CuH-Catalyzed Asymmetric Reduction of α,β-Unsaturated Carboxylic Acids to β-Chiral Aldehydes

Article abstract of DOI:10.1021/jacs.7b12260

The copper hydride (CuH)-catalyzed enantioselective reduction of α,β-unsaturated carboxylic acids to saturated aldehydes is reported. This protocol provides a new method to access a variety of β-chiral aldehydes in good yields, with high levels of enantioselectivity and broad functional group tolerance. A reaction pathway involving a ketene intermediate is proposed based on preliminary mechanistic studies and density functional theory calculations.

Full text of DOI:10.1021/jacs.7b12260

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Communication
CuH-Catalyzed Asymmetric Reduction of #,#-
Unsaturated Carboxylic Acids to #-Chiral Aldehydes
Yujing Zhou, Jeffrey S Bandar, Richard Y. Liu, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 28 Dec 2017
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CuH-Catalyzed Asymmetric Reduction of α,β-Unsaturated
Carboxylic Acids to β-Chiral Aldehydes
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Yujing Zhou, Jeffrey S. Bandar, Richard Y. Liu, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Supporting Information Placeholder
(a) General approaches to access β-chiral aldehydes
ABSTRACT: The copper hydride (CuH)ꢀcatalyzed enanꢀ
tioselective reduction of α,βꢀunsaturated carboxylic acꢀ
R’
O
reduction
R’
*
O
R’
isomerization
ids to saturated aldehydes is reported. This protocol proꢀ
vides a new method to access a variety of βꢀchiral aldeꢀ
hydes in good yields, with high levels of enantioselectivꢀ
ity and broad functional group tolerance. A reaction
pathway involving a ketene intermediate is proposed
based on preliminary mechanistic studies and density
functional theory calculations.
R
R
H
H
R
H
R
OH
O
conjugate
addition
β
-chiral aldehydes
(b) Conversion of α,β-unsaturated acids to aldehydes by hydroformylation
O
NH2
NH2
R’
O
R’
O
[Rh], Ligand
N
N
R
OH
R
H
13 bar CO/H2
Ligand
PPh2
(c) α,β-Unsaturated acid reduction to β-chiral aldehyde (this work)
Aldehydes featuring βꢀstereogenic centers represent a
class of important building blocks for the synthesis of
various natural products and pharmaceuticals.1 Due to
their utility, numerous strategies for their preparation
have been devised, including the asymmetric transferꢀ
hydrogenation of unsaturated aldehydes,2 the conjugate
addition of nucleophilic reagents to enals,3, 4 and the
enantioselective isomerization of allylic alcohols (Figure
1a).5 As an alternative, the direct conversion of α,βꢀ
unsaturated carboxylic acids to βꢀchiral aldehydes would
be valuable due to the ready accessibility and stability of
the starting acids. An elegant catalytic reduction process
of unsaturated acids to racemic saturated aldehydes has
been reported by Breit,6 which proceeds through the
consecutive Rhꢀcatalyzed hydroformylation and decarꢀ
boxylation reactions (Figure 1b). Herein we report a
CuHꢀcatalyzed asymmetric reduction protocol of α,βꢀ
unsaturated carboxylic acids as an approach to access
enantiomerically enriched aldehydes (Figure 1c).
R’ OSiR3
R’
O
L*CuH
R3SiH
R’
*
O
*
Ar
H
Ar
OH
Ar
H
R’ = alkyl, aryl
via silyl enol ether
Figure 1. (a) General Access to βꢀChiral Aldehydes (b)
Racemic and (c) Asymmetric Transformation from α,βꢀ
Unsaturated Carboxylic Acids to Saturated Aldehydes
(This work)
We recently disclosed an asymmetric olefin hydroacꢀ
ylation reaction involving the direct coupling of α,βꢀ
unsaturated acids with aryl alkenes to form αꢀchiral keꢀ
tones.9 During this study, when we attempted to couple a
trisubstituted alkene with crotonic acid, no desired keꢀ
tone product was generated. Instead, the silyl enol ether
1
of nꢀbutanal was observed by H NMR (Scheme 1a).
