 h. The reaction mixture
was allowed to stir for another 4 h at this temperature. The reaction
was then quenched with Et3N and saturated NaHCO3 solution. The
reaction mixture was warmed to room temperature, extracted with
Et2O (2×), dried over Na2SO4, and concentrated under vacuum. The
crude product was purified by flash chromatography.
(S)-2-(Cinnamyloxy)propanenitrile (32).
The general asymmetric hydrocyanation procedure was followed with
31 (48 mg, 0.3 mmol), catalyst 26 (11 mg, 0.0009 mmol), TMSCN
(76 μL, 0.6 mmol), phenol (28 mg, 0.3 mmol), and trifluorotoluene
(3 mL). The crude product was purified by flash chromatography (4%
to 5% EtOAc in hexane) to give 32 as a colorless oil (43 mg, 77%).
1H NMR (300 MHz, CDCl3) δ 7.43−7.28 (m, 5H), 6.70 (d, 1H, J =
15.9 Hz), 6.26 (ddd, 1H, J = 15.9, 6.9, 5.4 Hz), 4.47 (ddd, 1H, J =
12.0, 5.4, 1.2 Hz), 4.35 (q, 1H, J = 6.9 Hz), 4.21 (ddd, 1H, J = 12.3,
6.9, 1.2 Hz), 1.61 (d, 3H, J = 6.6 Hz); 13C NMR (100 MHz, CDCl3) δ
136.2, 134.9, 128.8, 128.4, 126.9, 123.7, 119.1, 71.0, 63.4, 20.0; IR
(neat) 3027, 2995, 2941, 2863, 1449, 1329, 1111, 969, 747, 693 cm−1;
HRMS (EI) m/z calcd for C12H13NO [M]+ 187.0997, found 187.1012;
(S)-2-(Benzyloxy)propanenitrile ((S)-2).
HPLC (Lux cellulose-3), 90:10 hexane/i-PrOH, 1 mL/min, tmajor
=
15.2 min, tminor = 20.8 min, er = 82:18; [α]2D5 = −96.9 (c 1.0, CHCl3).
Racemic material was prepared through cyanation of the α-chloro ether.
(S)-2-(Cyclohexyloxy)propanenitrile (34).
The general asymmetric hydrocyanation procedure was followed with
1 (107 mg, 0.8 mmol), catalyst 26 (5 mg, 0.0004 mmol, 0.005 equiv),
TMSCN (200 μL, 1.6 mmol), phenol (76 mg, 0.8 mmol), and
trifluorotoluene (6 mL). The crude product was purified by flash
chromatography (3% EtOAc in hexane) to give (S)-2 as a colorless oil
1
(108 mg, 84%). H NMR (300 MHz, CDCl3) δ 7.40−7.35 (m, 5H),
The general asymmetric hydrocyanation procedure was followed with
33 (50 mg, 0.4 mmol), catalyst 26 (14.6 mg, 0.0012 mmol), TMSCN
(101 μL, 0.8 mmol), phenol (37 mg, 0.4 mmol), and trifluorotoluene
(4 mL). The crude product was purified by flash chromatography (3%
to 5% EtOAc in hexane) to give 34 as a colorless oil (44 mg, 72%).
1H NMR (400 MHz, CDCl3) δ 4.36 (q, 1H, J = 6.8 Hz), 3.60−3.54
(m, 1H), 1.97−1.89 (m, 2H), 1.80−1.71 (m, 2H), 1.56 (d, 3H, J = 6.8
Hz), 1.45−1.17 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 120.0, 77.9,
4.86 (d, 1H, J = 11.4 Hz), 4.55 (d, 1H, J = 11.4 Hz), 4.27 (q, 1H, J =
6.6 Hz), 1.60 (d, 3H, J = 6.6 Hz); 13C NMR (100 MHz, CDCl3) δ
136.1, 128.9, 128.6, 128.4, 119.0, 72.3, 63.5, 20.0; IR (neat) 3066,
3034, 2996, 2872, 1455, 1330, 1111, 746, 699 cm−1; HRMS (EI) m/z
calcd for C10H11NO [M]+ 161.0841, found 161.0828. These data are
consistent with reported literature values.49 HPLC (Lux cellulose-3),
90:10 hexane/i-PrOH, 1 mL/min, tmajor = 7.7 min, tminor = 8.7 min,
er = 85:15; [α]2D5 = −123.3 (c 1.0, CHCl3). See the Supporting
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61.5, 32.9, 31.2, 25.7, 24.1, 24.0, 20.7; IR (neat) 2936, 2860, 1451,
1375, 1113, 1070, 981 cm−1; HRMS (EI) m/z calcd for C9H15NO
[M]+ 153.1154, found 153.1162; [α]D25 = −72.5 (c 1.0, CHCl3). The
enantiomeric ratio was determined from a derivative (see the
Supporting Information for details).
