Access to Functionalized Quaternary Stereocenters via the Copper-Catalyzed Conjugate Addition of Monoorganozinc Bromide Reagents Enabled by N, N-Dimethylacetamide

Article abstract of DOI:10.1021/acs.joc.8b02201

Monoorganozinc reagents, readily obtained from alkyl bromides, display excellent reactivity with β,β-disubstituted enones and TMSCl in the presence of Cu(I) and Cu(II) salts to synthesize a variety of cyclic functionalized β-quaternary ketones in 38-99% yields and 9:1-20:1 diastereoselectivities. The conjugate addition features a pronounced improvement in DMA using monoorganozinc bromide reagents. A simple one-pot protocol that harnesses in situ generated monoorganozinc reagents delivers comparable product yields.

Full text of DOI:10.1021/acs.joc.8b02201

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Note
Access to Functionalized Quaternary Stereocenters via the
Copper-Catalyzed Conjugate Addition of Monoorganozinc
Bromide Reagents Enabled by N,N-Dimethylacetamide
Tyler Fulton, Phebe L. Alley, Heather R. Rensch, Adriana
M. Ackerman, Cameron B. Berlin, and Michael R Krout
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02201 • Publication Date (Web): 30 Oct 2018
Downloaded from http://pubs.acs.org on October 30, 2018
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Access to Functionalized Quaternary Stereocenters via the Copper-Catalyzed Conjugate
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Addition of Monoorganozinc Bromide Reagents Enabled by N,N-Dimethylacetamide
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Tyler J. Fulton,† Phebe L. Alley,‡ Heather R. Rensch,§ Adriana M. Ackerman,‡ Cameron B.
Berlin,‡ Michael R. Krout‡,*
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†Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering,
California Institute of Technology, Pasadena, California 91125, United States
§Research and Development, Bimax, Inc., Glen Rock, Pennsylvania 17327, United States
‡Department of Chemistry, Bucknell University, Lewisburg, Pennsylvania 17837, United States
michael.krout@bucknell.edu
Abstract Image
O
O
CuBr•DMS (5 mol%)
TMSCl
30 examples
38–99% yield
9:1– 20:1 dr
(
)
(
)
n
n
BrZn
R
R
R4
R1
R4
DMA, 0 → 23 °C
R3
R3
R1
R2
R2
β-quaternary ketone
Abstract
Monoorganozinc reagents, readily obtained from alkyl bromides, display excellent reactivity
with β,β-disubstituted enones and TMSCl in the presence of Cu(I) and Cu(II) salts to synthesize
a variety of cyclic functionalized β-quaternary ketones in 38–99% yields and 9:1–20:1
diastereoselectivities. The conjugate addition features a pronounced improvement in DMA using
monoorganozinc bromide reagents. A simple one-pot protocol that harnesses in situ generated
monoorganozinc reagents delivers comparable product yields.
The metal-catalyzed formation of C–C bonds with organometallics represents a versatile
technology in organic synthesis. Organozinc reagents comprise an important class of
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organometallics that have earned widespread use due to their outstanding functional group
compatibility while maintaining sufficient reactivity.1,2,3,4 This enhanced chemoselectivity
coupled with reagent accessibility facilitates applications in the construction of highly
functionalized organics for complex molecule synthesis. Strategies have been developed to
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modulate the reactivity of mild organozinc species when engaged with challenging substrates, as
demonstrated in their conjugate addition to β,β-disubstituted α,β-unsaturated carbonyls. The
application of sensitive diorganozinc5,6,7 or mixed diorganozinc8 reagents has enabled the
synthesis of β-quaternary carbonyls that include recent enantioselective achievements.9,10,11
Monoorganozinc reagents, however, have been underutilized despite the appeal of their
simplified preparation via the direct insertion of zinc into a carbon–halogen bond. Examples that
leverage the addition of monoorganozinc reagents to sterically demanding β,β-disubstituted α,β-
unsaturated carbonyls are surprisingly limited and require stoichiometric cyanocuprate
reagents.12,13,14 Moreover, a single example demonstrating minimal catalyst turnover has been
reported.15 Our interest in this transformation came from a desire to prepare functionalized β-
quaternary ketones for synthesis applications. A key goal in this endeavor was to harness mild,
functionalized organometallics that are both economical and trivial to access. To this end, we
have developed a simple and efficient Cu-catalyzed addition of alkyl monoorganozinc bromide
(RZnBr) reagents to cyclic α,β-unsaturated ketones augmented by the polar solvent N,N-
dimethylacetamide (DMA).
We began our studies with monoorganozinc iodide reagent 1 (RZnI) and 3-
methylcyclohexenone (3) as our model substrates. A variety of conditions were examined that
comprised CuCN•2LiCl in combination with Lewis acids in order to establish a baseline of
reactivity for the production of β-quaternary ketone 6. The conjugate addition of 1 promoted by
stoichiometric CuCN•2LiCl with BF313 afforded only a modest yield of 6 (Table 1, entry 1).
Employing sub-stoichiometric copper failed to produce 6, although measurable quantities could
be realized with TMSCl upon acid or fluoride-mediated hydrolysis of an intermediate silyl enol
ether (entries 2 and 3). HMPA has been established as a beneficial component for conjugate
additions with TMSCl,15,16,17,18 and indeed the use of this polar additive improved the catalyst
efficiency and yield of 6 to 73% (entry 4). While there is an advantage with HMPA, the use of
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alternative non-carcinogenic Lewis bases is desirable.17 To this end, various polar, aprotic
solvents were considered for their compatibility with organozinc reagents.19,20,21 We were
pleased to find that the inclusion of DMA as an additive doubled the reaction efficiency
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8
9
compared to no polar additive, generating 6 in 49% yield (entry 5). Further utilizing DMA as the
reaction solvent with 1 (solution in DMA) yielded a modest increase in 6 to 56% (entry 6).
Organozinc iodide preparation is aided by the relative ease of zinc insertion into the weaker C–I
bond, although this limits application with respect to the modest options of commercial alkyl
iodides ostensibly due to their instability. Organozinc bromides are accessible from ubiquitous
alkyl bromides,19,20,22 including Huo’s convenient method of preparing stable23 solutions of
RZnBr reagents in polar, aprotic solvents. Gratifyingly, RZnBr reagent 2 performed
exceptionally in this conjugate addition to provide 6 in up to 90% yield with 5 mol% catalyst
(entries 7 and 8). The proficiency of this Cu-catalyzed conjugate addition for the synthesis of β-
quaternary ketone 6 is remarkable considering the use of simple RZnBr reagents in DMA, and it
is arguably superior to HMPA in terms of feasibility and chemical safety. Although further
investigation is necessary to ascertain to role of the halide (Br) and DMA in this transformation,
we posit that both components augment the reactivity of the monoorganozinc to facilitate
transmetalation to the Cu-catalyst. Recent studies have demonstrated similar halide effects in
polar solvents for both Cu-catalyzed24 and Pd-catalyzed25,26 Negishi cross-couplings. Amidic
solvents have also been hypothesized to increase the reactivity of organozinc reagents through
coordination to the zinc center.27
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Table 1. Optimization of the Cu-Catalyzed Conjugate Addition of Monoorganozinc Reagents.
OR
CuCN•2LiCl
Lewis acid
additive
AcOH
or
TBAF
O
O
CO2Et
CO2Et
CO2Et
solvent
0 → 23 °C
XZn
Me
Me
(R = BF3)
(R = TMS)
Me
1
(X = I)
4
5
3
6
2
(X = Br)
entrya RZnX
Cu
Lewis acid
solvent
additive
(equiv)
yield
(%)b
(mol%)
122
10
1
2
3
4
1
1
1
1
BF3•Et2O
BF3•Et2O
TMSCl
THF/Et2O
THF/Et2O
THF/Et2O
–
–
–
56
0
10
25
73
10
TMSCl
THF/Et2O HPMA (2.4)
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1
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10
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5
TMSCl
TMSCl
TMSCl
TMSCl
THF/Et2O DMA (2.4)
49
56
89
90
DMA
DMA
DMA
–
–
–
a
b
1.00 mmol 3, 1.4–2.0 equiv 1 or 2, and 2.4 equiv Lewis acid for up to 24 h.
Isolated yields.
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Our identification of DMA as an optimal solvent with RZnBr reagents (i.e., 2) led to further
examination of the reaction catalyst and conditions. A brief survey of common catalysts revealed
that a number of Cu(I) and Cu(II) salts are effective in the production of 6 (Table 2). It is
noteworthy that LiCl is no longer necessary for the solvation of CuCN, affording 6 in
comparable yield (cf. entries 1 and 2). Halide and carboxylate salts of Cu(I) and Cu(II) are
generally efficacious for this transformation (entries 3–6 and 8–10), whereas copper oxides
5
(entries 7 and 11) and Ni(acac)2 (entry 12) are substantially less effective. Although various
copper salts could be utilized in this transformation, we chose to advance our study with
CuBr•DMS given the convenience and reproducibility of this catalyst. Lowering the CuBr•DMS
loading to 2 mol% resulted in a diminished yield of 6 due to the incomplete conversion of 3 (cf.
entries 3 and 13). Further analysis of TMSCl and 2 revealed that lowering the equivalence to 1.2
also decreased the product yield due to incomplete conversion (entries 14 and 15). No product
was formed in the absence of either Cu-catalyst or TMSCl (entries 16 and 17). It is plausible that
DMA can also enhance enone silylation through activation of TMSCl.7
Table 2. Conjugate Addition Catalyst Survey.
