Reaction Optimization, Scalability, and Mechanistic Insight on the Catalytic Enantioselective Desymmetrization of 1,1-Diborylalkanes via Suzuki-Miyaura Cross-Coupling

Article abstract of DOI:10.1002/chem.201406680

A method for enantioselective desymmetrization of 1,1-diborylalkanes through a stereoselective Pd-catalyzed Suzuki-Miyaura cross-coupling has been thoroughly optimized. The most effective ligand was found to be a α,α,α,α-tetra-aryl-1,3-dioxolane-4,5-dimet

Full text of DOI:10.1002/chem.201406680

DOI: 10.1002/chem.201406680
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Catalysis |Hot Paper|
Reaction Optimization, Scalability, and Mechanistic Insight on the
Catalytic Enantioselective Desymmetrization of 1,1-Diborylalkanes
via Suzuki–Miyaura Cross-Coupling
Ho-Yan Sun,[a] Koji Kubota,[b] and Dennis G. Hall*[a]
Abstract: A method for enantioselective desymmetrization
of 1,1-diborylalkanes through a stereoselective Pd-catalyzed
Suzuki–Miyaura cross-coupling has been thoroughly opti-
mized. The most effective ligand was found to be a a,a,a,a-
tallation in cross-coupling reactions, mechanistic studies on
this desymmetrization process reveal that the base, in the
presence of KHF2, likely plays an additional role in the hy-
drolysis of the pinacol boronates to the corresponding bor-
onic acids. Through an in depth optimization of the chiral
ligand and mechanistic studies, it was possible to obtain ee
values over 90% for several aryl bromides and to develop
a reliably scalable process (up to one gram of 1,1-diborylal-
kane substrate).
tetra-aryl-1,3-dioxolane-4,5-dimethanol
(TADDOL)-derived
phosphoramidite. Results show that in order to achieve high
selectivity, a suitable balance between the sterics of the aryl
groups and the amino group on the ligand must be ach-
ieved. While the base has been known to facilitate transme-
Introduction
chiral secondary alkylboron intermediates, these issues are fur-
ther amplified by the challenge of stereocontrol.
The highly popular Nobel prize-winning class of palladium-cat-
alyzed cross-coupling reactions achieves carbonÀcarbon bond-
formation between sp2-hybridized carbon groups with a wide
substrate generality.[1] The Suzuki–Miyaura cross-coupling of
aryl and alkenyl halides with organoboron reagents,[2] in partic-
ular, has found wide application in both academic and industri-
al settings due in part to its mild reaction conditions as well as
the environmentally benign byproducts. In the past decade,
numerous new and effective methods have been developed
for the preparation of chiral alkyl- and allylboronates for use as
intermediates mainly toward formation of optically enriched al-
cohols (BÀC bond oxidation), and carbonyl allylboration, re-
spectively.[3] The ability to achieve stereoselective Suzuki–
Miyaura cross-coupling with these chiral boronates to establish
sp2-sp3 and sp3-sp3 CÀC bonds would greatly expand their utili-
ty and thus, provide a new strategic approach to assemble
chiral units of more complex molecules like natural products
and pharmaceutical drugs. Coupling of alkylboronates, howev-
er, is notoriously challenging. It is rendered difficult by
a slower transmetallation and possible side-reactions such as
b-hydride elimination and protodeboronation.[4] When using
Despite these hurdles, significant advances have been re-
ported in recent years (Figure 1).[5] Stereospecific cross-cou-
pling of optically enriched secondary alkylboronates was first
demonstrated by Crudden and co-workers [Figure 1, Eq. (1)].[5a]
These stereoretentive coupling conditions, however, were re-
stricted to the use of benzylic boronates as substrates. In 2010,
Suginome and co-workers reported stereoinvertive cross-
couplings of a-(acylamino)benzylboronic esters [Figure 1,
Eq. (2)].[5b,c] Subsequently, Molander and co-workers provided
the first example of stereospecific cross-coupling of a non-ben-
zylic, secondary alkyltrifluoroborate derivative [Figure 1,
Eq. (3)].[5d] More recently, stereoinvertive cross-couplings of
chiral secondary alkyl trifluoroborates was reported by Biscoe
and co-workers [Figure 1, Eq. (4)].[5f] Remarkably this cross-cou-
pling occurs without the need for any boron-activating group.
