Synthesis of diverse β-quaternary ketones via palladium-catalyzed asymmetric conjugate addition of arylboronic acids to cyclic enones

Article abstract of DOI:10.1016/j.tet.2014.11.048

Abstract The development and optimization of a palladium-catalyzed asymmetric conjugate addition of arylboronic acids to cyclic enone conjugate acceptors is described. These reactions employ air-stable and readily-available reagents in an operationally si

Full text of DOI:10.1016/j.tet.2014.11.048

Tetrahedron xxx (2014) 1e12
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of diverse
b
-quaternary ketones via palladium-catalyzed
asymmetric conjugate addition of arylboronic acids to cyclic enones
Jeffrey C. Holder, Emmett D. Goodman, Kotaro Kikushima, Michele Gatti,
*
Alexander N. Marziale, Brian M. Stoltz
Warren and Katharine Schlinger Laboratory of Chemistry and Chemical Engineering, California Institute of Technology,
1200 E California Blvd MC 101-20, Pasadena, CA 91125, United States of America
a r t i c l e i n f o
a b s t r a c t
Article history:
The development and optimization of a palladium-catalyzed asymmetric conjugate addition of ar-
ylboronic acids to cyclic enone conjugate acceptors is described. These reactions employ air-stable and
readily-available reagents in an operationally simple and robust transformation that yields b-quaternary
ketones in high yields and enantioselectivities. Notably, the reaction itself is highly tolerant of atmo-
spheric oxygen and moisture and therefore does not require the use of dry or deoxygenated solvents,
Received 5 October 2014
Received in revised form 15 November 2014
Accepted 17 November 2014
Available online xxx
specially purified reagents, or an inert atmosphere. The ring size and
highly variable, and a wide variety of -quaternary ketones can be synthesized. More recently, the use of
NH4PF6 has further expanded the substrate scope to include heteroatom-containing arylboronic acids
and -acyl enone substrates.
b-substituent of the enone are
Dedicated to Professor Barry M. Trost upon
receipt of the 2014 Tetrahedron Prize
b
b
Keywords:
Conjugate addition
Palladium
Ó 2014 Elsevier Ltd. All rights reserved.
Asymmetric catalysis
Quaternary center
Enone
Boronic acid
1. Introduction
sodium tetraaryl borates (Ar4BNa) and arylboroxines (ArBO)3 to
enones to afford products containing all-carbon quaternary ster-
eocenters.9,10 However, it should be noted that these reactions
cannot use common and commercially available arylboronic
acids.9e11
Synthesis of all-carbon quaternary stereocenters by means of
asymmetric catalysis remains a challenging problem in synthetic
chemistry.1 Historically, the 1,4-addition of a nucleophile to a suit-
able
a
,
b
-unsaturated conjugate acceptor has been a reliable means
Upon undertaking studies to develop a palladium-catalyzed
asymmetric conjugate addition capable of synthesizing quater-
nary stereocenters, we noted that there were only examples of
asymmetric synthesis of tertiary stereocenters in the palladium
literature.12 Concurrent with our early studies, Lu and co-workers
reported that the dicationic complex [(bpy)Pd(OH)]2$2BF4 was ca-
pable of catalyzing the conjugate addition of arylboronic acids to 3-
methylcyclohexenone to synthesize racemic products featuring
quaternary stereocenters.13 In 2011, we reported the discovery of an
asymmetric palladium-catalyzed conjugate addition based on
a catalyst derived in situ from Pd(OCOCF3)2 and a chiral pyr-
idinooxazoline (PyOx) ligand.14 These reactions were demonstrated
on a broad spectrum of arylboronic acid and enone substrates, and
were found to be remarkably tolerant of both oxygen and water.
Subsequently, we disclosed the use of NH4PF6 and water as syner-
gistic additives to accelerate the rate of the reaction. Fortuitously,
these additives also allowed reactions to be conducted at temper-
atures as low as ambient temperature.15
of synthesizing these challenging quaternary stereocenters.2 Many
groups have pioneered methods for this transformation that react
organometallic reagents (e.g., diorganozinc,3 triorganoaluminum,4
and organomagnesium reagents5) with electrophiles using a cop-
per catalyst. Rigorously anhydrous conditions are a requirement of
these approaches, as they uniformly utilize water-sensitive re-
agents. As an alternative, Hayashi developed chiral rhodium com-
plexes that successfully catalyze the asymmetric conjugate addition
of various organoboron reagents to conjugate acceptors in very
high yields and enantioselectivities.6,7 More recently, the rhodium
system has been expanded to include syntheses of quaternary
stereocenters.8 In particular, the development of chiral diene li-
gands has facilitated the rhodium-catalyzed conjugate addition of
* Corresponding author. Tel.: þ1 626 395 6064; fax: þ1 626 395 8436; e-mail
address: stoltz@caltech.edu (B.M. Stoltz).
http://dx.doi.org/10.1016/j.tet.2014.11.048
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
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J.C. Holder et al. / Tetrahedron xxx (2014) 1e12
Herein, we discuss report a full account of the development of
these reactions and discuss the full scope of the chemistry to date.
O
N
N
N
*
2. Development and optimization of reaction conditions
N
N
N
4
12
R
13
• 5-membered metallocycle chelate
• Narrow bite-angle
2.1. Identification of chemically competent ligand and re-
action conditions
Pyridinooxazoline (PyOx)
Ligand Scaffold
To achieve the desired enantioselective conjugate addition, the
reaction of 3-methylcyclohexen-2-one (1) with phenylboronic acid
(2) was investigated in the presence of various palladium catalysts
and chiral ligands (Table 1). We hypothesized dinitrogen ligands
that were less sterically bulky than large arylphosphine ligands
would successfully synthesize the highly congested quaternary
Fig. 1. Logical implementation of pyridinooxazoline ligands.
us to observe that polar, coordinating solvents hindered the re-
action (Table 2, entries 1e3). Moving toward non-polar solvents,
such as toluene (entry 4), encouraged higher conversions and
modest enantioinduction, however, heating these reactions (en-
tries 6 and 7) failed to drive the reactions to full conversion. For-
tuitously, dichloromethane (entry 5) provided 87% isolated yield of
the desired conjugate addition adduct in 91% ee.
stereocenter of b-disubstituted ketone 3, and were pleased to find
that bipyridine (bpy, 4) enabled full conversion of enone 1 when
treated with palladium(II) acetate and phenylboronic acid in protic
solvents. Unfortunately, a number of other standard ligand scaf-
folds failed to afford any conversion to the desired conjugate ad-
dition product under identical reaction conditions. Sparteine (6),
PyBox (7), and a variety of bis-oxazoline (9 and 10) and phosphi-
nooxazoline (8) did not enable the transformation. ‘Ligand-free’
conditions (5) also failed to provide any product. Notably, pyridine
(11, 12 mol%, 2 equiv with respect to Pd) failed to deliver any
product, insinuating that architectural features of the bidentate bpy
scaffold enabled the desired reaction.
Table 2
Preliminary solvent screena
Entry
Solvent
Temp (ꢀC)
Yield (%)
eed (%)
1
2
3
4
5
6
7
tert-Amyl alcohol
Dioxane
THF
Toluene
CH2CI2
40
40
40
40
40
60
60
14b
17b
31b
65b
87c
63c
68c
d
d
d
82
91
77
62
Table 1
Preliminary ligand screena
Toluene
Hexane
a
Conditions: Reactions were performed with phenylboronic acid (0.50 mmol), 3-
methylcyclohexen-2-one (0.25 mmol), Pd(OCOCF3)2 (5 mol %), and (S)-t-BuPyOx
(6 mol %) in solvent (1 mL) for 24 h.
b
NMR yield.
Isolated yield.
ee determined by chiral HPLC.
c
d
To further optimize the reaction, we next looked at the effect of
different palladium sources. The use of palladium(II) halides
afforded no reaction (Table 3, entries 1 and 2). The reactivity could
be rescued via halogen abstraction upon treatment with AgOTf
(entry 3), however, this reaction produced ketone 3 in low enan-
tioselectivity. In the presence of ligand 14, palladium(II) carboxylate
sources were capable of catalyzing the desired reaction (entries 4
and 5). The acetate counterion (entry 4) led to modest chemical
yields of the desired conjugate addition adduct in 93% ee. A catalyst
derived from palladium(II) trifluoroacetate and pyridinooxazoline
14 produced the desired ketone product 316 in 87% yield and 91% ee
(entry 5).17 By using 1,2-dichloroethane in place of dichloro-
methane as solvent, and increasing the reaction temperature from
40 to 60 ꢀC, ketone 3 was isolated in 99% yield and 93% ee (entry 6).
The high yield and enantioselectivity were maintained even upon
addition of 10 equiv of water (entry 7). Furthermore, the amount of
phenylboronic acid was reduced to 1.1 equiv with no detrimental
effects (entry 8).
a
Conditions: Reactions were performed with phenylboronic acid (0.50
mmol), 3-methylcyclohexen-2-one (0.25 mmol), Pd(OAc)2 (5 mol%), and
ligand (6 mol%) in solvent (1 mL) for 24 h. NMR yield. ee determined by
chiral HPLC.
Success with bpy and lack of success with chiral bis-oxazoline
ligands led us to propose that a C1 symmetry chiral ligand based
on the bpy scaffold would be a suitable catalyst. The presence of
a pyridine ring was required, however the small bite angle and five-
membered metallocycle chelate seemed equally important. We
reasoned that modification of one pyridine moiety of bpy would
allow for the introduction of a chiral group (Fig. 1, hypothetical li-
gand 12), while still maintaining the five-membered chelate and
narrow bite-angle. We quickly discovered that substituted pyr-
idinooxazoline ligands (13)14 provided high levels of
enantioselection.
A final examination of solvent and palladium sources was un-
dertaken following the disclosure of a highly enantioselective
palladium-catalyzed conjugate addition by Minnaard and co-
workers whereby a dicationic palladium catalyst is generated in
MeOH.18 However, we found that highly polar solvents failed to
produce product (Table 4, entries 2 and 3). Switching to dicationic
palladium by employing tetrakis acetonitrile palladium(II)
Identification of a functioning chiral ligand ((S)-t-BuPyOx, 14)
prompted us to consider the effects of solvent on the yield and
enantioselectivity of the reaction. A preliminary solvent screen led
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J.C. Holder et al. / Tetrahedron xxx (2014) 1e12
3
Table 3
Table 5
Optimization of palladium sourcea
PyOx and QuinOx ligand screena
Entry Pd source
Solvent
Temp (ꢀC) Yieldb (%) eec (%)
1
PdCI2
Pd(MeCN)2CI2
Pd(MeCN)2CI2, AgOTf CH2CI2
Pd(OAc)2
Pd(OCOCF)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF)2
CH2CI2
CH2CI2
40
40
40
40
40
d
d
2
d
d
3d
4
69
65
87
99
99
99
17
92
91
93
91
93
CH2CI2
CH2CI2
CICH2CH2CI 60
CICH2CH2CI 60
CICH2CH2CI 60
5
6
7e
8f
a
Conditions: Reactions were performed with phenylboronic acid (0.50 mmol), 3-
methylcyclohexen-2-one (0.25 mmol), Pd(OCOCF3)2 (5 mol %), and ligand 14 (6 mol
%) in solvent (1 mL) for 12 h, unless otherwise noted.
b
Isolated yield.
ee determined by chiral HPLC.
12 mol % AgOTf.
Reaction performed in the presence of added H2O (2.5 mmol, 10 equiv).