O
O
catalyst
CO2Et
CO2Et
TMSCl
BrZn
DMA
0 → 23 °C
Me
Me
(H+ or F– workup)
2
3
6
entrya
catalyst (mol%)
CuCN•2LiCl (5)
CuCN (5)
yield (%)b
1
2
3
4
5
90
87
92
90
90
CuBr•DMS (5)
CuCl (5)
CuI (5)
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CuTC (5)c
Cu2O (10)
82
35
92
92
92
11
0
7
8
CuBr2 (5)
9
CuCl2 (5)
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Cu(OAc)2 (5)
CuO (10)
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Ni(acac)2 (10)
CuBr•DMS (2)
CuBr•DMS (5)
CuBr•DMS (5)
CuBr•DMS (5)
–
78
81d
67e
0f
0
a 1.00 mmol 3, 2 equiv 2, and 2.4 equiv TMSCl for
up to 24 h. Isolated yields. TC = thiophene-2-
carboxylate. d 1.2 equiv 2. e 1.2 equiv TMSCl. f No
TMSCl.
b
c
With optimized conditions in hand, we examined the scope of monoorganozinc and α,β-
unsaturated ketones (enones; Scheme 1). A variety of functional monoorganozinc reagents
proved effective in this reaction, affording β-quaternary ketones that incorporate ester (6 and 7),
chloro (8), nitrile (9), and carbamate (10) groups in high yields. The cyclic enones could also
possess alternative β-functionality, with n-butyl (11), benzyl (12), and phenyl (13) groups well-
tolerated. The absence of examples of quaternary center formations with monoorganozinc
additions to enones of various ring sizes led us to survey five- and seven-membered ring
substrates. Both systems were effective in this reaction, demonstrated by the formation of
cycloheptenone 14 in 69% yield and cyclopentenone 15 in 51% yield. The yield of 15 could be
improved to 62% by increasing the catalyst loading, although the enone conversion remained
incomplete presumably due to the poor overlap of the conjugated system. The stereoselectivity of
the addition reaction with a variety of γ- and δ-substituted enones was also investigated. We
were pleased to find that the Cu-catalyzed reactions of simple monoorganozinc reagents
proceeds with excellent efficiencies and high diastereoselectivities (16–19). Isophorone was used
to examine the steric constraints of this reaction based on the highly methylated core of this
enone.28 Addition product 20 was obtained in a modest 45% yield due to incomplete conversion.
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Importantly, this positive result highlights the feasibility and potential of Cu-catalyzed additions
of monoorganozinc reagents to sterically demanding substrates.
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Scheme 1. Substrate Scope of the Cu-Catalyzed Conjugate Addition of Moonorganozinc
Reagents to Enonesa,b
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O
O
CuBr•DMS (5 mol%)
TMSCl
(
)
(
)
n
n
BrZn
R
R
R4
R1
R4
DMA, 0 → 23 °C
(H+ or F– workup)
R3
R3
R1
R2
R2
O
O
O
O
O
O
O
CO2Et
CO2Et
CO2Et
CO2Et
CN
R
NCbz
Ph
Me
Me
(R = OAc), 93% yield
Me
Me
Me
Ph
6
92% yield
10
89% yield
13
90% yield
7
8
9
81% yield
12
93% yield
11
86% yield
(R = Cl), 84% yield
O
O
R
O
O
O
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
R
Me
Me
14
Me
Me
Me
Me Me
15
51% yield
(62% yield)c
18 (R = Ph), 99% yield, > 20:1 dr
19 (R = Me), 97% yield, > 20:1 dr
20
45% yield
16 (R = OTBS), 94% yield, 9.2:1 dr
17 (R = CO2Me), 92% yield, 15:1 dr
69% yield
a 1.00 mmol enone, 2 equiv RZnBr, and 2.4 equiv TMSCl for up to 24 h. b Yields represent isolated analytically pure products. c 10 mol% CuBr•DMS.
The use of isolated monoorganozinc reagents in this transformation motivated our
development of a practical one-pot procedure to leverage in situ generated monoorganozincs in a
sequential addition reaction. This simplified protocol would minimize reagent manipulation, and
moreover, has the potential to facilitate expedient access to a more diverse collection of products
considering the accessibility and stability of 1° and 2° organobromides. The monoorganozinc
reagent was obtained by the direct insertion of zinc into organobromides (e.g., 21) at elevated
temperature in DMA.21 Upon completion, the reagent was cooled to 0 °C followed by addition of
CuBr•DMS, TMSCl and enone 3 to produce 6 in 34% yield (Equation 1). We surmised that the
remaining zinc and related insoluble salts may impact the catalyst efficiency, and accordingly
observed improved yields using higher catalyst loadings. Comparable yields were realized using
20 mol% catalyst, and we proceeded with these conditions as our standard one-pot procedure to
explore a broad substrate scope (Scheme 2). Monoorganozinc reagents that incorporate ester
functionality at various chain lengths afford addition products in high yields (7, 22, and 23),
including 6 in 92% yield on 5.0 mmol scale. Nitrogen-containing monoorganozincs were well
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tolerated to afford nitrile (9 and 24), carbamate (10), and phthalimide (25) products in good
yields. The addition reaction was efficient with various β-substituted cyclohexenones (11–13)
and cycloheptenone (14). Homoallyl (26), homobenzyl (27), and benzyl (28) monoorganozinc
reagents provide high yields of addition products, including para substituted benzyl-containing
products (29 and 30). The introduction of alkyl groups is facile (31), highlighted by use of a 2°
monoorganozinc reagent to afford 32 in 87% yield. Cyclopentenone substrates remained a
challenge, affording modest and variable yields with the incorporation of ester (15 and 33),
nitrile (34), and chloro (35) functionality with our conditions. Cyclohexenone substrates with γ-
and δ-substitution proceeded in high yields and diastereoselectivities for the one-pot additions
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(16–19). Cyclohexenone is among the most utilized substrates for this type of conjugate addition
reaction, and the expected 3° product (36) was formed in excellent yield.12,14,15,29
O
CuBr•DMS (cat.)
3
CO2Et
CO2Et
, TMSCl
(1)
X
DMA, 0 → 23 °C
(H+ or F– workup)
Me
21 (X = Br)
6
Zn
DMA
80 °C
5 mol% CuBr•DMS
10 mol%
20 mol%
34% yield
72% yield
90% yield
2 (X = ZnBr)
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Scheme 2. Substrate Scope for the One-Pot Synthesis and Conjugate Addition of
Monoorganozinc Reagentsa,b
7
8
9
O
O
CuBr•DMS (20 mol%)
TMSCl
Zn
(
)
(
)
n
n
R
Br
R
ZnBr
DMA, 23–80 °C
DMA, 0 → 23 °C
R3
R1
R3
R
R1
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(H+ or F– workup)
R2
O
R2
in situ
O
O
O
O
O
CO2Et
CN
NPhth
CO2Et
R
NCbz
(
)
n
(
)
n
R
Me
(R = OAc), 92% yield
Me
Me
Me
Me
(n = 1), 92% yieldc
22 (n = 2), 84% yield
23 (n = 3), 91% yield
11 (R = n-Bu), 91% yield
12 (R = CH2Ph), 92% yield
13 (R = Ph), 87% yield
6
7
8
9
(n = 1), 93% yield
24 (n = 4), 95% yield
10
80% yield
25
(R = Cl), 87% yield
66% yield
O
O
O
O
O
O
CO2Et
R
Ph
Me
Me
Me
Me
Me
Me
Me
31
32
28 (R = H), 96% yield
29 (R = Me), 78% yield
30 (R = Br), 63% yield
27
14
26
89% yield
88% yield
97% yield
69% yield
82% yield
O
O
O
O
O
O
CO2Et
CO2Et
CN
CO2Et
CO2Et
Cl
(
)
n
R
Me
R
Me
Me
Me
Me
36
15 (n = 1), 69% yield
33 (n = 2), 55% yield
34
38% yield
35
66% yield
18 (R = Ph), 73% yield, 15:1 dr
19 (R = Me), 71% yield, > 20:1 dr
16 (R = OTBS), 93% yield, 8:1 dr
17 (R = CO2Me), 90% yield, 16:1 dr
92% yield
a 1.00 mmol enone, 2 equiv RBr, 20 mol% CuBr•DMS, and 2.4 equiv TMSCl for up to 24 h. b Yields represent isolated analytically pure products. c 5.00 mmol enone.