When the alkene was excluded, further experiments
demonstrated that this process is general for a wide
range of unsaturated acids. Based on this and our prior
results, we reasoned that for substrates with two differꢀ
ent βꢀsubstituents, we could exploit this reduction proꢀ
cess to access βꢀchiral aldehydes with high levels of enꢀ
antiopurity.
Over the past two decades, the CuHꢀcatalyzed asymꢀ
metric 1,4ꢀreduction of α,βꢀunsaturated carbonyl comꢀ
pounds has been extensively developed as a method to
deliver optically active ketones and esters.7 A hallmark
of this chemistry is the 1,4ꢀchemoselectivity provided by
bisphosphineꢀligated CuH catalysts, which preserves the
oxidation state at the carbonyl carbon.8
Scheme 1. (a) Discovery and (b) Model Reaction of Unꢀ
saturated Acid Reduction Protocola, 10, 11
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a All yields represent average isolated yields of two runs,
performed with 1 mmol of acid. b 4 mol% Cu(OAc)2 and
1
2
4.4 mol% (S, S)ꢀPhꢀBPE were used.
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Having identified suitable reduction conditions, we
next examined the scope of this asymmetric reduction
protocol. As shown in Table 1, a variety of βꢀalkyl, βꢀ
aryl disubstituted unsaturated carboxylic acids were effiꢀ
ciently reduced to the aldehydes in good yields, and the
observed enantioselectivity is uniformly high regardless
of the electronic properties of the substituents. A diverse
set of functional groups, including aryl chlorides (2b),
heteroaryl bromides (2g), and thioethers (2c), were tolꢀ
erated. Substrates containing heterocycles, such as pyriꢀ
dine (2f), pyrazole (2g), and benzofuran (2h), are all
readily converted under the current conditions. In addiꢀ
tion to substrates bearing a methyl βꢀsubstituent, those
with more stericallyꢀdemanding ones such as ethyl (2i),
cyclopropyl (2j), functionalized propyl (2l, 2m), Nꢀ
pyrrolyl (2n) groups, and an exocyclic double bond (2k),
were also successfully converted to the aldehydes with
similarly high levels of enantioselectivity.
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a
(S,S)ꢀPhꢀBPE
diphenylphospholano)ethane.
=
1,2ꢀBis((2S,5S)ꢀ2,5ꢀ
We initiated our study of the asymmetric acid reducꢀ
tion reaction by subjecting (E)ꢀ3ꢀphenylbutꢀ2ꢀenoic acid
(1a) to conditions similar to those used for the previousꢀ
ly reported hydroacylation reaction (4 mol% catalyst).
The silyl enol ether shown was formed in 73% yield (1H
NMR). After workꢀup with NH4F, the corresponding
chiral aldehyde 2a was obtained in 86% ee (Scheme 1b).
Optimization of the reaction temperature and solvent
revealed that increased yield and enantiomeric excess
could be achieved when the reaction was run at 40 °C in
toluene. We also found that for reactions conducted on a
1 mmol scale, 1 mol% catalyst was sufficient to obtain
the desired βꢀchiral aldehyde without diminished yield
or enantioselectivity.
The reactivity of β,βꢀdiaryl acrylic acids was also inꢀ
vestigated (Table 2). When (E)ꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀ
phenylacrylic acid (1o) was subjected to the aboveꢀ
described reduction conditions, the desired aldehyde was
formed in high yield, but with a moderate level of enanꢀ
tioselectivity (70% ee). We reasoned that this might be
due to poor differentiation of the two similar aryl subꢀ
stituents by the ligand PhꢀBPE. We thus reꢀexamined a
range of common chiral ligands. Of these, the Josiphosꢀ
type ligand 3 provided the best results when the reaction
was conducted at room temperature.14 Under the new
reaction conditions, acids containing halides (2p, 2r), a
heterocycle (2q), and an orthoꢀsubstituted arene (2r),
were all efficiently converted to 3,3ꢀdiarylpropanals in
high yields and with excellent enantioselectivity.