Phenylboronic acid loading reduced to 1.1 equiv.
c
d
e
f
Table 4
Polar solvents screena
a
Conditions: Reactions were performed with phenylboronic acid (0.50
mmol), 3-methylcyclohexen-2-one (0.25 mmol), Pd(OCOCF3)2 (5 mol%),
and ligand (6 mol%) in ClCH2CH2Cl (1 mL) for 12 h. Isolated yield. ee
determined by chiral HPLC.
Entry Solvent
Metal source
Temp (ꢀC) Yieldb (%) eec (%)
1
2
3
4
5
6
7
DCE
acetone
DMF
MeOH
MeOH
Pd(OAc)2
Pd(TFA)2
Pd(TFA)2
Pd(CH,CN)4(BF4)2
Pd(CH3CN)4(BF4)2
60
60
60
60
25
25
Low
d
d
d
d
d
d
d
d
significantly depressed ee. Similarly, PyOx ligands without sub-
stitution at the 4-position (19) afford no appreciable enantiocontrol
and deliver ketone 3 nearly as a racemic mixture.
d
Trace
d
Following the discovery that the addition of NH4PF6 and water
accelerate the reaction (see Section 3 for discussion), we re-
examined a large number of chiral and achiral ligands to de-
termine if the new conditions facilitated an expanded class of li-
gands to successfully catalyze the reaction. Unfortunately, all
phosphine ligands we tried failed to achieve appreciable conver-
sion (Table 6, 23, 24, and 25). The drop in conversion from dppe (24)
to dppbz (25) led us to question whether ligand rigidity was det-
rimental to conversion. However, the nearly identical results ob-
served with bpy (4), phenanthroline (26), and bathophenanthroline
(27) suggest that rigidity of the ligand scaffold has minimal effect
on conversion.
DCE-MeOH Pd(CH3CN)4(BF4)2
acetone
d
((S)-t-BuPyOx)PdCl2+2 NaPF6 25
d
a
Conditions: Reactions were performed with phenylboronic acid (0.50 mmol), 3-
methylcyclohexen-2-one (0.25 mmol), Pd(OCOCF3)2 (5 mol %), and ligand 14 (6 mol
%) in solvent (1 mL) for 12 h.
b
Isolated yield.
ee determined by chiral HPLC.
c
tetrafluoroborate facilitated no conversion in methanol at a variety
of temperatures (entries 4e6), or as a mixture with dichloroethane
as cosolvent (entry 6). Finally, we failed to generate a catalyst in situ
from isolated (PyOx)PdCl2 by treatment with sodium hexa-
fluorophosphate (entry 7).
We screened a number of chiral diamine ligands under the
newly optimized conditions as well. The best conversion was ob-
served with a bis-oxazoline with a bite angle similar to that of bpy
(Table 6, 34), followed by proline-derived 32, which also features
2.2. Extended exploration of ligand scaffolds
a
five-membered metallocycle chelate. Ligands forming six-
membered metallocycles (28 and 29) performed poorly, however
those containing gem-dimethyl (31) or cyclopropyl (35) substituted
bridging methylene groups showed improved conversion. We be-
lieve this to be the result of the quaternary center on the ligand
backbone enforcing a smaller bite angle. Additionally, sparteine (6),
PHOX (33), and PyBox (30) ligands delivered no conversion to the
desired product.
Having successfully optimized the reaction conditions, we next
examined the reaction with other members of the PyOx or related
quinolinooxazoline (QuinOx) ligand series (Table 5, 17 and 18). Li-
gands with electron-donating (15) or electron-withdrawing (16)
substituents on the pyridine moiety both furnished the product in
high yield, but with decreased enantioselectivity. Next, employing
QuinOx ligands 17 or 18 resulted in a dramatic decrease in both the
reactivity and enantioselectivity, presumably due to poor chelation
of palladium due to the increased steric bulk adjacent to the pyri-
dine nitrogen. Modifying the chiral substituent to groups other
than tert-butyl also led to decreased enantioselectivity, as we ob-
served PyOx ligands bearing isobutyl (20), phenyl (21), or isopropyl
(22) substitution to deliver ketone 3 in quantitative yield, but
3. Determination of substrate scope
To determine the substrate scope, a wide variety of arylboronic
acids were exposed to the optimized reaction conditions (Table 7).
Generally, para-substituted arylboronic acids react with good yields
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J.C. Holder et al. / Tetrahedron xxx (2014) 1e12
Table 6
Table 7
Expanded ligand screena
Boronic acid substrate scopea
O
O
ligand (3 mol%)
B(OH)2
Pd(OCOCF3)2 (2.5 mol%)
+
NH4PF6 (30 mol%), H2O (5 equiv)
Ph
ClCH2CH2Cl, 40 °C, 12–48 h
1
2
3
Achiral Ligands
PPh2
Fe
Ph2P
PPh2
PPh2
N
N
Ph2P
PPh2
23
24
22% conversion
25
4
0% conversion
2% conversion
100% conversion
99% yield
Ph
Ph
N
N
N
N
26
27
100% conversion
99% yield
98% conversion
97% yield
Chiral Ligands
CN
O
O
O
O
O
O
N
N
N
N
HN
N
N
t-Bu
t-Bu
Ph
Ph
Ph
Ph
28
29
30
2% conversion
11% conversion
1% conversion
a
Conditions: Reactions were performed with phenylboronic acid (0.50
mmol), 3-methylcyclohexen-2-one (0.25 mmol), Pd(OCOCF3)2 (5 mol%),
and ligand 14 (6 mol%) in ClCH2CH2Cl (1 mL) at 40–80 °C for 12–24 h.
Isolated yield. ee determined by chiral HPLC.
OH
Ph
Ph
H
H
O
O
N
N
N
N
H
H
31
32
12% conversion
22% conversion
Table 8
Increased reaction yields with NH4PF6 and water as reaction additivesa
O
N
O
O
N
O
N
O
N
N
N
PPh2
N
Bn
Bn
Ph
Ph
t-Bu
0% conversion
33
6
34
35
20% conversion
0% conversion
35% conversion
a
Conditions: Reactions were performed with phenylboronic acid (0.50
mmol), 3-methylcyclohexen-2-one (0.25 mmol), Pd(OCOCF3)2 (2.5 mol%),
and ligand (3 mol%) in ClCH2CH2Cl (1 mL) for 12–48 h, , unless otherwise
noted. Conversion determined by 1H NMR.
and enantioselectivities. Alkyl substituted products (Table 7) are
generally formed in good yield and ee, such as those formed by 4-
methyl- and 4-ethylphenylboronic acids (36 and 37). However,
arylboronic acids bearing substituents with greater electron-
donating capacity, such as 4-benzyloxyphenylboronic acid or 4-
methoxyphenylboronic acid react to form products with di-
minished yields and enantioselectivities (38 and 39). A wide range
of functional groups can be utilized successfully. Even a silyl ether is
tolerated (e.g., 44), however in modest yield. Arylboronic acids
bearing electron-withdrawing substituents (blue colored) tend to
a Blue font: reported yield and ee of 47 in the absence of NH4PF6 and water
with reactions performed at 60 °C; red font: yield and ee of 47 with additives.
Conditions: Reactions were performed with phenylboronic acid (1.0 mmol),
3-methylcyclohexen-2-one (0.5 mmol), NH4PF6 (30 mol %), water (5 equiv.),
Pd(OCOCF3)2 (5 mol%), and (S)-t-BuPyOx (6 mol%) in ClCH2CH2Cl (2 mL)
at 40 °C. Isolated yield. ee was determined by chiral HPLC.
substrates that had reacted with good ee, but poor yields under the
initial reported conditions (in the absence of NH4PF6 and water). In
some cases, the isolated yield nearly doubled. For example, reaction
of 3-chlorophenylboronic acid to form ketone 47a increased from
55% to 96% yield (Table 8). Likewise, the product formed from 3-
bromophenylboronic acid (47b) increased from 44% yield to 84%
yield. Even 3-nitrophenylboronic acid saw an increase from 40% to
81% yield. Furthermore, 2-fluorophenylboronic acid reacted with
70% yield and 77% ee under the newly modified conditions. In each
of these cases, the increase in yield is met with effectively no
change in ee.
perform extremely well. Both
4-acylpheny- and 4-
trifluoromethylphenylboronic acids react with quantitative yield
and 96% ee to form ketones 40 and 41. The product of 4-
chlorophenylboronic acid (42) is formed in 94% yield and 95% ee,
and the product of 4-fluorophenylboronic acid (43) is afforded in
92% ee. Finally, meta-substitution on the arylboronic acid also fur-
nishes products in high ee and yield. 3-Methylphenylboronic acid
and 3-carbomethoxyphenyboronic acid both afford product ke-
tones (45 and 46, respectively) in greater than 90% ee.
More recently, we discovered that the addition of NH4PF6 and
water accelerate the reaction, and allow for lower temperatures to
be employed.15 Typically, reactions under these conditions occur
between room temperature and 40 ꢀC. Gratifyingly, we discovered
that these milder conditions facilitate increased yields with
Next, we tested a variety of b-substituted enones to examine the
scope of the enone reactant (Table 9). A wide variety of alkyl
substituted products can be formed, such as ethyl (48), n-butyl (49),
and benzyl (50) substituents at the b-position, all of which were
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J.C. Holder et al. / Tetrahedron xxx (2014) 1e12
5
Table 9
proposed catalytic cycle, or otherwise favor a resting state on the
productive catalytic cycle. This would have the effect of increasing
the relative concentration of the active catalyst species, leading to
the observed rate increase. We envision a catalytic cycle where
arylpalladium(II) 58 forms by transmetallation of arylboronic acid
with palladium hydroxide 57. Ligand substitution with substrate
ketone affords an equilibrium mixture of carbonyl-bound complex
60 and olefin-bound complex 59. Turnover-limiting olefin insertion
occurs from complex 59, and this insertion is also the enantiose-
lectivity-determining step. The lowest energy diastereomer of this
insertion reaction has been calculated to be transition state 59-
ts,15a which leads to the observed (R) stereochemistry of the
product ketones. The initial product of the olefin insertion step is
carbon-bound palladium enolate 62. This enolate probably isom-
erizes to its oxygen-bound tautomer (61) under the reaction con-
ditions. Hydrolysis of this latent cationic palladium enolate (61)
affords the product ketone (3) and regenerates the catalyst (57).
Enone substrate scopea
5. Expanded substrate scope
The discovery that reaction rates were dramatically increased by
the addition of hexafluorophosphate salts and additional water
represented an opportunity to expand the substrate scope. The
additives promote successful reaction at 40 ꢀC or lower, and thus
substantially facilitate the reaction of substrates with temperature-
sensitive functionalities (such as silyl ethers), or groups that may
react with trace palladium(0) formed by off-cycle pathways (such
as arylbromides). We next turned our attention to two other sub-
a
Conditions: Reactions were performed with phenylboronic acid (0.50
mmol), cycloalkenone (0.25 mmol), Pd(OCOCF3)2 (5 mol%), and ligand 14
(6 mol%) in ClCH2CH2Cl (1 mL) at 60 °C for 12 h.
afforded in greater than 90% ee. Furthermore, branched, bulky alkyl
substituents could be successfully utilized, forming products such
as isopropyl (51), cyclopropyl (52), and cyclohexyl (53). Heteroatom
linkers (e.g., 54) are suitable b-substituents as well. Finally, prod-
ucts formed from five- and seven-membered enones (55 and 56,
strate classes: (1)
containing nitrogen and other heteroatoms.