Inspired by Shibata’s discovery that 1,1-diborylalkanes can
be subjected to a single, chemoselective cross-coupling with
aryl halides,[6a] our laboratory reported the first synthesis and
stereospecific cross-coupling of an optically enriched 1,1-dibor-
yl compound made chiral by virtue of differentially protected
boronyl units [Figure 1, Eq. (5)].[5e] An alternate strategy would
consist in achieving enantioselective desymmetrization by
mono-cross-coupling of prochiral 1,1-diborylalkanes such as
bis-pinacolates. Such a method would represent an efficient
approach towards the construction of chiral diarylalkanes,
which are prominently featured motifs in important pharma-
ceutical compounds[7] (Figure 2).
[a] H.-Y. Sun, Prof. D. G. Hall
Department of Chemistry, University of Alberta
11227 Saskatchewan Drive, Edmonton AB, T6G 2G2 (Canada)
E-mail: dennis.hall@ualberta.ca
[b] K. Kubota
In the course of our own examination of this proposal
where we focused on a comprehensive optimization of both
the tetra-aryl core and the amine substituent of a,a,a,a-tetra-
aryl-1,3-dioxolane-4,5-dimethanol (TADDOL)-derived phosphor-
Faculty of Engineering, Hokkaido University
Kita 13 Nishi 8, Sapporo 060-8628 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406680.
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further optimizing our conditions to become reliably compe-
tent at producing significant amounts of products, we became
concerned with the reaction’s reproducibility at scales above
0.1 mmol. Herein, we report a thorough study on ligand struc-
ture for the discovery of a catalyst that complements that of
Morken and co-workers for certain substrates under conditions
that maintain high yields and enantioselectivities under larger
reaction scales, up to 2.4 mmol (1 g of diborylalkane). We also
provide new results that shed some light on the possible
mechanism of this desymmetrization process.
Results and Discussion
Optimization of reaction conditions
We began our studies with an examination of various chiral
phosphine ligands (Figure 3). We chose to use Shibata’s report-
ed conditions for the racemic coupling[6a] as a starting point,
however the palladium source was changed from Pd(PtBu3)2 to
Pd(OAc)2 in order to eliminate potential competition between
PtBu3 and the chiral ligand being examined. Diboryl compound
1 and aryl halide 2 were chosen as the coupling partners as
they were reported to undergo the racemic cross-coupling in
good yield.[6] Chiral bidentate ligands including Chiraphos (L2),
BINAP (L3), Tunephos (L5) and DTBM-Segphos (L9) were all
low-yielding and gave poor selectivity (Figure 3). Ferrocenyl-
based bidentate ligands like Mandyphos (L6), Josiphos (L7)
and Walphos (L8) were also unsuccessful, giving a low yield
with little to no enantioselectivity. Taniaphos (L11) gave 22%
ee, however attempts at increasing the enantioselectivity by
examining Taniaphos derivatives were unfruitful (not shown).
When BINOL-derived phosphoramidite L12 was used, the
product was formed in 16% ee. While the enantioselectivity
was not high, we believed that a comprehensive investigation
of various phosphoramidites should be pursued given the rela-
tive ease of access to this class of ligands. To our satisfaction, it
was encouraging to find that TADDOL-derived ligand 13 gave
the desired cross-coupled product in 36% ee. Phosphorami-
dites bearing the TADDOL core were a particularly attractive
class of ligands to examine due to the modularity of their syn-
thesis (Figure 4),[9] which makes steric and electronic tuning of
the ligand possible and relatively straightforward. The aryl
groups on the TADDOL backbone may be modified with a vari-
ety of substituted arenes, introduced simply through Grignard
additions to the tartrate precursor. Ligands bearing varying
amino groups were also accessible due to the commercial
availability of a large number of secondary amines.
Figure 1. Stereoselective cross-coupling of alkylboronates.
Screening of the synthesized TADDOL-derived ligands
(Table 1) revealed that increasing the size of the amine sub-
stituents had a positive effect on the outcome of the reaction
(Table 1, entries 1–5). More specifically, superior selectivities
were observed when diisopropylamino (L16) and 2,6-dimethyl-
piperidyl (L18) groups were used. Attempts at increasing the
size of the amino group (e.g., to di-tert-butylamino or 2,2,6,6-
tetramethylpiperidyl groups) were unsuccessful as the synthe-
sis of the desired ligands proved to be problematic with the
significant increase in size of the amine being used. The use of
Figure 2. Application of the desymmetrization of 1,1-diboron compounds
towards the synthesis of diarylalkanes.
amidite ligands, Morken and co-workers reported similar condi-
tions that can provide useful chiral alkylboronates with a range
of 68–90% ee at a scale of 0.1 mmol [Figure 1, Eq. (6)].[8a] While
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Figure 3. Initial screen of chiral phosphorous-based ligands. The reaction was run at a scale of 0.1 mmol of aryl bromide.