Table 1. Substrate Scope for the Reduction of βꢀAlkyl, βꢀ
Aryl Unsaturated Carboxylic Acids.a, 12, 13
Table 2. Examples of the Asymmetric Reduction of β,βꢀ
Diaryl Unsaturated Carboxylic Acidsa
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Yields represent average isolated yields of two runs,
a
silyl ester, 1,4ꢀreduction would result in the formation of
a Cu enolate,16 from which a βꢀalkoxide elimination
could generate a ketene intermediate. Rapid interception
of this ketene by L*CuH followed by σꢀbond metathesis
with a hydrosilane would afford the silyl enol ether and
regenerate the CuH catalyst. A simple stereochemical
model for ketene reduction indeed predicts a preference
for the formation of the Z silyl enol ether isomer in order
to minimize steric interactions in the transition state.
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performed with 1 mmol of acid.
We next set out to elucidate the mechanism of this
new reduction process. One possibility is proposed in
Scheme 2a. First, the carboxylic acid is silylated in the
presence of CuH catalyst and silane. Subsequent 1,2ꢀ
reduction of the silyl ester would give an α,βꢀunsaturated
aldehyde, which could be further reduced to silyl enol
ether by the L*CuH species. In order to test this hypothꢀ
esis, the corresponding unsaturated aldehyde of 1a was
prepared and subjected to the standard reaction condiꢀ
tions (Scheme 2b). In contrast to the 18:1 Z/E ratio of
silyl enol ether produced directly from the acid, the reꢀ
duction of the aldehyde favored the formation of E isoꢀ
mer in <1:20 Z/E ratio. This result rules out the inꢀ
volvement of this unsaturated aldehyde as an intermediꢀ
ate.
9
Density functional theory (DFT) calculations indicated
that the ketene pathway is energetically possible, with
comparable barriers for the initial hydrocupration of
silyl ester (18.2 kcal/mol ) and the collapse of the Cu
enolate to release the ketene (16.9 kcal/mol, see the
Supporting Information for details). Furthermore, the
reduction reaction was performed on a series of unsatuꢀ
rated carboxylic acids, and the Z/E ratio of silyl enol
ethers was measured by 1H NMR spectroscopy (Scheme
2d). These values closely match the computationally
predicted ratios for ketene reduction by L*CuH, providꢀ
ing further evidence for the presence of this ketene inꢀ
termediate in the reaction mechanism17, 18 (see the Supꢀ
porting Information for details). Thus far, we have not
been able to directly observe a ketene intermediate, preꢀ
sumably due to its expected high reactivity with L*CuH.
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Scheme 2. Proposed Mechanisms and Preliminary Mechaꢀ
nistic Studies
(a) Mechanism involving an α,β-unsaturated aldehyde intermediate
R’
O
L*CuH, R3SiH
R’
O
L*CuH, R3SiH
Ar
OSiR3
R'
silylation
1,2-reduction
Ar
OH
H
R’
O
L*CuH, R3SiH
1,4-reduction
Ar
OSiR3
Ar
H
Finally, the synthetic utility of this transformation is
demonstrated via a oneꢀpot reductive amination reaction
starting from carboxylic acids (Scheme 3). Several highꢀ
ly enantioenriched amines with γꢀstereocenters were
prepared in good yield, further highlighting the applicaꢀ
tion of our method to access interesting compounds.
(b) CuH reduction of α,β-unsaturated acid and aldehyde
Me OSiR3
*
L*CuH
Me
O
X = OH, Z/E = 18:1
X = H, Z/E < 1:20
DMMS, THF
Ph
Ph
X
(c) Alternative mechanism involving a ketene intermediate
R’
O
L*CuH
Scheme 3. Oneꢀpot Transformation from α, βꢀUnsaturated
Carboxylic Acids to Chiral Aminesa
Ar
OSiR3
R3SiH
( from the silylation of acids)
1,4-reduction
L*CuOSiR3
CuL*
R’
Ar
O
OSiR3
R’
O
C
L*CuH, R3SiH
R’ OSiR3
H
ketene reduction
Ar
Ar
(d) Theoretical studies of CuH catalyzed ketene reduction
a
R’
O
R1
R2
R1
R2
Reactions were conducted on 0.50 mmol scale. See the
O[Si]
L*CuH
L*CuH
O
R
OH
Supporting Information for detailed conditions.
predicted
observed
R2
In conclusion, we have developed a new asymmetric
reduction process that transforms α,βꢀunsaturated carꢀ
boxylic acids to saturated aldehydes. βꢀchiral aldehydes
with a variety of substitution patterns and functional
groups can be accessed from readily available starting
materials in an efficient process (1 mol% catalyst). Deꢀ
tailed mechanistic studies and the development of other
CuHꢀcatalyzed reactions involving carboxylic acids are
ongoing.