We considered that our -arylation reaction constituted a syn-
thetically useful means of synthesizing asymmetric 1,4-dicarbonyl
compounds. Beginning with -acyl cyclic enones (63), we were
b-acyl cyclic enones and (2) arylboronic acids
b
b
respectively) were reacted with greater than 90% ee.
able to react a variety of arylboronic acids to synthesize asymmetric
1,4-dicarbonyl compounds (Table 10, 64aeg). Interestingly, only
products from the olefin insertion that form quaternary stereo-
centers were observed. The isomeric addition product, which
would contain vicinal tertiary stereocenters, was not observed in
any of the crude reaction mixtures by NMR spectroscopy.
4. Plausible catalytic cycle
Computational and experimental work by our group in collab-
oration with the Houk laboratory suggests that the reaction is
catalyzed by a palladium(II) cationic species (Fig. 2, 57).15a We
propose that the active catalyst is likely a palladium(II) hydroxide,
which are known to undergo rapid transmetallation with arylbor-
onic acids.19 Though the precise role of NH4PF6 has not been
established, we postulate that the presence of the non-coordinating
counterion may stabilize the cationic intermediates on the
Table 10
b
-Acyl enone substrate scopea
O
+
B(OH)2
N
L
N
Pd
Ph
OH
3
hydrolysis
57
H2O
transmetallation
+
N
O
N
O
Pd
+
H
O
O
N
N
N
L
N
Pd
+
Pd
N
61
Ph
L
Pd
L
N
Ph
59-ts
62
58
insertion
enantioselectivity
determining step
+
N
+
N
Pd
O
N
Pd
N
O
coordination
O
60
59
a
Conditions: Reactions were performed with phenylboronic acid (0.50
mmol), cycloalkenone (0.25 mmol), Pd(OCOCF3)2 (5 mol%), and ligand 14
(6 mol%) in ClCH2CH2Cl (1 mL) at 60 °C for 12 h.
Fig. 2. Plausible catalytic cycle.
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6
J.C. Holder et al. / Tetrahedron xxx (2014) 1e12
Table 12
Next, we strived to demonstrate that the reaction was tolerant of
Challenging enone substratesa
heteroatom substitution on the arylboronic acid. We proposed that
aniline-derived boronic acids could be reacted when protected
with electron-withdrawing functional groups. Cbz-protected ani-
line boronic acid 65a reacted with modest yield (Table 11), but
a promising 76% ee. Modification to the pivaloyl protected boronic
acid 65b, facilitated higher yields, but had minimal effect on
enantioselectivity. Finally, trifluoroacetyl-protected 65c afforded
clean conversion to afford 98% of the conjugate addition adduct 66c
in 89% ee. The trifluoroacetyl group facilitated the reaction on
a number of aniline-derived arylboronic acids, including methox-
yphenyl trifluoroacetamide 65d, trisubstituted acetamide 65e, and
3-trifluoroacetamides 65f and 65g.
(S)-t-BuPyOx (6 mol %)
Pd(OCOCF3)2 (5 mol %)
NH4PF6, H2O
O
O
B(OH)2
R1
R1
R2
ClCH2CH2Cl
60 °C, 12 h
2 equiv
R2
O
O
O
N
67
68
69
O
O
O
S
Table 11
Trifluoroacetamide boronic acid nucleophilesa
Cl
70
71
72
O
(S)-t-BuPyOX (6 mol%)
O
Pd(OCOCF3)2 (5 mol%)
a Optimized reaction conditions afford trace or no conversion as observed by
1H NMR spectroscopy of the crude reaction mixture.
B(OH)2
NH4PF6, H2O
R
ClCH2CH2Cl 60 °C
R
2 equiv
1
66a-g
O
O
O
Table 13
Ph
O
NH
NH
F3C
NH
Challenging boronic acid substratesa
(S)-t-BuPyOx (6 mol %)
O
O
Pd(OCOCF3)2 (5 mol %)
NH4PF6, H2O
B(OH)2
R
R
B(OH)2
65a
B(OH)2
B(OH)2
ClCH2CH2Cl
60 °C, 12 h
65b
65c
98% yield
89% ee
2 equiv
45% yield
76% ee
72% yield
78% ee
O
O
OMe
O
O
Cl
Me
B(OH)2
F3C
NH
F3C
NH
B(OH)2
B(OH)2
F3C
NH
F3C
NH
O
I
MeO
B(OH)2
76
no product
detected
73
74
75
trace product
significant homocoupling
B(OH)2
B(OH)2
2% yield
37% ee
13% yield
22% ee
B(OH)2
B(OH)2
65d
65e
93% yield
90% ee
65f
60% yield
92% ee
65g
77% yield
88% ee
75% yield
88% ee
F
B(OH)2
B(OH)2
B(OH)2
O
a
B(OH)2
Conditions: Reactions were performed with phenylboronic acid (0.50
NC
mmol), 3-methylcyclohexenone (0.25 mmol), Pd(OCOCF3)2 (5 mol%), and
F
F
b
ligand 14 (6 mol%) in ClCH2CH2Cl (1 mL) at 60 °C for 12 h. Yield of
78
79
77
80
no product
detected
product (66). c ee of product (66).
no product
detected
no product
detected
no product
detected
Boc
N
B(OH)2
B(OH)2
6. Challenging substrates
MeO
81
no product
detected
82
no product
detected
Despite the many substrates that undergo facile conjugate ad-
dition, a number of substrates proved incompatible with the newly
developed methodology (Table 12). Pyridine 67 presumably co-
ordinates palladium and inhibits the catalyst, yielding no conjugate
addition product. Allyl enone 68 also did not react, nor did eny-
a Optimized reaction conditions afford trace or no conversion as observed by
1H NMR spectroscopy of the crude reaction mixture.
neone 69. b-Aromatic enones also failed, such as thiophene 70 and
congestion likely contributes to its poor performance as well. In-
terestingly, styrene moieties 79 and 82 also did not undergo ad-
dition. Additionally, it should be noted that electron-rich
arylboronic acids (e.g., dimethoxyphenylboronic acid (75)) undergo
rapid homocoupling and proteodeborylation under the reaction
conditions. Thus, it is difficult to achieve synthetically useful yields
of these electron-rich adducts. Furthermore, the enantioselectivity
seems to be lower for these electron-rich arylboronic acids.
chloroarene 71. Each of these substrates has functionality that can
potentially interact with palladium; such interactions are likely
detrimental to the catalyst.
Some arylboronic acids also proved to be poor nucleophiles.
ortho-Substituted arylboronic acids were generally poor substrates;
2-chlorophenylboronic acid (Table 13, 73) yielded only 2% of its
corresponding product in 37% ee, while 2-methylphenylboronic
acid (74) yielded 13% product in 22% ee. Arylboronic acids with
reactive groups, such as iodide 76 and furan 77, were not success-
fully employed in conjugate addition chemistry. Cyanophenylbor-
onic acid 80 also failed to react. In general, heterocycles are not well
tolerated, as observed by the lack of reactivity of indole 81. Steric
crowding of the reactive boronic acid site by the Boc protecting
group may play a role in the poor reactivity. Likewise, the very
electron poor fluoroarene 78 does not react, though steric
7. Conclusion and outlook
In summary, we have developed a widely applicable method for
the synthesis of
utilizing a palladium-catalyzed, asymmetric conjugate addition of
arylboronic acids to enone electrophiles. wide array of
b-quaternary ketones of a variety of ring sizes
A
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J.C. Holder et al. / Tetrahedron xxx (2014) 1e12
7
arylboronic acids and enones were successfully employed in this
8.3. Representative general procedure for the enantiose-
transformation. Critically, the reactions are compatible with protic
co-solvents, such as water, and display remarkable tolerance to
atmospheric oxygen. Furthermore, the optimized ligand, (S)-t-
BuPyOx (14), is easily synthesized and readily prepared on multi-
gram quantities.20 These features, in combination with the ease of
handling of arylboronic acids, result in an operationally simple
reaction with a straightforward procedure. All reactions described
herein were performed in screw-top vials and without purification
or distillation of any reagents or solvents. Application of this re-
action method toward the catalytic asymmetric total synthesis of
several natural product classes and the development of an asym-
metric conjugate addition of heteroaryl substrates are currently
underway in our laboratory.
lective 1,4-addition of arylboronic acids to
enones
b-substituted cyclic
A screw-top 1 dram vial was charged with a stir bar, Pd(O-
COCF3)2 (4.2 mg, 0.0125 mmol, 5 mol %), (S)-t-BuPyOx (3.1 mg,
0.015 mmol, 6 mol %), and PhB(OH)2 (61 mg, 0.50 mmol, 2.0 equiv).
The solids were dissolved in dichloroethane (0.5 mL) and 3-methyl-
2-cyclohexenone (29 mL, 0.25 mmol) was added. The walls of the
vial were rinsed with an additional portion of dichloroethane
(0.5 mL). The vial was capped with a Teflon/silicone septum and
stirred at 60 ꢀC in an oil bath for 12 h. Upon complete consumption
of the starting material (monitored by TLC, 4:1 hexanes/EtOAc, p-
anisaldehyde stain) the reaction was purified directly by column
chromatography (5:1 hexanes/EtOAc) to afford a clear colorless oil
(47 mg, 99% yield).
8. Experimental section
8.4. General procedure for the synthesis of racemic products
8.1. Materials and methods
Racemic products were synthesized in a manner analogous to
the general procedure using bipyridine (2.1 mg, 0.015 mmol, 6 mol
%) as an achiral ligand.
Unless otherwise stated, reactions were performed with no extra
precautions taken to exclude air or moisture. Commercially available
reagents were used as received from SigmaeAldrich unless other-
wise stated. Enone substrates (Table 3) were purchased from Sig-
maeAldrich
(3-methylcyclohexenone,
2-cyclohexene-1-one,
8.5. Spectroscopic data for enantioenriched
cyclic ketones
b,b-disubstituted
chromone) or were prepared according to literature procedure.21
Pyridinooxazoline ligands were synthesized according to literature
procedures.22 Reaction temperatures were controlled by an IKAmag
temperature modulator. Thin-layer chromatography (TLC) was per-
formed using E. Merck silica gel 60 F254 precoated plates (250 nm)
and visualized by UV fluorescence quenching, potassium perman-
ganate, or p-anisaldehyde staining. Silicycle SiliaFlash P60 Academic
Silica gel (particle size 40e63 nm) was used for flash chromatogra-
phy. Analytical chiral HPLC was performed with an Agilent 1100 Se-
ries HPLC utilizing a Chiralcel OJ column (4.6 mmꢁ25 cm) obtained
fromDaicelChemicalIndustries, Ltdwithvisualizationat254nmand
flow rate of 1 mL/min, unless otherwise stated. Analytical chiral SFC
was performed with a JASCO 2000 series instrument utilizing Chir-
alpak (AD-H or AS-H) or Chiralcel (OD-H, OJ-H, or OB-H) columns
(4.6 mmꢁ25 cm), ora Chiralpak IC column (4.6 mmꢁ10 cm) obtained
from Daicel Chemical Industries, Ltd with visualization at 210 or
254 nm and flow rates of 3 mL/min or 5 mL/min, as indicated below.
