Mukaiyama addition of (trimethylsilyl)acetonitrile to dimethyl acetals mediated by trimethylsilyl trifluoromethanesulfonate

Article abstract of DOI:10.1016/j.tetlet.2017.07.082

(Trimethylsilyl)acetonitrile reacts smoothly with dimethyl acetals in the presence of stoichiometric trimethylsilyl trifluoromethanesulfonate (TMSOTf) to yield β-methoxynitriles. The ideal substrates for this reaction are acetals derived from aromatic aldehydes. Elimination to the corresponding α,β-unsaturated nitriles is observed as the major product in the case of electron-rich acetals. A mechanistic hypothesis that includes isomerization of the silylnitrile to a nucleophilic N-silyl ketene imine is presented.

Full text of DOI:10.1016/j.tetlet.2017.07.082

Accepted Manuscript
Mukaiyama addition of (trimethylsilyl)acetonitrile to dimethyl acetals mediated
by trimethylsilyl trifluoromethanesulfonate
C. Wade Downey, Alice Y.-K. Lee, John R. Goodin, Courtney J. Botelho,
William M. Stith
PII:
S0040-4039(17)30946-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.082
TETL 49164
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
8 June 2017
14 July 2017
24 July 2017
Please cite this article as: Wade Downey, C., Y.-K. Lee, A., Goodin, J.R., Botelho, C.J., Stith, W.M., Mukaiyama
addition of (trimethylsilyl)acetonitrile to dimethyl acetals mediated by trimethylsilyl trifluoromethanesulfonate,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.07.082
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Mukaiyama addition of
trimethylsilyl)acetonitrile to dimethyl
Leave this area blank for abstract info.
(
acetals mediated by trimethylsilyl
trifluoromethanesulfonate
C. Wade Downey, Alice Y.-K. Lee, John R. Goodin, Courtney J. Botelho, and William M. Stith
Department of Chemistry, University of Richmond, Richmond, Virginia 23173, USA

1
Tetrahedron Letters
journal homepage: www.els evier.com
Mukaiyama addition of (trimethylsilyl)acetonitrile to dimethyl acetals mediated
by trimethylsilyl trifluoromethanesulfonate
a
C. Wade Downey ,* Alice Y.-K. Lee , John R. Goodin , Courtney J. Botelho , and William M. Stith
a
a
a
a
a
Department of Chemistry, University of Richmond, 28 Westhampton Way, Richmond, VA 23173, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
(Trimethylsilyl)acetonitrile reacts smoothly with dimethyl acetals in the presence of
stoichiometric trimethylsilyl trifluoromethanesulfonate (TMSOTf) to yield β-methoxynitriles.
The ideal substrates for this reaction are acetals derived from aromatic aldehydes. Elimination
to the corresponding α,β-unsaturated nitriles is observed as the major product in the case of
electron-rich acetals. A mechanistic hypothesis that includes isomerization of the silylnitrile to a
nucleophilic N-silyl ketene imine is presented.
Received in revised form
Accepted
Available online
Keywords:
2
009 Elsevier Ltd. All rights reserved.
Silicon Lewis acids;
Lewis acid catalysis;
Acetal reactions;
Silyl nitriles;
Methyl ethers
*Corresponding author. Tel: +1 804 484 1557; fax: +1 804 287 1897; e-mail address: wdowney@richmond.edu