The identity of the base was also found to be important in
this cross-coupling process. The reaction would only proceed
in the presence of strong bases like metal hydroxides, which
was in agreement with previously documented observations.[6a]
The use of weaker bases like carbonates and phosphonates
did not yield any product (Table 2, entries 1 and 2). What was
surprising, however, was that the counter ion of the hydroxide
base being used had a profound impact on the enantioselec-
tivity of the reaction. While KOH, LiOH and CsOH led to moder-
ate selectivities and yields (Table 2, entries 3–5), no conversion
was achieved with bases like Ba(OH)2 and NBu4OH (Table 2, en-
tries 9 and 10). The use of NaOH was found to give a signifi-
cantly higher ee than the rest of the bases screened, however
the yield of the cross-coupled product was quite low (Table 2,
entry 6).
Figure 4. Synthesis of TADDOL-derived chiral phosphoramidites.
the more electronically deficient N-methylaniline was found to
decrease the activity of the catalyst and led to both poor yield
and selectivity (Table 1, entry 6). Due to the simpler purification
of L16 in comparison to L18, L16 it was chosen as the optimal
catalyst. A screen of different solvents revealed that ethereal
solvents like dioxane and THF were the most compatible with
the reaction conditions (Table 1, entries 3 and 8). Other sol-
vents like dichloromethane, toluene and acetonitrile simply re-
sulted in decreased reactivity and enantioselectivity (Table 1,
entries 9–13).
In an attempt to improve the yield, KHF2 was added as an
additive, since fluoride has been known to help increase the
rate of Suzuki–Miyaura cross-couplings.[10] It was found that
the combination of NaOH with KHF2 was successful in increas-
ing the yield without affecting the selectivity (Table 2, entry 7).
The cross-coupling did not occur when KHF2 was used on its
own (Table 2, entry 8), indicating that NaOH plays an integral
role in this process.
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1) the hydroxide forms an anion-
ic borate 5, which then under-
goes transmetallation with oxi-
datively inserted palladium(II) 6,
or 2) the hydroxide is involved in
the formation of a palladium-hy-
droxo species 7 which may then
undergo transmetallation with
Table 1. Optimization of TADDOL-derived phosphoramidite ligand and reaction solvent.
neutral
organoboronate
4
(Figure 5).
We felt that these require-
ments for transmetallation alone
could not completely account
for the need of this system for
an additive like KHF2 in addition
to a large excess of NaOH when
it is known that Suzuki–Miyaura
couplings are capable of pro-
ceeding with the use of weaker
bases like K2CO3 in the presence
of water.[11b] For this reason, we
surmised that the base was in
fact playing the additional role
of hydrolyzing the pinacol boro-
nate prior to the cross-coupling
Entry
Ligand
NR1R2
Solvent
Yield[a] [%]
ee[b] [%]
1
2
3
4
5
6
7
8
L14
L15
L16
L17
L18
L19
L20
L16
L16
L16
L16
L16
L16
NMe2
NEt2
NiPr2
NiBu2
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
THF
toluene
MeCN
tBuMeO
2-MeTHF
DMF
54
60
41
45
63
30
50
56
trace
28
trace
trace
trace
36
54
55
53
59
2
6
59
–
2,6-dimethylpiperidyl
NPhMe
NCy2
NiPr2
NiPr2
NiPr2
NiPr2
NiPr2
NiPr2
9
10
11
12
13
25
–
–
–
The reaction was run at a scale of 0.1 mmol of aryl bromide. [a] Isolated yield. [b] Measured by chiral high-per-
formance liquid chromatography.
Table 2. Optimization of the base.
Entry
Base
Concentration
(in H2O)
Equiv
Yield[a]
[%]
ee[b]
[%]
1
2
3
4
5
6
7[c]
8[c]
9
K2CO3
K3PO4
KOH
8m
8m
8m
8m
8m
8m
8m
–
4.5
4.5
4.5
4.5
4.5
4.5
4.5
–
0
0
41
59
46
18
59
0
–
–
Figure 5. Proposed mechanisms of transmetallation in Suzuki–Miyaura reac-
tions.
