Br?nsted Acid Catalyzed Homoconjugate Addition of Organotrifluoroborates to Arylated Cyclopropyl Ketones

Article abstract of DOI:10.1021/acs.orglett.6b01795

A novel and practical homoconjugate addition of alkenyl, alkynyl, heteroaryl, and aryl trifluoroborates to arylated cyclopropyl ketones to synthesize γ,γ-disubstituted ketones is reported. A preliminary mechanistic proposal involving ketone protonation, a

Full text of DOI:10.1021/acs.orglett.6b01795

Letter
pubs.acs.org/OrgLett
Brønsted Acid Catalyzed Homoconjugate Addition of
Organotrifluoroborates to Arylated Cyclopropyl Ketones
Truong N. Nguyen, Thien S. Nguyen, 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: A novel and practical homoconjugate addition of
alkenyl, alkynyl, heteroaryl, and aryl trifluoroborates to arylated
cyclopropyl ketones to synthesize γ,γ-disubstituted ketones is
reported. A preliminary mechanistic proposal involving ketone
protonation, an intermediary carbocation, and intermolecular
nucleophile addition has been made based on control studies.
1
4
15
he homologation of reactions is a robust strategy to
expand the utility of a given transformation, as it allows
reactions, and oxocarbenium additions. An important
benefit of using alkenyl, alkynyl, and aryl boronates and
trifluoroborates is the broad functional group tolerance of these
nucleophiles, including the use of unprotected heterocycles
(see 4). Our successful use of trifluoroborate-based nucleo-
T
access to products with an additional CH unit. Homologous
2
1
2
3
4
enolate, crotylation,5 Nazarov, Cope rearrangement, and
conjugate addition reactions have been disclosed. In6
homoconjugate addition reactions for C−C bond formation,
anionic nucleophiles are typically added to cyclopropanes with
two electron-withdrawing groups, taking advantage of “spi-
12e
philes in conjugate additions inspired this investigation for
their use in homoconjugate additions to provide γ-function-
alized ketones.
Reaction initiation could be promoted in theory by the use of
Brønsted acid, Lewis acid, or iminium catalysis. We initially
looked at Brønsted acids as cost-effective reagents. An initial
screen of organic and inorganic acids (20 mol %) in
dichloromethane showed the formation of adduct 9 in every
5a−d,7
roactivation” as proposed by Danishefsky (Scheme 1).
A
Scheme 1. Homoconjugate Additions
case (Table 1, entries 1−5). KHSO appeared to be the best
4
acid for the reaction, outperforming the others by a factor of 4
or more. It appears that having an acid pK around 2 is optimal
a
+
for reactivity. The use of a more soluble salt, with n-Bu N as
4
the cation, improved the outcome, especially when 30 mol %
was used (Table 1, entries 6 and 7). Other solvents proved
inferior to dichloromethane (Table 1, entries 8−9). Toluene
worked similarly well at times, but not for all substrates. The
use of boronic acids in the reaction did not give measurable
amounts of products unless molecular sieves were used, and
few examples of cyclopropanes activated by a single electron-
withdrawing group have been reported. However, these either
16
even then the product was obtained in a low yield (entry 10).
5e
Variation of the trifluoroborate nucleophile showed that the
homoconjugate addition accommodates a wide range of
alkenyl, alkynyl, heteroaryl, and aryl nucleophiles (Table 2).
The addition of para substituents to the styrenyl trifluoroborate
did not greatly affect the reactivity (see 11a−f). The pentenyl
borate reacted well to give 12. Alkynyl nucleophiles were more
sensitive to the acidic conditions, but still afforded adducts
recapitulate spiroactivation via spirofused cyclopropyl ketones
or take advantage of cyclopropanes contained within a highly
5e,8
strained bridged bicycle or bicyclo[1.1.0]butane system.
Using a Lewis acidic nucleophile, perhaps generated from a
boronate or trifluoroborate such as 6, would allow acceptor/
9
donor cyclopropanes 4 to be used as substrates with
5f
intermediate carbocation formation. This strategy accommo-
dates substrates with a single withdrawing group that do not
need additional ring strain or spiroactivation, thus providing a
significant expansion of substrate scope for homoconjugate
additions.
13a−d in useful yields. Aryl and heteroaryl nucleophiles were
next examined. The γ,γ-biaryl products 14−16 show that both
para- and ortho-substituted aryl nucleophiles reacted well. An
unprotected phenolic hydroxyl created no problems (16b), nor
10
In addition to their use as coupling partners, organo-
