Oxyallyl Cation Capture via Electrophilic Deborylation of Organoboronates: Access to α, α′-Substituted Cyclic Ketones

Article abstract of DOI:10.1021/acs.orglett.9b02831

An umpolung strategy to synthesize α,α′-substituted cyclic ketones through the nucleophilic addition of organoboronates to α-hydroxyl silyl enol ethers is described. The reaction proceeds via the trapping of in situ generated oxyallyl cations via the electrophilic deborylation of C(sp²) and C(sp) borates. This efficient and straightforward method provides direct access to α-substituted silyl enol ethers in high yield with complete regioselectivity. Desilylation in a one-pot procedure provides the corresponding α,α′-disubstituted ketones with high diastereoselectivity.

Full text of DOI:10.1021/acs.orglett.9b02831

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Oxyallyl Cation Capture via Electrophilic Deborylation of
Organoboronates: Access to α,α′‑Substituted Cyclic Ketones
Truong N. Nguyen, Krit Setthakarn, and Jeremy A. May*
Department of Chemistry, University of Houston, 3585 Cullen Boulevard, Fleming Building Room 112, Houston, Texas
77204-5003, United States
S
* Supporting Information
ABSTRACT: An umpolung strategy to synthesize α,α′-substituted cyclic ketones through the nucleophilic addition of
organoboronates to α-hydroxyl silyl enol ethers is described. The reaction proceeds via the trapping of in situ generated oxyallyl
cations via the electrophilic deborylation of C(sp2) and C(sp) borates. This efficient and straightforward method provides direct
access to α-substituted silyl enol ethers in high yield with complete regioselectivity. Desilylation in a one-pot procedure provides
the corresponding α,α′-disubstituted ketones with high diastereoselectivity.
he carbonyl is among the most utilized functional groups
for C−C bond formation in organic synthesis. The α-
Scheme 1. Strategies for α-Functionalization of Ketones
T
functionalization of carbonyls has long been pursued through
the pregeneration or in situ formation of nucleophilic enols,
enolates, or alkyl/silyl enol ethers and the subsequent reaction
with carbon electrophiles (Scheme 1, eq 1). However,
unsaturated electrophiles (alkenyl and aryl) are not viable in
this approach. The transition-metal-catalyzed α-arylation of
ketones offers an alternative to enolate alkylation (Scheme 1,
eq 2).1 However, these reactions require inert conditions and/
or expensive ligands, and they often lack functional group
tolerance for halogens and heterocycles. Herein is reported a
robust strategy catalyzed by cationic lithium that is orthogonal
to enolate alkylation and metal-based catalysis to effect the α-
functionalization of α-hydroxy enol ethers with a wide range of
sp2 and sp carbon nucleophiles to access α,α′-disubstituted
ketones.
Oxyallyl cations have recently been electrophilic partners in
several C−C bond-forming strategies. These 2π-electron
species have been used in (4 + 3) cycloadditions with dienes,2
(3 + 2) cycloadditions with alkenes or alkynes,3 and (3 + 3)
cycloadditions with azides or nitrones,4 providing diverse
strategies for the construction of complex structures. Addi-
tionally, oxyallyl cations are intermediates in Nazarov
cyclizations that have been intercepted by electron-rich π-
nucleophiles both inter- and intramolecularly.5 Recently, this
umpolung reactivity has been utilized to synthesize α-
functionalized ketones that are not accessible by traditional
strategies. Elegant examples exist of the base-promoted in situ
generation of oxyallyl cations from α-halo ketones or α-
tosyloxyl ketones,6 with an enantioselective process reported
for the latter (Scheme 1, eq 3).6c Nonetheless, these seminal
works solely utilized symmetric ketones. Unsymmetrical
oxyallyl cations would be problematic due to the competitive
addition at the α and α′ positions. The use of α-hydroxyl silyl
enol ethers developed by Kartika and coworkers enabled the
Received: August 9, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02831
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
regioselective addition of various carbon nucleophiles to
generate α,α′-disubstituted silyl enol ethers, which could be
subsequently converted into ketones (Scheme 1, eq 4).7
Despite the advances mentioned above, the construction of
ketones with unsaturated α-substitution via oxyallyl cation
capture is still challenging, especially for ketones bearing α-
alkene and α-alkyne substituents, even though such products
are highly desirable for their synthetic utility. Moreover, acid-
promoted reactions would offer orthogonality to the previously
described base-promoted reactions.
acids was then carried out, and we observed the formation of
enol 3a in almost all cases.10 The yield of 3a increased to 65%
when Sc(OTf)3 (20 mol %) was employed (Table 1, entry 5).
