Stereoconvergent synthesis of chiral allylboronates from an E/Z mixture of allylic aryl ethers using a 6-NHC-Cu(I) catalyst

Article abstract of DOI:10.1021/ja1112518

We present a 6-NHC-Cu(I) complex that provides α-substituted allylboronates using allylic aryl ether substrates. The method was discovered by comparison of the chemoselectivities exhibited by complexes 1a, 1b, 2, and 3. We observed that 1a preferentially reacts with electron-rich alkenes over electron-deficient alkenes. Development of an asymmetric method revealed that 1b reacts with both the E and Z isomers to provide the same absolute configuration without showing E-Z isomerization. This stereoconvergent reaction occurs with high yields (av 86%), high S_N2′ selectivity (>99:1), and high ee (av 94%) and exhibits wide functional-group tolerance using pure E or Z isomer or E/Z alkene mixtures. The stereoconvergent feature enables the use of many different olefination strategies for substrate production, including cross-metathesis. Chiral allylboronates could be purified by silica gel chromatography and stored in the freezer without decomposition.

Full text of DOI:10.1021/ja1112518

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Stereoconvergent Synthesis of Chiral Allylboronates from an E/Z
Mixture of Allylic Aryl Ethers Using a 6-NHC-Cu(I) Catalyst
Jin Kyoon Park, Hershel H. Lackey, Brian A. Ondrusek, and D. Tyler McQuade*
Department of Chemistry & Biochemistry, Florida State University, Tallahassee, Florida 32306-4390, United States
S Supporting Information
b
expanded the substrate scope of these allylic substitutions from
ABSTRACT: We present a 6-NHC-Cu(I) complex that
provides R-substituted allylboronates using allylic aryl ether
substrates. The method was discovered by comparison of
the chemoselectivities exhibited by complexes 1a, 1b, 2, and
3. We observed that 1a preferentially reacts with electron-
rich alkenes over electron-deficient alkenes. Development
of an asymmetric method revealed that 1b reacts with both
the E and Z isomers to provide the same absolute config-
uration without showing E-Z isomerization. This stereo-
convergent reaction occurs with high yields (av 86%), high
SN20 selectivity (>99:1), and high ee (av 94%) and exhibits
wide functional-group tolerance using pure E or Z isomer or
E/Z alkene mixtures. The stereoconvergent feature enables
the use of many different olefination strategies for substrate
production, including cross-metathesis. Chiral allylboro-
nates could be purified by silica gel chromatography and
stored in the freezer without decomposition.
disubstituted to trisubstituted alkenes using chiral five-membered
N-heterocyclic carbene (5-NHC)-Cu(I) complexes with excellent
enantioselectivity. For disubstituted substrates, they have shown
that both (E)- and (Z)-alkenes afford high enantioselectivity.5c Both
Ito/Sawamura’s and Hoveyda’s reactions exhibit stereodivergence
with respect to acyclic E and Z substrates.5b,5c
Herein we present a stereoconvergent asymmetric synthesis of
chiral allylboronates. The transformation proceeds using bis-
(pinacolato)diboron (B2Pin2) and allylic aryl ethers and is cata-
lyzed by six-membered N-heterocyclic carbene (6-NHC)-Cu(I)
complexes 1a and 1b (see Table 3 for the structure of 1b). Aryl
ether substrates provide higher reaction rates and offer another
variable for maximizing the enantioselectivity, namely, changing of
substituents on the phenyl ring, in comparison with allylic
carbonates. The use of allylic aryl ethers in substitution reactions
is uncommon.9 The method requires a low loading of B2Pin2
(1.1 equiv) and catalyst (1 mol %) and provides high yields using
benchtop techniques.