2
Tetrahedron Letters
10
conversion to the desired product (entry 7).
Accordingly, we
chose to focus on TMSOTf as the Lewis acid of choice for this
transformation.
Aldol reactions of nitrile-derived enolate analogs have typically
been carried out under very basic conditions and are often prone to
retro-aldol reaction or dehydration to yield the α,β-unsaturated
nitrile. When nitriles are temporarily converted to α-silylnitriles,
Table 1
Optimization
1
however, addition to aldehydes is known to proceed under Lewis
basic conditions. Silyl transfer to the nascent aldolate produces a
silyl ether not prone to reversion or elimination (eq 1). A variety of
Lewis basic catalysts have proven capable of mediating this
2
3
4
5
reaction, including cyanide, fluoride, acetate, DMSO, and
6
phosphine derivatives. Aldol reactions of the related silyl ketene
7
imine nucleophiles have been rendered asymmetric by Denmark,
and certain silyl ketene imines have been generated in situ from α-
aryl nitriles by Yoshimura and Tanino.
8
We speculated that by replacement of the aldehyde with a
dimethyl acetal and introduction of a Lewis acid, an oxocarbenium
ion could be generated that would be attacked by the mild
silylnitrile nucleophile. Our previous experience with the use of
trimethylsilyl trifluoromethanesulfonate (TMSOTf) to activate
9
dimethyl acetals suggested the investigation of its utility in this
context. We now report that TMSOTf efficiently mediates the
condensation of (trimethylsilyl)acetonitrile with dimethyl acetals in
acetonitrile to provide β-methoxynitriles.
a
Conditions
A:
0.20
mmol
acetal,
0.20
mmol
(
trimethylsilyl)acetonitrile, 0.20 mmol TMOSTf, solvent, 1 h.
Conditions B: 0.22 mmol acetal, 0.24 mol catalyst, 0.16 mmol
trimethylsilyl)acetonitrile, 250 µL solvent, 1 h.
(
We began our study of the reaction of (trimethylsilyl)acetonitrile
with dimethyl acetals under reaction conditions very similar to
those reported by Mukaiyama for the acetate-catalyzed aldol
b
1
Determined by H NMR spectroscopy of the unpurified reaction
mixture
4
reactions of α-silylnitriles with aldehydes. In addition to the
precedented strategy of employing a nucleophilic catalyst to
activate the silylnitrile, we added the Lewis acidic TMSOTf to
activate the acetal. We found early success with the combination
TMSOTf and tetrabutylammonium acetate in toluene, but control
experiments quickly showed that only the TMSOTf was necessary
to mediate the reaction. To our surprise, a search of the literature
revealed no similar Lewis acid-mediated additions of silylnitriles to
acetals. Accordingly, we surveyed the ability of several common,
mild Lewis acids to facilitate this transformation.
Once the optimal solvent and Lewis acid were identified, the
reaction time was extended to 16 h to achieve full conversion with
the benzaldehyde dimethyl acetal substrate. When the reaction was
performed on a 1.0 mmol scale, 82% isolated yield of desired
methyl ether 1a was achieved. A description of the further scope of
this reaction is illustrated in Table 2. Acetals derived from
halobenzaldehydes were especially effective (entries 2-4). Tolyl-
substituted product 1e (entry 5), however, suffered a slightly
depressed yield because elimination to the cinnamonitrile
derivative proved facile under the reaction conditions and during
chromatography. Indeed, when product 1e was purified and
resubjected to TMSOTf in acetonitrile for a further 24 h, 43%
In the first round of experiments, 25 mol% catalyst (LiClO
MgBr •OEt , ZnBr , Yb(OTf) , In(OTf) , Cu(OAc) , BF •OEt , or
TMSOTf) was added to a solution of (trimethylsilyl)acetonitrile
and benzaldehyde dimethyl acetal in CH Cl After 1 h, only
4
,
2
2
2
3
3
2
3
2
11
2
2
.
conversion to the cinnamonitrile was observed.
On the other
TMSOTf showed any reactivity (8% conv). Intrigued by the
apparently unique reactivity of TMSOTf, we conducted further
optimization experiments under stoichiometric conditions (Table
hand, electron-poor acetals delivered the desired methyl ether
products 1 quite smoothly (Table 1, entries 6-7), and bulky
aromatic groups were also well tolerated (entries 8-9). Although
unbranched aliphatic acetals (e.g., propionaldehyde dimethyl acetal,
acetaldehyde dimethyl acetal) afforded no desired products under
these conditions, the branched cyclohexyl derivative provided 25%
yield (entry 10).
1). When the amount of TMSOTf was increased to 1.2 equiv, an
increase in reactivity was observed after 1 h in CH Cl (33% conv,
2
2
entry 1). A survey of common reaction solvents showed that
acetonitrile was optimal, providing 62% conv after 1 h (entry 5).
At this point, the original set of Lewis acids was re-tested under
stoichiometric conditions (entries 6-13). Again, most of the
potential catalysts effected no desired reactivity. Other than
3 2
TMSOTf, only BF •OEt showed any success, providing 23%