55
64
60
75
75
–
LiOH
CsOH
NaOH
NaOH
None
Ba(OH)2
NBu4OH
event. Indeed, when diboron compound 1 was subjected to
NaOH and KHF2 in a dioxane/H2O mixture in the absence of
palladium, ligand and aryl halide, followed by the addition of
pinanediol, the corresponding transesterified product 9 was
isolated in 75% yield [Figure 6, Eq. (6)]. This product was likely
formed via the intermediary of free boronic acids. In the ab-
sence of NaOH and KHF2, no transesterified product was ob-
tained [Figure 6, Eq. (7)]. These results suggest that hydrolysis
of the pinacol boronate groups is possible under the condi-
tions of the cross-coupling reaction. Unfortunately, attempts at
observing the evolution of free pinacol by NMR spectroscopic
analysis were unsuccessful due to the occurrence of too many
overlapping signals in the region of interest. Consequently, we
sought further support of this proposal through more experi-
mental evidence.
4m
40% w/w
2.2
4.5
trace
trace
–
–
10
The reaction was run at a scale of 0.1 mmol of aryl bromide. [a] Isolated
yield. [b] Measured by chiral high-performance liquid chromatography
[c] KHF2 (1.5 equiv) was added as an additive.
Mechanistic studies on the role of the base
We were interested in further investigating the roles of NaOH
and KHF2 in this cross-coupling process. Studies have shown
that hydroxide plays an essential role in the transmetallation
step of a Suzuki–Miyaura cross-coupling.[11]
To date, there have been two main proposals, both of which
have been corroborated by various computational studies:[12]
Since sterically hindered boronates like the corresponding
pinanediol derivative 9 are known to be quite hydrolytically
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Figure 7. Potential reaction pathways for the cross-coupling of diborylal-
kanes under hydrolytic conditions.
Figure 6. Hydrolysis of the diboron coupling partner.
Table 3. Modification of base stoichiometry.
stable, it was predicted that the cross-coupling of diboron
compound 9 would proceed more slowly than bis-pinacolate
1. In the event where 9 was used as the substrate, only trace
conversion to product was observed [Eq. (8)], which supports
the hypothesis that pre-hydrolysis of the boronic ester to the
boronic acid as a prerequisite to cross-coupling.
Entry
NaOH [equiv]
KHF2 [equiv]
Yield[a] [%]
ee[b] [%]
1
2
3
1.5
4.5
12.0
0.5
1.5
3.0
13
59
78
40
75
75
[a] Isolated yield. [b] Measured by chiral high performance liquid chroma-
tography.
the CÀBr bond of the aryl bromide gives palladium(II) complex
10. Ligand exchange with sodium hydroxide then gives the
palladium hydroxo species 11. The bispinacolate undergoes
hydrolysis under the reaction conditions to give the diboronic
acid, which may then undergo an enantio-determining trans-
metallation with 11 to give intermediate 12. Catalytic inter-
mediate 12 may then undergo hydroxide-assisted reductive
elimination[11c] to give the chiral secondary alkylboronic acid.
Since the isolated product of this reaction is in fact the secon-
dary pinacol boronate, we believe that the pinacol initially re-
leased during the hydrolysis step may condense onto the bor-
onic acid product to give the isolable pinacolate product.
If hydrolysis of the boronic ester is truly occurring, however,
one must consider the possibility of forming a racemic mono-
hydrolyzed product (Figure 7). The coupling of this racemic
compound could have a negative impact on the enantioselec-
tivity of the reaction. It was speculated that if hydrolysis of the
pinacol boronate was in fact a prerequisite to cross-coupling,
then the equivalents of base used should have an effect not
only on the yield, but also the selectivity of the reaction. If
a substoichiometric amount of base was used with respect to
the equivalents of pinacol boronate groups present in the re-
action mixture, a low enantiomeric excess may be expected
since this would likely result in incomplete hydrolysis of the di-
boryl substrate. In contrast, we reasoned that a large excess of
base would result in increased enantiomeric excess since the
excess of base should promote a higher concentration of the
doubly hydrolyzed diboron substrate.
Further ligand optimization
During the course of our studies, similar conditions were re-
ported by Morken and co-workers using L1—a TADDOL-de-
rived phosphoramidite bearing four tolyl groups.[8a] While this
study included a brief examination of the arene substitution,
the effect of the amino moiety was left unexplored. Since our
initial ligand optimization showed a significant effect of the
amino group on selectivity, we decided that a logical progres-
sion would be an examination of the combined effects of both
the aryl substituent and the amine moiety. Our efforts led to
the observation that both the steric size on the aryl substitu-
ent and the amine had a profound effect on the activity of the
catalyst. Ligand L1 gave poor yield and selectivity under our
reaction conditions (Table 4, entry 1). Selectivity was generally
observed to increase with increasing size of the alkyl substitu-
ent, although anomalies were observed in this trend when
Accordingly, we found that when only 1.5 equivalents of
NaOH and 0.5 equivalents of KHF2 were used in the presence
of 3.0 equivalents of pinacol boronate moieties (i.e., 1.5 equiv-
alents of diboron compound 1), the cross-coupled product
was obtained in only 13% yield and 40% ee (Table 3, entry 1).