1H and 13C NMR spectra were recorded on a Varian Inova 500
(500 MHz and 125 MHz, respectively) and a Varian Mercury 300
spectrometer (300 MHz and 75 MHz, respectively). Data for 1H NMR
8.5.1. (R)-3-Phenyl-3-methylcyclohexanone
according to the general procedure and purified by flash chroma-
tography (CH2Cl2) to afford a colorless oil (93% yield). [
(3). Synthesized
a
]
25 ꢂ56.1 (c
D
1.36, CHCl3, 92% ee). All characterization data match previously
reported data.9a,9b,4k,4f,4i,4c,13
8.5.2. (R)-3-(4-Methylphenyl)-3-methylcyclohexanone
(36). Synthesized according to the general procedure and purified
by flash chromatography (CH2Cl2) to afford a colorless oil (99%
yield). [
a]
25 ꢂ60.9 (c 1.11, CH2Cl2, 87% ee). All characterization data
D
match previously reported data.9a,4i,k
8. 5. 3 . (R)-3-(4-E thylp henyl )-3-m ethylcyclo hexan one
(37). Synthesized according to the general procedure and purified
by flash chromatography (hexanes/EtOAc¼100:0 to 95:5) to afford
a colorless oil (90% yield). 1H NMR (500 MHz, CDCl3)
d 7.23 (ddd,
J¼2.0, 8.5 Hz, 2H), 7.16 (ddd, J¼2.0, 8.5 Hz, 2H), 2.87 (d, J¼14.0 Hz,
1H), 2.62 (q, J¼7.5, 2H), 2.42 (d, J¼14.0 Hz, 1H), 2.35e2.26 (m, 2H),
2.20e2.15 (m,1H), 1.93e1.83 (m, 2H), 1.73e1.64 (m,1H), 1.31 (s, 3H),
spectra are reported as follows: chemical shift (
coupling constant (Hz), integration). Data for 1H NMR spectra are
referenced to the centerline of CDCl3 ( 7.26) as the internal standard
d ppm) (multiplicity,
1.23 (t, J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 211.6, 144.7,
d
142.0, 127.9, 125.5, 53.2, 42.5, 40.8, 38.0, 29.8, 28.2, 22.0, 15.4; IR
(Neat Film, NaCl): 2957, 2933, 2863, 1710, 1513, 1453, 1416, 1315,
and are reported in terms of chemical shift relative to Me4Si (d 0.00).
Data for 13C NMR spectra are referenced to the centerline of CDCl3 (
77.0) and are reported in terms of chemical shift relative to Me4Si (
d
1288, 1226, 1078 cmꢂ1; HRMS (MultiMode ESI/APCI) m/z calcd for
25
d
C
15H21O [MþH]þ: 217.1587, found 217.1592; [
a
]
ꢂ56.8 (c 1.61,
D
0.00). Infrared spectra were recorded on a PerkineElmer Paragon
1000 Spectrometer and are reported in frequency of absorption
(cmꢂ1). High-resolution mass spectra (HRMS) were obtained on an
Agilent6200 Series TOF with anAgilentG1978A Multimodesourcein
electrospray ionization (ESI), atmospheric pressure chemical ioni-
zation (APCI) or mixed (MultiMode ESI/APCI) ionization mode. Op-
tical rotations were measured on a Jasco P-2000 polarimeter using
a 100 mm path-length cell at 589 nm.
CHCl3, 85% ee).
8.5.4. (R)-3-(4-Benzyloxylphenyl)-3-methylcyclohexanone
(38). Synthesized according to the general procedure and purified
by flash chromatography (hexanes/EtOAc¼100:0 to 95:5) to afford
a colorless oil (96% yield). 1H NMR (500 MHz, CDCl3)
d 7.43 (ddd,
J¼1.5, 2.0, 7.5 Hz, 2H), 7.39 (ddd, J¼1.0, 7.0, 7.5, 2H), 7.33 (tt, J¼1.5,
7.0 Hz, 1H), 7.22 (ddd, J¼2.0, 3.5, 10.0 Hz, 2H), 6.93 (ddd, J¼2.0, 3.5,
10.0 Hz, 2H), 5.04 (s, 2H), 2.85 (d, J¼14.0 Hz, 1H), 2.42 (d, J¼14.0 Hz,
1H), 2.30 (t, J¼7.0 Hz, 2H), 2.18e2.13 (m, 1H), 1.92e1.83 (m, 2H),
1.71e1.62 (m, 1H), 1.30 (s, 3H), 0.97 (s, 9H), 0.19 (s, 6H); 13C NMR
8.2. Experimental procedures
(125 MHz, CDCl3)
d 211.6, 157.0, 139.7, 137.0, 128.6, 127.9, 127.5,
8.2.1. (S)-4-(tert-Butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole
(14). The ligand was prepared according to literature procedures.14,23
All characterization data match previously reported data.
126.7, 114.7, 70.0, 53.3, 42.3, 40.8, 38.0, 30.0, 22.0; IR (Neat Film,
NaCl) 3066, 3027, 2947, 2873, 1710, 1609, 1579, 1510, 1453, 1426,
1379, 1312, 1290, 1246, 1181, 1021 cmꢂ1; HRMS (MultiMode ESI/
Please cite this article in press as: Holder, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.048

8
J.C. Holder et al. / Tetrahedron xxx (2014) 1e12
APCI) m/z calcd for C20H23O2 [MþH]þ: 295.1693, found 295.1673;
9.0 Hz, 1H), 7.39 (dd, J¼9.0 Hz, 1H), 3.91 (s, 3H), 2.88 (d, J¼14.0 Hz,
1H), 2.47 (d, J¼14.0 Hz, 1H), 2.37e2.28 (m, 2H), 2.24e2.19 (m, 1H),
1.98e1.86 (m, 2H), 1.73e1.65 (m, 1H), 1.33 (s, 3H); 13C NMR
[
a]
25 ꢂ26.8 (c 4.90, CHCl3, 74% ee).
D
8.5.5. (R)-3-(4-Methoxyphenyl)-3-methylcyclohexanone
(125 MHz, CDCl3) d 210.9, 167.1, 147.9, 130.4, 130.2, 128.6, 127.5,
(39). Synthesized according to the general procedure and purified
126.7, 53.0, 52.1, 42.8, 40.7, 37.7, 29.3, 22.0; IR (Neat Film, NaCl)
2952, 2878, 1720, 1604, 1582, 1438, 1350, 1310, 1273, 1243, 1209,
by flash chromatography (hexanes/EtOAc¼100:0 to 90:10) as col-
25
orless oil (58% yield). [
a]
ꢂ47.9 (c 1.05, CHCl3, 69% ee). All char-
1194, 1120, 1085 cmꢂ1; HRMS (MultiMode ESI/APCI) m/z calcd for
D
25
acterization data match previously reported data.9b,4k,f,c,i
C
15H19O3 [MþH]þ: 247.1329, found 247.1334; [
a
]
ꢂ58.9 (c 1.39,
D
CHCl3, 95% ee).
8.5.6. (R)-3-(4-Acetylphenyl)-3-methylcyclohexanone
(40). Synthesized according to the general procedure and purified
by flash chromatography (CH2Cl2/EtOAc¼100:0 to 98:2) to afford
8.5.13. (R)-3-(3-Chlorophenyl)-3-methylcyclohexanone
(47a). Synthesized according to the general procedure and pu-
colorless oil (99% yield). 1H NMR (500 MHz, CDCl3)
d
7.92 (ddd,
rified by flash chromatography (hexanes/EtOAc¼100:0 to 95:5)
25
J¼2.0, 9.0 Hz, 2H), 7.42 (ddd, J¼2.0, 9.0 Hz, 2H), 2.90 (d, J¼14.0 Hz,
1H), 2.58 (s, 3H), 2.47 (d, J¼14.0 Hz, 1H), 2.38e2.26 (m, 2H),
2.25e2.20 (m, 1H), 1.98e1.88 (m, 2H), 1.68e1.59 (m, 1H), 1.34 (s,
to afford a colorless oil (55% yield). [
a
]
ꢂ56.7 (c 1.48, CHCl3,
D
96% ee). All characterization data match previously reported
data.9a,b
3H); 13C NMR (125 MHz, CDCl3)
d 210.8, 197.6, 152.9, 135.2, 128.6,
125.9, 52.8, 43.2, 40.7, 37.8, 29.7, 26.5, 22.0; IR (Neat Film, NaCl)
2957, 2868, 1708, 1683, 1607, 1569, 1456, 1421, 1404, 1359, 1312,
8.5.14. (R)-3-(3-Bromophenyl)-3-methylcyclohexanone
(47b). Synthesized according to the general procedure and purified
by flash chromatography (CH2Cl2) to afford a colorless oil (44%
1268, 1228, 1194 cmꢂ1; HRMS (MultiMode ESI/APCI) m/z calcd for
25
C
15H19O [MþH]þ: 231.1379, found 231.1380; [
a
]
ꢂ58.9 (c 1.39,
yield). [
a]
25 ꢂ56.7 (c 0.68, CHCl3, 85% ee). All characterization data
D
D
CHCl3, 96% ee).
match previously reported data.4i
8.5.7. (R)-3-(4-Trifluoromethylphenyl)-3-methylcyclohexanone
(41). Synthesized according to the general procedure and purified
8.5.15. (R)-3-(3-Nitrophenyl)-3-methylcyclohexanone
(47c). Synthesized according to the general procedure and purified
by flash chromatography (CH2Cl2) to afford a colorless oil (40%
by flash chromatography (hexanes/EtOAc¼100:0 to 95:5) to afford
a colorless oil (99% yield). [
a
]
ꢂ58.5 (c 0.92, CHCl3, 96% ee). All
yield). 1H NMR (500 MHz, CDCl3)
d
8.22 (t, J¼2.0 Hz, 1H), 8.08 (ddd,
25
D
characterization data match previously reported data.4k,f,i
J¼1.0, 2.0, 8.0 Hz, 1H), 7.66 (ddd, J¼1.0, 2.0, 8.0 Hz, 1H), 7.50 (t,
J¼8.0 Hz, 1H), 2.88 (d, J¼14.0 Hz, 1H), 2.53 (ddd, J¼1.0, 1.5, 14.0 Hz,
1H), 2.41e2.31 (m, 2H), 2.26e2.20 (m, 1H), 2.03e1.90 (m, 2H),
8.5.8. (R)-3-(4-Chlorophenyl)-3-methylcyclohexanone
(42). Synthesized according to the general procedure and purified
1.74e1.66 (m, 1H), 1.37 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 210.1,
by flash chromatography (hexanes/EtOAc¼100:0 to 95:5) to afford
149.7, 148.6, 131.9, 129.5, 121.4, 120.7, 52.8, 43.1, 40.6, 37.6, 29.4,
22.0; IR (Neat Film, NaCl) 2957, 2873, 1713, 1525, 1480, 1453, 1426,
25
a white solid (94% yield). [
a
]
ꢂ69.4 (c 0.56, CHCl3, 95% ee). All
D
characterization data match previously reported data.9b
1347, 1298, 1226, 1107, 1075 cmꢂ1; HRMS (MultiMode ESI/APCI) m/z
25
calcd for C13H15O3N [M]: 233.1052, found 233.1055; [
0.96, CHCl3, 92% ee).