(500 MHz, CDCl3) δ 7.41−7.33 (m, 5H), 4.87 (d, 1H, J = 11.5 Hz),
4.55 (d, 1H, J = 11.5 Hz), 4.12 (t, 1H, J = 6.5 Hz), 1.91 (quin, 2H, J =
7.5 Hz), 1.09 (t, 3H, J = 7.5 Hz); 13C NMR (125 MHz, CDCl3) δ
136.3, 128.9, 128.6, 128.4, 118.4, 72.4, 69.1, 27.1, 9.4; IR (neat) 3033,
2974, 2938, 2880, 1455, 1335, 1110, 742, 699 cm−1; HRMS (EI) m/z
calcd for C11H13NO [M]+ 175.0997, found 175.0980; HPLC (Lux
(S)-3-(1-Cyanoethoxy)propyl Benzoate (36).
cellulose-3), 95:5 hexane/i-PrOH, 1 mL/min, tmajor = 7.3 min, tminor
8.7 min, er = 80.5:19.5; [α]2D5 = −94.5 (c 1.0, CHCl3).
(S)-2-Methoxy-4-phenylbutanenitrile ((S)-17).
=
The general asymmetric hydrocyanation procedure was followed with
35 (62 mg, 0.3 mmol), catalyst 26 (11 mg, 0.0009 mmol), TMSCN
(76 μL, 0.6 mmol), phenol (28 mg, 0.3 mmol), and trifluorotoluene
(3 mL). The crude product was purified by flash chromatography (2%
EtOAc in toluene) to give 36 as a colorless oil (61 mg, 87%). 1H NMR
(400 MHz, CDCl3) δ 8.05 (d, 2H, J = 7.6 Hz), 7.57 (t, 1H, J = 7.2
Hz), 7.45 (t, 2H, J = 7.6 Hz), 4.50−4.38 (m, 2H), 4.25 (q, 1H, J = 6.8
Hz), 3.94 (dt, 1H, J = 9.2, 6.0 Hz), 3.63 (dt, 1H, J = 9.2, 6.0 Hz), 2.10
(quin, 2H, J = 6.4 Hz), 1.57 (d, 3H, J = 6.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 166.7, 133.2, 130.4, 129.8, 128.6, 119.0, 67.2, 64.9, 61.8,
29.0, 20.0; IR (neat) 3064, 2962, 1719, 1276, 1115, 713 cm−1; HRMS
(ASAP) m/z calcd for C13H16NO3 [M + H]+ 234.1130, found
234.1122; HPLC (Lux cellulose-3), 90:10 hexane/i-PrOH, 1 mL/min,
tmajor = 14.5 min, tminor = 16.1 min, er = 83:17; [α]2D5 = −37.8 (c 1.0,
CHCl3).
The general asymmetric hydrocyanation procedure was followed with
41 (24 mg, 0.16 mmol), catalyst 26 (17.6 mg, 0.014 mmol), TMSCN
(80 μL, 0.64 mmol), phenol (15 mg, 0.16 mmol), and trifluorotoluene
(1.6 mL). The crude product was purified by flash chromatography
(4% EtOAc in hexane) to give (S)-17 as a colorless oil (24 mg, 86%).
1H NMR (400 MHz, CDCl3) δ 7.32 (t, 2H, J = 7.2 Hz), 7.24 (t, 1H,
J = 7.2 Hz), 7.20 (d, 2H, J = 7.2 Hz), 3.98 (t, 1H, J = 6.4 Hz), 3.50 (s,
3H), 2.83 (t, 2H, J = 7.6 Hz), 2.24−2.09 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 139.9, 128.9, 128.7, 126.7, 118.2, 69.7, 58.2, 35.1,
30.9. These data are consistent with reported literature values.50
HPLC (Lux cellulose-3), 90:10 hexane/i-PrOH, 1 mL/min, tmajor = 7.6
min, tminor = 8.4 min, er = 74:26; [α]2D5 = +17.1 (c 1.0, CHCl3).
When (E)-vinyl ether 16 (44 mg, 0.3 mmol), catalyst 26 (33 mg,
0.027 mmol), TMSCN (152 μL, 1.2 mmol), phenol (28 mg, 0.3 mmol),
and trifluorotoluene (3.0 mL) were used, the crude product was purified
by flash chromatography (4% EtOAc in hexane) to give (S)-17 as a
colorless oil (7 mg, 13%, 22% conversion based on crude NMR), er =
74:26.
(S)-2-(2-(Benzylthio)ethoxy)propanenitrile ((S)-13).
