Preparation of chiral secondary boronic esters via copper-catalyzed enantioselective conjugate reduction of β-boronyl-β-alkyl α,β-unsaturated esters

Article abstract of DOI:10.1016/j.tet.2011.07.088

A new methodology involving the copper(I)-catalyzed enantioselective conjugate reduction of β-boronyl-β-alkyl enoates was developed. Various chiral secondary boronate derivatives can be accessed in excellent yields and good to high levels of enantioselectivity through this efficient copper-catalyzed process using polymethylhydrosiloxane (PMHS) as hydride source.

Full text of DOI:10.1016/j.tet.2011.07.088

Tetrahedron 68 (2012) 3428e3434
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Preparation of chiral secondary boronic esters via copper-catalyzed
enantioselective conjugate reduction of b-boronyl-b-alkyl a,b-unsaturated esters
*
Jinyue Ding, Dennis G. Hall
Department of Chemistry, W5-07 Gunning-Lemieux Chemistry Centre, University of Alberta, Edmonton, Alberta, T6G 2G2 Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
A new methodology involving the copper(I)-catalyzed enantioselective conjugate reduction of
b-bor-
Received 31 March 2011
Received in revised form 22 July 2011
Accepted 28 July 2011
onyl- -alkyl enoates was developed. Various chiral secondary boronate derivatives can be accessed in
b
excellent yields and good to high levels of enantioselectivity through this efficient copper-catalyzed
process using polymethylhydrosiloxane (PMHS) as hydride source.
Ó 2011 Elsevier Ltd. All rights reserved.
Available online 3 August 2011
Keywords:
Asymmetric reduction
b-Boronoacrylates
Chiral alkylboronates
Copper (I)
Polymethylhydrosiloxane
1. Introduction
provide a useful alternative methodology. Herein, we describe the
development of this method using copper-catalyzed conjugate re-
The emergence of boronic acids and their derivatives as a ver-
satile class of synthetic intermediates1 has spurred the de-
velopment of new methods to prepare chiral organoboronate
derivatives in optically enriched form.2 These intermediates may be
employed in cross-coupling chemistry,3 or can be used as pre-
cursors of alcohols and amines following a BeC bond oxidation. In
this regard, the boronate group may be viewed as a surrogate for
oxygen-containing nucleophiles in conjugate addition reactions.
Oxy-Michael reactions are notoriously difficult,4 thus borylative
duction with polymethylhydrosiloxane (PMHS) as hydride source.
Yun,6 Fernandéz,7
Hall and Lee11
Hoveyda,8 Shibasaki,9
Nishiyama10
organometallic
O
R
O
O
addition
borylation
R'O
R'O
R'O
RM, Cu(I)
(X2)2B2
or X2BH
BX2
BX2
R
*
conjugate additions5 as recently demonstrated by the groups of
7
Yun,6 Fernandez, Hoveyda,8 Shibasaki9 and Nishiyama10 provides
H–, Cu(I)
ꢀ
reduction
an attractive alternative. Recently, our group proposed a comple-
mentary conceptual approach where the boronate unit is pre-
installed on a universal a,b-unsaturated ester substrate employed
in a catalytic asymmetric conjugate addition with unstabilized
carbanions (Fig. 1).11 We showed that when using a copper-
catalyzed enantioselective addition of organomagnesium reagents
with chiral biphosphine ligands, enantioselectivity excesses up to
98% can be obtained. As part of our ongoing search for new ways to
access chiral secondary boronate derivatives, we reasoned that
the corresponding copper-catalyzed enantioselective conjugate
O
R
This work
R'O
BX2
Fig. 1. Possible conjugate addition approaches to chiral secondary boronates.
2. Results and discussion
2.1. Optimization of reaction conditions
reduction of
b-boronyl-b-alkyl a,b-unsaturated esters would
To the best of our knowledge, there are no examples of catalytic
conjugate reduction on
b-borylated a,b-unsaturated carbonyl
compounds. We anticipated that the chemical compatibility of the
boronate substituent could be a major challenge in the design and
* Corresponding author. Tel.: þ1 780 492 3141; fax: þ1 780 492 8231; e-mail
address: dennis.hall@ualberta.ca (D.G. Hall).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.088

J. Ding, D.G. Hall / Tetrahedron 68 (2012) 3428e3434
3429
Table 1
optimization of this reaction. Possible undesired pathways include
insertion into the BeC bond leading to deboronative processes. The
first round of yield optimization employed -methyl- -boryl
Optimization of reaction conditions for conjugate reduction of
b-boronyl
b
-methyl
a,b
-unsaturated ester 1aa
b
b
enoate 1a as model substrate under conditions described by Lip-
shutz and co-workers.12 These conditions were selected as a start-
ing point because they featured an impressively low catalysis
loading (substrate-to-ligand ratio of 7700:1), affording superior
ee’s (95ꢀ99% range) compared to previously reported protocols.