a
]
ꢂ61.5 (c
D
8.5.9. (R)-3-(4-Fluorophenyl)-3-methylcyclohexanone
(43). Synthesized according to the general procedure and purified
by flash chromatography (hexanes/EtOAc¼100:0 to 95:5) to afford
8.5.16. (R)-3-(2-Fluorophenyl)-3-methylcyclohexanone
(47d). Synthesized according to the general procedure and purified
by flash chromatography (hexanes/EtOAc¼100:0 to 95:5) to afford
25
a colorless oil (84% yield). [
a]
ꢂ59.5 (c 1.00, CHCl3, 92% ee). All
D
characterization data match previously reported data.9a,b
a colorless oil (32% yield). 1H NMR (500 MHz, CDCl3)
d 7.25e7.19 (m,
8. 5.10 . (R)-3-(4- tert-Butyl di m e t hylsi l ox yl ph e nyl) -3 -
methylcyclohexanone (44). Synthesized according to the general
procedure and purified by flash chromatography (hexanes/
EtOAc¼100:0 to 95:5) to afford a colorless oil (52% yield). 1H NMR
2H), 7.07 (ddd, J¼1.5, 2.0, 7.5 Hz, 2H), 7.39 (ddd, J¼1.0, 7.0, 7.5 Hz,
2H), 7.33 (tt, J¼1.5, 7.0 Hz, 1H), 7.22 (ddd, J¼1.5, 7.5 Hz, 1H), 7.02
(ddd, J¼1.5, 8.0, 13.0 Hz, 1H), 2.94 (d, J¼14.5 Hz, 1H), 2.44 (d,
J¼14.5 Hz, 1H), 2.48e2.44 (m, 1H), 2.37e2.28 (m, 2H), 1.96e1.87 (m,
2H), 1.67e1.60 (m, 1H), 1.41 (s, 3H), 13C NMR (125 MHz, CDCl3)
(500 MHz, CDCl3)
d
7.15 (ddd, J¼2.0, 3.0, 9.0 Hz, 2H), 6.71 (ddd,
J¼2.0, 3.0, 9.0 Hz, 2H), 2.83 (d, J¼14.0 Hz, 1H), 2.40 (d, J¼14.0 Hz,
1H), 2.30 (t, J¼7.0 Hz, 2H), 2.16e2.10 (m, 1H), 1.90e1.81 (m, 2H),
1.70e1.61 (m, 1H), 1.29 (s, 3H), 0.97 (s, 9H), 0.19 (s, 6H); 13C NMR
d 211.3, 128.3, 128.0, 127.9, 124.1, 116.7, 53.2, 42.4, 40.9, 35.7, 27.1; IR
(Neat Film, NaCl) 2957, 2933, 2873, 1710, 1611, 1577, 1488, 1443,
1315, 1290, 1214, 1117, 1083 cmꢂ1; HRMS (MultiMode ESI/APCI) m/z
(125 MHz, CDCl3)
d
211.7, 153.8, 140.1, 126.5, 119.8, 53.3, 42.3, 40.8,
calcd for C13H16OF [MþH]þ: 207.1180, found 207.1188; [
a
]
25 ꢂ41.0 (c
D
38.1, 29.9, 25.6, 22.0, 18.1, ꢂ4.4; IR (Neat Film, NaCl) 2952, 2933,
2858, 1713, 1607, 1510, 1473, 1458, 1263, 1181 cmꢂ1; HRMS (Multi-
Mode ESI/APCI) m/z calcd for C19H31O2Si [MþH]þ: 319.2088, found
0.64, CHCl3, 77% ee).
8.5.17. (R)-3-Phenyl-3-ethylcyclohexanone
(48). Synthesized
319.2090; [
a
]
25 ꢂ36.4 (c 1.11, CHCl3, 82% ee).
according to the general procedure and purified by flash chroma-
tography (hexanes/EtOAc¼100:0 to 95:5) to afford a colorless oil
D
8.5.11. (R)-3-Methyl-3-(m-tolyl)cyclohexanone
(45). Synthesized
(96% yield). [
a]
25 ꢂ74.5 (c 3.39, CHCl3, 92% ee). All characterization
D
according to the general procedure and purified by flash chroma-
data match previously reported data.4c,i,k,9a
tography (CH2Cl2) to afford a colorless oil (99% yield). [
a
]
25 ꢂ59.8 (c
D
2.95, CH2Cl2, 91% ee). All characterization data match previously
8.5.18. (R)-3-Phenyl-3-n-butylcyclohexanone
(49). Synthesized
reported data.9a,4k,f
according to the general procedure and purified by flash chroma-
tography (hexanes/EtOAc¼100:0 to 95:5) to afford colorless oil
8.5.12. (R)-3-(3-Methoxycarbonylphenyl)-3-methylcyclohexanone
(46). Synthesized according to the general procedure and purified
by flash chromatography (CH2Cl2/EtOAc 100:0 to 98:2) to afford
(95% yield). [
a]
25 ꢂ56.7 (c 1.48, CHCl3, 91% ee). All characterization
D
data match previously reported data.4c
a white solid (91% yield). 1H NMR (500 MHz, CDCl3)
d
8.03 (dd,
8.5.19. (R)-3-Benzyl-3-phenylcyclohexanone
(50). Synthesized
J¼1.5, 2.0 Hz, 1H), 7.88 (dd, J¼1.5, 9.0 Hz, 1H), 7.51 (dd, J¼2.0,
according to the general procedure and purified by flash
Please cite this article in press as: Holder, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.048

J.C. Holder et al. / Tetrahedron xxx (2014) 1e12
9
25
chromatography (hexanes/EtOAc¼100:0 to 95:5) to afford a color-
a colorless oil (85% yield). [
a]
ꢂ75.1 (c 1.34, CHCl3, 93% ee). All
D
25
less oil (74% yield). [
a]
þ01.0(c 3.83, CHCl3, 91% ee). All charac-
characterization data match previously reported data.4i,k,9a
D
terization data match previously reported data.13
8.6. General procedure for the synthesis of 3-acetyl-3-aryl
cyclic ketones
8.5.20. (R)-3-Phenyl-3-iso-propylcyclohexanone (51). Synthesized
according to the general procedure and purified by flash chroma-
tography (hexanes/EtOAc¼100:0 to 95:5) to afford a colorless oil
8.6.1. (S)-3-Acetyl-3-phenylcyclopentanone (64e). A screw-top 1
dram vial was charged with a stir bar, Pd(OCOCF3)2 (3.4 mg,
0.01 mmol, 5 mol %), (S)-t-BuPyOx (2.5 mg, 0.012 mmol, 6 mol %),
and PhB(OH)2 (48 mg, 0.40 mmol, 2.0 equiv). The solids were sus-
pended in dichloroethane (1 mL) and stirred at ambient tempera-
ture for 5 min, at which time a yellow color was observed. 3-
Acetylcyclopent-2-enone (25 mg, 0.20 mmol, 1 equiv) and water
(86% yield). [
a
]
25 ꢂ79.4 (c 3.24, CHCl3, 79% ee). All characterization
D
data match previously reported data.13
8.5.21. (R)-3-Phenyl-3-cyclopropylcyclohexanone (52). Synthesized
according to the general procedure and purified by flash chroma-
tography (CH2Cl2) to afford a colorless oil (68% yield). 1H NMR
(500 MHz, CDCl3)
d 7.30e7.28 (m, 4H), 7.21e7.17 (m, 1H), 2.90 (dt,
(50 mL, 10 equiv) were added and the vial was capped with a Teflon/
silicone septum and stirred at 60 ꢀC in a heat block for 12 h. Upon
complete consumption of the starting material (monitored by TLC,
20% acetone/hexanes, p-anisaldehyde stain) the reaction was puri-
fied directly by column chromatography (eluent gradient: 10% ace-
tone/hexanes to 20% acetone/hexanes) to afford a clear colorless oil
J¼2.0, 14.5 Hz, 1H), 2.48 (d, J¼14.5 Hz, 1H), 2.31e2.19 (m, 3H),
1.94e1.86 (m, 2H), 1.60e1.51 (m, 1H), 0.99 (tt, J¼5.5, 8.5, 1H),
0.45e0.39 (m, 1H), 0.35e0.29 (m, 1H), 0.24e0.19 (m, 1H), 0.17e0.12
(m, 1H); 13C NMR (125 MHz, CDCl3)
d 210.8, 143.2, 127.6, 126.5,
125.7, 50.0, 44.9, 40.3, 34.1, 23.1, 20.8, 1.1, 0.0; IR (Neat Film, NaCl)
3081, 3057, 3007, 2947, 2873, 1708, 1498, 1443, 1421, 1315, 1285,
(29 mg, 72% yield). 1H NMR (500 MHz, CDCl3)
d 7.44e7.24 (m, 5H),
1226, 1046, 1023 cmꢂ1; HRMS (MultiMode ESI/APCI) m/z calcd for
3.13 (ddd, J¼18.0,1.7, 0.7 Hz,1H), 2.77e2.69 (m,1H), 2.53 (dt, J¼17.9,
25
C15H19O [MþH]þ: 215.1430, found 215.1425; [
a
]
ꢂ83.1 (c 1.39,
D
0.8 Hz,1H), 2.47e2.37 (m,1H), 2.32 (dddd, J¼8.5, 6.8, 4.1, 0.9 Hz, 2H),
1.97 (d, J¼0.6 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 214.9, 207.7,140.7,
129.2, 127.7, 126.5, 61.2, 47.1, 36.5, 30.8, 25.4; IR (Neat Film, NaCl):
CHCl3, 88% ee).
3059, 3026,1745,1705,159,1495,1446,1407,1355,1203,1151 cmꢂ1
;
8.5.22. (R)-3-Phenyl-3-cyclohexylcyclohexanone (53). Synthesized
according to the general procedure and purified by flash chro-
matography (hexanes/EtOAc¼100:0 to 95:5) to afford a colorless
HRMS (MultiMode ESI/APCI) m/z calcd for C13H15O2 [MþH]þ:
203.1072, found 203.1066; [a]
25 100.8 (c 1.5, CHCl3, 93% ee).
D
oil (86% yield). 1H NMR (500 MHz, CDCl3)
d
7.29 (ddd, J¼2.0, 7.0,
8.0 Hz, 2H), 7.23 (ddd, J¼1.0, 2.0, 8.0 Hz, 2H), 7.18 (tt, J¼1.0, 7.0 Hz,
1H), 2.97 (dd, J¼2.0, 15.0 Hz, 1H), 2.46 (d, J¼15.0 Hz, 1H), 2.26e2.17
(m, 3H), 2.07 (ddd, J¼3.5, 12.5, 13.5 Hz, 1H), 1.94e1.88 (m, 1H),
1.84e1.75 (m, 2H), 1.68e1.56 (m, 2H), 1.52e1.45 (m, 1H), 1.44e1.38
(m, 1H), 1.37e1.31 (m, 1H), 1.26e1.17 (m, 1H), 1.11e0.95 (m, 2H),
8. 6. 2. (R) -3-(4-C hl oropheny) -3-a cetylcyc lohexano ne
(64a). Synthesized according to the general procedure, 0.25 mmol
scale. The title compound was isolated as an off-white solid (53 mg,
85% yield). 1H NMR (300 MHz, CDCl3)
d 7.35 (m, 2H), 7.18 (m, 2H),
2.85 (dt, J¼1.4, 14.8 Hz, 1H), 2.63 (dt, J¼1.1, 14.8 Hz, 1H), 2.48e2.20
(m, 4H), 1.87 (s, 3H), 1.80e1.69 (m, 2H); 13C NMR (125 MHz, CDCl3)
208.3, 208.1, 139.3, 133.8, 129.5, 127.8, 59.6, 48.6, 40.3, 31.5, 25.3,
21.1; FTIR (Neat Film, NaCl) 3397, 2951, 2875,1708,1490,1455,1420,
0.88e0.75 (m, 2H); 13C NMR (125 MHz, CDCl3)
d 212.0, 143.8,
128.1, 127.4, 125.9, 49.5, 49.0, 47.2, 41.0, 33.6, 27.5, 27.4, 26.9, 26.5,
21.4; IR (Neat Film, NaCl) 2928, 2853, 1713, 1495, 1443, 1315, 1285,
1228 cmꢂ1; HRMS (MultiMode ESI/APCI) m/z calcd for C18H24
O
1402, 1356, 1319, 1235, 1183, 1140, 1097, 1012, 970, 829, 717 cmꢂ1
;
[MþH]þ: 257.1900, found 257.1888; [
a
]
25 ꢂ52.4 (c 3.87, CHCl3, 85%
HRMS (MultiMode ESI/APCI) m/z calcd for C14H15ClO2 [MþH]þ:
D
25 ꢂ6.74 (c 3.2, CHCl3, 96% ee).
ee).