The general asymmetric hydrocyanation procedure was followed with
12 (58 mg, 0.3 mmol), catalyst 26 (11 mg, 0.0009 mmol), TMSCN
(76 μL, 0.6 mmol), phenol (28 mg, 0.3 mmol), and trifluorotoluene
(3 mL). The crude product was purified by flash chromatography (4%
EtOAc in hexane) to give (S)-13 as a colorless oil (50 mg, 71%).
1H NMR (400 MHz, CDCl3) δ 7.35−7.25 (m, 5H), 4.23 (q, 1H, J =
6.8 Hz), 3.88 (dt, 1H, J = 9.6, 6.4 Hz), 3.79 (s, 2H), 3.57 (dt, 1H, J =
9.2, 6.8 Hz), 2.66 (t, 2H, J = 6.4 Hz), 1.58 (d, 3H, J = 6.8 Hz); 13C
NMR (100 MHz, CDCl3) δ 138.3, 129.1, 128.8, 127.4, 118.9, 70.1,
64.8, 36.9, 30.4, 20.0; IR (neat) 3062, 3028, 2920, 2870, 1453, 1329,
1114, 1073, 1016, 704 cm−1; HRMS (EI) m/z calcd for C12H15NOS
[M]+ 221.0874, found 221.0893; [α]D25 = −39.6 (c 1.0, CHCl3). The
enantiomeric ratio was determined from a derivative (see the
Supporting Information for details).
(S)-2-((R)-1-Phenylethoxy)propanenitrile (43).
The general asymmetric hydrocyanation procedure was followed with
42 (59 mg, 0.4 mmol), catalyst 26 (14.6 mg, 0.0012 mmol), TMSCN
(101 μL, 0.8 mmol), phenol (37 mg, 0.4 mmol), and trifluorotoluene
(4 mL). The crude product was passed through a short pad of silica
gel (5% EtOAc in hexane) to remove the catalyst. The eluent was
then concentrated under vacuum for HPLC analysis. HPLC (Lux
cellulose-3), 90:10 hexane/i-PrOH, 1 mL/min, tminor,RR = 6.3 min,
tmajor,SR = 7.2 min, d.r. = 28:1. The crude product was further purified
by flash chromatography (3% EtOAc in hexane) to give 43 as a
colorless oil (56 mg, 80%). 1H NMR (500 MHz, CDCl3) δ 7.41−7.30
(m, 5H), 4.68 (q, 1H, J = 6.5 Hz), 4.31 (q, 1H, J = 7.0 Hz), 1.57 (d,
3H, J = 7.0 Hz), 1.51 (d, 3H, J = 6.5 Hz); 13C NMR (125 MHz,
CDCl3) δ 141.9, 128.8, 128.5, 126.6, 119.4, 78.2, 62.2, 22.6, 20.4; IR
(neat) 3034, 2980, 2933, 1453, 1377, 1109, 762, 700 cm−1; HRMS
(EI) m/z calcd for C11H13NO [M]+ 175.0997, found 175.0986;
[α]2D5 = +9.4 (c 1.0, CHCl3). See the Supporting Information for the
determination of the relative stereochemistry.
(S)-2-(Naphthalen-2-ylmethoxy)propanenitrile (38).
The general asymmetric hydrocyanation procedure was followed with
37 (55 mg, 0.3 mmol), catalyst 26 (11 mg, 0.0009 mmol), TMSCN
(76 μL, 0.6 mmol), phenol (28 mg, 0.3 mmol), and trifluorotoluene
(3 mL). The crude product was purified by flash chromatography (7%
EtOAc in hexane) to give 38 as a colorless oil (56 mg, 88%). 1H NMR
(400 MHz, CDCl3) δ 7.89−7.84 (m, 4H), 7.54−7.47 (m, 3H), 5.02
(d, 1H, J = 12.0 Hz), 4.71 (d, 1H, J = 12.0 Hz), 4.30 (q, 1H, J = 6.8
Hz), 1.62 (d, 3H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 133.5,
133.5, 133.4, 128.8, 128.2, 127.9, 127.6, 126.6, 126.6, 125.9, 119.0,
72.4, 63.4, 20.0; IR (neat) 3049, 2990, 2919, 1463, 1336, 1136, 863,
824, 748 cm−1; HRMS (EI) m/z calcd for C14H13NO [M]+ 211.0997,
found 211.1007; HPLC (Lux cellulose-3), 65:35 hexane/i-PrOH,
(S)-2-((S)-1-Phenylethoxy)propanenitrile (44).
The general asymmetric cyanation procedure for vinyl ethers was
followed with vinyl ether 14 (59 mg, 0.4 mmol), catalyst 26 (14.6 mg,
0.0012 mmol), TMSCN (101 μL, 0.8 mmol), phenol (37 mg, 0.4 mmol),
and trifluorotoluene (4 mL). The crude product was purified by flash
chromatography (3% EtOAc in hexane) to give two diastereomers
(57 mg, 81%, d.r. = 1.2:1, crude NMR ratio 1.4:1). The faster-eluting
product was the major diastereomer 44. For characterization, see 15.