Notably, lithium salts gave higher yields and cleaner reactions
(Table 1, entries 6−8), although they required a higher loading
(0.5 equiv).8e Cationic lithium is a cheap, highly functional
group-tolerant and benign reagent.11 LiPF6 appeared to be the
most effective catalyst, as it afforded 3a in 79% yield (Table 1,
entry 8). It should be noted that the product 3a was not
observed in nonpolar solvents such as CH2Cl2 or PhMe,
supporting the formation of a charged oxyallyl cation
intermediate.
This study was driven by our long-standing interest8 in
organotrifluoroborate nucleophiles9 due to their bench
stability, low toxicity, and wide functional group tolerance.
An underutilized feature of unsaturated organoboronates is
their reaction as electron-rich π-nucleophiles with cationic
intermediates via electrophilic deborylation (comparative to
protodeborylation). We have been enabling new C−C bond-
forming transformations from organoboronates in combination
with a variety of electrophiles. Inspired by the above work, we
envisioned that electrophilic oxyallyl cations generated from α-
hydroxyl silyl enol ethers could be trapped by nucleophilic
organoborates at the α-carbon with complete regioselectivity,
affording unsaturated α,α′-substituted silyl enol ethers as
masked ketones (Scheme 1, eq 5). The success of this strategy
would provide a robust way for synthesizing ketones bearing
unsaturated substituents at the α-positions.
With optimized conditions in hand, we then explored the
substrate scope using a variety of α-hydroxyl silyl enol ethers.
Various substituents at the α-carbon of the cyclic silyl enol
ethers were incorporated for testing (Scheme 2). The results
a
Scheme 2. Oxyallyl Cation Substitution Effects
Our investigation began with α-hydroxyl silyl enol ether 1a
reacting with 4-methoxyphenyl trifluoroborate (2). The
success of this reaction critically depended on finding a
catalyst that could ionize 1a without negatively affecting the
organotrifluoroborate. The performance of various Brønsted
and Lewis acids was first examined. No significant conversion
of enol ether 1a to arylated adduct 3a was observed when
using Py·TfOH in CH2Cl2 at room temperature7 (Table 1,
a
Table 1. Identifying Effective Reaction Conditions
a
Reaction conditions: 1 (0.2 mmol), styrenyltrifluoroborate (0.4
mmol), and LiPF6 (0.5 equiv) in MeCN (2 mL) at room temperature.
b
c
b
Isolated in 82% yield when running on a 5.0 mmol scale. Reaction
entry
catalyst
Py·TfOH
Py·TfOH
equiv
solvent
yield
completed in 5 min.
1
2
3
4
5
6
7
8
1
1
1
0.5
0.2
0.5
0.5
0.5
CH2Cl2
MeCN
CH2Cl2
MeCN
MeCN
MeCN
MeCN
MeCN
-
-
c
Brønsted acids
<10
41
65
67
71
showed that the α-substituents did not significantly affect the
reaction outcomes. The nucleophilic addition of organo-
trifluoroborates unsurprisingly occurred at the less substituted
α′-carbon, providing the silyl enol ether products with
complete regioselectivity and in high yield in every case (see
3b−k). Substrates bearing aryl substituents afforded products
3b and 3c in >90% yield. More weakly activating substituents,
such as vinyl or allyl groups, furnished adducts 3d and 3e in 88
and 83% yield, respectively. An alkynyl-substituted substrate
gave product 3f in 85% yield without any problems. Substrates
with aliphatic α-substituents also afforded products 3g and 3h
in good yield. Unfortunately, products from acyclic substrates
or substrates without α-substituents have not yet been
observed, indicating that the generated oxyallyl cations require
resonance stabilization from π-donating groups, inductive
stabilization from alkyl groups, or the rigidity of a ring system.
We then turned our attention to five-membered ring
substrates. The reactions proceeded at a high rate, providing
3i−k within 5 min.