We recently reported an efficient asymmetric β-borylation reaction
using chiral 6-NHC-Cu(I) complex 1a.10 While establishing that 1a
catalyzes β-borylations with high selectivity and excellent activity, we
also found that 1a provides unique chemoselectivity relative to
catalysts 2 and 3, which are known to perform β-borylations4g,11 or
allylic substitution reactions.5 AsshowninTable1, weobservedthat4
was converted into 5a by 1a, in contrast to the results using 2 (which
yields 5b exclusively) and 3-Cu(I) (which yields both products in
low yield).12
ynthetic methods that convert racemic starting materials into
S
single enantiomers are valuable tools. These stereoconvergent
methods can be achieved through a number of mechanisms, includ-
ing dynamic kinetic resolution, dynamic kinetic transformation,1 or
direct enantioconvergent transformation.2 Despite recent inter-
est in stereoconvergent reactions, there are only a few methods
that transform both E and Z alkenes into a single enantiomer.3
Among these, we found only one example involving direct
enantioconvergence, and it exhibits low enantioselectivity.3a In
most asymmetric reactions involving alkenes, E and Z alkenes
provide stereodivergent products, that is, products with different
absolute configurations.4,5
Chiral allylboronates are very versatile reagents that can provide
allylic alcohols, amines, or C-C bonds via direct reaction of the C-B
bond or homoallylic alcohols or amines through addition to carbonyls
(e.g., Brown or Roush allylation).6 Approaches to the synthesis of
chiral allylboronates include (1) stoichiometric reactions using chiral
auxiliaries,7 (2) asymmetric catalysis such as [4 þ 2] reactions,8a (3)
1,4-silaboration,8b (4) diboration,8c and (5) alkylation.8d,8e Recently,
chiral allylboronates have been synthesized using a Cu(I)-catalyzed
asymmetric allylic substitution reaction.2a,5b,5c In a series of reports,
the Ito and Sawamura group demonstrated first a nonasymmetric
version of this reaction5a and then an asymmetric version using a chiral
diphosphine ligand (QuinoxP).5b While excellent enantioselectivity
was observed using pure cis substrates, the trans substrates showed
poor enantioselectivity. More recently, the Ito and Sawamura group
reported enantioconvergent allylic substitutions using racemic cyclic
allylic alkyl ethers with excellent selectivity.2a The Hoveyda group has
Intrigued by the chemoselectivity preference of 1a, we compared
allylic substitution on a simpler disubstituted alkene using catalysts
1a, 2, and3(Table 2). Only catalyst 1a provided the branched allylic
substitutions in high yield. Catalyst 2 gave a low yield of only the
branched product (entry 2), and 3 gave a low yield with a detectable
amount of linear product. Excited by the observed reactivity
Received: December 14, 2010
Published: February 3, 2011
r
2011 American Chemical Society
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Table 1. Chemoselectivity Comparison Results
Table 3. Optimization of the Leaving Group for Allylic
Substitutions
entry
substrate (Ar)
trans-7a (phenyl)
yield (%)a ee (%)b
entry catalyst
temp
time
5a/5b ratioa
yield (%)b
1
2
3
4
5
6
7
8
9
91
91
86
95
79
47
94
74
92
84 (S)
80 (S)
88 (S)
65 (S)
89 (S)
91 (S)
87 (S)
84 (S)
62 (S)
trans-7b (2-methylphenyl)
trans-7c (3,5-dimethyphenyl)
trans-7d (3,5-bis(trifluoromethyl)phenyl)
trans-7e (3-nitrophenyl)
1
1a
2
-20 °C 10 min
-20 °C 20 min
25/1
1/24
1/1.5
88 (5a) (70)
88 (5b) (71)
65 (5a þ 5b) (16d)
2
3c
3
rt
6 h
a Ratios were determined by 1H NMR spectroscopy. b Yields were
1
cis-7e (3-nitrophenyl)
determined by H NMR spectroscopy; isolated yields are shown in
parentheses. c The reaction was run in THF (see the Supporting
trans-7f (4-nitrophenyl)
Information). d Isolated yield of 5a.
trans-7g (3-methyl-4-nitrophenyl)
trans-7h (4-methoxyphenyl)
a Determined by GC using an internal standard. b Determined by GC
analysis after oxidation and acetylation.
Table 2. Catalyst Comparison for Allylic Substitution
Reactions
entry
catalyst (mol %)
time
6a/6ba
yield (%)b
1
1a (1)
2 (1)
3 (3)
20 min
3 h
>99/1
>99/1
14/1
91 (47c)
17
2
3d
22 h
11
a Ratios were determined by GC analysis (see the Supporting Informa-
tion for more details). b Yields were determined by GC using an internal
standard. c Product ee. d The reaction was carried out in THF at rt.
differences, we compared aryl ethers to carbonates using 1a and
found that allyl carbonates required much longer reaction times
under the same conditions (3 h vs 20 min).
Figure 1. Reaction profiles for the trans and cis substrates.
While the 6-NHC-Cu(I) complex 1a appeared to be optimal
for the formation of the branched product, its enantioselectivity
was modest (47% ee; Table 2, entry 1). On the basis of molecular
models, we hypothesized that installation of a bulky substituent
(tert-butyl) at the para position of the N-aryl group would
enhance the energy difference between the favored and un-
favored transition states (see eq 2 below). We were gratified to
discover that 1b provided much higher enantioselectivity (84%
ee; Table 3, entry 1).