When 12.0 equivalents of NaOH and 3.0 equivalents of KHF2
were used, the product was obtained in 78% yield and 75% ee
(Table 3, entry 3).
From these findings, we propose the following mechanism
(Figure 8): oxidative addition of ligand-bound palladium(0) into
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Figure 8. Proposed mechanism for the desymmetrization of 1,1-diboron compounds.
comparing ethyl substitution to n-propyl substitution (Table 4,
entries 7–10). This observation hints that the aryl and amino
sites of the Pd-bound ligand are not independent of one an-
other. The use of isopropyl groups resulted in the highest ee.
Further increasing the size of the alkyl substituent to a tert-
butyl group had little effect on the selectivity of the reaction.
It was also found that larger amine size led to higher selectivi-
ty. Thus, the phosphoramidite bearing isopropyl groups on the
arene units in combination with a 2,6-dimethylpiperidyl group
(L31) was determined to be the optimal ligand (Table 4,
entry 12).
Reaction scope and scalability
Through our screening of cata-
lysts and mechanistic findings,
we obtained the optimal condi-
tions for this cross-coupling
[Figure 9, Eq. (9)], which allowed
for subsequent examination of
the scope of substrates for the
cross-coupling of diborylalkanes
(Figure 9). Most aryl halides were
found to cross-couple effectively
giving the desired products in
good yields and high enantio-
meric excesses. An electron-defi-
Table 4. Second-round optimization of the ligand.
Entry
Ligand
Diboryl
R1
NR2R3
Yield[a] [%]
ee[b] [%]
cient aryl halide bearing a fluo-
ride substituent gave the prod-
uct 16 in a lower yield and ee,
but we were pleased to find that
under these conditions, sterically
hindered electrophiles like 2-bro-
motoluene and 2-bromoanisole
were able to efficiently give the
1
2
3
4
5
6
7
8
L1
1
1
13
1
13
13
13
13
13
13
13
13
13
Me
Me
Me
Et
Et
Et
nPr
nPr
nPr
nPr
nPr
iPr
NMe2
NEt2
NiPr2
NMe2
NEt2
NiPr2
NMe2
NEt2
NiPr2
NiBu2
2,6-dimethylpiperidyl
2,6-dimethylpiperidyl
2,6-dimethylpiperidyl
46
30
83
63
50
77
20
21
35
60
80
80
70
44
54
81
51
78
87
70
66
80
80
88
89
87
L21
L22
L23
L24
L25
L26
L27
L28
L29
L30
L31
L32
9
corresponding
cross-coupled
10
11
12
13
products 18 and 20, respectively,
with high selectivity. Unfortu-
nately, vinyl bromides could not
be successfully cross-coupled to
give the corresponding chiral al-
tBu
The reaction was run at a scale of 0.1 mmol of aryl bromide. [a] Isolated yield. [b] Enantiomeric excesses of the
corresponding alcohols were measured by chiral high-performance liquid chromatography.
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lylboronates (not shown). Cross-coupling using bispinacolate
1 bearing a longer alkyl chain was also attempted and it was
found to also give the cross-coupled product 3 with good ste-
reoselectivity. It is notable that when Morken’s optimal ligand
L1 was used under our reaction conditions (Table 4, entry 1),
the selectivity was significantly lower (44% ee compared to
90% ee). When compared to the existing literature,[8a] only one
cross-coupling was achieved in lower selectivity (Figure 9,
product 16), while all other examples were achieved in equal
or higher selectivities, showing our conditions to be compli-
mentary to those that were previously reported. The successful
stereospecific cross-coupling of these chiral secondary boro-
nate products has been previously reported,[5h,8a] thus this
method is a direct and efficient route towards the synthesis of
optically enriched diarylalkanes.
0.2 mmol had no detrimental effect on neither the yield nor
the enantioselectivity, while cross-coupling at 0.4 mmol scale
resulted only in a small decrease in yield (~10% decrease). It is
noteworthy that the cross-coupling was found to maintain its
effectiveness even at over 20 times the original scale of the re-
action (Table 5, entry 7). At a reaction scale requiring 1 g of di-
borylalkane 13, the desired cross-coupled product was ob-
tained in lower yield (66%), but the selectivity of the reaction
was maintained (88% ee).