The efficient one-pot procedure enabled us to demonstrate a broad scope of the
monoorganozinc bromide reagents in the addition reaction with a few exceptions. Stabilized
monoorganozincs, such as enolate 37, homoenolate 38,30 and allyl (39) did not yield any addition
products (Figure 1). Benzylic monoorganozincs appear to deviate from this trend (28–30),
although electronic tuning by a withdrawing p-ester group (40) resulted in a failed addition.
Monoorganozincs that contain β- or γ-NHBoc groups (41 and 42) did not provide addition
products despite their reported use with less demanding electrophiles.31 The conjugate addition
was also found to be sensitive to organozinc sterics, indicated by unsuccessful additions with
ortho substituted (43) or β-quaternary (44) organozincs.
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CO2Et
BrZn
BrZn
( )n
CO2Me
BrZn
5
6
37 (n = 0)
38 (n = 1)
39
40
OBn
Me
7
8
9
BrZn
BrZn
( )n
BrZn
NHBoc
Me
41 (n = 1)
42 (n = 2)
43
44
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Figure 1. Unreactive Monoorganozinc Reagents in Conjugate Additions.
The standard reaction conditions and one-pot procedure both provide facile access to a
variety of chiral β-quaternary ketones. The addition products shown in Scheme 1 and Scheme 2
are obtained via the hydrolysis of an intermediate silyl enol ether. Importantly, these reactive
intermediates poised for subsequent functionalization32,33,34 are moderately stable35 and can be
isolated in high yield using a modified workup (Equation 2).
O
OTMS
CuBr•DMS (5 mol%)
2, TMSCl
CO2Et
(2)
DMA, 0 → 23 °C
Me
Me
NaHCO3 workup
3
5, 94% yield
We have established a general and practical reaction protocol for the Cu-catalyzed conjugate
addition of simple monoorganozinc reagents to form diverse functionalized β-quaternary ketones
with excellent efficiency. In contrast to the limited known examples, this method is highlighted
by a significant positive influence of the solvent DMA with RZnBr reagents, facilitating access
to five-, six-, and seven-membered ring products in high yields and diastereoselectivities. Efforts
to expand the unsaturated carbonyl substrate scope, clarify the nature of the reagent
enhancement, as well as further applications are under investigation.
Experimental Section
General Methods. Reactions, Reagents and Solvents. Unless otherwise noted, all reactions
were performed in flame-dried Schlenk glassware under an argon or nitrogen atmosphere using
dry solvents. Solvents were dried by passage through an activated alumina column under
nitrogen and stored over activated 3 Å MS. Molecular sieves were activated by microwave
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irradiation and cooled under vacuum. All starting materials were purchased from commercial
sources and used as received, unless otherwise stated. A 1 M solution of CuCN•2LiCl in THF
was prepared according to Knochel12 and stored in a sealed tube. Liquids and solutions were
transferred via syringe or positive-pressure cannulation. Brine solutions refer to saturated
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aqueous sodium chloride solutions. Zinc dust was activated over 1 M HCl. The following liquids
were refluxed over CaH2 and stored in a Straus flask over 3 Å molecular sieves prior to use:
toluene, HMPA, DMF, Et3N. TMSCl was cannulated into a sealed tube and stored under
nitrogen. Reagent grade acetone was stored over CaSO4. MeOH was refluxed over Mg turnings,
distilled and stored over 3 Å molecular sieves. Unless stated otherwise, all reactions were stirred
with a magnetic stir bar and monitored by gas chromatography (GC) with an FID or thin layer
chromatography (TLC).
Instruments, Purification and Analysis. Thin-layer chromatography was performed using 6.5
x 2.2 cm EMD Milipore 60 g F254 precoated plates (9.5–11.5 µm particle size) and visualized by
UV fluorescence quenching and p-anisaldehyde staining. Column or flash chromatography
(silica) was performed with the indicated solvents using SiO2 (VWR, 60 Å pore size, 40–63 µm
particle size; or Biotage KP-Sil, 60 Å pore size, 40–60 µm particle size). Automated flash
chromatography was performed on a Biotage Isolera One with UV/VIS detection (254, 280,
200–400 nm), unless otherwise noted. All crude samples were dissolved in a minimal amount of
Et2O or CH2Cl2 and loaded onto a Biotage dry load vessel (DLV) packed with SiO2 (generally
10–25 g). A reduced pressure was then used to pull the sample onto the DLV and remove excess
solvent. The DLV was then used with the Biotage Isolera One pre-packed SiO2 columns as
indicated. Infrared spectra were obtained on a Thermo Nicolet 4700 FT-IR with a Pike
GladiATR ATR using a diamond cell and are reported in wavenumbers (cm–1). 1H and 13C{1H}
NMR spectra were recorded on a Varian 400 MHz (400 and 101 MHz, respectively) or an
Oxford 600 MHz (600 and 151 MHz, respectively). Chemical shifts (δ) are reported relative to
internal Me4Si (1H and 13C{1H}, δ 0.00 ppm), chloroform (1H, δ 7.26 ppm, 13C{1H} 77.16 ppm)
or benzene (1H, δ 7.16 ppm, 13C{1H} 128.06 ppm). High-resolution mass spectra were acquired
using a Thermo Exactive Orbitrap mass spectrometer with an IonSense ID-Cube DART source
in APCI ionization mode. Melting point measurements are uncorrected.
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General Procedure. To a 25 mL Schlenk tube charged with CuBr•DMS (10.3 mg, 0.050
mmol, 0.050 equiv) and DMA (0.3 M; volume adjusted to account for RZnX) at 0 °C was added
a solution of the RZnX (2.00 mmol, 2.0 equiv). After 10 min, TMSCl (305 µL, 2.40 mmol, 2.4
equiv) and enone (1.00 mmol, 1.0 equiv) were added. The solution was allowed to warm to 23 °C
after ca. 1 h and stirred until consumption of the enone by TLC analysis, or 24 h. The reaction was
quenched with glacial acetic acid (290 µL, 5.0 mmol, 5.0 equiv) and stirred until hydrolysis of the
silyl enol ether was observed by TLC. In some cases, the addition of TBAF (0.5–1.1 mL of a 1.0
M solution in THF) was required for complete hydrolysis of the silyl enol ether. The reaction was
then added HCl (5 mL, 1 M aq) and transferred to a separatory funnel with Et2O (5 mL) and H2O
(5 mL). The layers were mixed, separated, and the aqueous layer was extracted with Et2O (3 x 10
mL). The combined organics were washed with NaHCO3 (5 mL), brine (5 mL), and then dried
over anhydrous MgSO4, filtered, and concentrated to provide a crude oil. Purification by
automated flash column chromatography on SiO2 afforded the conjugated addition products.
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Organozinc Reagents. DMA solutions of the organozinc bromide reagents employed in Table
1, Table 2 and Scheme 1 were prepared according to Huo21 and Fu,36 as represented by the
preparation of 2. To a 100 mL sealed reaction tube was added zinc dust (4.908 g, 75.07 mmol,
1.25 equiv), I2 (760 g, 2.99 mmol, 0.05 equiv) and DMA (25.0 mL, 2.4 M). The contents were
stirred vigorously until the color faded (ca. 1–5 min), and to this gray suspension was added ethyl
4-bromobutyrate (21; 8.60 mL, 60.1 mmol, 1.0 equiv). The reaction tube was sealed, immersed in
an 80 °C oil bath and monitored by GC analysis for consumption of the organohalide (NH4Cl
aliquot quench; Et2O extraction; required 6–10 h depending on scale). Upon completion of the
organozinc formation, the reaction is cooled to ambient temperature and the stirring is ceased to
allow the solids to settle for 12–24 h. The partially separated suspension was slowly filtered into a
dry disposable syringe equipped with a 0.45 µm PTFE syringe filter, the needle was exchanged
and the reagent was then transferred to a dry sealed storage tube. The resulting clear, dark red
orange solution of 2 was quantified using iodometric titration to give concentrations in the range
of 1.3–1.5 M.37 It is recommended to perform the first titration past the end point due to the varied
color of organozinc solutions. We have observed only minor changes in the titer (< 0.05–0.1 M)
over a period of at least 6 months for the RZnBr solutions used in this study. Organozinc iodide
reagent 1 required warming the ethyl 4-iodobutyrate to 40–50 °C.
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General One-Pot Procedure. To a 25 mL Schlenk tube charged with zinc dust (163.5 mg,
2.50 mmol, 2.5 equiv) and iodine (25.4 mg, 0.10 mmol, 0.10 equiv) was added DMA (1.2 mL).
The contents were stirred vigorously until the color faded (ca. 1–5 min), and to this gray suspension
was added organohalide (2.0 mmol, 2.0 equiv). The reaction tube was immersed in an 80 °C oil
bath and monitored by GC analysis for consumption of the organohalide (NH4Cl aliquot quench;
Et2O extraction). Upon completion of the organozinc formation, the reaction was cooled to 0 °C
and was added CuBr•DMS (41.1 mg, 0.200 mmol, 0.20 equiv) and DMA (2.1 mL, 0.3 M total).