(E)-allylic substrate with 91% ee (entry 6); this was our first
evidence of stereoconvergence. This finding is in contrast to the
Ito/Sawamura and Hoveyda allylic substitution methods, which
provide stereodivergent outcomes.5,13
We suspected this result might arise from E-Z isomerization14
through a π-allyl-copper complex (eq 1):
We then screened aryl leaving groups by changing the steric and
electronic properties with the goal of optimizing the enantioselec-
tivity. We found that m-dimethyl (entry 3) and m- or p-nitro groups
(entries 5 and 7) on the aryl leaving group are optimal. In the course
of this optimization study, we were surprised to observe entries 5
and 6. We had expected to find that cis and trans substrates would
yield products with opposite configurations but instead observed
that the (Z)-allylic substrate provided the same configuration as the
1
However, no isomerization was detected by H NMR analysis
during the course of the reaction using the pure cis isomer as the
substrate. In addition, though the π-allyl-copper complex should
provide some linear product, none was observed by NMR or GC
analysis. However, we also recognized that this observation cannot
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rule out the hypothesis of irreversible formation of a π-allyl-copper
complex.
Table 4. Substrate Scope for Allylic Substitutions
After monitoring the reaction by GC and 1H NMR spectroscopy
using a 1:1 E/Z mixture of alkenes, we observed that the reaction of
the trans isomer is faster than that of the cis isomer [the mixture
provides a 94% ee outcome, which is between 93 and 96% (Figure 1;
also see Table 4, entry 1)]. On the basis of this result, we speculate
that the (E)-alkene has a lower-barrier transition state than the
(Z)-alkene and that the catalyst reacts with the same face of the
(E)- and (Z)-alkenes as shown in eq 2.
There are many olefination methods for the synthesis of
disubstituted alkenes that provide excellent E/Z selectivity.15
However, access to allylic substrates (i.e., allylic ethers and allylic
carbonates) using these methods often requires multiple steps.
On the other hand, methods providing direct access, such as
cross-metathesis, suffer from poor E/Z selectivity and require
difficult separations.16 The stereoconvergent nature of the re-
activity of complex 1b enables the formation of allylic substrates
from many entry points, including cross-metathesis (Scheme 1).
The data in Table 4 underscore the flexibility of our method, as
we used E/Z mixtures for many of the entries. The synthesis of the
substrates for entries 3-9 was accomplished via cross-metathesis.
Pure trans- and cis-3-nitrophenyl ether starting materials (entries 1
and 2) were prepared using nucleophilic aromatic substitutions,17
and the substrate for entry 9 was prepared using CuI and phen-
anthroline.18 The Williamson ether synthesis was used for entry 10.
As shown in Table 4, E/Z mixtures of various allylic aryl ethers
were successfully reacted with 1 mol % 1b to give products in
high ee and yield. Pure cis-10a gave a higher ee than the trans
isomer (entry 1). A pure trans substrate with a bulky group in the
R-position gave >99% ee (entry 2). E/Z mixtures of substrates
featuring aryl, bromide, ketone and ester substituents were well-
tolerated (entries 3-8). TBDMS-protected alcohols and Boc-
protected amines were also excellent substrates, providing highly
functionalized chiral allylboronates (entries 9 and 10). As a
comparison of steric accessibility, 10k was tested, and only the
disubstituted alkene reacted (eq 3).
a Isolated yields. b Determined by GC analysis after transformation to an
alcohol or acetate. c Synthesized by cross-metathesis. d Isolated yield
of 12.
Scheme 1. Substrate Synthesis
In summary, both complexes 1a and 1b exhibit unique
chemoselectivity relative to the 5-NHC-Cu(I) complex 2 and
the complex of diphosphine 3 with Cu(I). Complex 1b catalyzes
allylic substitutions with diboron using aryl ether substrates and
shows high ee and yield. This catalyst also exhibits a preference
for the same face of both (E)- and (Z)-alkenes, providing
stereoconvergent outcomes. Studies to better understand the
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mechanism are currently in progress.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
spectroscopic data for the reaction products. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
mcquade@chem.fsu.edu
’ ACKNOWLEDGMENT
The authors thank the NSF (CHE-0809261), Pfizer, and FSU
for support and the FSU VP of Research and Dean of Arts and
Sciences for NMR upgrades. We thank Prof. B. Moon Kim for
help in editing the manuscript.
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