(n-Bu)4NHSO4
Sc(OTf)3
LiOTf
LiClO4
LiPF6
d
79
a
Reaction conditions: 1a (0.2 mmol), 4-MeO-C6H4-BF3K (0.4
mmol), and catalyst in solvent (2 mL) at room temperature (23
b
°C). Via 1H NMR peak integration relative to 4-nitrobenzoate.
c
d
Brønsted acids = TFAA, TfOH, and (+)-CSA. Isolated in 78% yield.
entry 1). Theoretically, polar solvents would facilitate the
formation of the charged oxyallyl cations. However, the
replacement of CH2Cl2 with MeCN7d in the presence of Py·
TfOH did not improve the reaction outcome (Table 1, entry
2). Other Brønsted acids such as TFAA, TfOH, or (+)-CSA
also failed to afford a substantial amount of product 3a (Table
8b
1, entry 3). Encouragingly, the use of (n-Bu)4NHSO4 in
MeCN provided 3a in 41% yield. A screening of various Lewis
B
DOI: 10.1021/acs.orglett.9b02831
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Organic Letters
Letter
Silyl enol ethers 3j,k were obtained as expected. However, if
the reaction forming 3j was continued for more than 5 min,
then a mixture of diastereomers was obtained due to olefin
isomerization. The same phenomenon was seen in 3i, where
the conjugation to the added styrene results in only the
isomerized product isolated. The greater facility for isomer-
ization in the cyclopentane products is currently under
investigation.12
Next, we examined a variety of trifluoroborate π-
nucleophiles. A wide range of alkenyl-, alkynyl-, and aryl/
heteroaryl trifluoroborates was found to perform well with
these reaction conditions (Scheme 3). Styrenyl nucleophiles
A methylthioether group was compatible with the reaction
conditions, and 6a was provided in 75% yield. A similar yield
was obtained when using 3,4-(methylenedioxy)phenyl boro-
nate (6b). The steric hindrance of the o,o′-disubstitution on
mesitylene trifluoroborate was not a problem (6c). Sensitive
heteroaryl borates like 2-thiophene and 2-furan afforded
products 6d and 6e in acceptable yield,14 whereas
benzothiophene and protected indole nucleophiles gave
products 6f and 6g in higher yield. Organoborate nucleophiles
were also tested with cyclopentyl substrates. As was previously
the case, alkenyl, alkynyl, and aryl borates were all reactive in
good yield (3i−k, 7a,b).
To gain insight into the hypothesized reaction mechanism, a
control reaction between enol 1a and styrene or phenyl-
acetylene under the same conditions was run (Scheme 4, eq 1).
a
Scheme 3. Scope of Organoborate π-Nucleophiles
Scheme 4. Control Experiments
Neither product 3b nor 5a was observed, suggesting the
essential activating role of the borate in the carbon
nucleophiles. Furthermore, the replacement of the hydroxyl
leaving group with a silyl ether in 8 did not significantly affect
the reaction outcome, although we cannot exclude Li-
promoted hydroxyl deprotection (Scheme 4, eq 2). This result
favors an intermolecular addition of organoboronates to
discrete oxyallyl cations rather than an intramolecular process
via the coordination between the hydroxyl group and the
nucleophile, followed by concerted C−C bond formation with
C−O bond cleavage.15 More detailed investigations into the
mechanism of ionization to the oxyallyl cation and the C−C
bond formation have been initiated.
To highlight the practicality and versatility of this strategy,
reactions of 1 with several organoboronate nucleophiles were
conducted on a larger scale (Scheme 5). A variety of highly
useful transformations are available from silyl enol ethers.16 To
fulfill the primary purpose of this methodology, the substituted
silyl enol ether products were converted to the corresponding
ketones by adding 4 N HCl directly to the reaction mixtures.
cis-Disubstituted ketones 9−12 (d.r. ≥ 5:1) were obtained as
the major diastereomers from cyclohexanol substrates, whereas
cyclopentenols provided trans-disubstituted ketones 13 (d.r. =
6:1) and 14 (d.r. = 3.4:1). Both ring sizes show
thermodynamic control in the outcomes, and the stereo-
chemical assignment was confirmed by crystal structures for 9
and 13. To maintain the integrity of the alkyne, a solid-
supported Brønsted acid was necessary. These results illustrate
that diverse α,α′-disubstituted ketones can be efficiently
synthesized by this method in a single step.
a
Reactions were carried out with silyl enol ethers 1 (0.2 mmol),
organotrifluoroborates (0.4 mmol), and LiPF6 (0.5 equiv) in MeCN
(2 mL) at room temperature. Isolated in 82% yield when running on
a 5.0 mmol scale. Isolated in 83% yield when running on a 3.0 mmol
scale. Reaction completed in 5 min.