Thus, different chiral biphosphines 3e9 (Fig. 2) were exploited with
copper hydride in the presence of PMHS and tert-butanol in toluene
at 0 ꢁC (entries 1e7, Table 1). The reaction was found to be relatively
slow, requiring as long as 36 h of stirring time. Under these con-
ditions, a high yield and excellent enantiomeric excess were
obtained when JOSIPHOS 6 was used as the ligand (entry 4, Table 1).
Fine-tuning of the catalyst loading revealed that less than 1 mol %
of copper catalyst was sufficient for an efficient reaction (entry 8,
Table 1). Using the optimal ligand and loading of catalyst, the in-
fluence of the solvent and temperature on the yield and enantio-
selectivity was examined next (entries 10e14, Table 1). When
tetrahydrofuran was utilized as a solvent, none of the desired
product was obtained at either 0 ꢁC or room temperature (entries
11 and 12, Table 1). This outcome is presumably due to the co-
ordination to the copper centre. In the end, methylene chloride was
found to be the most suitable solvent at 0 ꢁC, leading to a high yield
and the highest enantiomeric excess of 96% (entry 13, Table 1).
Entry
Ligand
Solvent
Temp
Time (h)
Yield (%)
ee (%)d
1
2
3
4
5
6
7
8
3
4
5
6
7
8
9
6
6
6
6
6
6
6
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
0 ꢁ
0 ꢁ
C
C
36
36
36
24
48
36
36
24
16
24
48
48
24
24
44
34
24
92
0
d
d
d
92
d
d
d
94
95
91
d
d
96
92
0
0
0
0
0
0
ꢁC
ꢁC
ꢁC
ꢁC
ꢁC
ꢁC
13
16
95b
94c
91b
0b
9
0 ꢁ
rt
C
10
11
12
13
14
0
ꢁC
THF
CH2CI2
CH2CI2
rt
0b
0 ꢁ
rt
C
93b
94b
a
Reaction conditions: 1a (1.0 mmol), 0.4 mol % (Ph3P)CuH (0.4
m
mol), 0.2 mol %
ligand (0.2 mmol), t-BuOH (1.1 mmol), PMHS (2.0 mmol), solvent (1 mL).
b
(Ph3P)CuH (0.8 mol %), 0.4 mol % ligand 6.
(Ph3P)CuH (1.6 mol %), 0.8 mol % ligand 6.
Measured by chiral HPLC after oxidation, see Supplementary data for details.
c
d
Absolute configuration assigned by comparison with optical rotation of known
compound.11
2.2. Substrate scope with the (Ph3P)CuH method
Using the optimal conditions of Table 1 (entry 13), we then
carried out the study of the scope for various substrates (Table 2).
Surprisingly, substrate 1b did not give a level of enantioselectivity
as high as expected compared to 1a (entry 2, Table 2). As a result,
further optimization was carried out varying the ratio of catalyst
loading using 1b as a substrate (entries 3 and 4, Table 2). It was
found that even though an increase in the catalyst loading up to
The scope of substrates regarding the
examined under the optimal conditions identified for
methyl enoate 1a. The requisite substrates 1beg were prepared in
one-step from ynoates according to the method developed by Yun
and co-workers13 (Scheme 1, method I). Alternatively, substrates
b
-alkyl substituent was
b-boronyl-b-
1hei were prepared in two steps from
b-ketoesters using the
method of Miyaura and co-workers14 (Scheme 1, method II).
Fig. 2. Structures of ligands evaluated in the conjugate reduction of 1a.

3430
J. Ding, D.G. Hall / Tetrahedron 68 (2012) 3428e3434
1.6 mol % (Ph3P)CuH, 0.8 mol % JOSIPHOS (entry 3, Table 2) short-
ened the reaction time, the enantiomeric excess did not improve.