After 10 min, TMSCl (305 µL, 2.40 mmol, 2.4 equiv) and enone (1.00 mmol, 1.0 equiv) were
added. The solution was allowed to warm to 23 °C after ca. 1 h and stirred until consumption of
the enone by TLC analysis, or 24 h. The reaction was then quenched, worked up and purified
according to the General Procedure.
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Enol ether isolation. Upon completion of the reaction as described in the General Procedure,
NaHCO3 (5 mL) is slowly added with vigorous stirring. The reaction was then transferred to a
separatory funnel with Et2O and H2O (10 mL). The layers were mixed, separated, and the aqueous
layer was extracted with Et2O (3 x 10 mL). The combined organics were washed with brine (5
mL), dried over anhydrous MgSO4, filtered, and concentrated to provide a crude oil. Purification
by automated flash column chromatography on SiO2 afforded the silyl enol ether product.
Initial Screening Procedure of 1. To a 25 mL sealed reaction tube38 charged with zinc dust
(94.8 mg, 1.45 mmol, 1.45 equiv) was added 1,2-dibromoethane (3.5 µL, 0.04 mmol, 0.04 equiv)
and THF (1.0 mL, 1.4 M with respect to 1). The reaction tube was sealed and the gray suspension
was heated for approximately 20 seconds with a heat gun until a slight reflux of THF was observed,
and then cooled to room temperature. To this was added TMSCl (5.1 µL, 0.04 mmol, 0.04 equiv)
and ethyl 4-iodobutyrate (338.9 mg, 1.40 mmol, 1.4 equiv), and the reaction tube was sealed and
immersed in a 40 °C oil bath. The reaction was monitored by GC analysis for consumption of 1
(NH4Cl aliquot quench), and cooled to 0 °C upon completion. A solution of CuCN•2LiCl (110 µL,
0.10 mmol, 0.10 equiv or 1.3 mL, 1.22 mmol, 1.22 equiv of a 0.92 M solution in THF) and the
polar additive (2.4 mmol, 2.4 equiv) were added. [Note: when 110 µL of CuCN•2LiCl solution
was used, an additional 1.1 mL of THF was also added.] After 10 min, a solution of 3 (113 µL,
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1.00 mmol, 1.0 equiv) and Lewis acid (2.40 mmol, 2.4 equiv) in Et2O (1.0 mL, 0.30 M overall;
solution prepared in a 5 mL sealed tube) were added via syringe transfer. The solution was allowed
to warm to 23 °C overnight and stirred until consumption of the enone by TLC analysis, or 24 h.
The reaction was then quenched, worked up and purified according to the General Procedure.
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Ethyl 4-(1-methyl-3-((trimethylsilyl)oxy)cyclohex-2-en-1-yl)butanoate (5). Purification:
25 g SiO2, 3 ® 25% EtOAc in hexanes; General Procedure: isolated 280.9 mg (0.9410 mmol, 94
1
% yield) of a clear, colorless oil. Rf = 0.48 (6:1 hexanes/EtOAc); H NMR (400 MHz, C6D6): δ
4.75 (s, 1H), 3.97 (q, J = 7.1 Hz, 2H), 2.13 (t, J = 7.3 Hz, 2H), 1.98 (td, J = 6.4, 1.2 Hz, 2H), 1.62
(dt, J = 16.4, 7.9 Hz, 2H), 1.57–1.51 (m, 2H), 1.32 (ddd, J = 13.0, 8.3, 4.8 Hz, 1H), 1.27–1.13 (m,
3H), 0.98 (t, J = 7.1 Hz, 3H), 0.95 (s, 3H), 0.20 (s, 9H); 13C{1H} NMR (101 MHz, C6D6): δ 172.9,
150.1, 113.7, 60.0, 43.3, 35.1, 34.79, 34.75, 30.4, 28.4, 20.4, 20.0, 14.4, 0.5; IR (ATR): 2954,
2938, 1737, 1662, 1365, 1251, 1186, 842, 7545; HRMS (DART+) m/z: [M + H]+ calcd for
C16H31O3Si 299.2037, found 299.2028.
Ethyl 4-(1-methyl-3-oxocyclohexyl)butanoate (6). Purification: 25 g SiO2, 5 ® 25% EtOAc
in hexanes; General Procedure: isolated 208.4 mg (0.9208 mmol, 92% yield) as a clear, colorless
oil; One-Pot Procedure: isolated 1.0372 g (4.583 mmol, 92% yield; 5.00 mmol scale). Rf = 0.21
(4:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3): δ 4.13 (q, J = 7.1 Hz, 2H), 2.32–2.23 (m, 4H),
2.15 (ABq, DdAB = 0.06, JAB = 13.5 Hz, 2H), 1.87 (quintet, J = 6.4 Hz, 2H), 1.60 (dtt, J = 23.3,
15.4, 7.6 Hz, 4H), 1.34–1.21 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H), 0.94 (s, 3H). All other spectral data
are consistent with reported values.39
4-(1-Methyl-3-oxocyclohexyl)butyl acetate (7). Purification: 25 g SiO2, 8 ® 50% EtOAc in
hexanes; General Procedure: isolated 211.5 mg (0.9345 mmol, 93% yield) as a clear, colorless oil;
One-Pot Procedure: isolated 208.8 mg (0.9226 mmol, 92% yield). Rf = 0.31 (2:1 hexanes/EtOAc);
1H NMR (400 MHz, CDCl3): δ 4.06 (t, J = 6.7 Hz, 2H), 2.29–2.26 (m, 2H), 2.15 (ABq, DdAB
=
0.07, JAB = 13.5 Hz, 2H), 2.05 (s, 3H), 1.89–1.85 (m, 2H), 1.63–1.52 (m, 4H), 1.32–1.24 (m, 4H),
0.92 (s, 3H). All other spectral data are consistent with reported values.9
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3-(4-Chlorobutyl)-3-methylcyclohexan-1-one (8). Purification: 25 g SiO2, 5 ® 25% EtOAc
in hexanes; General Procedure: isolated 170.5 mg (0.8411 mmol, 84% yield) as a clear, colorless
oil; One-Pot Procedure: isolated 175.7 mg (0.8667 mmol, 87% yield). Rf = 0.28 (4:1
hexanes/EtOAc); 1H NMR (400 MHz, CDCl3): δ 3.55 (t, J = 6.6 Hz, 2H), 2.28 (app t, J = 6.8 Hz,
2H), 2.15 (ABq, DdAB = 0.06, JAB = 13.4, 2H), 1.87 (tt, J = 8.8, 4.5 Hz, 2H), 1.78–1.71 (m, 2H),
1.64 (dt, J = 13.4, 6.6 Hz, 1H), 1.56 (dt, J = 13.5, 6.6 Hz, 1H), 1.45–1.38 (m, 2H), 1.30–1.24 (m,
2H), 0.93 (s, 3H). All other spectral data are consistent with reported values.8
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4-(1-Methyl-3-oxocyclohexyl)butanenitrile (9). Purification: 25 g SiO2, 13 ® 50% EtOAc
in hexanes; General Procedure: isolated 145.0 mg (0.8089 mmol, 81% yield) as a clear, colorless
oil; One-Pot Procedure: isolated 166.7 mg (0.9299 mmol, 93% yield). This compound has been
reported but characterization data was not included.15 Rf = 0.33 (1:1 hexanes/EtOAc); 1H NMR
(400 MHz, CDCl3): δ 2.36 (td, J = 7.0, 1.8 2H), 2.29 (app t, J = 6.8 Hz, 2H), 2.17 (ABq, DdAB =
0.06 , JAB = 13.4, 2H), 1.92–1.85 (m, 2H), 1.67–1.55 (m, 4H), 1.47–1.35 (m, 2H), 0.95 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3): δ 212.3, 173.5, 60.4, 52.3, 41.2, 40.9, 36.91, 36.74, 34.7,
33.8, 25.1, 23.4, 21.7, 18.6, 14.34, 14.14; IR (ATR): 2942, 2875 2244, 1706, 1459, 1425, 1313,
1292, 1229, 508; HRMS (DART+) m/z: [M + H]+ calcd for C11H18NO 180.1383, found
180.1379.