b
c
d
afforded products in excellent yield (4a,b). The addition of an
electron withdrawing group at the para position in the phenyl
ring did not significantly affect the reactivity. A less reactive
nucleophile, such as pentenyl trifluoroborate, provided product
4c, but in a lower yield. Although alkynyl boronates are often
sensitive to acidic conditions, they were competent in the
reaction to give alkynyl α-substituted silyl enol ethers (5a−f),
which would be quite challenging to synthesize via other
methods. Phenylethynyl trifluoroborate afforded 5a in 90%
yield. The use of a more electron-rich alkynyl borate
surprisingly gave a lower yield (5b), assumingly due to an
increased rate of product decomposition.13 Ethynyltrimethylsi-
lane trifluoroborate reacted to afford 5d in 61% yield. The less
reactive aliphatic alkynyl borates were also viable in the
reaction to give 5e and 5f in useful yield. Aryl and heteroaryl
borates were next tested. In general, LiPF6 was able to promote
the addition of electron-rich aromatic borates in moderate to
high yield (3a, 6, and 7).
In conclusion, a general procedure for capturing oxyallyl
cations by a wide range of alkenyl, alkynyl, and aryl/heteroaryl
organotrifluoroborates via electrophilic deborylation was
developed. This method afforded unsaturated α,α′-disubsti-
tuted silyl enol ethers as masked ketones in high yield with
C
DOI: 10.1021/acs.orglett.9b02831
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
R. P. Chem. Sci. 2010, 1, 387. (f) Lohse, A. G.; Hsung, R. P. Chem. -
Eur. J. 2011, 17, 3812. (g) Lo, B.; Lam, S.; Wong, W.-T.; Chiu, P.
Angew. Chem., Int. Ed. 2012, 51, 12120. (h) Lam, S. K.; Lam, S.;
Wong, W.-T.; Chiu, P. Chem. Commun. 2014, 50, 1738. (i) Wu, Y.-K.;
Dunbar, C. R.; McDonald, R.; Ferguson, M. J.; West, F. G. J. Am.
Chem. Soc. 2014, 136, 14903. (j) LeFort, F. M.; Mishra, V.; Dexter, G.
D.; Morgan, T. D. R.; Burnell, D. J. J. Org. Chem. 2015, 80, 5877.
(k) Topinka, M.; Zawatzky, K.; Barnes, C. L.; Welch, C. J.; Harmata,
M. Org. Lett. 2017, 19, 4106.
Scheme 5. One-Pot Synthesis of Disubstituted Ketones
(3) For reviews, see: (a) Li, H.; Wu, J. Synthesis 2014, 47, 22. For
selected examples, see: (b) Hardinger, S. A.; Bayne, C.; Kantorowski,
E.; McClellan, R.; Larres, L.; Nuesse, M. J. Org. Chem. 1995, 60, 1104.
(c) Mizuno, H.; Domon, K.; Masuya, K.; Tanino, K.; Kuwajima, I. J.
Org. Chem. 1999, 64, 2648. (d) Krenske, E. H.; He, S.; Huang, J.; Du,
Y.; Houk, K. N.; Hsung, R. P. J. Am. Chem. Soc. 2013, 135, 5242.
(e) Li, H.; Hughes, R. P.; Wu, J. J. Am. Chem. Soc. 2014, 136, 6288.
(4) (a) Scadeng, O.; Ferguson, M. J.; West, F. G. Org. Lett. 2011, 13,
114. (b) Cordier, M.; Archambeau, A. Org. Lett. 2018, 20, 2265.
(c) Hu, L.; Rombola, M.; Rawal, V. H. Org. Lett. 2018, 20, 5384.
(5) (a) Grant, T. N.; Rieder, C. J.; West, F. G. Chem. Commun.
2009, 5676. (b) Wu, Y.-K.; McDonald, R.; West, F. G. Org. Lett.
2011, 13, 3584. (c) Vaidya, T.; Eisenberg, R.; Frontier, A. J.
ChemCatChem 2011, 3, 1531. (d) Basak, A. K.; Tius, M. A. Org. Lett.
2008, 10, 4073. (e) Marx, V. M.; Burnell, D. J. J. Am. Chem. Soc. 2010,
132, 1685.
(6) (a) Tang, Q.; Chen, X.; Tiwari, B.; Chi, Y. R. Org. Lett. 2012, 14,
1922. (b) Vander Wal, M. N.; Dilger, A. K.; MacMillan, D. W. C.