Adjusting the ratio of catalyst loadings to 1:1 (0.8 mol % (Ph3P)CuH,
0.8 mol % JOSIPHOS) again did not increase the enantiomeric excess
(entry 4, Table 2). Based on this observation, it can be concluded
that the catalyst loading does not play a crucial role. At this point,
the influence of sterics of the ester on the enantiomeric excess was
studied. The methyl ester 1c was reacted under the same reaction
conditions (entry 5, Table 2). Unfortunately, the enantiomeric ex-
cess still did not improve significantly by utilizing a smaller car-
boxyester. A number of b-alkyl substituted substrates with longer
chains were also tested, and it was found that lower enantiomeric
excesses were obtained (entries 6 and 7, Table 2). Therefore, the
Scheme 1. Two methods of preparation for substrates 1aei.
enantioselection is very sensitive to the size of the
b-alkyl
Table 2
Scope of b-boronyl-b-alkyl a,b
-unsaturated esters in the catalytic enantioselective conjugate reduction (Method A)a
Entry
Substrates
Product
Time (h)
24
Yield (%)
95
ee (%)e
96
1
2
24
91
75
3
4
12b
33c
93b
92c
74
72
5
6
16
36
95
92
81
79
7
8
9
48
72d
48
88
81d
85
71
d
66
10
11
48
48
0
0
d
d
12
48
0
d
a
Reaction conditions: 1a (0.5 mmol), 0.8 mol % (Ph3P)CuH (0.4
(Ph3P)CuH (1.6 mol %), 0.8 mol % ligand 6.
(Ph3P)CuH (0.8 mol %), 0.8 mol % ligand 6.
mmol), 0.4 mol % ligand (0.2 mmol), t-BuOH (0.55 mmol), PMHS (1.0 mmol), CH2CI2 (0.5 mL).
b
c
d
e
(Ph3P)CuH (0.8 mol %), without using any chiral ligands.
Measured by chiral HPLC after oxidation, see Supplementary data for details. Absolute configuration assigned by comparison with optical rotation of known compound.11

J. Ding, D.G. Hall / Tetrahedron 68 (2012) 3428e3434
3431
substituent. Whereas the
b
-methyl enoate gave 96% ee, the
b
-ethyl
other possible pathway II (Scheme 2), the oxygen of the copper
enolate (intermediate B in Scheme 3) could transmetallate with the
Bpin unit to form the corresponding boron enolate 10. This in-
termediate could then react with tert-butanol to afford the un-
desired deboronated product.
and -n-propyl enoates 2bed provided ee’s around the 80% mark.
b
To investigate the cause of this drop in enantioselectivity, a back-
ground reaction without chiral ligand 6 was performed (entry 8).
It was found that the conjugate reduction of b-n-hexyl enoate 2e
occurred smoothly without the assistance of a diphosphine ligand,
albeit with longer reaction time and lower yield (entry 8). Thus, it is
presumed that the bisphosphine-less background reaction com-
petes with the enantioselective reaction for the bulky substrates,
leading to diminished enantioselectivity. A further drop of selec-
2.3. Alternative systems with in situ generation of copper(I)
hydride
tivity was observed with the
b-cyclohexyl enoate 1f (entry 9),
As discussed above, the low enantioselectivity for substrates
1bef is presumably due to the steric hindrance at the b-position as
and the bulkier -tert-butyl enoate 1g was found to be unreactive
b
(entry 10). Unfortunately, under the conditions attempted, the cy-
clic substrates 1h and 1i failed to provide the desired conjugate
reduction products (entries 11 and 12). Instead, protodeboronation
products were isolated. Two possible pathways are proposed for
the protodeboronation process (Scheme 2). For pathway I, the bo-
ronic acid pinacol ester (Bpin), which is cis to the carboxylate, could
coordinate to the ester oxygen. This would activate the boronyl unit
towards protodeboronation. Due to the additional steric hindrance
well as the competitive background reaction when Stryker’s re-
agent16 was used as the copper hydride source. Therefore, in order
to avoid the background reaction, alternative copper(I) catalytic
systems that can generate copper(I) hydride in situ without the use
of triphenylphosphine were explored. For this purpose, Yun’s
(Method B, Table 3)17 and Buchwald’s (Method C, Table 3)15 cop-
per(I) catalyzed conjugate reduction systems were investigated
owing to their mild conditions and wide applicability. As shown in
Table 3, both methods B and C showed no background reaction
(entry 1). In addition, compared to method A (Table 2), both
methods B and C showed higher catalytic reactivity, as indicated by
the equally high yields within shorter reaction time observed for
substrates 1aee (entries 2e5, Table 3). In terms of enantiose-
lectivity, method C was found to be more efficient in most cases.