251.0833, found: 251.0829; [
a]
D
8.5.23. (S)-3-(3-(Benzyloxy)propyl)-3-phenylcyclohexanone
(54). Synthesized according to the general procedure and puri-
fied by flash chromatography (hexanes/EtOAc¼100:0 to 95:5) to
afford a colorless oil (65% yield). 1H NMR (500 MHz, CDCl3)
8. 6. 3 . (S )-3 -Acetyl-3 -(4- flu oro phenyl) cyc lohexa no ne
(64b). Synthesized according to the general procedure, 0.22 mmol
scale. Title compound isolated as a pale yellow oil (45 mg, 92%
yield). 1H NMR (500 MHz, CDCl3)
d 7.26e7.19 (m, 2H), 7.11e7.03 (m,
d
7.33e7.28 (m, 4H), 7.27e7.24 (m, 5H), 7.18 (tt, J¼1.5, 7.0 Hz, 1H),
2H), 2.87 (dt, J¼14.8, 1.5 Hz, 1H), 2.65 (dt, J¼14.8, 1.3 Hz, 1H),
4.37 (s, 2H), 3.30 (dt, J¼1.5, 6.5 Hz, 2H), 2.93 (d, J¼14.5 Hz, 1H),
2.43 (d, J¼14.5 Hz, 1H), 2.33e2.26 (m, 2H), 2.22e2.16 (m, 1H),
1.98 (ddd, J¼3.0, 10.0, 13.5 Hz, 1H), 1.86e1.77 (m, 2H), 1.68 (ddd,
J¼4.5, 12.0 Hz, 1H), 1.61e1.53 (m, 1H), 1.43e1.32 (m, 1H),
2.38e2.34 (m, 2H), 2.32e2.24 (m, 2H), 1.88 (s, 3H) 1.80e1.71 (m,
2H); 13C NMR (125 MHz, CDCl3)
d 208.1, 208.0, 162.1 (d, JC-
¼247.8 Hz), 136.3 (d, JC-F¼3.3 Hz), 128.1 (d, JC-F¼8.1 Hz), 116.1 (d, JC-
F
¼21.4 Hz), 59.3, 48.5, 40.1, 31.6, 25.0, 20.9; IR (Neat Film, NaCl):
F
1.23e1.14 (m, 1H); 13C NMR (125 MHz, CDCl3)
d 211.2, 144.8,
2950, 1708, 1601, 1510, 1355, 1231, 1186, 1164 cmꢂ1; HRMS (Multi-
Mode ESI/APCI) m/z calcd for C14H16FO2 [MþH]þ: 235.1134, found
138.4, 128.5, 128.3, 127.6, 127.5, 126.4, 126.2, 72.7, 70.4, 51.0, 45.9,
41.0, 39.7, 36.6, 23.9, 21.4; IR (Neat Film, NaCl) 3057, 3027, 2947,
2858, 1710, 1602, 1495, 1451, 1359, 1312, 1280, 1228, 1100, 1075,
25
235.1132; [
a
]
ꢂ0.3 (c 1.5, CHCl3, 90% ee).
D
1026 cmꢂ1; HRMS (MultiMode ESI/APCI) m/z calcd for C22H26O2
8.6.4. (S)-3-Acetyl-3-(m-tolyl)cyclohexanone
(64c). Synthesized
25
[MþH]þ: 323.2006, found 323.1993; [
a
]
ꢂ42.9 (c 4.25, CHCl3,
D
according to the general procedure, 0.22 mmol scale. Title com-
pound isolated as an off-white solid (33 mg, 66% yield). 1H NMR
91% ee).
(500 MHz, CDCl3)
J¼14.9, 1.6 Hz, 1H), 2.65 (dt, J¼14.8, 1.2 Hz, 1H), 2.48e2.22 (m, 7H),
1.92e1.66 (m, 5H); 13C NMR (125 MHz, CDCl3)
208.5, 140.6, 138.9,
129.1, 128.3, 126.9, 123.3, 59.7, 48.6, 40.2, 31.4, 25.1, 21.5, 21.0; IR
d 7.30e7.23 (m, 1H), 7.14e7.01 (m, 3H), 2.87 (dt,
8.5.24. (R)-3-Phenyl-3-methylcyclopentanone
according to the general procedure and purified by flash chroma-
(55). Synthesized
d
tography (hexanes/EtOAc¼100:0 to 95:5) to afford a colorless oil
25
(84% yield). [
a
]
þ21.3 (c 1.51, CHCl3, 91% ee). All characterization
(Neat Film, NaCl): 2949, 1708, 1558, 1456, 1354, 1182, 1158 cmꢂ1
;
D
data match previously reported data.4f,i,k
HRMS (MultiMode ESI/APCI) m/z calcd for C15H19O2 [MþH]þ:
231.1385, found 231.1383; [
a
]
25 ꢂ4.6 (c 1.6, CHCl3, 92% ee).
D
8.5.25. (R)-3-Phenyl-3-methylcycloheptanone (56). This product
was synthesized according to the general procedure and purified by
flash chromatography (hexanes/EtOAc¼100:0 to 95:5) to afford
8.6.5. (S)-N-(5-(1-Acetyl-3-oxocyclohexyl)-2-methylphenyl)-2,2,2-
trifluoroacetamide (64d). Synthesized according to the general
Please cite this article in press as: Holder, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.048

10
J.C. Holder et al. / Tetrahedron xxx (2014) 1e12
procedure, 0.22 mmol scale. Title compound isolated as an off-
white solid (54 mg, 73% yield). 1H NMR (500 MHz, CDCl3)
dropwise and the obtained mixture was stirred for 2 h at this
temperature. Triisopropylborate (2.7 mL, 11.7 mmol, 3 equiv) was
then added via syringe and the mixture was stirred for 10 min at
ꢂ78 ꢀC and for 1 h at room temperature. A solution of HCl (2 M in
water, 10 mL) was added and the biphasic mixture was vigorously
stirred for another hour and then extracted with EtOAc (3ꢁ30 mL).
The combined organic phases were washed with brine (2ꢁ20 mL)
and dried over MgSO4. Upon evaporation of the solvent under re-
duced pressure an off-white solid was obtained. It was suspended
in hexane and stirred until a fine powder was formed. It was filtered
and dried in high vacuum for 30 min (0.58 g, 67% yield). (General
note for all trifluoroacetamide substrates: If the obtained product is
not clean from NMR analysis then a 10:1 mixture of hexane/Et2O or
hexane/CH2Cl2 can be used instead of hexanes to suspend the
compound. If the crude aryl boronic acid is obtained as an oil and
does not solidify, then add ether, water, and a 1 M solution of NaOH
(5 equiv) to the crude mixture. After extraction, the isolated water
phase can be acidified with a 1 M aqueous HCl solution and
extracted with EtOAc. The organic phased is washed with water,
brine, and concentrated in vacuo. Upon evaporation of the solvent
and trituration with pentane or hexane the desired product should
be obtained as an off-white solid.) 1H NMR (300 MHz, acetone-d6)
d
7.98e7.94 (m, 1H), 7.73 (dt, J¼5.2, 2.5 Hz, 1H), 7.27 (t, J¼4.0 Hz,
1H), 7.06 (dd, J¼8.1, 2.0 Hz, 1H), 2.90 (d, J¼14.9 Hz, 1H), 2.60 (d,
J¼15.0 Hz, 1H), 2.50e2.41 (m, 1H), 2.41e2.21 (m, 7H), 1.91 (s, 3H),
1.90e1.79 (m, 1H), 1.78e1.66 (m, 1H); 13C NMR (125 MHz, CDCl3)
d
208.2, 208.0, 155.1 (q, JC-F¼37.2 Hz), 139.8, 133.7, 131.7, 129.8, 125.1,
121.4, 115.9 (q, JC-F¼288.8 Hz), 59.6, 48.6, 40.0, 31.2, 25.1, 21.0, 16.9;
IR (Neat Film, NaCl): 3279, 2954, 1708, 1541, 1506, 1356, 1256, 1201,
1158 cmꢂ1; HRMS (MultiMode ESI/APCI) m/z calcd for C17H19O3F3N
[MþH]þ: 342.1317, found 342.1313; [
a]
D
25 18.7 (c 1.1, CHCl3, 91% ee).
8.6.6. (S)-3-Acetyl-3-(m-tolyl)cyclopentanone
(64f). Synthesized
according to the general procedure, the title compound was iso-
lated as a pale yellow oil (31 mg, 72% yield). 1H NMR (500 MHz,
CDCl3)
d
7.32e7.25 (m, 1H), 7.14 (dddt, J¼7.6, 1.9, 1.3, 0.6 Hz, 1H),
7.10e7.03 (m, 2H), 3.10 (ddd, J¼18.0, 1.7, 0.8 Hz, 1H), 2.71 (dddd,
J¼13.0, 7.7, 5.5, 1.7 Hz, 1H), 2.57e2.49 (m, 1H), 2.46e2.27 (m, 6H),
1.98 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 215.2, 207.9, 140.7, 138.9,
129.0, 128.50, 127.2, 123.5, 123.5, 47.1, 36.5, 30.8, 25.3, 21.5; IR (Neat
Film, NaCl): 2921, 1745, 1704, 1605, 1489, 1407, 1354, 1150 cmꢂ1
;
HRMS (MultiMode ESI/APCI) m/z calcd for C14H17O2 [MþH]þ:
217.1229, found 217.1218; [
a]
25 75.2 (c 1.5, CHCl3, 90% ee).
d
8.11 (br s, 1H), 7.81 (m, 1H), 7.74 (dt, J¼7.4, 1.0 Hz, 1H), 7.40 (t,
D
J¼7.7 Hz, 1H), 7.28 (s, 1H); (The obtained 13C NMR is complex due to
8.6. 7. (S)-3-Acetyl-3-(4-fluorophenyl)cyclopentanone
(64g). Synthesized according to the general procedure, the title
compound was isolated as a pale yellow oil (25 mg, 57% yield). 1H
the presence of two rotamers in solution) 13C NMR (125 MHz,
CDCl3)
d
154.8 (q, J¼36.9 Hz), 154.7 (q, J¼36.8 Hz), 135.8, 135.7,
131.5, 128.2, 126.7, 126.6, 123.0, 122.9, 116.2 (q, J¼288.1 Hz); 19F
NMR (500 MHz, CDCl3)
d
7.29e7.21 (m, 2H), 7.14e7.06 (m, 2H), 3.12
NMR (282 MHz, CDCl3)
d
ꢂ76.22, ꢂ76.25; FTIR (Neat Film, NaCl):
(dd, J¼17.8, 1.7 Hz, 1H), 2.78e2.69 (m, 1H), 2.49 (dd, J¼17.9, 0.9 Hz,
3305, 1701, 1585, 1554, 1437, 1334, 1264, 1182, 1031, 780 cmꢂ1
;
1H), 2.43e2.27 (m, 3H), 1.97 (s, 3H); 13C NMR (125 MHz, CDCl3)
HRMS (MultiMode ESI/APCI) m/z calcd for C8H7BrF3NO [MꢂH]ꢂ:
d
214.5, 207.4, 162.2 (d, JC-F¼247.8 Hz), 136.6 (d, JC-F¼3.3 Hz), 128.2
231.0435, found: 231.0433.