boronates and borates have served as nucleophiles for
Received: June 20, 2016
11
12,13
allylations and crotylations, conjugate additions,
Pestasis
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01795
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
16
Table 1. Identifying Effective Reaction Conditions
results (Table 3). Substitution, including an electron-with-
drawing group, could be made on the indole aryl ring (24a−b)
Table 3. Reaction Scope: Electrophiles
a
b
entry
acid (pKa)
solvent
CH Cl
yield (%)
c
1
2
3
4
5
6
7
8
9
F CCO H (−0.26)
Cl CHCO H (1.29)
7
3
2
2
2
d
CH Cl
13
2
2
2
2
2
2
2
2
2
KHSO (1.99)
CH Cl
87
4
2
d
H PO (2.12)
CH Cl
23
d
3
4
2
o-(NO )C H CO H (2.17)
CH Cl
14
2
6
4
2
2
Bu NHSO
CH Cl
89
96
90
87
4
4
4
4
4
4
2
e
Bu NHSO
CH Cl
4
2
Bu NHSO
PhMe
THF
4
Bu NHSO
4
f
10
Bu NHSO
CH Cl
19
4
2
2
a
17
b
c
pK in H O.
Isolated yield (average of 2 runs). Yield based on
d
a
2
1
integration in H NMR relative to methyl 4-nitrobenzoate. Starting
material was recovered from the reaction. 30 mol % used. Boronic
e
f
acid and 4 Å MS used.
Table 2. Reaction Scope: Nucleophiles
or on the nitrogen (25a−b) without any loss in reactivity.
Diester-, phenylketone-, and acylimidazole-substituted cyclo-
propanes gave 26, 27a, and 27b, respectively, without
problems. The latter may be used as a synthetic equivalent
18
for esters and amides. Aryl cyclopropanes reacted well as long
as electron-donating substituents were present. Again, o,o-
disubstitution was not a problem, and ketones 28−30 were
obtained in useful yields.
All of the substrates in the above-mentioned tables were
obtained as racemic mixtures. Mechanistically, either a
stereospecific mechanism where the nucleophile attacks the
cyclopropane 31 to produce enol 34 (Scheme 2) with inversion
Scheme 2. Possible Reaction Mechanisms
did the steric hindrance of o,o-disubstitution (14). Hetero-
aromatics performed less well in the presence of acid, though
at the point of attack or an initial cyclopropane fragmentation
to the achiral cation 33 could be operative. Consequently, we
ran an experimental control with enantioenriched cyclopropane
36 (Scheme 3). While the substrate was introduced to the
reaction with an er of 81:19, the product was obtained as
essentially a racemate. If the reaction was run to only partial
completion (4, 8, or 12 h), loss of enatioenrichment in the
1
7−21 were obtained in useful yields.
The tolerance for substitution around the cyclopropane was
next examined. Unfortunately, electron-poor aromatics or an
unsubstituted phenyl group in place of the indole of 8 provided
1
6
no products. This is consistent with the hypothesized
carbocationic intermediate. However, a range of electron-rich
aromatics and heteroaromatics could be used with satisfactory
16
starting material 34 from 81:19 er to 50.5:49.5 er was seen.
These data suggest that a rapid equilibration between
B
DOI: 10.1021/acs.orglett.6b01795
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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slower nucleophilic attack at the carbocation.
In light of the proposed mechanism, we believe a
1
9
stereoablative enantioselective version of this reaction will
be possible. However, preliminary trials with typical chiral
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In conclusion, we report a novel and practical homoconju-
gate addition of alkenyl, alkynyl, heteroaryl, and aryl
trifluoroborates to arylated cyclopropyl ketones to synthesize
γ,γ-disubstituted ketones. A preliminary mechanistic proposal
has been made based on control studies. Efforts to find
conditions to effect an enantioselective transformation are
ongoing.
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ASSOCIATED CONTENT
Supporting Information
■
(
3
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01795.
́
̈
(
A full list of control experiments, reaction conditions
examined, experimental procedures, and physical charac-
terization may be found (PDF)
(
5
̂
(
AUTHOR INFORMATION
Corresponding Author
■
(
(
f) Lennox, A. J. J.; Lloyd- Jones, G. C. Isr. J. Chem. 2010, 50, 664.
g) Lennox, A. J. J.; Lloyd- Jones, G. C. J. Am. Chem. Soc. 2012, 134,
*E-mail: jmay@uh.edu.
7
431.
Notes
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The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
We are grateful to the Welch foundation for a grant (E-1744)
to support this research.
■
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DOI: 10.1021/acs.orglett.6b01795
Org. Lett. XXXX, XXX, XXX−XXX