However, both catalytic methods B and C showed the same sub-
strate limitations as Lipshutz’s method (Method A, Table 2). High
enantioselectivities are still limited to the less sterically hindered
at the
a
position, the
b
-protonation pathway may compete more
-protonation pathway. As shown in the
efficiently with the desired
a
primary
b-alkyl substituents (entries 2e5, Table 3), while the
enantioselectivity for a secondary
b
-alkyl substituent (entry 6,
Table 3) dropped significantly. Additionally, like method A (Table 2),
both Yun’s and Buchwald’s copper(I) catalytic systems are in-
effective towards tertiary
(entries 7 and 8). In spite of this limitation, Method C represents an
effective alternative for enantioselective conjugate reduction of
b-alkyl substitution and cyclic substrates
b
-
Scheme 2. Proposed pathways for protodeboronation for the cyclic substrates.
boronyl
b
-alkyl
a,b
-unsaturated esters 1.
(Ph3P)CuH
R
O
O
L*
O
Me
Si
B
O
R
O
O
O
1
L*-CuH
O
B
O
O
more nucleophilic
C
t-BuOH
L*
L*
PPh2
R
O
H
(Cy)2P
Cu(I)
O
R
O
Fe
B
O
O
B
6
O
2
O
H
O
A
Cu(I) L*
O
R
O
O
PMHS
Si O Si O Si
B
O
n
H
B
Scheme 3. Proposed mechanism for the copper(I)-catalyzed conjugate reduction of b-boronyl b-alkyl a,b-unsaturated esters 1.

3432
J. Ding, D.G. Hall / Tetrahedron 68 (2012) 3428e3434
Table 3
Scope of
b
-boronyl-b-alkyl
a,b-unsaturated esters under two other catalytic systems
Entry
Substrate
Product
Time (h)
Yield (%)
ee (%)d
Method Ba
Method Cb
Method Ba
Method Cb
Method Ba
Method Cb
1c
2
24
7
24
5
0
93
92
0
92
95
d
70
76
d
97
96
3
12
17
4
12
17
91
94
80
96
5
6
14
14
17
48
82
80
90
79
68
48
94
81
7
72
72
72
72
0
0
0
0
d
d
d
d
8
a
Method B: 0.5 M 1 in toluene with 3 mol % Cu(OAc)2, 3 mol % Ligand 6, 4 equiv of PMHS and t-BuOH at 0 ꢁC.
Method C: 0.25 M 1 in toluene with 4 equiv of PMHS, 5 mol % CuCI, 5 mol % NaO t-Bu, and 10 mol % (R)-p-tol-BINAP at room temperature.
Background reaction (without using phosphine ligands).
b
c
d Measured by chiral HPLC after oxidation, see Supplementary data for details. Absolute configuration assigned by comparison with optical rotation of known compound.11
2.4. Proposed mechanism
copper(I) catalytic systems for enantioselective conjugate re-
duction were explored. In the beginning, Method A (modified
Lipshutz’s catalytic system, Tables 1 and 2) was investigated for the
optimization of reaction conditions and a substrate scope study was
Based on the proposed mechanism by Buchwald and co-
workers15 as well as the substrate scope observed in our study,
a probable reaction pathway for the copper(I)-catalyzed conjugate
realized using this method. Due to strict limitations of
b-sub-
reduction of
b
-boronyl
b
-alkyl
a
,
b
-unsaturated ester can be pro-
stitution in the enoate substrate observed in Method A, alternative
copper(I) catalytic systems (Method B and C, Table 3) that generate
copper(I) hydride in situ were explored. Although the same sub-
strate scope was observed, Method C based on conditions de-
veloped by Buchwald and co-workers was found to be the most
efficient, giving excellent yields and high enantiomeric excesses for
posed. As shown in Scheme 3, after ligand exchange with the
electron rich chiral bisphosphine ligand JOSIPHOS, a more nucle-
ophilic copper(I) hydride complex is formed. It then reacts with
enoate 1 to give the corresponding intermediate A, which allows
the asymmetric conjugate reduction to take place to form the
copper enolate B. Regeneration of the copper hydride complex with
polymethylhydrosiloxane (PMHS) affords the silylketene acetal
all cases of b-primary alkyl substrates. Applications of these chiral
secondary boronate derivatives in SuzukieMiyaura cross-coupling3
intermediate C, which then undergoes
the enantioriched product 2. As shown in intermediate A, the de-
livery of hydride is strongly influenced by the bulkiness at the
position. As a result, the smaller achiral triphenylphospine cop-
per(I) hydride can approach the -carbon more efficiently in the
case of bulky -alkyl substituted substrates, leading to a lower
s
-bond metathesis to give
are under investigation. With respect to applications in natural
product synthesis, we note that b-boronyl b-methyl product 2a,
which was obtained in 95% yield and 97% ee using our methodol-
ogy, constitutes a potentially very useful synthon for the con-
struction of propionate units and other methylated natural
products.
b
-
b
b
enantioselectivity compared to 1a.