Chem. Sci. 2013, 4, 3075. (c) Liu, C.; Oblak, E. Z.; Vander Wal, M.
N.; Dilger, A. K.; Almstead, D. K.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2016, 138, 2134.
(7) (a) Ayala, C. E.; Dange, N. S.; Fronczek, F. R.; Kartika, R. Angew.
Chem., Int. Ed. 2015, 54, 4641. (b) Dange, N. S.; Stepherson, J. R.;
Ayala, C. E.; Fronczek, F. R.; Kartika, R. Chem. Sci. 2015, 6, 6312.
(c) Ayala, C. E.; Dange, N. S.; Stepherson, J. R.; Henry, J. L.;
Fronczek, F. R.; Kartika, R. Org. Lett. 2016, 18, 1084. (d) Malone, J.
A.; Cleveland, A. H.; Fronczek, F. R.; Kartika, R. Org. Lett. 2016, 18,
4408. (e) Stepherson, J. R.; Fronczek, F. R.; Kartika, R. Chem.
Commun. 2016, 52, 2300.
(8) (a) Shih, J.-L.; Nguyen, T. S.; May, J. A. Angew. Chem., Int. Ed.
2015, 54, 9931. (b) Nguyen, T. N.; Nguyen, T. S.; May, J. A. Org.
Lett. 2016, 18, 3786. (c) Nguyen, T. N.; May, J. A. Tetrahedron Lett.
2017, 58, 1535. (d) Nguyen, T. N.; May, J. A. Org. Lett. 2018, 20,
112. (e) Nguyen, T. N.; May, J. A. Org. Lett. 2018, 20, 3618.
(9) (a) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275.
(b) Molander, G. A. J. Org. Chem. 2015, 80, 7837.
(10) Please see the Supporting Information for a full list of
experiments.
(11) (a) Karimi, B.; Maleki, J. J. Org. Chem. 2003, 68, 4951.
(b) Kurono, N.; Yamaguchi, M.; Suzuki, K.; Ohkuma, T. J. Org. Chem.
2005, 70, 6530. (c) Malona, J. A.; Colbourne, J. M.; Frontier, A. J.
Org. Lett. 2006, 8, 5661. (d) Sai, M.; Matsubara, S. Synlett 2014, 25,
2067.
a
PMA/SiO2 = phosphomolybdic acid supported on silica gel.17
complete regioselectivities. The silyl enol ether products can be
easily transformed into the corresponding α,α′-disubstituted
ketones in the same reaction.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02831.
Complete experimental procedures and compound
characterization data are provided (PDF)
Accession Codes
CCDC 1947177 and 1947185 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jmay@uh.edu.
ORCID
Jeremy A. May: 0000-0003-3319-0077
Notes
(12) The working mechanistic hypothesis is that the addition to the
allyl cation initially generates the isomer seen in the cyclohexene
series.
(13) All of the alkyne products were prone to decomposition.
(14) These trifluoroboronates are highly prone to protodeborona-
tion.
(15) Kabalka, G. W.; Venkataiah, B.; Dong, G. Tetrahedron Lett.
2004, 45, 729.
(16) For reviews, see: (a) Kuwajima, I.; Nakamura, E. Acc. Chem.
Res. 1985, 18, 181. (b) Fleming, I.; Barbero, A.; Walter, D. Chem. Rev.
1997, 97, 2063.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Welch Foundation (grant E-1744) and the NSF
(grant CHE-1800499) for generous financial support.
REFERENCES
■
(1) (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
(b) Johansson, C. C. C.; Colacot, T. J. Angew. Chem., Int. Ed. 2010,
49, 676. (c) Huang, Z.; Lim, H. N.; Mo, F.; Young, M. C.; Dong, G.
Chem. Soc. Rev. 2015, 44, 7764.
(17) Kishore Kumar, G. D.; Baskaran, S. J. Org. Chem. 2005, 70,
4520.
(2) For reviews, see: (a) Harmata, M. Chem. Commun. 2010, 46,
8886. (b) Harmata, M. Chem. Commun. 2010, 46, 8904. For selected
examples, see: (c) Fort, A. W. J. Am. Chem. Soc. 1962, 84, 4979.
(d) Harmata, M.; Carter, K. W. Tetrahedron Lett. 1997, 38, 7985.
(e) Krenske, E. H.; Houk, K. N.; Lohse, A. G.; Antoline, J. E.; Hsung,
D
DOI: 10.1021/acs.orglett.9b02831
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