R1 R2
observed E/Z
predicted E/Z
disfavored
(E-isomer)
H
CuL*
C
Et
iPr
nBu
iBu
Et
H
H
1:6
1:14
1:7
1:6
< 1:20
1:6
O
RL
H
C
favored
(Z-isomer)
H
1:10
1:2.4
1:9
RS
Me
H
CuL*
1:2
Based on the unusual Zꢀpreference observed in this
reduction reaction, as well as previous studies of CuH
chemistry,7a,15 we postulated an alternative mechanism,
shown in Scheme 2c. Instead of 1,2ꢀreduction of the
ASSOCIATED CONTENT
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Page 4 of 6
Laquidara, J. M.; Sowa, J. R. Angew. Chem., Int. Ed. 2012, 51, 2106.
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website.
Experimental procedures and characterization data for all
compounds (PDF).
(h) Arai, N.; Sato, K.; Azuma, K.; Ohkuma, T. Angew. Chem., Int. Ed.
2012, 51, 12786. (i) Larionov, E.; Lin, L.; Guénée, L.; Mazet, C. J.
Am. Chem. Soc. 2014, 136, 16882.
1
2
3
4
5
6
7
8
(6) (a) Šmejkal, T.; Breit, B. Angew. Chem., Int. Ed. 2008, 47, 3946.
(b) Diab, L.; Gellrich, U.; Breit, B. Chem. Commun. 2013, 49, 9737.
(7) For reviews and selected examples, see: (a) Deutsch, C.; Krause,
N.; Lipshutz, B. H. Chem. Rev. 2008, 108, 2916. (b) Lipshutz, B. H.
Synlett 2009, 4, 0509. (c) Appella, D. H.; Moritani, Y.; Shintani, R.;
Ferreira, E. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9473.
(d) Moritani, Y.; Appella, D. H.; Jurkauskas, V.; Buchwald, S. L. J.
Am. Chem. Soc. 2000, 122, 6797. (e) Lipshutz, B. H.; Servesko, J. M.
Angew. Chem., Int. Ed. 2003, 42, 4789. (f) Hughes, G.; Kimura, M.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11253. (g) Lipshutz, B.
H.; Servesko, J. M.; Taft, B. R. J. Am. Chem. Soc. 2004, 126, 8352.
(h) Lipshutz, B. H.; Servesko, J. M.; Petersen, T. B.; Papa, P. P.; Lovꢀ
er, A. A. Org. Lett. 2004, 6, 1273.
(8) For examples of chemoselective 1, 2ꢀreduction of α,βꢀunsaturated
carbonyl compounds, see: (a) Moser, R.; Bošković, Ž. V.; Crowe, C.
S.; Lipshutz, B. H. J. Am. Chem. Soc. 2010, 132, 7852. (b) Voigtritter,
K. R.; Isley, N. A.; Moser, R.; Aue D. H.; Lipshutz, B. H. Tetrahe-
dron 2012, 68, 3410. (c) Shi, S.ꢀL.; Wong, Z. L.; Buchwald, S. L.
Nature 2016, 532, 353. (d) Malkov, A. V. Angew. Chem., Int. Ed.
2010, 49, 9814. (e) Gallagher, B. D.; Taft, B. R.; Lipshutz, B. H. Org.
Lett. 2009, 11, 5374. (f) Waidmann, C. R.; Silks, L. A.; Wu, R.; Gorꢀ
don, J. C. Catal. Sci. Technol. 2013, 3, 1240.
AUTHOR INFORMATION
Corresponding Author
*sbuchwal@mit.edu
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
Research reported in this publication was supported by the
National Institutes of Health (GM46059, GM122483). We
also thank the NIH for a supplemental grant for the purꢀ
chase of supercritical fluid chromatography (SFC) equipꢀ
ment (GM058160ꢀ17S1) and for a postdoctoral fellowship
for J. S. B. (GM112197). We acknowledge Michael Gribble
for helpful discussion on reaction mechanisms. We thank
Dr. Nicholas White for advice on this manuscript.