Table 5. Examination of the scalability of the cross-coupling reaction.
Entry
Conditions
ArX [mmol]
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
A
A
A
B
B
B
B
0.1
0.2
0.4
0.1
0.2
0.4
2.4
82
58
39
80
82
71
66
88
78
52
89
89
86
88
[a] Conditions A: 4-iodoanisole (x mmol), Pd(OAc)2 (5 mol%), L1
(10 mol%), KOH (15 equiv), dioxane/H2O, RT, 12 h. [b] Conditions B: 4-bro-
moanisole (x mmol), Pd(OAc)2 (5 mol%), L31 (10 mol%), NaOH (12 equiv),
KHF2 (3 equiv), dioxane/H2O, RT, 12 h. [b] Isolated yield. [c] Enantiomeric
excesses of the corresponding alcohols were measured by chiral high
performance liquid chromatography.
Conclusion
In summary, we have reported an in depth study on the opti-
mization of ligand structure for the desymmetrization of pro-
chiral 1,1-diborylalkanes through a Pd-catalyzed asymmetric
Suzuki–Miyaura reaction. A thorough ligand optimization has
demonstrated that both the size of the aryl groups and the
amine groups on the phosphoramidite have significant effect
on catalyst activity. Mechanistic studies have also shown that
NaOH and KHF2 likely serve to hydrolyze the pinacolboronates
to the corresponding diboronic acids, and this hydrolysis event
could be a prerequisite to cross-coupling. According to the re-
sults of our studies, improved conditions were developed,
which allows this robust reaction procedure to be scaled more
reliably. Given the numerous known methods of derivatizing
chiral boronates[14] the chiral secondary boronates produced
through this desymmetrization process may be used as useful
and versatile precursors in the synthesis of even more complex
molecules.
Figure 9. Reaction scope of the asymmetric Suzuki–Miyaura cross-coupling
of 1,1-diborylalkanes. Enantiomeric excesses of the corresponding alcohol
were measured by chiral high performance liquid chromatography. [a] Yields
and selectivities in brackets are those reported in ref. [8a]. [b] Yield over two
steps (cross-coupling then oxidation). The crude cross-coupled product was
directly oxidized to the corresponding alcohol for ee measurement.
During the course of our studies, we found that the cross-
coupling under the original literature conditions[8a] could not
be reliably performed at a scale larger than that reported
(0.1 mmol of aryl halide). In organic chemistry, problems in the
scaling up of batch reactions have been known to arise from
various issues including inefficient mixing and heat transfer.[13]
When the scale of the cross-coupling under literature condi-
tions[8a] was doubled to 0.2 mmol, it was found that the yield
decreased from 82 to 58% and the selectivity also decreased
significantly from 88 to 78% ee (Table 5, entry 2). Further in-
creasing the scale to 0.4 mmol resulted in further diminished
yield (39%) and enantiomeric excess (52%; Table 5, entry 3). In
contrast, when the cross-coupling was performed using our
optimized conditions, it was found that the scale of the reac-
tion had little effect on the outcome of the process. We were
pleased to find that doubling the reaction scale from 0.1 to
Experimental Section
Preparation of 1,1-diborylalkanes
2,2’-(5-Phenylpentane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-diox-
aborolane) (1): The title compound was prepared according to the
literature procedure[6b] with some minor modifications. To a 25 mL
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round-bottomed flask equipped with a magnetic stir bar was
added [Rh(COD)Cl]2 (43 mg, 0.09 mmol) and DPPB (89 mg,
0.21 mmol). The reaction vessel was capped with a rubber septum
and was evacuated and refilled with nitrogen gas. DCE (3.5 mL)
was added via syringe, followed by 5-phenyl-1-pentyne (0.52 mL,
3.47 mmol). Pinacol borane (1.5 mL, 10.41 mmol) was then added
dropwise via syringe. The resulting solution was allowed to stir at
room temperature for 24 h. The reaction was diluted with Et2O and
was then filtered through a pad of silica. The filtrate was concen-
trated in vacuo and purified by flash silica column chromatography
(EtOAc/hexanes, 5:95) to give the desired product as a yellow oil.
1H NMR (400 MHz, CDCl3): d=7.23–7.19 (m, 2H), 7.14–7.10 (m, 3H),
2.59 (t, J=7.6 Hz, 2H), 1.52–1.61 (m, 4H), 1.26–1.34 (m, 2H), 1.21 (s,
12H), 1.20 (s, 12H), 0.72 ppm (t, J=7.9 Hz, 1H). Full characteriza-
tion data is available in ref. [6b].