Benzyl 4-((1-methyl-3-oxocyclohexyl)methyl)piperidine-1-carboxylate (10). Purification:
25 g SiO2, 13 ® 50% EtOAc in hexanes; General Procedure: isolated 305.0 mg (0.8880 mmol,
89% yield) as a clear, viscous colorless oil; One-Pot Procedure: isolated 273.4 mg (0.7960 mmol,
80% yield). Rf = 0.40 (1:1 hexanes/EtOAc); 1H NMR (600 MHz, CDCl3): δ 7.35–7.30 (m, 5H),
5.12 (br s, 2H), 4.10 (br s, 2H), 2.79 (br s, 2H), 2.31–2.24 (m, 2H), 3.24 (ABq, DdAB = 0.11, JAB
=
13.4, 2H), 1.87 (dq, J = 12.3, 6.4 Hz, 2H), 1.66–1.50 (m, 4H), 1.23 (d, J = 4.8 Hz, 2H), 1.19 (br s,
2H), 0.96 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 211.8, 155.2, 136.9, 128.4, 127.9, 127.8,
66.9, 54.0, 48.3, 44.2, 40.9, 39.3, 36.5, 34.4, 31.6, 25.4, 22.1; IR (ATR): 2917, 2851, 1692, 1427,
1283, 1223, 1111, 1072, 731, 697; HRMS (DART+) m/z: [M + H]+ calcd for C21H30NO3 344.2220,
found 344.2210.
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Ethyl 4-(1-butyl-3-oxocyclohexyl)butanoate (11). Purification: 25 g SiO2, 6 ® 25% EtOAc
in hexanes; General Procedure: isolated 230.1 mg (0.8573 mmol, 86% yield) as a clear, colorless
oil; One-Pot Procedure: isolated 259.4 mg (0.9057 mmol, 91% yield). Rf = 0.35 (3:1
hexanes/EtOAc);1H NMR (400 MHz, CDCl3): δ 4.13 (q, J = 7.1 Hz, 2H), 2.33–2.22 (m, 4H), 2.17
(app t, J =13.5 Hz, 2H), 1.84 (dt, J = 12.6, 6.4 Hz, 2H), 1.61 (dd, J = 6.3, 5.7 Hz, 2H), 1.57–1.49
(m, 2H), 1.32–1.13 (m, 11H), 0.90 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 212.3,
173.5, 60.4, 52.3, 41.2, 40.9, 36.9, 36.7, 34.7, 33.8, 25.1, 23.4, 21.7, 18.6, 14.3, 14.1; IR (ATR):
2932, 2871, 1731, 1708, 1458, 1372, 1175, 1033; HRMS (DART+) m/z: [M + H]+ calcd for
C16H29O3 269.2111, found 269.2109.
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Ethyl 4-(1-benzyl-3-oxocyclohexyl)butanoate (12). Purification: 25 g SiO2, 6 ® 25% EtOAc
in hexanes; General Procedure: isolated 281.8 mg (0.9318 mmol, 93% yield) as a clear, pale yellow
oil; One-Pot Procedure: isolated 278.5 mg (0.9209 mmol, 92% yield). Rf = 0.29 (3:1
hexanes/EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.30–7.21 (m, 3H), 7.10 (d, J = 6.8 Hz, 2H), 4.13
(q, J = 7.1 Hz, 2H), 2.62 (ABq, DdAB = 0.07, JAB = 13.4 Hz, 2H), 2.30–2.16 (m, 5H), 2.10 (d, J =
13.6 Hz, 1H), 1.99–1.91 (m, 1H), 1.88–1.79 (m, 1H), 1.76–1.54 (m, 4H), 1.27–1.13 (m, 2H), 1.25
(t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 212.2, 173.5, 137.4, 130.7, 128.2, 126.5,
60.5, 51.5, 44.5, 42.2, 40.9, 36.0, 34.6, 32.8, 21.7, 18.8, 14.4; IR (ATR): 2939, 2873, 1728, 1706,
1453, 1265, 1178, 1031, 731, 702; HRMS (DART+) m/z: [M + H]+ calcd for C19H27O3 303.1955,
found 303.1952.
Ethyl 4-(3-oxo-1-phenylcyclohexyl)butanoate (13). Purification: 25 g SiO2, 5 ® 25% EtOAc
in hexanes; General Procedure: isolated 258.9 mg (0.8977 mmol, 90% yield) as a clear, colorless
oil that solidifies over time; One-Pot Procedure: isolated 249.8 mg (0.8662 mmol, 87% yield). Rf
1
= 0.32 (2:1 hexanes/EtOAc); white waxy solid, mp 54–57 °C; H NMR (400 MHz, CDCl3): δ
7.33–7.25 (m, 4H), 7.21–7.18 (m, 1H), 4.06 (q, J = 7.1 Hz, 2H), 2.92 (d, J = 14.2 Hz, 1H), 2.45
(d, J = 14.3 Hz, 1H), 2.31–2.28 (m, 2H), 2.20–2.13 (m, 1H), 2,14 (t, J = 7.2 Hz, 2H), 2.01 (ddd, J
= 13.6, 10.1, 4.3 Hz, 1H), 1.84 (dtd, J = 16.8, 6.3, 3.2 Hz, 1H), 1.75 (td, J = 13.0, 4.5 Hz, 1H),
1.66–1.54 (m, 2H), 1.44–1.33 (m, 1H), 1.26–1.15 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(101 MHz, CDCl3): δ 211.2, 173.3, 144.8, 128.6, 126.4, 126.3, 60.3, 51.2, 46.1, 42.5, 41.1, 36.4,
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34.4, 21.5, 19.2, 14.3; IR (ATR): 2943, 2902, 2869, 1717, 1707, 1364, 1201, 1177, 1096, 700;
HRMS (DART+) m/z: [M + H]+ calcd for C18H25O3 289.1798, found 289.1797.
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Ethyl 4-(1-methyl-3-oxocycloheptyl)butanoate (14). Purification: 25 g SiO2, 6 ® 25%
EtOAc in hexanes; General Procedure: isolated 164.9 mg (0.6861 mmol, 69% yield) as a clear,
pale yellow oil; One-Pot Procedure: isolated 166.7 mg (0.6936 mmol, 69% yield). Rf = 0.28 (3:1
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hexanes/EtOAc); H NMR (400 MHz, CDCl3): δ 4.13 (q, J = 7.1 Hz, 2H), 2.52 (d, J = 12.1 Hz,
1H), 2.42–2.38 (m, 3H), 2.26 (td, J = 7.4, 4.1 Hz, 2H), 1.80–1.48 (m, 8H), 1.32-1.20 (m, 2H), 1.26
13
(t, J = 7.1 Hz, 3H), 0.92 (s, 3H); C{1H} NMR (151 MHz, CDCl3): δ 213.8, 173.5, 60.2, 54.7,
44.0, 42.3, 41.7, 35.2, 34.7, 26.0, 24.6, 24.1, 19.1, 14.3; IR (ATR): 2930, 1730, 1693, 1457, 1374,
1249, 1179, 1033; HRMS (DART+) m/z: [M + H]+ calcd for C14H25O3 241.1798, found 241.1797.
Ethyl 4-(1-methyl-3-oxocyclopentyl)butanoate (15). Purification: 25 g SiO2, 5 ® 33%
EtOAc in hexanes; General Procedure: isolated 131.7 mg (0.6204 mmol, 62% yield) as a clear,
colorless oil; One-Pot Procedure: isolated 147.3 mg (0.6939 mmol, 69% yield). Rf = 0.37 (2:1
hexanes/EtOAc); 1H NMR (400 MHz, CDCl3): δ 4.14 (q, J = 7.1 Hz, 2H), 2.33–2.27 (m, 4H), 2.06
(ABq, DdAB = 0.04, JAB = 17.7 Hz, 2H), 1.86–1.76 (m, 2H), 1.72–1.57 (m, 2H), 1.45–1.41 (m,
2H), 1.26 (t, J = 7.1 Hz, 3H), 1.07 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 219.8, 173.5, 60.5,
52.3, 41.3, 39.6, 36.9, 35.2, 34.8, 25.0, 20.5, 14.4; IR (ATR): 2957, 1730, 1374, 1180, 1155, 1025,
499; HRMS (DART+) m/z: [M + NH4]+ calcd for C12H24O3N 230.1751, found 230.1750.
Ethyl 4-(2-((tert-butyldimethylsilyl)oxy)-1-methyl-5-oxocyclohexyl)butanoate (16).