General Procedure for Asymmetric Cyanide Addition to
Acetals. To a solution of catalyst 26 (0.03 equiv) in anhydrous α,α,α-
trifluorotoluene at room temperature under Ar was added TMSCN.
The reaction mixture was stirred at room temperature for 15 min and
then cooled to −25 °C. A solution of the acetal (1.0 equiv) in tri-
fluorotoluene (0.6 mL) was added to the reaction mixture via a syringe
pump using a 3 mL syringe at a rate of 0.03 mL/h over 20 h. The
reaction mixture was allowed to stir for another 4 h at this temperature
1 mL/min, tmajor = 12.9 min, tminor = 19.3 min, er = 84.5:15.5; [α]D25
−117.5 (c 1.0, CHCl3).
(S)-2-(Benzyloxy)butanenitrile (40).
=
The general asymmetric hydrocyanation procedure was followed with
39 (44 mg, 0.3 mmol), catalyst 26 (11 mg, 0.0009 mmol), TMSCN
(76 μL, 0.6 mmol), phenol (28 mg, 0.3 mmol), and trifluorotoluene
(3 mL). The crude product was purified by flash chromatography (2%
EtOAc in hexane) to give 40 as a colorless oil (39 mg, 74%). 1H NMR
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Article
after the addition was complete. The reaction was then quenched with
Et3N and saturated NaHCO3 solution. The reaction mixture was warmed
to room temperature, extracted with Et2O (2×), dried over Na2SO4, and
concentrated under vacuum. The crude product was purified by flash
chromatography.
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(S)-2-(Benzyloxy)propanenitrile ((S)-2).
The general asymmetric acetal cyanation procedure was followed with
45 (73 mg, 0.3 mmol), catalyst 26 (11 mg, 0.009 mmol, 0.03 equiv),
TMSCN (76 μL, 0.6 mmol), and trifluorotoluene (2.5 mL). The crude
product was purified by flash chromatography (3% EtOAc in hexane)
to give (S)-2 as a colorless oil (41 mg, 85%), er = 82.5:17.5. Spectral
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(S)-2-Methoxy-4-phenylbutanenitrile ((S)-17).
The general asymmetric acetal cyanation procedure was followed with
46 (36 mg, 0.2 mmol), catalyst 26 (7 mg, 0.006 mmol, 0.03 equiv),
TMSCN (100 μL, 0.8 mmol), and trifluorotoluene (2 mL). The crude
product was purified by flash chromatography (4% EtOAc in hexane)
to give (S)-17 as a colorless oil (32 mg, 91%), er = 73:27. Spectral and
HPLC data are consistent with previously reported values.
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atoms, the 6-311G(3df,3pd) basis set was used. A large number of initial
structures were used to initiate the geometry optimizations, and local
minima were confirmed by frequency calculations.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds, HPLC traces
for enantiomeric ratio determinations, methods for determining
product absolute stereochemistry, and coordinates of computa-
tionally derived structures. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: florean@pitt.edu.
(21) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128,
9626.
Notes
(22) (a) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am. Chem. Soc.
2009, 131, 3430. (b) Zhang, Q.-W.; Fan, C.-A.; Zhang, H.-J.; Tu, Y.-
Q.; Zhao, Y.-M.; Gu, P.; Chen, Z.-M. Angew. Chem., Int. Ed. 2009, 48,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
̌
8572. (c) Coric,
́
I.; Vellalath, S.; List, B. J. Am. Chem. Soc. 2010, 132,
́
I.; Muller, S.; List, B. J. Am. Chem. Soc. 2010, 132,
■
̌
8536. (d) Coric,
̈
We thank the National Institutes of Health (P50-GM067082)
(C.L. and P.E.F.) and the National Science Foundation (CHE-
1111235) (X.S.) for generous support of this work. We thank
Professor Ken Jordan (University of Pittsburgh) for a critical
reading of the computational section of the manuscript.
̌
́
17370. (e) Coric, I.; List, B. Nature 2012, 483, 315. (f) Sun, Z.;
Winschel, G. A.; Borovika, A.; Nagorny, P. J. Am. Chem. Soc. 2012,
134, 8074. (g) Hsiao, C.-C.; Liao, H.-H.; Sugiono, E.; Atodiresai, I.;
Rueping, M. Chem.Eur. J. 2013, 19, 9775.
(23) Cui, Y.; Villafane, L. A.; Clausen, D. J.; Floreancig, P. E.
Tetrahedron 2013, 69, 7618.
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