4. Experimental section
4.1. General information
3. Conclusion
In summary, we have successfully developed an alternative
approach to access synthetically valuable secondary boronate de-
rivatives through copper(I)-catalyzed enantioselective conjugate
Unless otherwise stated, all reactions were performed under
a nitrogen atmosphere using flame-dried glassware. Acetonitrile
was distilled from CaH2. THF, toluene, dichloromethane and
reductions of
b-boronyl-b-alkyl a,b-unsaturated esters. Three

J. Ding, D.G. Hall / Tetrahedron 68 (2012) 3428e3434
3433
methanol were obtained from an MBraun MB SPS* solvent system
prior to use. (Ph3P)CuH was purchased form Acros Organics, þ97%;
chiral ligands 3e9 were generously provided by Solvias AG. Thin
layer chromatography (TLC) was performed on Merck Silica Gel 60
F254 plates and was visualized with UV light and KMnO4 stain.
NMR spectra were recorded on Varian INOVA-300, INOVA-400 or
INOVA-500 MHz instruments. The residual solvent protons (1H) or
the solvent carbons (13C) were used as internal standards. Boron
NMR spectra are referenced to external BF3$OEt2. 1H NMR data is
the literature.14 The characterization data for this compound
matched that of a previous report.14
4.3. General procedure for the asymmetric conjugate
reduction of enoates 1
Method A (Table 2): To a 15 mL Schlenk tube, flame dried and
purged with nitrogen, was added (Ph3P)CuH (1.7 mg, 0.004 mmol)
and (R)-(S)-JOSIPHOS (1.7 mg, 0.002 mmol). Methylene chloride
presented as follows: chemical shift in ppm (d) downfield from
tetramethylsilane (multiplicity, coupling constant, integration).
The following abbreviations are used in reporting NMR data: s,
singlet; br s, broad singlet; d, doublet; t, triplet; q, quartet; dd,
doublet of doublets; qt, quartet of triplets; m, multiplet. High-
resolution mass spectra were recorded by the University of
Alberta mass spectrometry services laboratory using either elec-
tron impact (EI) or electrospray ionization (ESI) techniques. In-
(0.5 mL) was added and the solution cooled to 0 ꢁC. PMHS (66
1 mmol) was introduced via syringe followed by t-BuOH (54
m
m
L,
L,
0.55 mmol) and enoate 1 (0.5 mmol) by syringe. The mixture was
stirred at 0 ꢁC until the reaction was deemed complete by TLC
(eluent: 10% ethyl acetate/hexane). The reaction was quenched by
pouring into aqueous satd NaHCO3, diluted with Et2O/H2O, and
then stirred for 2 h at room temperature. The aqueous layer was
extracted twice with Et2O and the combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered through
a pad of silica gel and rinsed with Et2O until no product remained
on the silica gel by TLC. The filtrate was then concentrated by
rotary evaporation. The crude oil was purified by flash chroma-
tography (10% ethyl acetate/hexane) to afford the title product as
a clear oil.
Method B (Table 3): To a 15 mL Schlenk tube, flame dried and
purged with nitrogen, was added Cu(OAc)2 (2.7 mg, 0.015 mmol)
and (R)-(S)-JOSIPHOS (10.2 mg, 0.015 mmol). PMHS (0.12 mL,
2 mmol) and toluene (0.5 mL) were added under nitrogen. The
reaction mixture was stirred for 5 min at 0 ꢁC and then enoate 1
(0.5 mmol) was added by syringe, followed by t-BuOH (0.19 mL,
2.0 mmol). The reaction tube was washed with toluene (0.5 mL)
and sealed, and the reaction mixture was stirred until no starting
material was detected by TLC (eluent: 10% ethyl acetate/hexane).
The work up procedure is the same as above.
frared spectra were obtained on
a Nicolet Magna-IR with
frequencies expressed in cmꢀ1
.
4.2. Preparation of b-boronyl-b-alkyl a,b-unsaturated esters 1
4.2.1. Ethyl (Z)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-
2-enoate 1a. Compound 1a was prepared according to the litera-
ture.13 The characterization data for this compound matched that of
a previous report.13
4.2.2. Ethyl (Z)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-
2-enoate 1b. Compound 1b was prepared according to the litera-
ture.13 The characterization data for this compound matched that of
a previous report.13
4.2.3. Methyl
(Z)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
but-2-enoate 1c. Compound 1c was prepared according to the lit-
erature.13 The characterization data for this compound matched
that of a previous report.13
Method C (Table 3): To a 15 mL Schlenk tube, flame dried and
purged with nitrogen, was added CuCl (2.7 mg, 0.027 mmol), (R)-p-
tol-BINAP (37 mg, 0.054 mmol) and t-BuONa (2.7 mg, 0.027 mmol).