Purification: 25 g SiO2, 6 ® 25% EtOAc in hexanes; General Procedure: isolated 333.6 mg
(0.9356 mmol, 94% yield, 9.2:1 dr) as a clear, colorless oil; One-Pot Procedure: isolated 317.0
mg (0.9254 mmol, 93% yield, 8:1 dr). The diastereomer ratio was measured by 1H NMR
integration of the –CH(OTBS)– absorption at δ 3.72 (major) and δ 3.68 (minor). Relative
stereochemical assignment based upon literature precedent.40 Rf = 0.44 (3:1 hexanes/EtOAc);
major diastereomer: 1H NMR (600 MHz, CDCl3): δ 4.12 (q, J = 7.1 Hz, 2H), 3.72 (dd, J = 5.0,
2.7 Hz, 1H), 2.55–2.50 (m, 1H), 2.50 (d, J = 13.1 Hz, 1H), 2.30–2.17 (m, 3H), 2.03–1.97 (m,
1H), 2.01 (d, J = 13.7 Hz, 1H), 1.91–1.86 (m, 1H), 1.61–1.52 (m, 2H),1.27–1.17 (m, 2H),1.25 (t,
J = 7.1 Hz, 3H), 0.95 (s, 3H), 0.92 (s, 9H), 0.101(s, 3H), 0.097 (s, 3H); 13C{1H} NMR (151
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MHz, CDCl3): δ 211.7, 173.3, 72.4, 60.3, 49.1, 43.1, 38.4, 36.4, 34.7, 29.6, 25.9, 21.8, 18.7,
18.1, 14.3, -4.2, -4.8; minor diastereomer (selected peaks): 1H NMR (600 MHz, CDCl3): δ 3.68
(dd, J = 3.5, 3.5 Hz, 0.9H), 0.86 (s, 0.24H); 13C{1H} NMR (151 MHz, CDCl3): δ 211.7, 173.4,
72.5, 60.3, 49.1, 43.0, 37.6, 36.3, 34.9, 29.6, 25.9, 22.5, 18.9, 18.2, 14.3, -4.1, -5.0; IR (ATR):
2953, 2929, 2856, 1733, 1713, 1472, 1463, 1251, 1176, 1077, 835, 773; HRMS (DART+) m/z:
[M + H]+ calcd for C19H37O4Si 357.2456, found 357.2453.
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Methyl
2-(4-ethoxy-4-oxobutyl)-2-methyl-4-oxocyclohexane-1-carboxylate
(17).
Purification: 25 g SiO2, 8 ® 50% EtOAc in hexanes; General Procedure: isolated 261.7 mg
(0.9203 mmol, 92% yield, 15.5:1 dr) as a clear, colorless oil; One-Pot Procedure: isolated 257.0
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mg (0.9038 mmol, 90% yield, 16:1 dr). The diastereomer ratio was measured by H NMR
integration of the 4° –CH3 at δ 1.02 (minor) and δ 0.99 (major). Relative stereochemical
assignment based upon literature precedent.41 Rf = 0.24 (2:1 hexanes/EtOAc); major diastereomer:
1H NMR (600 MHz, CDCl3): δ 4.12 (q, J = 7.1 Hz, 2H), 27.1 (s, 3H), 2.73 (dd, J = 8.5, 34.7 Hz,
1H), 2.57 (dtd, J = 14.5, 6.2, 1.4 Hz, 1H), 2.43 (dd, J = 13.8, 1.5 Hz, 1H), 2.32–2.22 (m, 4H),
2.15–2.04 (m, 2H), 10.73–1.66 (m, 1H), 1.60–1.53 (m, 1H), 1.36 (td, J = 13.0, 4.6 Hz, 1H), 1.31
(td, J = 12.6, 4.7 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H), 0.99 (s, 3H); 13C{1H} NMR (151 MHz, CDCl3):
δ 210.4, 174.3, 173.3, 60.5, 51.7, 47.7, 40.6, 40.3, 38.9, 34.6, 24.9, 22.0, 18.9, 14.4; minor
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diastereomer (selected peaks): H NMR (600 MHz, CDCl3): δ 3.72 (s, 0.21H), 1.02 (s, 0.21H) ;
13C{1H} NMR (151 MHz, CDCl3): δ 60.5, 50.8, 48.6, 40.3, 38.2, 37.9, 34.8, 25.1, 24.8; IR (ATR):
2954, 1724, 1434, 1368, 1156, 1025, 757; HRMS (DART+) m/z: [M + H]+ calcd for C15H25O5
285.1696, found 285.1693.
Ethyl 4-(1-methyl-3-oxo-5-phenylcyclohexyl)butanoate (18). Purification: 25 g SiO2, 6 ®
25% EtOAc in hexanes; General Procedure: isolated 299.2 mg (0.9894 mmol, 99% yield, > 20:1
dr) as a clear, viscous colorless oil; One-Pot Procedure: isolated 296.6 mg (0.9808 mmol, 73%
yield, 8:1 dr; 1.34 mmol scale). The minor diastereomer was not observed by 1H NMR. Relative
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stereochemistry is assigned by analogy to product 17. Rf = 0.35 (3:1 hexanes/EtOAc); H NMR
(600 MHz, CDCl3): δ 7.35–7.32 (m, 2H), 7.25–7.23 (m, 3H), 4.14 (q, J = 7.1 Hz, 2H), 3.11 (tt, J
= 13.0, 3.9 Hz, 1H), 2.55 (ddd, J = 13.8, 4.2, 2.0 Hz, 1H), 2.45 (app t, J = 13.4 Hz, 1H), 2.35–2.24
(m, 4H), 1.95 (dt, J = 13.8, 1.6 Hz, 1H), 1.74 (app t, J = 13.4 Hz, 1H), 1.60 (dq, J = 9.7, 7.3 Hz,
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2H), 1.41–1.36 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H), 1.27–1.22 (m, 1H), 1.08 (s, 3H); 13C{1H} NMR
(151 MHz, CDCl3): δ 210.9, 173.4, 144.2, 128.8, 126.84, 126.72, 60.4, 53.9, 48.1, 43.7, 39.6, 37.8,
37.0, 34.5, 28.3, 19.1, 14.4; IR (ATR): 2955, 1730, 1710, 1454, 1372, 1184, 1028, 754, 700;
HRMS (DART+) m/z: [M + H]+ calcd for C19H27O3 303.1955, found 303.1951.
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Ethyl 4-(1,3-dimethyl-5-oxocyclohexyl)butanoate (19). Purification: 25 g SiO2, 6 ® 25%
EtOAc in hexanes; General Procedure: isolated 232.0 mg (0.9653 mmol, 97% yield, > 20:1 dr) as
a clear, colorless oil; One-Pot Procedure: isolated 170.0 mg (0.7073 mmol, 71% yield, > 20:1 dr).
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comparison to analogous compounds.8,42 Rf = 0.35 (3:1 hexanes/EtOAc); H NMR (600 MHz,
CDCl3): δ 4.12 (q, J = 7.1 Hz, 2H), 2.33 (dt, J = 13.4, 2.0 Hz, 1H), 2.29–2.19 (m, 2H), 2.13 (ABq,
DdAB = 0.02, JAB = 13.6 Hz, 2H), 1.99–1.93 (m, 1H), 1.88 (app t, J = 13.0 Hz, 1H), 1.74 (dt, J =
13.8, 1.5 Hz, 1H), 1.59–1.49 (m, 2H), 1.25 (t, J =7.1 Hz, 3H), 1.26–1.19 (m, 2H), 1.13 (td, J =
13
12.9, 5.0 Hz, 1H), 1.01 (d, J = 6.2 Hz, 3H), 1.01 (s, 3H); C{1H} NMR (151 MHz, CDCl3): δ
211.9, 173.6, 60.5, 53.8, 49.4, 44.7, 37.8, 37.3, 34.7, 29.2, 28.4, 22.7, 19.2, 14.4; IR (ATR): 2954,
2871, 1731, 1711, 1456, 1375, 1271, 1177; HRMS (DART+) m/z: [M + H]+ calcd for C14H25O3
241.1798, found 241.1791.
Ethyl 4-(1,3,3-trimethyl-5-oxocyclohexyl)butanoate (20). Purification: 25 g SiO2, 5 ® 25%
EtOAc in hexanes; General Procedure: isolated 113.7 mg (0.4470 mmol, 45% yield) as a clear,
colorless oil. Rf = 0.21 (4:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3): δ 4.13 (q, J = 7.1 Hz,
2H), 2.27 (app t, J = 7.4 Hz, 2H), 2.15 (ABq, DdAB = 0.06, JAB = 13.2 Hz, 4H), 1.65–1.58 (m, 2H),
1.57 (ABq, DdAB = 0.09, JAB = 15.9 Hz, 2H), 1.38 (td, J = 11.5, 6.8 Hz, 1H), 1.30-1.22 (m, 1H),
1.26 (t, J = 7.1 Hz, 3H), 1.05 (s, 3H), 1.04 (s, 3H), 1.02 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3):
δ 212.2, 173.5, 60.3, 54.3, 53.1, 48.9, 44.2, 38.7, 36.1, 34.7, 32.3, 30.6, 27.3, 19.5, 14.3; IR (ATR):
2954, 2908, 1732, 1711, 1462, 1368, 1280, 1181, 1030; HRMS (DART+) m/z: [M + H]+ calcd for
C15H27O3 255.1955, found 255.1946.
Ethyl 5-(1-methyl-3-oxocyclohexyl)pentanoate (22). Purification: 25 g SiO2, 3 ® 25%
EtOAc in hexanes; One-Pot Procedure: isolated 201.9 mg (0.8400 mmol, 84% yield) as a clear,
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pale yellow oil. Rf = 0.17 (4:1 hexanes/EtOAc); H NMR (400 MHz, CDCl3): δ 4.13 (q, J = 7.1
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Hz, 2H), 2.29 (dt, J = 12.4, 6.5 Hz, 4H), 2.14 (ABq, DdAB = 0.07, JAB = 13.5 Hz, 2H), 1.86 (quintet,
J = 6.4 Hz, 2H), 1.65–1.50 (m, 4H), 1.34–1.24 (m, 4H), 1.25 (t, J = 7.1 Hz, 3H), 0.91 (s, 3H);
13C{1H} NMR (400 MHz, CDCl3): δ 212.3, 173.7, 60.4, 53.9, 41.4, 41.2, 38.7, 35.9, 34.4, 25.7,
25.1, 23.1, 22.3, 14.4; IR (ATR): 2937, 2870, 1731, 1710, 1462, 1170, 1031; HRMS (DART+)
m/z: [M + H]+ calcd for C14H25O3 241.1798, found 241.1793.