(d, JC-F¼8.2 Hz), 116.1 (d, JC-F¼21.5 Hz), 60.6, 47.2, 36.5, 30.9, 25.2; IR
(Neat Film, NaCl): 2925, 1745, 1704, 1599, 1509, 1408, 1355, 1223,
1142 cmꢂ1; HRMS (MultiMode ESI/APCI) m/z calcd for C13H14O2F
8.7.3. 4-(2,2,2-Trifluroacetamide)-phenylboronic
acid
(65c). Obtained using the representative procedure in 65% yield. 1H
[MþH]þ: 221.0978, found 221.0984; [
a]
25 65.9 (c 1.0, CHCl3, 92% ee).
NMR (300 MHz, acetone-d6)
d
10.22 (br s,1H), 7.91 (d, J¼8.4 Hz, 2H),
D
7.72 (d, J¼8.4 Hz, 1H), 7.20 (s, 1H); 13C NMR (125 MHz, acetone-d6)
8.7. Representative procedure for the synthesis of N-tri-
fluoroacetamide boronic acids
d
155.6 (q, JC-F¼37.2 Hz), 136.3, 139.2, 135.9, 120.5, 119.2 (q, JC-
¼288.3 Hz); 19F NMR (282 MHz, acetone-d6)
ꢂ76.21, ꢂ76.24; FTIR
d
F
(Neat Film, NaCl) 3297, 1714, 1595, 1539, 1408, 1275, 1244, 1183,
1113, 1008, 832, 798 cmꢂ1; HRMS (MultiMode ESI/APCI) m/z calcd
for C8H7BrF3NO [MꢂH]ꢂ: 231.0435, found: 231.0443.
8.7.1. N-(3-Bromophenyl)-2,2,2-trifluoroacetamide. In
a 100 mL
round bottom flask were added consecutively 3-bromoaniline
(1.7 g, 10.0 mmol, 1 equiv), DMAP (0.12 g, 1.0 mmol, 0.1 equiv),
20 mL of CH2Cl2 and Et3N (1.7 mL, 12.0 mmol, 1.2 equiv). The so-
lution was cooled to 0 ꢀC and trifluoroacetic anhydride (2.1 mL,
15.0 mmol, 1.5 equiv) was added dropwise. The obtained mixture
was stirred at room temperature until all the starting material was
consumed (TLC hexane/EtOAc 4:1) and then it was extracted with
CH2Cl2 (3ꢁ20 mL) and washed with brine (2ꢁ20 mL). The com-
bined organic phases were dried with MgSO4 and the solvent was
evaporated to give an off-white solid that was purified via silica gel
column chromatography (2.35 g, 88% yield). 1H NMR (300 MHz,
8.7.4. 4-(2,2,2-Trifluroacetamide)-3-methoxyphenylboronic
acid
(65d). Obtained as an off-white solid in 35% yield following the
general procedure and using the required trifluoroacetanilide
(1.4 g, 4.9 mmol, 1 equiv), n-BuLi (4.4 mL of a 2.4 M solution,
10.7 mmol, 2.2 equiv) and triisopropylborate (3.4 mL, 14.6 mmol,
3 equiv). 1H NMR (300 MHz, acetone-d6)
d
9.34 (s, 1H), 8.05 (dd,
J¼3.0, 6.9 Hz,1H), 7.58 (s 1H), 7.54 (dd, J¼7.9, 1.0 Hz, 1H) 7.29 (s, 1H),
3.93 (s, 3H); 13C NMR (125 MHz, acetone-d6)
154.3 (q, JC-
d
¼150 Hz), 149.3, 126.8, 126.6, 120.5, 116.1, 115.8 (q, JC-F¼288 Hz),
F
CDCl3)
d
7.84 (t, J¼2.0 Hz, 1H), 7.80 (br s, 1H), 7.51 (dd, J¼8.1, 1.2 Hz,
112.5, 55.4; IR (Neat Film, NaCl): 3298, 1708, 1591, 1537, 1503, 1465,
1404, 1342, 1294, 1273, 1224, 1161, 1123, 1015; HRMS (MultiMode
ESI/APCI) m/z calcd for C9H8BO4NF3 [MꢂH]ꢂ: 261.0590, found:
261.0497.
1H), 7.39 (d, J¼8.2 Hz, 1H), 7.30e7.24 (m, 1H); 13C NMR (125 MHz,
CDCl3)
d
155.1 (q, JC-F¼37.7 Hz), 136.3, 130.7, 129.7, 123.8, 123.0,
119.3, 115.6 (q, JC-F¼288.5 Hz); 19F NMR (282 MHz, CDCl3)
ꢂ75.72,
d
ꢂ75.73; FTIR (Neat Film, NaCl) 3288, 1709, 1593, 1538, 1470, 1429,
1338, 1263, 1251, 1171, 1153, 1069, 997, 975, 925, 873, 865, 785,
739 cmꢂ1; HRMS (MultiMode ESI/APCI) m/z calcd for C8H5BrF3NO
[MꢂH]ꢂ: 265.9434, found: 295.9426.
8.7.5. 4-(2,2,2-Trifluroacetamide)-2,6-dimethyl-phenylboronic acid
(65e). Obtained as an off-white solid in 66% yield following the
general procedure and using the required trifluoroacetanilide
(1.0 g, 3.4 mmol, 1 equiv), n-BuLi (3.2 mL of a 2.3 M solution,
7.44 mmol, 2.2 equiv) and triisopropylborate (2.3 mL, 10.1 mmol,
8.7.2. 3-(2,2,2-Trifluroacetamide)-phenylboronic acid (65f). A flame
dried one neck round bottom flask was charged with the required
trifluoroacetanilide (1.0 g, 3.7 mmol, 1 equiv). The flask was sealed,
evacuated, and backfilled with argon. THF (20 mL) was added via
syringe and the obtained mixture was cooled to ꢂ78 ꢀC. n-BuLi
(2.3 M solution in hexane, 3.6 Ml, 8.2 mmol, 2.2 equiv) was added
3 equiv). 1H NMR (300 MHz, acetone-d6)
d 7.62 (s, 2H), 7.20 (s, 1H),
2.25 (s, 6H); 13C NMR (125 MHz, acetone-d6)
d
155.1 (q, J¼36.5 Hz),
134.2, 134.2, 134.1, 133.9, 116.5 (q, J¼286.0 Hz), 17.1; 19F NMR
(282 MHz, acetone-d6)
d
ꢂ75.97, ꢂ75.99; FTIR (Neat Film, NaCl):
3233, 1705, 1602, 1533, 1340, 1219, 1192, 1160 cmꢂ1; HRMS
Please cite this article in press as: Holder, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.048

J.C. Holder et al. / Tetrahedron xxx (2014) 1e12
11
(MultiMode ESI/APCI) m/z calcd for C10H11NBrF3O [MꢂH]ꢂ:
1.72e1.58 (m, 1H), 1.31 (s, 9H), 1.29 (s, 3H); 13C NMR (125 MHz,
CDCl3) 211.6, 176.7, 143.4, 136.2, 126.3, 120.1, 53.2, 42.7, 40.9, 39.7,
259.0748, found 259.0749.
d
38.1, 30.1, 27.8, 22.1; FTIR (Neat Film, NaCl) 3379, 2961, 1685, 1594,
1518, 1400, 1318, 1301, 1255, 1189 cmꢂ1; HRMS (MultiMode ESI/
APCI) m/z calcd for C18H26NO2 [MþH]þ: 288.1964, found 288.1969;
8.7.6. 3-(2,2,2-Trifluroacetamide)-4-methylphenylboronic
acid
(65g). Obtained as an off-white solid in 66% yield following the
general procedure and using the required trifluoroacetanilide
(2.0 g, 3.7 mmol, 1 equiv), n-BuLi (3.6 mL of a 2.3 M solution,
8.2 mmol, 2.2 equiv) and triisopropylborate (2.6 mL, 11.2 mmol,
[a
]
25 ꢂ52.5 (c 1.01, CHCl3, 78% ee).
D
8.8.4. (R)-3-(4-(2,2,2-Trifluoroacetamide)-3-methoxyphenyl)-3-
methylcyclohexanone (66d). Following the general procedure the
desired product was obtained as white solid (67 mg, 75% yield). 1H
3 equiv). 1H NMR (300 MHz, acetone-d6)
d 7.82 (s, 1H), 7.75 (dd,
J¼6.5, 10 Hz, 1H), 7.32 (d, J¼7.5 Hz, 1H) 7.24 (s, 1H); 13C NMR
(125 MHz, acetone-d6)
d
155.4 (q, J¼37.5 Hz), 136.2, 133.5, 132.9,
NMR (300 MHz, CDCl3)
d
8.50 (br s, 1H), 8.24 (d, J¼8.5 Hz, 2H), 6.96
132.1, 130.1, 116.4 (q, J¼288.0 Hz); FTIR (Neat Film, NaCl) 3270, 1708,
(dd, J¼8.5, 2.1 Hz, 1H), 6.87 (d, J¼2.1 Hz, 1H), 3.93 (s, 3H), 2.87 (d,
J¼14.1 Hz, 1H), 2.45 (d, J¼14.2 Hz, 1H), 2.32 (m, 1H), 2.24e2.14 (m,
1H), 2.0e1.8 (m, 1H), 1.68e2.5 (m, 1H), 1.32 (s, 3H); FTIR (neat,
NaCl): 3362, 2960, 2871, 1706, 1665, 1594, 1515, 1479, 1402, 1321,
1617, 1533, 1406, 1351, 1259, 1180, 1162, 1092, 1036, 898, 825 cmꢂ1
;
HRMS (MultiMode ESI/APCI) m/z calcd for C9H8BF3NO3 [MꢂH]ꢂ:
245.0477, found 245.0591.
1228, 1193, 1164 cmꢂ1; HRMS (MultiMode ESI/APCI) m/z calcd for
25
8.8. Representative general procedure for the enantiose-
C
16H17F3NO3 [MꢂOH]: 328.1161, found: 328.1167; [
a]
ꢂ61.3 (c
D
lective 1,4-addition of arylboronic acids to
enones
b-substituted cyclic
1.25, CHCl3, 88% ee).
8.8.5. (R)-3-(4-(2,2,2-Trifluoroacetamide)-2,6-dimethylphenyl)-3-
methylcyclohexanone (66e). Following the general procedure the
desired product was obtained in 93% yield as a white solid (90% ee,
SFC column 1 (AD-H) 5 mL/min 5% MeOH). 1H NMR (300 MHz,
8 . 8 .1. ( R ) - 3 - ( 4 - ( 2 , 2 , 2 -Tr i flu o ro a c e t a m i d e ) p h e nyl ) - 3 -
methylcyclohexanone (66c). A screw-top 5 mL vial was charged
with a stir bar, Pd(OCOF3)2 (4.5 mg, 0.014 mmol, 0.05 equiv), (S)-t-
BuPyOx (3.3 mg, 0.016 mmol, 0.06 equiv), boronic acid (95 mg,
0.41 mmol, 1.5 equiv), and NH4PF6 (13 mg, 0.08 mmol, 0.3 equiv).