Toluene (1 mL) was added under nitrogen, and the resulting solu-
tion was stirred for 10 min. PMHS (0.12 mL, 2 mmol) was added,
and the reaction mixture was stirred for another 10 min, followed
by addition of enoate 1 (0.5 mmol) by syringe. The reaction tube
was washed with toluene (1 mL) and sealed, and the reaction
mixture was stirred until no starting material was detected by TLC
(eluent: 10% ethyl acetate/hexane). The work up procedure is the
same as above.
4.2.4. Ethyl (Z)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-
2-enoate 1d. Compound 1d was prepared according to the litera-
ture.13 The characterization data for this compound matched that of
a previous report.13
4.2.5. Ethyl (Z)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)non-
2-enoate 1e. Compound 1e was prepared according to the litera-
ture.13 The characterization data for this compound matched that of
a previous report.13
4.3.1. (R)-Ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)buta-
noate 2a. The title compound 2a was isolated as a colourless oil. 1H
NMR (400 MHz, CDCl3)
2H), 1.40 (q, J¼7.4 Hz, 1H), 1.29e1.23 (m, 15H), 1.02 (d, J¼7.4 Hz, 3H).
13C NMR (125 MHz, CDCl3)
173.9, 83.1, 60.1, 37.7, 24.8, 24.6, 15.1,
14.3. 11B NMR (160 MHz, CDCl3) 33.9. IR (microscope, cmꢀ1) 2979,
d
4.14 (dd, J¼14.3, 7.2 Hz, 2H), 2.52e2.27 (m,
4.2.6. Ethyl (Z)-3-cyclohexyl-3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)acrylate 1f. Compound 1f was prepared accord-
ing to the literature.13 The characterization data for this compound
matched that of a previous report.13
d
d
2935, 2876, 1735. HRMS (EI) for C12H23BO4: calcd 242.16895; found
242.16863. ½a 2D0
ꢀ8.66 (c 1.36, CHCl3) (Table 2, Method A); ꢀ4.32
ꢂ
4.2.7. Ethyl (Z)-4,4-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)pent-2-enoate 1g. Compound 1g was prepared
according to the literature.13 The characterization data for this
compound matched that of a previous report.13
(c¼0.79, CHCl3) (Table 3, Method B); ꢀ7.71 (c¼0.82, CHCl3) (Table 3,
Method C).
4.3.2. (R)-Ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pen-
tanoate 2b. The title compound 2b was isolated as a colourless
4.2.8. Ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-
cyclopentene-1-carboxylate 1h. Compound 1h was prepared
according to the literature.14 The characterization data for this
compound matched that of a previous report.14
oil. 1H NMR (400 MHz, CDCl3)
d
4.11 (dq, J¼7.2, 1.6 Hz, 2H),
2.45e2.38 (m, 2H), 1.53e1.36 (m, 2H), 1.32e1.27 (m, 1H),
1.27e1.22 (m, 15H), 0.93 (t, J¼7.4 Hz, 3H). 13C NMR (125 MHz,
CDCl3)
(160 MHz, CDCl3)
d
174.0, 83.1, 60.1, 35.5, 24.8, 24.7, 23.5, 14.3, 13.2. 11B NMR
d
33.9. IR (microscope, cmꢀ1) 2979, 2934, 2875,
4.2.9. 5,5-Dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
2-cyclohexen-1-one 1i. Compound 1i was prepared according to
1735. HRMS (EI) for C13H25BO4: calcd 256.18460; found
256.18457. ½a 2D0
ꢀ2.8 (c 1.00, CHCl3) (Table 2, Method A); ꢀ2.64
ꢂ

3434
J. Ding, D.G. Hall / Tetrahedron 68 (2012) 3428e3434
(c¼0.92, CHCl3) (Table 3, Method B); ꢀ6.3 (c¼0.82, CHCl3) (Table
Supplementary data
3, Method C).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.07.088.
4.3.3. (R)-Methyl
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
pentanoate 2c. The title compound 2c was isolated as a colourless
oil. The characterization data for this compound matched our
References and notes
previous report.11
½
a 2D0
ꢂ
ꢀ1.11 (c 0.56, CHCl3).
1. Hall, D. G. Boronic Acids; Wiley-VCH: Weinheim, 2005.
2. (a) Matteson, D. S. Tetrahedron 1998, 54, 10555e10607; (b) Gao, X.; Hall, D. G. J.
Am. Chem. Soc. 2003, 125, 9308e9309; (c) Crudden, C. M.; Hleba, Y. B.; Chen, A.