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Ethyl 6-(1-methyl-3-oxocyclohexyl)hexanoate (23). Purification: 25 g SiO2, 5 ® 25%
EtOAc in hexanes; One-Pot Procedure: isolated 231.4 mg (0.9097 mmol, 91% yield) as a clear,
colorless oil. Rf = 0.20 (4:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3): δ 4.13 (q, J = 7.1 Hz,
2H), 2.28 (q, J = 6.9 Hz, 4H), 2.14 (DdAB = 0.07 , JAB = 13.5 Hz, 2H), 1.86 (quintet, J = 6.4 Hz,
2H), 1.66–1.50 (m, 4H), 1.30–1.24 (m, 6H), 1.26 (t, J = 7.1 Hz, 3H), 0.91 (s, 3H); 13C{1H} NMR
(400 MHz, CDCl3): δ 212.4, 173.9, 60.3, 53.9, 41.6, 41.2, 38.7, 36.0, 34.4, 29.9, 25.19, 25.05,
23.2, 22.3, 14.4; IR (ATR): 2933, 2870, 1731, 1710, 1463, 1176, 1031; HRMS (DART+) m/z: [M
+ H]+ calcd for C15H27O3 255.1955, found 255.1948.
7-(1-Methyl-3-oxocyclohexyl)heptanenitrile (24). Purification: 25 g SiO2, 4 ® 25% EtOAc
in hexanes; One-Pot Procedure: isolated 211.1 mg (0.9537 mmol, 95% yield) as a clear, colorless
oil. Rf = 0.27 (2:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3): δ 2.35 (t, J = 7.1 Hz, 2H), 2.27
(t, J = 6.8 Hz, 2H), 2.14 (ABq, DdAB = 0.07, JAB = 13.4 Hz, 2H), 1.86 (quintet, J = 6.4 Hz, 2H),
1.69–1.42 (m, 6H), 1.30–1.26 (m, 6H), 0.91 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 212.2,
119.7, 53.7, 41.3, 41.0, 38.5, 35.8, 29.4, 28.5, 25.3, 25.0, 23.0, 22.1, 17.0; IR (ATR): 2931, 2859,
2245,1706, 1457, 1424, 1227, 731, 510; HRMS (DART+) m/z: [M + H]+ calcd for C14H24ON
222.1852, found 222.1851.
2-(3-(1-Methyl-3-oxocyclohexyl)propyl)phthalimide (25). Purification: 25 g SiO2, 12 ®
50% EtOAc in hexanes; One-Pot Procedure: isolated 198.9 mg (0.6641 mmol, 66% yield) as a
clear, viscous colorless oil. Rf = 0.44 (1:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.85
(dd, J = 5.3, 3.0 Hz, 2H), 7.73 (dd, J = 5.3, 3.0 Hz, 2H), 3.66 (t, J = 7.2 Hz, 2H), 2.32–2.24 (m,
2H), 2.14 (ABq, DdAB = 0.08, JAB = 13.6 Hz, 2H), 1.86 (dq, J = 12.0, 6.3 Hz, 2H), 1.71–1.53 (m,
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4H), 1.36–1.32 (m, 2H), 0.91 (s, 3H); C{1H} NMR (101 MHz, CDCl3): δ 211.7, 168.3, 133.9,
132.1, 123.2, 53.6, 41.0, 38.9, 38.42, 38.35, 35.7, 24.6, 22.8, 22.1; IR (ATR): 2941, 2873, 2843,
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1770, 1702, 1395, 1359, 717; HRMS (DART+) m/z: [M + H]+ calcd for C18H22O3N 300.1592,
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3-(But-3-en-1-yl)-3-methylcyclohexan-1-one (26). Purification: 25 g SiO2, 5 ® 25% EtOAc
in hexanes; One-Pot Procedure: isolated 136.3 mg (0.8198 mmol, 82% yield) as a clear, colorless
oil. Rf = 0.42 (4:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3): δ 5.79 (ddt, J = 17.0, 10.3, 6.6
Hz, 1H), 5.01 (dd, J =17.2, 1.3 Hz, 1H), 4.94 (dt, J = 10.1, 0.5 Hz, 1H), 2.28 (t, J = 6.8 Hz, 2H),
2.16 (ABq, DdAB = 0.08, JAB = 13.5 Hz, 2H), 2.05–1.99 (m, 2H), 1.91–1.84 (m, 2H), 1.68–1.53
(m, 2H), 1.38–1.34 (m, 2H), 0.94 (s, 3H); IR (ATR): 2935, 2851, 1709, 1640, 1452, 1427, 1312,
1227, 995, 908, 507; HRMS (DART+) m/z: [M + H]+ calcd for C11H19O 167.1430, found
167.1430. All other spectral data are consistent with reported values.43
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3-Methyl-3-phenethylcyclohexan-1-one (27). Purification: 25 g SiO2, 5 ® 25% EtOAc in
hexanes; One-Pot Procedure: isolated 210.7 mg (0.9740 mmol, 97% yield) as a clear, pale yellow
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oil. Rf = 0.31 (4:1 hexanes/EtOAc); H NMR (400 MHz, CDCl3): δ 7.26 (app t, J = 7.4 Hz, 2H),
7.16 (app t, J = 7.4 Hz, 3H), 2.56 (td, J = 8.6, 3.2 Hz, 2H), 2.32–2.27 (m, 2H), 2.21 (ABq, DdAB
=
0.08, JAB = 13.4 Hz, 2H), 1.92–1.85 (m, 2H), 1.73–1.55 (m, 4H), 1.01 (s, 3H). All other spectral
data are consistent with reported values.44
3-Benzyl-3-methylcyclohexan-1-one (28). Purification: 25 g SiO2, 5 ® 25% EtOAc in
hexanes; One-Pot Procedure: isolated 194.4 mg (0.9634 mmol, 96% yield) as a clear, viscous pale
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yellow oil. Rf = 0.31 (4:1 hexanes/EtOAc); H NMR (400 MHz, CDCl3): δ 7.30–7.23 (m, 3H),
7.12 (d, J = 6.9 Hz, 2H), 2.59 (ABq, DdAB = 0.05, JAB = 13.2 Hz, 2H), 2.34–2.20 (m, 3H), 2.08 (dt,
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J = 13.4, 1.4 Hz, 1H), 2.03–1.81 (m, 2H), 1.70–1.54 (m, 2H), 0.91 (s, 3H); C{1H} NMR (101
MHz, CDCl3): δ 212.0, 137.4, 130.6, 127.9, 126.2, 52.8, 48.3, 40.8, 39.7, 35.7, 24.8, 22.0. All
other spectral data are consistent with reported values.45
3-Methyl-3-(4-methylbenzyl)cyclohexan-1-one (29). Purification: 25 g SiO2, 8 ® 50%
EtOAc in hexanes; One-Pot Procedure: isolated 168.9 mg (0.7808 mmol, 78% yield) as a clear,
colorless oil. Rf = 0.47 (2:1 hexanes/EtOAc); 1H NMR (600 MHz, CDCl3): δ 7.09 (d, J = 7.6 Hz,
2H), 7.00 (d, J = 7.8 Hz, 2H), 2.54 (ABq, DdAB = 0.05, JAB = 13.3 Hz, 2H), 2.33 (s, 3H), 2.30–2.20
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(m, 3H), 2.07 (d, J = 13.4 Hz, 1H), 1.99–1.94 (m, 1H), 1.89–1.81 (m, 1H), 1.64 (td, J = 11.8, 3.8
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Hz, 1H), 1.56–1.54 (m, 1H), 0.90 (s, 3H); C{1H} NMR (101 MHz, CDCl3): δ 212.4, 135.8,
134.4, 130.6, 128.7, 53.0, 48.0, 41.0, 39.8, 35.7, 25.0, 22.2, 21.1; IR (ATR): 2920, 1707, 1513,
1455, 1227, 811, 508; HRMS (DART+) m/z: [M + NH4]+ calcd for C15H24ON 234.1852, found
234.1846.