REFERENCES
(9) Zhou, Y.; Bandar, J. S.; Buchwald, S. L. J. Am. Chem. Soc. 2017,
139, 8126.
(1) (a) Brossi, A.; Grethe, G.; Teltel, S. Wildman, W. C.; Bailey, D.
T. J. Org. Chem. 1970, 35, 1100. (b) Welch, W. M.; Kraska, A. R.;
Sarges, R.; Koe, B. K. J. Med. Chem. 1984, 27, 1508. (c) Hyttel, J.;
Larsen, J. J. J. Neurochem. 1985, 44, 1615. (d) Nilvebrant, L.; Anꢀ
dersson, K.ꢀE.; Gillberg, P.ꢀG.; Stahl, M.; Sparf, B. Eur. J. Pharma-
col. 1997, 327, 195. (e) Andersson, P. G.; Schink, H. E.; Österlund,
K. J. Org. Chem. 1998, 63, 8067. (f) C. Selenski, T. R. R. Pettus, J.
Org. Chem. 2004, 69, 9196.
(2) For reviews and selected examples, see: (a) Zheng, C.; You, S.ꢀL.
Chem. Soc. Rev. 2012, 41, 2498. (b) Phillips, A. M. F.; Pombeiro, A.
J. L. Org. Biomol. Chem. 2017, 15, 2307. (c) Ouellet, S. G.; Tuttle, J.
B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32. (d) Yang,
J. W.; Hechavarria Fonseca, M. T.; List, B. Angew. Chem., Int. Ed.
2004, 43, 6660. (e) Mayer, S.; List, B. Angew. Chem., Int. Ed. 2006,
45, 4193.
(3) For selected examples of transitionꢀmetalꢀcatalyzed asymmetric
conjugated addition reactions, see: (a) Itooka, R.; Iguchi, Y.; Miyaura,
N. J. Org. Chem. 2003, 68, 6000. (b) Paquin, J.ꢀF.; Defieber, C.; Steꢀ
phenson, C. R. J.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127,
10850. (c) Hayashi, T.; Tokunaga, N.; Okamoto, K.; Shintani, R.
Chem. Lett. 2005, 34, 1480. (d) Bräse, S.; Höfener, S. Angew. Chem.,
Int. Ed. 2005, 44, 7879. (e) Nishimura, T.; Sawano, T.; Hayashi, T.
Angew. Chem., Int. Ed. 2009, 48, 8057. (f) Ibrahem, I.; Ma, G.;
Afewerki, S.; Córdova, A. Angew. Chem., Int. Ed. 2013, 52, 878.
(4) For selected examples of organocatalysis catalyzed asymmetric
conjugated addition, see: (a) Paras, N. A.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2002, 124, 7894. (b) Ooi, T.; Doda, K.; Maruoka, K.
J. Am. Chem. Soc. 2003, 125, 9022. (c) Wang, W.; Li, H.; Wang, J.
Org. Lett. 2005, 7, 1637. (d) Wu, F.; Li, H.; Hong, R.; Khan, J.; Liu,
X.; Deng, L. Angew. Chem., Int. Ed. 2006, 45, 4301. (e) Brandau, S.;
Landa, A.; Franzén, J.; Marigo, M.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2006, 45, 4305. (f) Chen, Y. K.; Yoshida, M.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2006, 128, 9328. (g) Lee, S.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2007, 129, 15438. (h) Akagawa, K.; Kudo,
K. Angew. Chem., Int. Ed. 2012, 51, 12786.
(10) For detailed information about the safe handling of diꢀ
methoxy(methyl)silane (DMMS), see the Supporting Information.
(11) For applications of BPE ligands, see: (a) Burk, M. J. Acc. Chem.
Res. 2000, 33, 363. (b) Lennon, I. C.; Pilkington, C. J. Synthesis 2003,
11, 1639. Also see reference 15 and references therein.