C. J. Am. Chem. Soc. 2004, 126, 9200e9201; (d) Gao, X.; Hall, D. G. J. Am. Chem.
Soc. 2005, 127, 1628e1629; (e) Gao, X.; Hall, D. G.; Deligny, M.; Favre, A.; Car-
reaux, F.; Carboni, B. Chem.dEur. J. 2006, 13, 3132e3142; (f) Carosi, L.; Hall, D. G.
Can. J. Chem. 2009, 87, 650e661; (g) Lessard, S.; Peng, F.; Hall, D. G. J. Am. Chem.
Soc. 2009, 131, 9612e9613; (h) Thomas, S. P.; French, R. M.; Jheengut, V.; Ag-
garwal, V. K. Chem. Rec. 2009, 9, 24e39; (i) Ros, A.; Aggarwal, V. K. Angew. Chem.
, Int. Ed. 2009, 48, 6289e6292; (j) Dutheuil, G.; Webster, M. P.; Worthington, P.
A.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2009, 48, 6317e6319; (k) Thomas, S. P.;
Aggarwal, V. K. Angew. Chem., Int. Ed. 2009, 48, 1896e1898; (l) Schmidt, F.;
Keller, F.; Vedrenne, E.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2009, 48,
1149e1152; (m) Noh, D.; Chea, H.; Ju, J.; Yun, J. Angew. Chem., Int. Ed. 2009, 48,
6062e6064; (n) Lee, K.-S.; Zhugralin, A. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2009, 131, 7253e7255; (o) Ely, R. J.; Morken, J. P. Org. Lett. 2010, 12, 4348e4351.
3. (a) Imao, D.; Glasspoole, B. W.; Laberge, V. S.; Crudden, C. M. J. Am. Chem. Soc.
2009, 131, 5024e5025; (b) Crudden, C. M.; Glasspoole, B. W.; Lata, C. J. Chem.
Commun. 2009, 6704e6716; (c) Ohmura, T.; Awano, T.; Suginome, M. J. Am.
4.3.4. (R)-Ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hex-
anoate 2d. The title compound 2d was isolated as a colourless oil.
1H NMR (400 MHz, CDCl3)
d
4.10 (dq, J¼7.1, 1.6 Hz, 2H), 2.45e2.34
(m, 2H), 1.46e1.28 (m, 5H), 1.27e1.22 (m, 15H), 0.88 (t, J¼7.2 Hz,
3H). 13C NMR (125 MHz, CDCl3)
173.6, 82.7, 59.7, 35.4, 32.4, 24.4,
24.3, 21.5, 13.9, 13.8. 11B NMR (160 MHz, CDCl3)
33.9. IR (micro-
d
d
scope, cmꢀ1) 2979, 2931, 2873, 1735. HRMS (EI) for C14H27BO4:
calcd 270.20023; found 270.20026. ½a D20
ꢀ2.38 (c 1.00, CHCl3)
ꢂ
(Table 2, Method A); ꢀ2.72 (c¼0.65, CHCl3) (Table 3, Method B);
ꢀ6.3 (c¼0.82, CHCl3) (Table 3, Method C).
4.3.5. (R)-Ethyl 3-n-hexyl-3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)propanoate 2e. The title compound 2e was
isolated as a colourless oil. 1H NMR (400 MHz, CDCl3)
d 4.13 (dq,
ꢀ
Chem. Soc. 2010, 132, 13191e13193; (d) Sandrock, D.; Jean-Gerard, L.; Chen, C. Y.;
J¼7.2, 2.3 Hz, 2H), 2.47e2.37 (m, 2H), 1.50e1.20 (m, 26H), 0.90
Dreher, S. D.; Molander, G. A. J. Am. Chem. Soc. 2010, 132, 17109e17110.
4. (a) Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2003, 125,
8696e9697; (b) Ramachary, D. B.; Mondal, R. Tetrahedron Lett. 2006, 47,
7689e7693.
(t, J¼7.2 Hz, 3H). 13C NMR (125 MHz, CDCl3)
d 174.0, 83.1, 60.1,
35.8, 31.8, 30.6, 29.4, 28.7, 24.8, 24.7, 22.6, 14.3, 14.1. 11B NMR
(160 MHz, CDCl3)
d
33.8. IR (microscope, cmꢀ1) 2978, 2959, 2928,
€
5. Schiffner, J. A.; Muther, K.; Oestreich, M. Angew. Chem., Int. Ed. 2010, 49,
2857, 1735. HRMS (EI) for C17H33BO4: calcd 312.24719; found
1194e1196.