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3-(4-Bromobenzyl)-3-methylcyclohexan-1-one (30). Purification: 25 g SiO2, 5 ® 25%
EtOAc in hexanes; One-Pot Procedure: isolated 177.0 mg (0.6295 mmol, 63% yield) as a clear,
colorless oil. Rf = 0.28 (4:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.41 (d, J = 8.3 Hz,
2H), 6.99 (d, J = 8.3 Hz, 2H), 2.54 (ABq, DdAB = 0.06, JAB = 13.3, 2H), 2.34–2.21 (m, 3H), 2.07
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(d, J = 13.4 Hz, 1H), 2.02–1.81 (m, 2H), 1.67–1.54 (m, 3H), 0.89 (s, 3H); C{1H} NMR (101
MHz, CDCl3): δ 211.8, 136.5, 132.4, 131.1, 120.4, 52.8, 47.6, 40.9, 39.8, 35.9, 25.0, 22.1;IR
(ATR): 2935, 2875, 2848, 1706, 1487, 1456, 1422, 1227, 1142, 1071, 1011, 840, 770, 729, 645,
506; HRMS (DART+) m/z: [M + NH4]+ calcd for C14H21ONBr 298.0801, found 298.0797.
3-Hexyl-3-methylcyclohexan-1-one (31). Purification: 25 g SiO2, 5 ® 25% EtOAc in
hexanes; One-Pot Procedure: isolated 175.4 mg (0.8934 mmol, 89% yield) as a clear, colorless oil.
Rf = 0.44 (4:1 hexanes/EtOAc);1H NMR (400 MHz, CDCl3): δ 2.27 (t, J = 6.8 Hz, 2H), 2.14 (ABq,
DdAB = 0.08, JAB = 13.5 Hz, 2H), 1.86 (quintet, J = 6.5 Hz, 2H), 1.63 (dt, J = 13.5, 6.6 Hz, 1H),
1.53 (dt, J =12.7, 5.8 Hz, 1H), 1.32–1.21 (m, 10H), 0.91 (s, 3H), 0.88 (t, J = 6.9 Hz, 3H). All other
spectral data are consistent with reported values.46
1-Methyl-[1,1'-bi(cyclohexan)]-3-one (32). Purification: 25 g SiO2, 5 ® 25% EtOAc in
hexanes; One-Pot Procedure: isolated 170.3 mg (0.8764 mmol, 88% yield) as a clear, pale yellow
oil. Rf = 0.47 (4:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3): δ 2.30–2.24 (m, 3H), 2.08 (d, J
=13.4 Hz, 1H), 1.92–1.52 (m, 9H), 1.24–1.08 (m, 4H), 1.01–0.91 (m, 2H), 0.82 (s, 3H); IR (ATR):
2924, 2851, 1706, 1449, 1226, 520. All other spectral data are consistent with reported
values.Error! Bookmark not defined.
Ethyl 5-(1-methyl-3-oxocyclopentyl)pentanoate (33). Purification: 25 g SiO2, 5 ® 25%
EtOAc in hexanes; One-Pot Procedure: isolated 122.6 mg (0.5417 mmol, 54% yield) as a clear,
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colorless oil. Rf = 0.18 (4:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3): δ 4.13 (q, J = 7.1 Hz,
2H), 2.33–2.26 (m, 4H), 2.04 (ABq, DdAB = 0.04, JAB = 17.9 Hz , 2H), 1.84–1.72 (m, 2H), 1.63
(quintet, J = 7.3 Hz, 2H), 1.45–1.30 (m, 4H), 1.26 (t, J = 7.1 Hz, 3H), 1.04 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3): δ 220.0, 173.7, 60.4, 52.4, 41.6, 39.6, 36.9, 35.4, 34.4, 25.7, 25.1, 24.5, 14.4;
IR (ATR): 2937, 2870, 1730, 1405, 1175, 1031, 501; HRMS (DART+) m/z: [M + H]+ calcd for
C13H23O3 227.1647, found 227.1637.
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4-(1-Methyl-3-oxocyclopentyl)butanenitrile (34). Purification: 25 g SiO2, 12 ® 100%
EtOAc in hexanes; One-Pot Procedure: isolated 62.3 mg (0.3770 mmol, 38% yield) as a clear,
yellow oil. Rf = 0.31 (1:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3): δ 2.38 (m, 2H), 2.32 (td,
J = 7.9, 3.1 Hz, 2H), 2.12–2.03 (app s, 2H), 1.82 (t, J = 7.9 Hz, 2H), 1.74–1.55 (m, 4H), 1.08 (s,
13
3H); C{1H} NMR (101 MHz, CDCl3): δ 218.9, 119.5, 52.0, 40.8, 39.2, 36.6, 35.1, 24.7, 21.1,
17.7; IR (ATR): 2953, 2875, 2245, 1733, 1457, 1404, 1160, 1160, 497; HRMS (DART+) m/z: [M
+ H]+ calcd for C10H16ON 166.1226, found 166.1227.
3-(4-Chlorobutyl)-3-methylcyclopentan-1-one (35). Purification: 25 g SiO2, 5 ® 25%
EtOAc in hexanes; One-Pot Procedure: isolated 124.5 mg (0.6598 mmol, 66% yield) as a clear,
colorless oil. Rf = 0.29 (4:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3): δ 3.56 (t, J = 6.6 Hz,
2H), 2.32–2.27 (m, 2H), 2.06 (ABq, DdAB = 0.04, JAB = 17.8 Hz, 2H), 1.83–1.77 (m, 4H), 1.56–
1.43 (m, 4H), 1.07 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 219.8, 52.3, 45.0, 41.1, 39.6, 36.9,
35.3, 33.2, 25.1, 22.3; IR (ATR): 2953, 2670, 1745, 1457, 1404, 1287, 1154; HRMS (DART+)
m/z: [M + H]+ calcd for C10H18OCl 189.1041, found 189.1041.
ethyl 4-(3-oxocyclohexyl)butanoate (36). Purification: 25 g SiO2, 5 ® 25% EtOAc in
hexanes; One-Pot Procedure: isolated 195.4 mg (0.9158 mmol, 92% yield) as a clear, pale yellow
oil. Rf = 0.32 (2:1 hexanes/EtOAc); 1H NMR (400 MHz, CDCl3): δ 4.13 (q, J = 7.1 Hz, 2H), 2.43
(ddt, J = 13.7, 4.0, 1.9 Hz, 1H), 2.38–2.33 (m, 1H), 2.31–2.21 (m, 3H), 2.08–1.98 (m, 2H), 1.94–
1.88 (m, 1H), 1.84–1.73 (m, 1H), 1.70–1.59 (m, 3H), 1.43–1.29 (m, 3H), 1.26 (t, J = 7.1 Hz, 3H).
All other spectral data are consistent with reported values.47
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Me
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45 (R = Me)
46 (R = Ph)
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δ-Substituted enones 3,5-dimethylcyclohex-2-en-1-one (45) and 5-methyl-1,6-dihydro-
[1,1’-biphenyl]-3(2H)-one (46). Enones 45 and 46 were prepared using the same method,48 as
represented by the following procedure for 46. To a round-bottom flask was added methyl 3-
methyl-5-oxo-1,2,5,6-tetrahydro-[1,1'-biphenyl]-2-carboxylate (1.009 g, 4.130 mmol, 1.0 equiv),
DMSO (14.7 mL), H2O (6 mL; 2.5:1 DMSO/H2O, 0.2 M) and LiCl (700 mg, 16.5 mmol, 4 equiv).
A condenser was affixed to the flask and the contents were warmed to 145 °C until consumption
by TLC analysis. The reaction was then cooled to ambient temperature and the contents were
transferred to a separatory funnel with Et2O (125 mL). The contents were mixed, separated, and
the organic layer was washed with H2O (6 x 20 mL). The combined aq layers were extracted with
Et2O (4 x 20 mL), and the combined organic layers were washed with brine (20 mL), dried over
MgSO4, filtered and concentrated in vacuo. Purification by manual flash chromatography (2.5 x
17 cm SiO2, 1:1 pet. ether/Et2O) afforded 46 (739.0 mg, 3.969 mmol, 96% yield) as a pale
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orange/brown oil that partially solidifies upon refrigeration. Rf = 0.23 (3:1 hexanes/EtOAc); H
NMR (400 MHz, CDCl3): δ 7.35 (t, J = 7.3 Hz, 2H), 7.28–7.24 (m, 3H), 5.98 (s, 1H), 3.37–3.29
(m, 1H), 2.66 (dd, J = 16.1, 4.1 Hz, 1H), 2.59–2.51 (m, 3H), 2.01 (s, 3H). All other spectral data
were consistent with reported values.49
Supporting Information
Additional preliminary reaction screen and compound spectra (1H and 13C{1H}) are available
in the Supporting Information.
Acknowledgements
The authors thank the American Chemical Society (ACS) Petroleum Research Fund
Undergraduate New Investigator Program (Award No. 58488-UNI1), the ACS and Pfizer
(research fellowship to T.J.F.), Bucknell University (research fellowships to H.R.R. and T.J.F.)
and the Department of Chemistry (research fellowships to P.L.A, A.M.A. and C.B.B.) for
generous support of this work. Dr. Peter M. Findeis and Brian Breczinski are acknowledged for
experimental and instrumentation assistance.
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