3
With the scope and limitations of the reaction thus established,
we performed preliminary experiments toward elucidating the
mechanism of this interesting reaction. Any compelling
Table 2
Reaction scope
mechanism must include some rationale to explain why TMSOTf is
so much more effective than other Lewis acids, as well as an
explanation for how C-alkylation of the nitrile occurs. Our
proposed mechanistic scheme is outlined in Figure 1. Activation of
dimethyl acetals with TMSOTf is well documented to supply the
13
oxocarbenium electrophile.
Of greater interest here is the
activation of the (trimethylsilyl)acetonitrile, which is highlighted in
red. Coordination of a TMS group to the nitrile provides a bis-
silylated cation prone to desilylation at either of two positions.
Desilylation at carbon may be carried out by one of the weak Lewis
bases in solution, such as the acetonitrile solvent, the
trifluoromethanesulfonate anion, or the TMSOMe generated by the
breakdown of the dimethyl acetal. This process generates the key
N-silylated ketene imine, an intermediate not easily accessible from
(trimethylsilyl)acetonitrile with metallic or protic Lewis acids.
Mukaiyama addition of the silyl ketene imine to the oxocarbenium
14
ion and silyl transfer then provides the final product.
Figure 1. Proposed Mechanistic Scheme
a
Reaction conditions: 1.0 mmol acetal, 1.2 mmol TMSOTf, 1.4
mmol (trimethylsilyl)acetonitrile, 5 mL MeCN, 16 h, rt.
b
Isolated yield after chromatography
When the strongly electron-rich anisyl derivative was used,
cinnamonitrile 2 was observed to be the major reaction product,
even at shorter reaction times (eq 3). Accordingly, the reaction
conditions for this specific substrate were re-optimized to favor
α,β-unsaturated product 2. When the reaction was stirred at reflux
for 1 h, an 87% yield of the cinnamonitrile (85:15 trans:cis) was
obtained. Other electron-rich acetals (2-furyl, 2-thiophenyl),
however, decomposed under all reaction conditions and yielded no
identifiable products.
Although this mechanism accounts for the regiochemistry of the
reaction (i.e., C-alkylation of the (trimethylsilyl)acetonitrile), the
intermediacy of the silyl ketene imine remains unconfirmed. When
(
3
trimethylsilyl)acetonitrile is mixed with TMSOTf in CD CN, no
Despite the apparent simplicity β-methoxynitriles 1a-j, to our
knowledge only products 1a and 1i have ever been synthesized in
the literature and even in those cases no spectral data was
reported, which demonstrates the importance of our new
methodology. Accordingly, efforts were made to extend the
1
silyl ketene imine is evident by H or C NMR spectroscopy.
13
Direct activation of the silylnitrile at carbon by a Lewis base in
solution cannot be ruled out and would be in accord with
previously reported reactions.
bases present under our conditions appear to be as potent as those
reported to activate similar silylnitriles in the absence of TMSOTf
12
2,3,4,5,6
Nonetheless, none of the Lewis
reaction scope to related species.
For example,
trimethylsilyl)acetonitrile was replaced with 3-phenyl-2-
trimethylsilyl)propionitrile (3) and moderate reactivity was
(
(
-
-
-
3
(i.e., F , NC , AcO , R P). Therefore, we propose that preliminary
activation of the silylnitrile by coordination of a TMS group at
nitrogen prior to desilylation at carbon is the most likely course of
the reaction. Alternatively, the (trimethylsilyl)acetonitrile nitrogen
might directly attack the oxocarbenium ion, temporarily forming an
N-(alkoxy)alkylated ketene imine that could attack another
oxocarbenium ion and generate the desired product (eq 4). Such a
pathway, however, would be accessible to all Lewis acids and not
just TMSOTf, which does not match the reactivity profile
documented in Table 1.
observed (50-80% conv under various conditions). Unfortunately,
the desired β-methoxynitrile could not be separated
chromatographically from unreacted nitrile 3 or the major
byproduct, the desilylated parent nitrile (3-phenylpropionitrile). In
another series of experiments, the acetal was replaced with either
cyclohexanone dimethyl ketal or trimethyl orthobenzoate, but only
hydrolysis products were observed when they were treated with
(trimethylsilyl)acetonitrile and TMSOTf.