Dichloroethane (1 mL) was added and the mixture was stirred until
a homogeneous suspension was formed (1 min). 3-Methyl-2-
cyclohexenone (30 mg, 0.27 mmol, 1 equiv) was then added dis-
solved in 1.7 mL of dichloroethane (yields are improved with the
CDCl3)
d
7.41 (br s, 1H), 7.05 (s, 2H), 2.84 (d, J¼14.2 Hz, 1H), 2.42 (d,
J¼14.1 Hz, 1H), 2.32 (m, 2H), 2.24 (s, 6H), 2.21e2.10 (m, 1H),
1.96e1.80 (m, 2H), 1.76e1.60 (m, 1H), 1.30 (s, 3H); 13C NMR
(125 MHz, CDCl3)
d
211.8, 156.2 (q, J¼36.4 Hz), 147.6, 135.1, 128.9,
125.7, 118.2 (q, J¼279.9 Hz), 52.8, 42.4, 40.6, 37.6, 29.4, 21.9, 18.2;
FTIR (Neat Film, NaCl) 2958, 2863, 1715, 1651, 1583, 1568, 1538,
1479, 1441, 1359, 1314, 1228, 1198, 1157, 1101 cmꢂ1; HRMS (Multi-
Mode ESI/APCI) m/z calcd for C17H20F3NO2 [MꢂH]ꢂ: 326.1373,
addition of enone as a solution). Water (25 mL, 1.3 mmol, 5 equiv)
was added, and the vial was sealed and the reaction was stirred at
60 ꢀC for 3 h. After this time almost all the solid in the vial was
consumed and from TLC (hexane/EtOAc 4:1) all the starting enone
disappeared. The mixture was cooled to ambient temperature and
it was charged directly into a silica gel column for purification. The
desired product was isolated as white powder (80 mg, 98% yield,
89% ee SFC column 6 (IC) 5 mL/min 4% MeOH). 1H NMR (300 MHz,
found 326.1370; [
a
]
25 ꢂ54.3 (c 2.10, CHCl3, 90% ee).
D
8. 8. 6. (R) -3-(3 -(2, 2 , 2 -Tri flu o roa c e t a m id e )p h enyl) - 3 -
methylcyclohexanone (66f). Following the general procedure the
desired product was obtained in 60% yield as transparent oil (92%
ee, SFC column 1 (AD-H) 5 mL/min 5% MeOH). 1H NMR (300 MHz,
CDCl3)
d
7.91 (br s,1H), 7.53 (m, 2H), 7.36 (m, 2H), 2.85 (d, J¼14.2 Hz,
CDCl3)
d
7.91 (br s, 1H), 7.55e7.45 (m, 2H), 7.36 (t, J¼7.9 Hz,1H), 7.20
1H), 2.45 (d, J¼14.0 Hz, 1H), 2.32 (m, 2H), 2.25e2.12 (m, 1H),
(m,1H), 2.87 (d, J¼14.2 Hz,1H), 2.46 (d, J¼14.2 Hz,1H), 2.32 (m, 2H),
1.98e1.82 (m, 2H), 1.71e1.57 (m, 1H), 1.32 (s, 3H); 13C NMR
2.27e2.17 (m, 1H),1.98e1.82 (m, 2H),1.71e1.57 (m,1H),1.33 (s, 3H);
(125 MHz, CDCl3)
d
211.8, 154.9 (q, J¼37.4 Hz), 145.2, 133.5, 126.7,
13C NMR (125 MHz, CDCl3)
d
211.5, 154.9 (q, J¼37.0 Hz), 148.9, 135.5,
120.6, 115.7 (q, J¼289.0 Hz), 52.9, 42.9, 40.7, 37.9, 30.4, 22.0; FTIR
(Neat Film, NaCl) 3292, 2958, 1706, 1609, 1545, 1517, 1412, 1285,
1252, 1193, 1155, 901, 835 cmꢂ1; HRMS (MultiMode ESI/APCI) m/z
129.5, 123.6, 118.5, 118.0, 115.6 (q, J¼289.2 Hz), 52.9, 43.0, 40.7, 37.8,
30.0, 22.0; FTIR (Neat Film, NaCl) 3298, 3157, 3111, 2959, 2876, 1713,
1616, 1595, 1563, 1493, 1442, 1421, 1291, 1239, 1201, 1156 cmꢂ1
;
calcd for C15H16F3NO [MꢂH]ꢂ: 298.106, found 289.1049; [
(c 2.10, CHCl3, 89% ee).
a
]
25 ꢂ47.5
HRMS (MultiMode ESI/APCI) m/z calcd for C15H16F3NO2 [MꢂH]ꢂ:
D
25
298.1055, found: 298.1050; [
a
]
ꢂ28.9 (c 2.10, CHCl3, 92% ee).
D
8.8.2. (R)-3-(4-(N-Carbobenzyloxy)phenyl)-3-methylcyclohexanone
(66a). Following the general procedure the desired product was
obtained as a clear oil (35 mg, 45% yield, 76% ee, SFC column 6 (IC)
8.8.7. (R)-3-(3-(2,2,2-Trifluoroacetamide)-4-methylpheny)-3-
methylcyclohexanone (66g). Following the general procedure the
desired product was obtained in 77% yield as a white solid (91% ee,
OD-H column, 5 mL/min, 5% MeOH). 1H NMR (300 MHz, CDCl3)
5 mL/min 15% MeOH). 1H NMR (300 MHz, CDCl3)
d 7.44e7.30 (m,
6H), 7.25e7.22 (m, 3H), 6.63 (br s,1H), 5.20 (s, 2H), 2.84 (d, J¼14.2 Hz,
1H), 2.42 (d, J¼14.1 Hz, 1H), 2.31 (m, 2H), 2.21e2.10 (m, 1H),
1.95e1.80 (m, 2H),1.73e1.60 (m,1H),1.30 (s, 3H); 13C NMR (125 MHz,
d
7.94 (br s, 1H), 7.66 (s, 1H), 7.16 (d, J¼8.1 Hz, 1H), 7.11 (dd, J¼8.1,
1.9 Hz, 1H), 2.85 (d, J¼14.1 Hz, 1H), 2.44 (d, J¼14.1 Hz, 1H), 2.32 (m,
2H), 2.26 (s, 3H), 2.24e2.07 (m, 1H), 1.97e1.80 (m, 2H), 1.78e1.60
CDCl3)
d
211.6, 153.5, 142.7, 136.1, 135.9, 128.7, 128.5, 128.4, 126.5,
(m, 1H), 1.31 (s, 3H). 13C NMR (125 MHz, CDCl3)
d 211.3, 156.2 (q,
118.9, 67.2, 53.3, 42.6, 40.9, 38.0, 30.1, 22.1; FTIR (Neat Film, NaCl)
J¼36.4 Hz), 146.6, 132.9, 131.4, 130.9, 128.3, 124.4, 118.1 (q,
J¼279.8 Hz), 53.0, 42.7, 40.7, 37.7, 29.6, 22.0, 16.9; FTIR (Neat Film,
NaCl) 3277, 3060, 2959, 2873, 1711, 1617, 1577, 1540, 1507, 1452,
1420, 1316, 1281, 1257, 1200, 1162 cmꢂ1; HRMS (MultiMode ESI/
3306, 2953, 1705, 1597, 1534, 1454, 1409, 1323, 1220, 1052 cmꢂ1
;
HRMS (MultiMode ESI/APCI) m/z calcd for C21H24NO3 [MþH]þ:
338.1756, found 338.1760; [
a
]
D
25 ꢂ26.8 (c 1.40, CHCl3, 76% ee).
APCI) m/z calcd for
C
16H18F3NO2 [MþH]þ: 314.1362, found:
8.8.3. (R)-3-(4-(N-Pivaloyl)phenyl)-3-methylcyclohexanone
(66b). Following the general procedure the desired product was
obtained as a white solid (56 mg, 72% yield, 78% ee SFC column 5
314.1370. [
a]
25 ꢂ45.6 (c 5.3, CHCl3, 88% ee).
D
Acknowledgements
(OBeH) 5 mL/min 10% MeOH). 1H NMR (300 MHz, CDCl3)
d 7.47 (d,
J¼8.7 Hz, 2H), 7.33e7.24 (m, 2H), 2.85 (d, J¼14.2 Hz, 1H), 2.42 (d,
We are thankful to the NIH-NIGMS (R01GM080269), Caltech,
Amgen, the American Chemical Society Division of Organic
J¼14.2 Hz, 1H), 2.31 (m, 2H), 2.21e2.11 (m, 1H), 1.95e1.80 (m, 2H),
Please cite this article in press as: Holder, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.048

12
J.C. Holder et al. / Tetrahedron xxx (2014) 1e12
A. Angew. Chem., Int. Ed. 2008, 47, 9122; (d) Matsumoto, Y.; Yamada, K.-I.; To-
mioka, K. J. Org. Chem. 2008, 73, 4578.
6. (a) For the seminal report in this area, see: Takaya, Y.; Ogasawara, M.; Hayashi,
T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579; (b) For an excellent
review, see: Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829.
Chemistry (predoctoral fellowship to J.C.H.), the Swiss National
Science Foundation (postdoctoral fellowship to M.G.), the Japan
Society for the Promotion of Science (postdoctoral fellowship to
K.K.), and the German National Academy of Sciences Leopoldina
(LPDS 2011-12 postdoctoral fellowship to A.N.M.) for financial
support. Prof. Theodor Agapie, Prof. Sarah E. Reisman, and Mr.
Robert A. Craig, II (Caltech) are thanked for helpful discussions. Dr.
David VanderVelde (Caltech) is thanked for invaluable assistance
with NMR experiments and helpful discussions. The Varian
400 MHz NMR spectrometer at Caltech was purchased via an NIH
grant (RR027690).
7. For selected recent examples, see: (a) Hayashi, T.; Ueyama, K.; Tokunaga, N.;
Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508; (b) Shintani, R.; Ueyama, K.;
Yamada, I.; Hayashi, T. Org. Lett. 2004, 6, 3425; (c) Otomaru, Y.; Okamoto, K.;
Shintani, R.; Hayashi, T. J. Org. Chem. 2005, 70, 2503; (d) Paquin, J.-F.; Defieber,
C.; Stephenson, C. R. J.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 10850.
ꢀ
8. (a) Mauleon, P.; Carretero, J. C. Chem. Commun. 2005, 4961; (b) Shintani, R.;
Duan, W.-L.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 5628.
9. (a) Shintani, R.; Tsutsumi, Y.; Nagaosa, M.; Nishimura, T.; Hayashi, T. J. Am.
Chem. Soc. 2009, 131, 13588; (b) Shintani, R.; Takeda, M.; Nishimura, T.; Hayashi,
T. Angew. Chem., Int. Ed. 2010, 49, 3969.
10. The same group also reported additions to
esters, see: Shintani, R.; Hayashi, T. Org. Lett. 2011, 13, 350.
11. A recent paper describing the use of a Rh$OlefOx (olefin-oxazoline) complex
provided single example of phenylboronic acid addition to 3-
b,b-disubstituted a,b-unsaturated
Supplementary data
a
a
methylcyclohexen-2-one (i.e., 1þ2/3). Unfortunately, ketone 3 was isolated
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.11.048.
€
in only 36% yield and 85% ee, see: Hahn, B. T.; Tewes, F.; Frohlich, R.; Glorius, F.
Angew. Chem., Int. Ed. 2010, 49, 1143.
12. For excellent review articles, see: (a) Gutnov, A. Eur. J. Org. Chem. 2008, 4547;
€
(b) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rossle, M. Synthesis 2007, 1279; (c)
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Please cite this article in press as: Holder, J. C.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.11.048