312.24737. ½a 2D0
ꢀ2.58 (c 1.80, CHCl3) (Table 2, Method A); ꢀ2.12
ꢂ
6. (a) Mun, S.; Lee, J.-E.; Yun, J. Org. Lett. 2006, 8, 4887e4889; (b) Lee, J.-E.; Yun, J.
Angew. Chem., Int. Ed. 2008, 47, 145e147; (c) Sim, H.-S.; Feng, X.; Yun, J. Chem.
dEur. J. 2009, 15, 1939e1943; (d) Chea, H.; Sim, H.; Yun, J. Adv. Synth. Catal.
2009, 351, 855e858.
(c¼0.79, CHCl3) (Table 3, Method B); ꢀ4.71 (c¼1.20, CHCl3) (Table
3, Method C).
ꢀ
7. (a) Lillo, V.; Prieto, A.; Bonet, A.; Díaz-Requejo, M. M.; Ramírez, J.; Perez, P. J.;
ꢀ
€
Fernandez, E. Organometallics 2009, 28, 659e662; (b) Fleming, W. J.; Muller-
4.3.6. (R)-Ethyl 3-cyclohexyl-3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)propanoate 2f. The title compound 2f was iso-
ꢀ
Bunz, H.; Lillo, V.; Fernandez, E.; Guiry, P. J. Org. Biomol. Chem. 2009, 7,
2520e2524; (c) Lillo, V.; Geier, M. J.; Westcott, S. A.; Fernandez, E. Org. Biomol.
Chem. 2009, 7, 4674e4676.
ꢀ
lated as a colourless oil. 1H NMR (400 MHz, CDCl3)
d
4.13 (J¼25.9,
7.2 Hz, 2H), 2.52e2.38 (m, 2H), 1.76e1.63 (m, 5H), 1.46e1.01 (m,
22H). 13C NMR (125 MHz, CDCl3)
174.5, 83.1, 60.1, 39.2, 33.7, 32.5,
32.2, 26.7, 25.0, 24.7, 14.3. 11B NMR (160 MHz, CDCl3)
33.7. IR
8. Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3160e3161.
9. Chen, I.-H.; Yin, L.; Itano, W.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131,
11664e11665.
10. Shiomi, T.; Adachi, T.; Toribatake, K.; Zhou, L.; Nishiyama, H. Chem. Commun.
2009, 5987e5989.
11. Lee, J. C. H.; Hall, D. G. J. Am. Chem. Soc. 2010, 132, 5544e5545.
12. (a) Lipshutz, B. H.; Servesko, J. M.; Taft, B. R. J. Am. Chem. Soc. 2004, 126,
8352e8353; (b) Lipshutz, B. H.; Servesko, J. M.; Petersen, T. B.; Papa, P. P.; Lover,
A. A. Org. Lett. 2004, 6, 1273e1275.
13. Lee, J.-E.; Kwon, J.; Yun, J. Chem. Commun. 2008, 733e734.
14. Ishiyama, T.; Takagi, J.; Kamon, A.; Miyaura, N. J. Organomet. Chem. 2003, 687,
284e290; For the preparation of the vinyl triflates, see: Babonski, D.; SOltani,
O.; Frantz, D. E. Org. Lett. 2008, 13, 2901e2904.
d
d
(microscope, cmꢀ1
) 2979, 2926, 2853, 1735. HRMS (EI) for
C17H31BO4: calcd 310.23154; found 310.23231. ½a D20
ꢀ2.89 (c 0.70,
ꢂ
CHCl3) (Table 2, Method A); ꢀ1.12 (c¼0.76, CHCl3) (Table 3, Method
B); ꢀ4.1 (c¼1.0, CHCl3) (Table 3, Method C).
Acknowledgements
15. Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 9473e9474.
This research was funded by the Natural Sciences and Engi-
neering Research Council (NSERC) of Canada, and the University
of Alberta. The authors would also like to thank Solvias AG
(Dr. H. Steiner and Dr. H.-U. Blaser) for the generous gift of chiral
ligands.
16. (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem. Soc. 1988, 110,
291e293; (b) For the application of Stryker’s reagent, see: Rendler, S.;
Oestreich, M. Angew. Chem., Int. Ed. 2007, 46, 498e504; (c) Deutsch, C.; Krause,
N.; Lipshutz, B. H. Chem. Rev. 2008, 108, 2916e2927.
17. (a) Lee, D.; Kim, D.; Yun, J. Angew. Chem., Int. Ed. 2006, 45, 2785e2787; (b) Lee,
D.; Yang, Y.; Yun, J. Org. Lett. 2007, 9, 2749e2751.