7.1 Hz, 2H), 7.47 (d, J=7.2 Hz, 2H), 7.42 (d, J=7.1 Hz, 2H), 7.32–
7.16 (m, 12H), 5.17 (dd, J=8.6, 3.6 Hz, 1H), 4.74 (d, J=8.5 Hz, 2H),
3.24 (m, 4H), 1.32 (s, 3H), 1.15 (t, J=7.1 Hz, 6H), 0.27 ppm (s, 3H);
13C NMR (125 MHz, CDCl3): d=147.3, 146.7, 142.5, 141.9, 129.1,
128.8, 128.8, 128.0, 127.6, 127.4, 127.3, 127.2, 127.2, 127.1, 127.1,
127.0, 126.9, 111.4, 82.6, 82.6, 82.4, 82.2, 81.5, 81.2, 81.2, 39.0, 38.8,
27.6, 25.3, 15.3, 15.2 ppm; 31P NMR (162 MHz, CDCl3): d=
141.4 ppm; IR (microscope; CHCl3): v˜ =3089, 3040, 2970, 2932,
2869, 1447, 1381, 1215, 1028, 917, 823, 758 cmÀ1; HRMS (ESI) for
C35H39NO4P [M+H]+: calcd: 568.2611; found: 568.2604; [a]2D0
À132.77 (c=0.35, CHCl3); m.p. 149–1518C.
=
(3aR,8aR)-N,N-Diisopropyl-2,2-dimethyl-4,4,8,8-tetraphenyltetra-
hydro-[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-amine (L16):
1H NMR (400 MHz, CDCl3): d=7.82 (d, J=8.1 Hz, 2H), 7.63 (d, J=
8.0 Hz, 2H), 7.47 (d, J=7.2 Hz, 2H), 7.44 (d, J=7.2 Hz, 2H), 7.31–
7.14 (m, 12H), 5.19 (dd, J=8.6, 3.8 Hz, 1H), 4.62 (d, J=8.6 Hz, 1H),
3.98 (sep, J=6.2 Hz, 2H), 1.42 (s, 3H), 1.24 (d, J=6.8 Hz, 6H), 1.20
(d, J=6.8 Hz, 6H), 0.24 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=
147.5, 147.0, 142.9, 142.1, 129.1, 128.7, 128.7, 127.8, 127.4, 127.3,
127.1, 127.1, 127.1, 126.9, 126.8, 111.0, 83.1, 83.1, 82.6, 82.4, 81.1,
81.1, 80.7, 80.7, 44.3, 44.2, 27.8, 25.0, 24.4, 24.3, 24.2, 24.1 ppm;
31P NMR (162 MHz, CDCl3): d=140.4 ppm; IR (microscope, CHCl3):
v˜ =3089, 3025, 2967, 2933, 2903, 1395, 1216, 1183, 1003, 981, 878,
736 cmÀ1; HRMS (ESI) for C37H43NO4P [M+H]+: calcd: 596.2924;
found: 596.2924; [a]2D0 =À96.64 (c=0.82, CHCl3); m.p. 135–1388C.
(2R,6S)-2,6-Dimethyl-1-((3aR,8aR)-4,4,8,8-tetrakis(4-isopropyl-
phenyl)-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-e][1,3,2]dioxa-
phosphepin-6-yl)piperidine (L31): 1H NMR (400 MHz, CDCl3): d=
7.71 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz,
2H), 7.32 (d, J = 8.4 Hz, 2H), 7.14–7.10 (m, 6H), 7.07 (d, J =8.3 Hz,
2H), 5.12 (dd, J = 8.6, 3.6 Hz, 1H), 4.60 (d, J = 8.5 Hz, 1H), 4.11–
4.03 (m, 2H), 2.91–2.79 (m, 4H), 1.98–1.84 (m, 1H), 1.79–1.64 (m,
2H), 1.61–1.49 (m, 3H), 1.39 (s, 3H), 1.38 (d, J = 7.9 Hz, 3H), 1.31
(d, J = 7.1 Hz, 3H), 1.24–1.21 (m, 21H), 1.17 (dd, J = 6.9, 2.0 Hz,
9H), 0.19 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=147.4, 147.3,
147.1, 146.8, 145.0, 144.5, 140.2, 139.6, 129.0, 128.4, 127.0, 126.9,
125.9, 125.6, 125.4, 125.0, 110.9, 83.2, 83.2, 82.8, 82.6, 81.0, 80.9,
80.6, 46.4, 46.2, 45.9, 45.7, 33.6, 33.6, 33.5, 33.5, 31.6, 31.4, 27.7,
24.9, 24.0, 23.9, 23.9, 23.8, 14.8 ppm; 31P NMR (162 MHz, CDCl3):
d=139.1 ppm; IR (microscope, CHCl3): v˜ =2961, 2931, 2870, 1510,
2,2’-(3-Phenylpropane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-diox-
aborolane) (13): The title compound was prepared according to
the literature procedure[8a] with slight modifications. To a 25 mL
round-bottomed flask equipped with a magnetic stir bar was
added CuI (19.2 mg, 0.10 mmol), B2pin2 (508 mg, 2.00 mmol), PPh3
(34.4 mg, 0.13 mmol) and LiOMe (114 mg, 3 mmol). The reaction
vessel was capped with a rubber septum and was evacuated and
refilled with nitrogen gas. A solution of (3,3-dibromopropyl)ben-
zene prepared according to literature procedure[15] (278 mg,
1.00 mmol) in DMF was added via syringe. The resulting solution
was allowed to stir at room temperature for 24 h. The reaction was
then diluted with Et2O (6 mL) and filtered through a plug of Celite.