4
Tetrahedron Letters
Supplementary data associated with this article can found, in the
online version, at xxx. These data include MOL files of the most
important compounds described in this article.
In addition, we have confirmed that the silylnitrile is a necessary
References and notes
component of the reaction mixture: subjection of the acetal to
TMSOTf in acetonitrile in the absence of the preformed α-
silylnitrile yields no methyl ether products. It is also conceivable
that the reaction is catalyzed by trace amounts of
trifluoromethanesulfonic acid (TfOH) in the mixture, but when the
TMSOTf was premixed with a drop of water in acetonitrile prior to
addition of the acetal and (trimethylsilyl)acetonitrile, which would
presumably generate TfOH in situ, only hydrolysis of the acetal and
1.
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2
O was observed. The same result was
O) or
2
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TMSOTf. To further investigate the possibility of catalysis by
TfOH, a mild base was added to the reaction mixture to neutralize
any Brønsted acids present. Accordingly, 25 mol% of the mild
amine base 2,6-lutidine was added to the standard reaction
conditions and 100% conversion to the β-methoxynitrile was still
observed. When the amount of 2,6-lutidine was raised to 100
mol%, 74% conversion to products was observed, but the products
consisted of a complex mixture including elimination products
4
5
.
.
1
508-1509.
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7
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(trans:cis:desired = 2:1:1). Catalysis under these conditions by an
ammonium salt like lutidinium triflate is highly unlikely: No
reaction other than acetal hydrolysis was observed when
pyridinium p-toluenesulfonate (PPTS) was used in place of
TMSOTf. Taken as a whole, these results strongly suggest that
TfOH is not an active participant in the reaction.
8.
(a) Yoshimura, F.; Abe, T.; Tanino, K. Synlett 2014, 1863-1868. (b)
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(a) Downey, C. W.; Johnson, M. W.; Tracy, K. J. J. Org. Chem.
In conclusion, we have discovered a new reaction between
trimethylsilyl)acetonitrile and dimethyl acetals to yield β-
9
.
(
2
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methoxynitriles, providing a series of products not previously
synthesized in the literature. The reaction is especially effective
with acetals derived from benzaldehydes, and may proceed through
a silyl ketene imine generated in situ. Although the course of our
experiments led first to acetal electrophiles, future work targets
additions to other electrophiles. Indeed, preliminary experiments
show that the addition of (trimethylsilyl)acetonitrile to
benzaldehyde (eq 5) proceeds smoothly under reaction conditions
otherwise identical to the acetal chemistry described above. We
look forward to reporting on this and further reactions in due
course.
2
Obenschain, D. C.; Halliday, E.; Rague, J. T.; Confair, D. N.
Tetrahedron Lett. 2014, 55, 5213-5215.
1
1
3 2
0. Conceivably, BF •OEt may catalyze the reaction by acting as either
a Lewis acid or a fluoride source. For ample evidence of fluoride
catalysis of related reactions, see reference 3.
1
1. An additional byproduct that gives H NMR spectra consistent with
insertion of acetonitrile into the C-O bond of product 1e is also
observed. This byproduct has been tentatively identified as a methyl
imidate, but characterization is incomplete.
1
2. For a two-step synthesis of compound 1a from α-
cyanoacetophenone, see (a) Coady, T. M.; Coffey, L. V.; O’Reilly,
C.; Lennon, C. M. Eur. J. Org. Chem. 2015, 1108-116. For a two-
step synthesis of compound 1i from 2-naphthaldehyde, see: (b)
Ellingboe, J. W.; Lombardo, L. J.; Alessi, T. R.; Nguyen, T. T.;
Guzzo, F.; Guinosso, C. J.; Bullington, J.; Browne, E. N. C.; Bagli, J.
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2
485-2493.
1
1
3. For a seminal reference, see: (a) Noyori, R.; Murata, S.; Suzuki, M.
Tetrahedron Lett. 1981, 37, 3899-3910.
4. For examples of Mukaiyama additions of silyl ketene imines to
aldehydes, anhydrides, and nitrones, see references 7 and 8.
Acknowledgments
We thank the National Science Foundation RUI program (CHE-
057591) for funding. We thank the Donors of the American
1
Chemical Society Petroleum Research Fund for partial support of
this research (55852-UR1). W.M.S. thanks HHMI for funding a
summer fellowship. We gratefully acknowledge Prof. Kristine
Nolin for helpful discussions.
Supplementary data