(12) β,βꢀDialkyl unsaturated carboxylic acids provided less satisfactoꢀ
ry results under the current conditions. When geranic acid was used,
the corresponding aldehyde was isolated in 58% yield, with 70% ee.
(13) The reactivity of αꢀsubstituted unsaturated acids was also examꢀ
ined. For instance, when the reduction reaction was conducted with
(E)ꢀ2ꢀmethylꢀ3ꢀphenylacrylic acid, the corresponding silyl enol ether
was obtained in 30% NMR yield, with 1.4:1 Z/E ratio.
(14) For applications of Josiphos ligands, see: (a) Blaser, H.ꢀU.;
Brieden, W.; Pugin, B.; Spindler, F.; Studer, M.; Togni, A. Top.
Catal. 2002, 19, 3. (b) Blaser, H.ꢀU.; Pugin, B.; Spindler, F.; Mejia,
E.; Togni, A. Josiphos Ligands: From Discovery to Technical Appliꢀ
cation; In Privileged Chiral Ligands and Catalyst. Zhou, Q.ꢀL., Eds.;
WileyꢀVCH: Weinheim, Germany, 2011; pp 93–136; and references
therein.
(15) For recent reviews and mechanistic studies, see: (a) Pirnot, M.
T.; Wang, Y.ꢀM.; Buchwald, S. L. Angew. Chem., Int. Ed. 2016, 55,
48. (b) Mohr, J.; Oestreich, M. Angew. Chem., Int. Ed. 2016, 55,
12148. (c) Jordan, A. J.; Lalic, G.; Sadighi, J. P. Chem. Rev. 2016,
116, 8318. (d) Nguyen, K. D.; Park, B. Y.; Luong, T.; Sato, H.; Garꢀ
za, V. J.; Krische, M. J. Science 2016, 354, 300. (e) Bandar, J. S.;
Pirnot, M. T.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 14812.
(f) Issenhuth, J.ꢀT.; Notter, F.ꢀP.; Dagorne, S.; Dedieu, A.; Belleminꢀ
Laponnaz, S. Eur. J. Inorg. Chem. 2010, 2010, 529. (g) Tobisch, S.
Chem. Eur. J. 2016, 22, 8290. (h) Dang, L.; Zhao, H.; Lin, Z.;
Marder, T. B. Organometallics 2007, 26, 2824. (i) Xi, Y.; Hartwig, J.
F. J. Am. Chem. Soc. 2017, 139, 12758. (j) Lee, J.; Radomkit, S.;
Torker, S.; del Pozo, J.; Hoveyda, A. H. Nat. Chem. 2018, 10, 99.
(16) DFT calculations indicate that 1,2ꢀhydrocupration to form the Cꢀ
enolate is more facile than 1,4ꢀhydrocupration to form the Oꢀenolate.
However, DFT also predicts that the Cꢀ and Oꢀenolate species are
similar in energy and can interconvert quickly.
(5) For reviews and selected examples, see: (a) Cahard, D.; Gaillard,
S.; Renaud, J.ꢀL. Tetrahedron Lett. 2015, 56, 6159. (b) Li, H.; Mazet,
C. Acc. Chem. Res. 2016, 49, 1232. (c) Tanaka, K.; Qiao, S.; Tobisu,
M.; Lo, M. M. C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 9870. (d)
Doppiu, A.; Salzer, A. Eur. J. Inorg. Chem. 2004, 2244. (e) Mantilli,
L.; Gérard, D.; Torche, S.; Besnard, C.; Mazet, C. Angew. Chem., Int.
Ed. 2009, 48, 5413. (f) Quintard, A.; Alexakis, A.; Mazet, C. Angew.
Chem., Int. Ed. 2011, 50, 2354. (g) Wu, R.; Beauchamps, M. G.;
(17) A disilyl ketene acetal species may also be a reactive intermediꢀ
ate. However, the barrier to hydrocupration of this acetal is predicted
to be significantly higher than for alternative pathways. Calculations
also indicate that subsequent elimination will preferentially afford the
E silyl enol ether product. See the Supporting Information for details.
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(18) Methylphenyl ketene was subjected to the standard reduction
conditions. The corresponding silyl enol ether was observed by H
NMR (10% yield). See the Supporting Information for details.
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