The filtrate was washed with water (3”10 mL) and dried over
MgSO4(s), filtered, then concentrated in vacuo. The crude mixture
was purified flash silica column chromatography (1–5% EtOAc/hex-
1
anes) to give the desired product as a white solid (75%). H NMR
(400 MHz, CDCl3): d=7.23–7.19 (m, 2H), 7.15–7.08 (m, 3H), 2.56 (t,
J=7.9 Hz, 2H), 1.82 (q, J=7.9 Hz, 2H), 1.20 (s, 12H), 1.20 (s, 12H),
0.78 ppm (t, J=7.9 Hz, 1H). Full characterization data are available
in ref. [8a].
General procedure for the synthesis of TADDOL-derived
phosphoramidites
All phosphoramidites were synthesized according to literature pro-
cedure[7b] with slight modification. To a 25 mL round-bottomed
flask equipped with a magnetic stir bar was added the diol
(0.60 mmol). THF (3 mL) followed by Et3N (0.29 mL, 0.95 mmol)
were added via syringe, and the resulting solution was cooled to
08C before the dropwise addition of phosphorous trichloride
(58 mL, 0.66 mmol). The reaction mixture was stirred for 1 h and
the amine (2.70 mmol) was then slowly added at 08C. The reaction
was warmed to room temperature and stirred, overnight. The reac-
tion was then diluted with Et2O (15 mL) and filtered through a pad
of Celite. The filtrate was concentrated in vacuo and the resulting
crude mixture was purified by flash silica column chromatography
(0–2%EtOAc/1% Et3N/hexanes).
1215, 1020, 1002, 842, 812, 781, 758 cmÀ1
; HRMS (ESI) for
C50H67NO4P [M+H]+: calcd: 776.4802; found: 776.4789; [a]2D0
À92.71 (c = 0.41, CHCl3); m.p. 116–1208C.
=
Acknowledgements
This research was generously funded by the Natural Science
and Engineering Research Council of Canada, and the Universi-
ty of Alberta. H.-Y.S. was supported by a NSERC Canada Gradu-
ate Scholarship-D and an Alberta Innovates Health Solutions
Studentship. K.K. thanks the Japan Society for the Promotion
of Science (JSPS) for scholarship support allowing a research
exchange at the University of Alberta.
(3aR,8aR)-N,N,2,2-Tetramethyl-4,4,8,8-tetra-p-tolyltetrahydro-
[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepin-6-amine (L1): 1H NMR
(400 MHz, CDCl3): d=7.62 (d, J=8.3 Hz, 2H), 7.46 (d, J=8.2 Hz,
2H), 7.34 (d, J=8.3 Hz, 2H), 7.29 (d, J=8.2 Hz, 2H), 7.12–7.07 (m,
6H), 7.04 (d, J=8.0 Hz, 2H), 5.12 (dd, J=8.4, 3.2 Hz, 1H), 4.77 (d,
J=8.5 Hz, 1H), 2.74 (s, 3H), 2.71 (s, 3H), 2.31 (s, 3H), 2.30 (s, 6H),
2.27 (s, 3H), 1.30 (s, 3H), 0.31 ppm (s, 3H). Full characterization
data are available in ref. [8a].
Keywords: catalysis
·
cross-coupling
·
organoboron
·
palladium · stereoselectivity
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Published online on April 1, 2015
Chem. Eur. J. 2015, 21, 19186 – 19194
www.chemeurj.org
19194
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim