Allylation reactions of aldehydes with allylboronates in aqueous media: Unique reactivity and selectivity that are only observed in the presence of water

Article abstract of DOI:10.1002/asia.201300440

Zn(OH)₂-catalyzed allylation reactions of aldehydes with allylboronates in aqueous media have been developed. In contrast to conventional allylboration reactions of aldehydes in organic solvents, the α-addition products were obtained exclusively. A catalytic cycle in which the allylzinc species was generated through a B-to-Zn exchange process is proposed and kinetic studies were performed. The key intermediate, an allylzinc species, was detected by HRMS (ESI) analysis and by online continuous MS (ESI) analysis. This analysis revealed that, in aqueous media, the allylzinc species competitively reacted with the aldehydes and water. An investigation of the reactivity and selectivity of the allylzinc species by using several typical allylboronates (6a, 6b, 6c, 6d) clarified several important roles of water in this allylation reaction. The allylation reactions of aldehydes with allylboronic acid 2,2-dimethyl-1,3-propanediol esters proceeded smoothly in the presence of catalytic amounts of Zn(OH)₂ and achiral ligand 4d in aqueous media to afford the corresponding syn-adducts in high yields with high diastereoselectivities. In all cases, the α-addition products were obtained and a wide substrate scope was tolerated. Furthermore, this reaction was applied to asymmetric catalysis by using chiral ligand 9. Based on the X-ray structure of the Zn-9 complex, several nonsymmetrical chiral ligands were also found to be effective. This reaction was further applied to catalytic asymmetric alkylallylation, chloroallylation, and alkoxyallylation processes and the synthetic utility of these reactions has been demonstrated. Still waters run deep: The Zn(OH)₂-catalyzed allylation of aldehydes with allylboronates in aqueous media exclusively afford the α-addition products. This reaction was also applied to alkylallylation, chloroallylation, and alkoxyallylation reactions. The role of water is discussed. Copyright

Full text of DOI:10.1002/asia.201300440

FULL PAPER
FULL PAPER
Allylation
Shu¯ Kobayashi,* Toshimitsu Endo,
Takumi Yoshino, Uwe Schneider,
Masaharu Ueno
&&&& — &&&&
Allylation Reactions of Aldehydes
with Allylboronates in Aqueous
Media: Unique Reactivity and Selec-
tivity that are Only Observed in the
Presence of Water
Still waters run deep: The Zn(OH)2-
catalyzed allylation of aldehydes with
allylboronates in aqueous media exclu-
sively afford the a-addition products.
This reaction was also applied to alky-
lallylation, chloroallylation, and alkox-
yallylation reactions. The role of water
is discussed.
1
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Shu¯ Kobayashi et al.
DOI: 10.1002/asia.201300440
Allylation Reactions of Aldehydes with Allylboronates in Aqueous Media:
Unique Reactivity and Selectivity that are Only Observed in the Presence of
Water
Shu Kobayashi,* Toshimitsu Endo, Takumi Yoshino, Uwe Schneider, and
¯
Masaharu Ueno[a]
Abstract: Zn(OH)2-catalyzed allylation
tively reacted with the aldehydes and
water. An investigation of the reactivi-
ty and selectivity of the allylzinc spe-
cies by using several typical allylboro-
nates (6a–6d) clarified several impor-
tant roles of water in this allylation re-
action. The allylation reactions of alde-
hydes with allylboronic acid 2,2-
dimethyl-1,3-propanediol esters pro-
ceeded smoothly in the presence of cat-
alytic amounts of Zn(OH)2 and achiral
ligand 4d in aqueous media to afford
reactions of aldehydes with allylboro-
nates in aqueous media have been de-
veloped. In contrast to conventional al-
lylboration reactions of aldehydes in
organic solvents, the a-addition prod-
ucts were obtained exclusively. A cata-
lytic cycle in which the allylzinc species
was generated through a B-to-Zn ex-
change process is proposed and kinetic
studies were performed. The key inter-
mediate, an allylzinc species, was de-
tected by HRMS (ESI) analysis and by
online continuous MS (ESI) analysis.
This analysis revealed that, in aqueous
media, the allylzinc species competi-
the corresponding syn-adducts in high
yields with high diastereoselectivities.
In all cases, the a-addition products
were obtained and a wide substrate
scope was tolerated. Furthermore, this
reaction was applied to asymmetric cat-
alysis by using chiral ligand 9. Based
on the X-ray structure of the Zn-9
complex, several nonsymmetrical chiral
ligands were also found to be effective.
This reaction was further applied to
catalytic asymmetric alkylallylation,
chloroallylation, and alkoxyallylation
processes and the synthetic utility of
these reactions has been demonstrated.
Keywords: aldehydes · allylation ·
À
C C bond formation
chemistry · zinc
·
water
Introduction
The allylation of aldehydes to provide homoallylic alco-
À
hols is one of the most-important carbon carbon bond-
In modern organic chemistry, organic reactions are generally
conducted in organic solvents. The use of water as a reaction
medium is very rare, even though water is safe, environmen-
tally benign, and inexpensive compared with organic sol-
vents. Today’s environmental consciousness befits the con-
sideration of water as a solvent by both industrial and aca-
demic chemists.[1] However, there are two major obstacles to
be surmounted for performing organic reactions in water:
First, many reactive substrates, reagents, and catalysts are
decomposed or deactivated by water (stability issue) and
second, most organic substances are insoluble in water (sol-
ubility issue). On the other hand, unique reactivities and se-
lectivities that are not observed in organic solvents have
been reported in aqueous media.[2]
forming reactions in organic synthesis.[3] To date, several
allyl-metal/metalloid reagents have been developed for this
transformation; of these reagents, allylboron reagents have
been established as being among the most useful[4] because
they are less toxic and more reactive than other allyl-metal/
metalloid reagents, such as allylsilanes[4b,5] and allyltins.[6]
The first allylboration of aldehydes was reported by Mikhai-
lov and Bubnov in 1964 by using triallylborane.[7] Two years
later, Favre, Gaudemar, and co-workers reported the allyla-
tion of aldehydes by using allylboronic ester.[8] Many funda-
mental studies were carried out by Hoffmann and co-work-
ers, who reported regio- and diastereoselective crotylation
reactions of both (E)- and (Z)-crotylboronates[9] and the re-
gioselective allylation of a-substituted allylboronates.[10] The
reactions proceeded without catalysts on the basis of
a Lewis acidic boron atom through Zimmerman’s six-mem-
bered transition states to exclusively afford g-addition prod-
ucts.[11] Asymmetric allylation reactions that employ chiral
allylboron reagents with auxiliaries have been reported by
the groups of Hoffmann,[12] Roush,[13] Corey,[14] Reetz,[15]
Masamune,[16] Brown,[17] and Soderquist.[18] Although high
diastereo- and enantioselectivities were attained, stoichio-
metric amounts of the chiral sources were needed, even
though some chiral sources could be recovered. More re-
[a] Prof. Dr. S. Kobayashi, T. Endo, T. Yoshino, Dr. U. Schneider,
Dr. M. Ueno
Department of Chemistry, School of Science
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax : (+81)3-5684-0634
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300440.
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Shu¯ Kobayashi et al.
cently, Lewis acid catalyzed allylboration reactions were in-
Results and Discussion
dependently reported by Hall and co-workers[19,20] and by
Miyaura and co-workers.[21] These allylation reactions were
accelerated by catalytic amounts of external Lewis acids.
Chiral Lewis acid catalyzed allylation reactions of aldehydes
with allylboronates have also been developed to achieve
asymmetric synthesis by using catalytic amounts of chiral
sources. Jain and Antilla reported chiral-phosphoric-acid-
catalyzed highly enantioselective allylboration reactions.[22]
One of the most characteristic features of the allylbora-
tion reaction is that the g-addition step proceeds through
Zimmerman’s six-membered transition states to afford high
stereoselectivity. To the best of our knowledge, there have
been no reports of a-selective allylboration reactions with
aldehydes, except for one example of the rearrangement of
the g-addition products.[23] The use of chiral Lewis or
Brønsted acids in asymmetric synthesis is promising because
only catalytic amounts of chiral sources can provide large
amounts of optically active compounds.[24] On the other
hand, thus far, most of the catalytic asymmetric reactions
have been performed at low temperatures (mostly at
À788C), because the allylboration reactions of aldehydes
proceed spontaneously without catalysts.[25] Moreover,
whereas the use of these reactions resulted in high yields
with high diastereo- and enantioselectivities, they were per-
formed under anhydrous conditions in many cases, because
most chiral catalysts are easily decomposed in the presence
of water. Furthermore, to the best of our knowledge, only
the crotylation (a-methylallylation) reaction has been re-
ported among the catalytic asymmetric a-alkylallylboration
reactions of aldehydes.[26]
In 2008, we reported the ZnF2-catalyzed asymmetric ally-
lation reactions of acylhydrazones with allylboronates in
aqueous media:[27] The acylhydrazones reacted with a-sub-
stituted allylboronates in the presence of catalytic amounts
of ZnF2 and a chiral diamine ligand to exclusively afford a-
addition products. This report is a very rare example of the
reaction of allylboronates with electrophiles to afford a-ad-
dition products.[23] Moreover, it was found that the use of
water (aqueous media) was essential for this reaction, be-
cause no reaction occurred in anhydrous organic solvents.
We became very interested in these unique reactivities and
selectivities in aqueous media and we decided to investigate
more-general reactions of aldehydes with allylboro-
nates.[28,29]
Initial Study of a-Selective Addition Reactions
In the ZnF2-catalyzed asymmetric allylation of acylhydra-
zones with allylboronates, Zn(OH)2 was assumed to be the
“real” catalyst after an investigation of the catalytic cycle.
Zn(OH)2 is an inexpensive and ubiquitous compound that is
very stable in water. Given these features, Zn(OH)2 ap-
peared to be a suitable catalyst in aqueous media and,
hence, we examined the reaction of a-methyl-substituted al-
lylboronate 1a with benzaldehyde in the presence of
10 mol% Zn(OH)2 in CH3CN/H2O (4:1).[28] The reaction
proceeded at room temperature to afford a mixture of a-ad-
dition product 2 and g-addition product 3 (2/3=45:55) in
86% yield (Table 1, entry 1). The reaction of another allyl-
Table 1. Reactions of a-methyl-substituted allylboronates 1a and 1b.
Entry
B
L
Yield [%]
2/3
45:55
95:5
81:19
82:18
33:67
99:1
syn/anti (2)
1
2
3
4
5
6
7
8
1a
1b
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
–
–
86
94
81
81
84
82
83
82
94
64
76
62
97
2:1
1:1
24:1
24:1
4:1
13:1
16:1
49:1
2:1
4a
4b
4c
4d
4e
4 f
4g
4h
4i
96:4
93:7
9
48:52
25:75
99:1
15:85
>99:<1
10
11
12
13
3:1
19:1
3:1
4j
4d
9:1
Herein, we report a full, detailed account of our efforts to
develop a Zn-catalyzed aldehyde allylation reaction in an
aqueous environment. We focus on the mechanistic aspects
and an elucidation of the details of this process, with an em-
phasis on the conceptual and mechanistic details rather than
the practical utility of the reaction.
boronate (1b) with benzaldehyde also proceeded smoothly
under the same reaction conditions to afford a-addition
product 2 with higher selectivity (2/3=95:5) in 94% yield
(Table 1, entry 2). Furthermore, we found a remarkable
effect of the ligand on the a selectivity and diastereoselec-
tivity of compound 2: Both the a selectivity and syn selectiv-
ity of compound 2 increased significantly by using ligands
4a, 4b, 4d, 4e, 4 f, and 4i with Zn(OH)2 (Table 1, entries 3,
4, 6, 7, 8, and 11).[30] Only a-addition product 2 was obtained
in excellent yield when allylboronate 1b and ligand 4d were
used (Table 1, entry 13). Notably, the a-addition of allylbor-
onate, which was previously observed in reactions with acyl-
3
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Shu¯ Kobayashi et al.
Figure 1. Allylation reaction of benzaldehyde with allylboronate 1a.[a]
[a] g-Addition product 3 was obtained without a catalyst.
Figure 2. Allylation reaction of benzaldehyde with crotylboronate (E)-5a.
hydrazones, was also observed in a reaction with an alde-
hyde. Next, we carefully examined the reaction rate and
found that remarkable catalyst acceleration occurred in this
reaction (Figure 1). In the absence of any catalyst, g-addi-
tion product 3 was obtained from benzaldehyde and allyl-
boronate 1a through a cyclic transition state because of the
Lewis acidity of the boron atom in compound 1a. On the
other hand, in the presence of Zn(OH)2 and ligand 4d, the
reactivity of the allylation reaction increased dramatically
and the reaction was complete within 5 min.
Next, we examined the reactions of (E)- and (Z)-crotyl-
boronates ((E)-5a and (Z)-5a) with benzaldehyde. We
found that, as distinct from the allylation reactions of com-
pound 1a, the reactions proceeded very slowly and g-addi-
tion product 2 was obtained exclusively. We carefully fol-
lowed these reactions and found that no catalyst accelera-
tion by Zn(OH)2/4d occurred, that is, similar reaction pro-
files were observed in the presence and absence of
Zn(OH)2/4d (Figure 2 and Figure 3). Moreover, stereospe-
cific reactions proceeded in these cases; syn- and anti-ad-
ducts of compound 2 were obtained from crotylboronates
(Z)-5a and (E)-5a, respectively.
Figure 3. Allylation reaction of benzaldehyde with crotylboronate (Z)-5a.
We further examined the reaction of simple allylboronate
6a with benzaldehyde and found that the reaction proceed-
ed faster in the presence of Zn(OH)2/4d than without a cata-
lyst (Figure 4).
Catalytic Cycle and Reaction Mechanism
In our initial studies, a-addition products were obtained
from the reactions of an aldehyde with a-substituted allyl-
boronates catalyzed by Zn(OH)2/4d in aqueous media. To
the best of our knowledge, this reaction a very rare example
of an a addition with an aldehyde during the relatively long
history of allylboration,[23] which made us interested in the
reaction mechanism. Based on the obtained results, we pro-
posed a catalytic cycle and reaction pathway for the
Figure 4. Allylation reaction of benzaldehyde with allylboronate 6a.
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Shu¯ Kobayashi et al.
Zn(OH)2-catalyzed allylation reactions of aldehydes with a-
methyl-substituted allylboronates in aqueous media
(Figure 5): Initially, allylboronate 1a, which is coordinated
by a H2O molecule, may attack Zn(OH)2 to induce a B-to-
Zn exchange process. This exchange may proceed in a g-ad-
dition fashion via a six-membered transition state to form
(Z)-crotylzincate, which may react with an aldehyde in a g-
addition fashion via another six-membered transition state
to predominantly produce a syn-Zn amide, followed by pro-
tonation with H2O to give homoallylic alcohol, along with
the regeneration of Zn(OH)2. Consequently, two g-addition
steps could give a-addition product 2.
Figure 5. Proposed catalytic cycle.
Figure 6. Detection of the crotylzincate species by MS (ESI) analysis:
a) Experimental and b) calculated HRMS data. c) Online monitoring of
the crotylzincate species by MS (ESI) analysis (without stirring). d–g) MS
(ESI) data for Zn(OH)2, compound 1a, and compound 4d in CH3CN/
H2O with stirring for 1.5, 10, 20, and 30 min, respectively.
The key step in this catalytic cycle is the exchange process
from B to Zn to generate the crotylzincate species. Next, we
attempted to detect the crotylzincate species. When
Zn(OH)2, compound 1a, and compound 4d were combined
in CH3CN/H2O (4:1), the major signals of the crotylzincate
species were detected by electrospray-ionization high-reso-
lution mass spectrometry (HRMS (ESI), Figure 6a). The
isotope pattern was identical to the calculated pattern (Fig-
ure 6b).[31] We also found that this crotylzincate species
gradually decomposed in the aqueous media (reacted with
H2O). This decomposition (hydrolysis) was monitored by
online continuous MS (ESI) analysis (Figure 6c), which was
performed without stirring for technical reasons. Independ-
ently, we monitored the reaction between Zn(OH)2, com-
pound 1a, and compound 4d with stirring (Figure 6d–g).
We found that the signals of the crotylzincate species were
even detected after 1.5 min and that the signals disappeared
after 30 min. Furthermore, another control experiment was
conducted by changing the order of addition in the allyla-
tion reaction (Table 2). Namely, allylboronate 1a and
Zn(OH)2/4d were combined for appropriate periods and
then benzaldehyde was added. The yield of allylation prod-
uct 2a was dependent on the mixing time of compound 1a
Table 2. Control experiments by changing the addition order of the ally-
lation reaction.
Entry
t [min]
Yield [%]
a/g
syn/anti
1
2
3
4
5
6
0
5
15
30
45
60
85[a]
75[a]
51[b]
16[b]
7[b]
99:1
99:1
99:1
99:1
99:1
–
12:1
10:1
8:1
4:1
2:1
–
0[b]
[a] Yield of isolated product. [b] Yield calculated from the crude NMR
spectrum.
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Shu¯ Kobayashi et al.
and Zn(OH)2/4d. After the B-to-Zn exchange, the as-
formed crotylzincate species competitively reacted with an
aldehyde and H2O.
Scheme 1. Isomerization of deuterated allylzincate.
Then, we conducted kinetic investigations on the allyla-
tion reaction of 3-phenylpropanal with allylboronate 1a.
With benzaldehyde at room temperature, the reaction was
too fast to follow by NMR spectroscopy; thus, we used 3-
phenylpropanal instead of benzaldehyde. First-order de-
pendence on allylboronate 1a and zero-order dependence
on the aldehyde were observed, which indicated that the
rate-determining step was the formation of the allylzincate
through the B-to-Zn exchange reaction.[32]
By assuming the catalytic cycle and the reaction pathway
shown in Figure 5, several experimental results can be ex-
plained: Whereas a-methyl-substituted allylboronate 1a
smoothly reacted to afford the a-addition product, the reac-
tions of crotylboronates (E)-5a and (Z)-5a proceeded
slowly to give the g-addition product. The B-to-Zn exchange
proceeded smoothly in the former case and it was assumed
to be inhibited in the latter case because of steric hindrance
at the g position of the crotylboronates. Uncatalyzed reac-
tions were assumed to proceed through Zimmerman’s six-
membered transition states to stereospecifically afford syn-
adduct 2 from compound (Z)-5a and anti-adduct 2 from
compound (Z)-5a.
Role of H2O: Organic Solvents versus Aqueous Solvents
Unique reactivities and selectivities were observed in the
Zn-catalyzed allylation reactions of several allylboronates in
aqueous media. We assumed that H2O played a key role in
the reactivities and selectivities because such reactivities and
selectivities were not observed in organic solvents; thus, the
effect of the amount of H2O was examined next (Table 4):
In the absence or presence of a small amount of H2O
Table 4. Effect of the amount of H2O.
Entry
Solvent
H2O[a]
[equiv]
Yield
[%]
2/3
syn/anti
(2)
1
2
3
4
CH3CN
CH3CN
CH3CN
CH3CN/H2O
(9:1)
–
10
100
–
61
66
74
77
3:97 2:1
2:98 2:1
80:20 19:1
99:1 16:1
In the reactions of simple (nonsubstituted) allylboronates,
the catalyzed reaction was found to proceed much faster
than the uncatalyzed reaction in the reaction profiles shown
in Figure 4. We further examined this reaction by using deu-
terated allylboronate [D]-6a (Table 3). We found that g-ad-
dition product 8 was exclusively obtained in 44% yield with-
5
CH3CN/H2O
(4:1)
–
82
99:1 13:1
6
7
8
9
CH3CN/H2O (1:1)
CH3CN/H2O (1:4)
CH3CN/H2O (1:9)
H2O
–
–
–
–
74
74
74
70
93:7 12:1
65:35 6:1
37:63 5:1
23:77 3:1
Table 3. Deuterium-scrambling experiments.
[a] Equivalents to benzaldehyde.
(10 equiv to the amount of benzaldehyde), g-addition prod-
uct 3 was obtained (Table 4, entries 1 and 2); however, when
the amount of water was increased, a-addition product 2
was obtained selectively (Table 4, entries 3–7). Moreover,
when the amount of H2O was increased further, g-addition
product 3 was dominantly produced (Table 4, entries 8 and
9).
Entry
Catalyst
Yield [%]
7/8
1
2
without catalyst
Zn(OH)2+4d
44
89
<1:>99
50:50
To further elucidate the role of H2O in the allylation reac-
tions, we examined the reactivities of allylboronates 6a–6d
in organic solvents and aqueous media in the presence and
absence of Zn(OH)2 (Figure 7). In CD2Cl2, we found that
compound 6c showed the highest reactivity, followed by 6a
and 6b, which were much less reactive; compound 6d
showed the lowest reactivity (Figure 7a). This order of reac-
tivity was almost consistent with that reported by Brown
et al.[17i] Similar reactivity differences were observed in
CD3CN: Compound 6c gave the highest reactivity, whilst
compounds 6a, 6b, and 6d showed much-lower reactivities
(Figure 7b). In contrast, very different reactivities were ob-
served in aqueous medium (CD3CN/D2O=4:1, Figure 7c):
Compound 6a gave the highest reactivity, whilst the other
out a catalyst, whereas a mixture of a-addition product 7
and g-addition product 8 (7/8=50:50) was obtained in 89%
yield in the presence of Zn(OH)2/4d.
We assumed that isomerization occurred in deuterated al-
lylzincate, which was formed from allylboronates and
Zn(OH)2/4d through g addition (Scheme 1). A similar iso-
merization is anticipated for (Z)-crotylzincate to form (E)-
crotylzincate (Figure 5), which may explain the time-de-
pendence of the syn/anti ratio of the products shown in
Table 2.
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Shu¯ Kobayashi et al.
Figure 7. Allylation reactions of benzaldehyde with compounds 6a–6d in a) CD2Cl2, b) CD3CN, c) CD3CN/D2O (4:1), and d) in the presence of
Zn(OH)2/4d in CH3CN/H2O (4:1).
Table 5. 11B NMR chemical shifts [ppm] in compounds 6a–6d.
three boronates showed almost-similar and lower reactivi-
ties. Next, we conducted the reactions in the presence of
10 mol% Zn(OH)2/4d in CH3CN/H2O (4:1). Because the
reaction system was heterogeneous and the reaction rates
were very fast, it was difficult to follow the reactions by
NMR spectroscopy. Therefore, we quenched the reactions
after 1.5 min and compared the yields directly (Figure 7d,
average of three experiments). Notably, in all cases, the re-
action rates increased significantly in the presence of
Zn(OH)2/4d. Moreover, the order of reactivity changed to:
6d>6bꢀ6c@6a. It was interesting that compound 6a was
the most reactive in aqueous media without a catalyst but
was the least reactive in the same solvent in the presence of
Zn(OH)2/4d. The reactivity order is summarized in
Scheme 2.
Solvent
6a
6b
6c
6d
CD2Cl2
CD3CN
CD3CN/D2O 4:1
32.8
33.6
33.3
29.1
29.9
29.8
33.5
34.2
31.8
29.5
30.2
28.7
steric hindrance of the four methyl groups on compound 6a.
On the other hand, similar transition states are assumed in
uncatalyzed reactions in aqueous media. The 11B NMR spec-
trum in CD3CN/H2O suggests that compound 6a is the most
Lewis acidic, which corresponds to the highest reactivity of
compound 6a in CD3CN/H2O. In aqueous media, H2O coor-
dinates to the B atom to decrease its Lewis acidity. Owing
to steric reasons, the coordination of H2O to allylboronate
6a is more difficult than that to compound 6c and, hence,
compound 6a retains its high Lewis acidity, even in aqueous
media. On the other hand, in the Zn(OH)2/4d-catalyzed re-
actions in aqueous media, the rate-determining step is the
B-to-Zn exchange process to generate the allylzincate spe-
cies. In this step, H2O coordinates to the B atom of the allyl-
boronates to form borates to accelerate the exchange pro-
cess. Although H2O also coordinates to Zn, the exchange-
rate constant of the inner-sphere H2O ligand is much faster
for Zn than for B.[33] This result means that Zn can retain its
Lewis acidity in the presence of H2O, in contrast to B.
Under these conditions, we assume that the borate forma-
tion is slower for compound 6a than for allylboronates 6b–
6d, which may be why compound 6a shows the lowest reac-
tivity. Because of the steric hindrance of the two methyl
groups in compound 6b, it shows lower reactivity than com-
pound 6d; however, it is noted that compound 6b is much
more reactive than compound 6a under these conditions.
Because compound 6d, with its six-membered ring, is more
sterically unstable after the coordination of H2O than com-
pound 6c, with its five-membered ring, compound 6d is con-
Scheme 2. Order of reactivity of compounds 6a–6d in various solvent sys-
tems.
In organic solvents, the allylation reactions proceed
through Zimmerman’s six-membered transition states to
afford g-addition products and the reactivity is mainly de-
pendent on the Lewis acidity of the boron atom of the allyl-
boronates. The 11B NMR chemical shifts of allylboronates
6a–6d are shown in Table 5, which indicate that the five-
membered allylboronates (6a and 6c) are more Lewis acidic
than the six-membered allylboronates (6b and 6d) in
CD2Cl2 and CD3CN. Thus, the highest reactivity of com-
pound 6c in both CD2Cl2 and CD3CN corresponds well with
its 11B NMR chemical shift and the lower reactivity of com-
pound 6a than compound 6c could be explained by the
7
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Shu¯ Kobayashi et al.
sidered to be more reactive than compound 6c. Thus, some
Asymmetric Reactions
key roles of H2O in the allylation reaction are revealed. It is
further noted that H2O also plays a key role in the protona-
tion of Zn amides to give the products, along with the regen-
eration of Zn(OH)2 (Figure 5).[34]
À
Thus, we have developed a new reaction to create C C
bonds, in which the relative stereochemistry could be con-
trolled. Next, we intended to control the absolute configura-
tions of the newly created stereogenic centers, which is re-
garded as the “ultimate goal” in developing a new reaction;
in other words, the reaction would provide a new route to
optically active compounds. Among the several methods
that are used to obtain optically active compounds, we fo-
cused on asymmetric catalysis because, by using this
method, large amounts of optically active com-
pounds can be obtained by using small amounts of
chiral sources.[36]
Substrate Scope (Achiral Reactions)
Several aldehydes and allylboronates were examined in the
presence of Zn(OH)2 (5 mol%) and compound 4d
(6 mol%) in aqueous media (Table 6). We selected allylbor-
Table 6. Substrate scope.
Based on the catalytic cycle shown in Figure 5,
we decided to search for appropriate chiral ligands
for allylzincates that worked well in aqueous media.
Asymmetric catalysis in aqueous media is extremely
difficult because most chiral catalysts are not stable
Entry
R1
R2
Conditions[a]
t [h]
Yield [%]
syn/anti
in the presence of even a small amount of H2O.
1
2
3
4
5
6
7
8
Ph
4-Me-C6H4
4-OMe-C6H4
4-Br-C6H4
4-NO2-C6H4
2-MeO-C6H4
3-MeO-C6H4
1-naphthyl
4-pyridinyl
2-thienyl
Me (1b)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
nBu
iBu
A
B
A
B
B
B
A
B
B
A
A
A
B
B
B
B
2
1
2
1
4
3
4
3
1
12
4
4
2
3
88
86
81
19:1
13:1
24:1
After the discovery of water-compatible Lewis
acids,[37] we searched for appropriate chiral ligands
quant.[b]
94
12:1
12:1
16:1
19:1
99:1
9:1
13:1
5:1
3:1
1:1
6:1
6:1
6:1
for these Lewis acids to develop chiral Lewis acid
catalysis in aqueous media and we found chiral
crown ethers to be appropriate ligands for our pur-
pose.[38] Furthermore, we showed that the combina-
94
94
96
83
91
81
92
94
tion of the ScACTHNUTRGNE(UNG OTf)3/chiral bipyridine ligand 9,
9
whose structure is a “half-crown ether”, worked
well for asymmetric hydroxymethylation reactions
in aqueous media.[39,40]
Against this background, we examined com-
pound 9[41] as a chiral ligand for allylzincate species.
In the presence of Zn(OH)2 (10 mol%) and com-
pound 9 (12 mol%), allylboronate 1b reacted with
benzaldehyde in CH3CN/H2O (7:3) at 08C to exclu-
sively afford the desired a-addition product with
high syn-selectivity (syn/anti=10:1) and the enan-
10
11
12
13
14
15
16
5-Me-2-furyl
(E)-PhCH=CH
PhCH2CH2
Ph
96
81
90
Ph
Ph
2
1
[a] Conditions A: CH3CN/H2O=12:1 (0.02m), À208C; conditions B: CH3CN/H2O=
4:1 (0.025m), À108C. [b] quant.=quantitative yield.
onic acid 2,2-dimethyl-1,3-propanediol esters rather than pi-
nacol allylboronates because the catalyzed reactions were
faster than the uncatalyzed reactions with allylboronic acid
2,2-dimethyl-1,3-propanediol esters and because 2,2-dimeth-
yl-1,3-propanediol was less expensive than pinacol.[35] Ben-
zaldehyde derivatives that contained electron-donating and
electron-withdrawing groups smoothly reacted with allylbor-
onate 1b to afford the desired adducts in high yields with
high syn-selectivities (Table 6, entries 1–7). Another aromat-
ic aldehyde and heteroaromatic aldehydes also worked well
under these conditions (Table 6, entries 8–11). In the reac-
tion of cinnamaldehyde with compound 1b, high yields and
moderate diastereoselectivities were obtained (Table 6,
entry 12). 3-Phenylpropionaldehyde also reacted with com-
pound 1b to give an allylated product in high yield, but with
low diastereoselectivity (Table 6, entry 13). Other allylboro-
nates reacted smoothly to afford the desired compounds in
high yields with good diastereoselectivities (Table 6, en-
tries 14–16). Notably, in all cases, only the a-addition prod-
ucts were obtained exclusively.
tiomeric ratio (e.r.) of the syn adduct was 86.5:13.5; no g-ad-
dition product was obtained. To further improve the enan-
tioselectivity, we examined the X-ray crystallographic struc-
ture of the Zn-9 complex.[40b] For comparison, Figure 8 also
shows the X-ray crystallographic structure of Sc-9,[39f,i] which
is a typical Lewis acid and works well in aqueous media.
In the Sc-9 complex, the two nitrogen atoms and two
oxygen atoms of compound 9 are bound to the ScIII center
in a tetradentate manner and the complex adopts a pentago-
nal-bipyramidal structure. On the other hand, the Zn-9 com-
plex adopts a square-pyramidal structure, in which two ni-
trogen atoms and only one of the oxygen atoms of com-
pound 9 are attached to the ZnII center in a tridentate
manner. Based on these structures, we assumed that the tet-
rahedral ligands were not absolutely necessary. Then, we de-
signed several bipyridine ligands, including tridentate li-
gands, and tested them in the asymmetric allylation reaction
of benzaldehyde with compound 1b in aqueous media
(Table 7).
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Interestingly, some nonsymmetrical ligands showed good
enantioselectivity: In the asymmetric reactions with the Sc-9
complex as a catalyst, no selectivity was obtained with com-
pound 10 as a ligand.[40c] However, when compound 10 was
used as a ligand for the allylation reaction, the desired prod-
uct was obtained in high diastereoselectivity and good enan-
tioselectivity (Table 6, entry 2). Ligands 10–12, which con-
tained smaller ethers, gave higher enantioselectivities than
those that contained bulky ethers, such as ligands 13 and 14
(Table 6, entries 3–6). Moreover, even some 2-alkyl-substi-
tuted bipyridine ligands (16 and 17) showed promising selec-
tivities (Table 6, entries 8 and 9). Ligand 18 might be too
bulky to coordinate to the Zn center in a bidentate fashion
(Table 6, entry 10). Whereas other ligands (19 and 20) also
showed good enantioselectivities (Table 6, entries 11 and
12), ligand 21, which did not contain an alcohol moiety, gave
no enantioselectivity (Table 6, entry 13).
The substrate scope of the asymmetric allylation reactions
is shown in Table 8. We examined the reactions of aromatic,
heteroaromatic, a,b-unsaturated, and aliphatic aldehydes
with a-alkyl-substituted allylboronates in the presence of
Zn(OH)2 (3–10 mol%) and ligand 9 (3.6–12 mol%) in aque-
ous media. In all cases, the reactions proceeded well and the
a-addition products were predominantly obtained. As a gen-
eral tendency of the selectivities, aromatic, heteroaromatic,
and a,b-unsaturated aldehydes gave high diastereoselectivi-
ties and good enantioselectivities, whereas aliphatic alde-
hydes showed good diastereoselectivities and high enantio-
selectivities.
Figure 8. X-ray structure of the [ScBr2·H2O·9]+ moiety in the X-ray struc-
tures of [ScBr2·H2O·9]·Br·H2O (top) and [ZnBr2·9] (bottom); hydrogen
atoms are omitted for clarity. CCDC 253182 (top) and CCDC 827315
(bottom) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Table 7. Effect of chiral ligands.
This asymmetric reaction was also applicable to several
synthetically useful procedures. a-Chloroallylboronate 22
smoothly reacted with various aldehydes to afford chloroal-
lylated products in high yields with high diastereo- and
enantioselectivities (Table 9). In all cases, no g-addition
products were obtained. The products, 2-chloro-homoallylic
alcohols, could be converted into optically active epoxides
and other compounds, which could act as versatile chiral
building blocks. As a demonstration of the utility of this pro-
cedure, we performed the reaction of 3-tert-butyldimethylsi-
loxy-propionaldehyde with compound 22 in the presence of
Zn(OH)2/9. The reaction proceeded smoothly at 08C in
aqueous media to afford chloroallylated product 23 in high
yield and high stereoselectivity. Adduct 23 is an intermedi-
ate in the synthesis of spirastrellolide A (Scheme 3).[42,43]
Another example is the synthesis of an intermediate of dis-
parlure (Scheme 4).[44,45] The reaction of dodecanal with
compound 22 in the presence of 2 mol% Zn(OH)2 and
2.4 mol% ligand 9 proceeded smoothly to afford the corre-
sponding chloroallylated adduct 24, which is the intermedi-
ate, in high yield with high diastereo- and enantioselectivi-
ties. In these cases, previous methods utilized stoichiometric
amounts of chiral sources and the reactions were conducted
at À958C under strictly anhydrous conditions. Notably, this
method can be performed by using a catalytic amount of
a chiral ligand and the reactions proceed under mild condi-
tions in aqueous media. Furthermore, chiral aldehyde 25
was successfully employed in this asymmetric allylation re-
Entry
Ligand
Yield [%]
syn/anti
e.r. (syn)
1
2
3
4
5
6
7
8
9
85
56
84
79
93
10:1
10:1
12:1
8:1
4:1
4:1
24:1
16:1
4:1
4:1
9:1
86.5:13.5
82:18
82.5:17.5
78.5:21.5
60.5:39.5
56:44
68:32
80.5:19.5
79:21
10
11
12
13
14
15
16
17
18
19
20
21
90
86[a]
89
9
87
88
91
96
10
11
12
13
50:50
82.5:17.5
84.5:15.5
50.5:49.5
3:1
1:1.2
93
[a] a/g=87:13.
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Shu¯ Kobayashi et al.
Table 8. Substrate scope of the asymmetric allylation reaction.
is an intermediate in the synthesis of Botryolide B
(Scheme 5).[46]
The reaction of 2-methylpropionaldehyde (isobu-
tyraldehyde) with compound 1b in the presence of
Zn(OH)2/9 also proceeded smoothly to afford the
corresponding adduct (27),[47] which is an intermedi-
ate in the syntheses of RK-397[48] and Mycoticin,[49]
in good yield with high diastereo- and enantioselec-
tivities (Scheme 6). The enantiomer of compound
27 is also an intermediate in the synthesis of (À)-
Madumicin II (Scheme 6).[50]
Furthermore, this reaction can also be applied to
the synthesis of optically active diols. The reactions
of benzyloxyallylboronate 28 with aldehydes
smoothly proceeded in an exclusive a-addition fash-
ion to afford the corresponding 2-benzyloxyhomoal-
lylic alcohols in high yields with high diastereo- and
enantioselectivities (Scheme 7). It is noteworthy
that the products are useful chiral synthons.[51]
The assumed transition states of these catalytic
asymmetric allylation reactions are shown in
Scheme 8. We assumed a cyclic transition state of
the chiral allylzinc species with an aldehyde, in
which the aldehyde is activated by Zn. One face of
the allylzincate is shielded by the chiral ligand (9)
and the aldehyde reacts with the Si face of the allyl-
zinc species.
Entry
R1
R2
Loading[a]
[mol%]
Yield
[%]
Syn/
Anti
e.r.
(syn)
N
1
2
3
4
5
6
7
8
9
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
10
10
5
10
10
10
10
10
10
85
84
79
10:1
12:1
19:1
13:1
32:1
16:1
16:1
16:1
6:1
86.5:13.5
83:17
87:13
4-Me-C6H4
4-Me-C6H4
4-MeO-C6H4
2-MeO-C6H4
3-MeO-C6H4
2-thienyl
5-Me-2-furyl
(E)-PhCH=
CH
78
88:12
94
85.5:14.5
85.5:14.5
92.5:7.5
95:5
59[d]
92
67
89
88:12
10
11
12
13
PhCH2CH2
PhCH2CH2
Me
Me
Me
Me
Et
iBu
nBu
Et
10
5
3
3
5
5
5
10
10
94
94
94
80
96
6:1
5:1
7:1
5:1
3:1
3:1
3:1
6:1
3.5:1
94:6
92.5:7.5
91:9
98.5:1.5
95.5:4.5
95.5:4.5
95:5
CH
3A
c-C6H11
PhCH2CH2
PhCH2CH2
PhCH2CH2
Ph
14[b]
15[b]
16[b]
17[c]
18[c]
95
97
95[e]
83
90:10
91:9
Ph
iBu
[a] Conditions A: CH3CN/H2O=12:1 (0.02m), À208C; Conditions B: CH3CN/H2O=
4:1 (0.025m), À108C. [b] Slow addition of the aldehyde over 3 h. [c] Slow addition of
the aldehyde over 2 h. [d] a/g=95:5. [e] a/g=93:7.
Table 9. Asymmetric chloroallylation reactions.
Conclusions
In summary, we have developed Zn(OH)2-catalyzed
allylation reactions of aldehydes with allylboronates
in aqueous media. In contrast to conventional allyl-
boration reactions of aldehydes in organic solvents,
the a-addition products were exclusively obtained.
A catalytic cycle in which the allylzinc species was
generated through a B-to-Zn exchange process was
proposed and kinetic studies were also performed.
The key intermediate, an allylzinc species, was de-
tected by HRMS (ESI) analysis and by online con-
tinuous MS (ESI) analysis. In aqueous media, the
allylzinc species competitively reacted with alde-
hydes and H2O. Several important roles of H2O in
this allylation reaction were also clarified by a com-
parison of the reactivity and selectivity of the allyl-
zinc species that were generated from several typi-
cal allylboronates (6a–6d). The allylation reactions
of aldehydes with allylboronic acid 2,2-dimethyl-
1,3-propanediol esters proceeded smoothly in the
presence of catalytic amounts of Zn(OH)2 and achi-
ral ligand 4d in aqueous media to afford the corre-
sponding syn adducts in high yields with high dia-
Entry
R
X
Yield [%]
syn/anti
e.r. (syn)
1
2
3
4
5
6
7
8
Ph
Ph
10
5
10
3
93
92
94
91
97
99:1
24:1
99:1
24:1
99:1
19:1
32:1
19:1
19:1
13:1
19:1
16:1
19:1
13:1
13:1
49:1
19:1
94:6
94:6
4-MeC6H4
4-MeC6H4
3-MeOC6H4
3-MeOC6H4
4-BrC6H4
4-BrC6H4
1-naphthyl
1-naphthyl
(E)-PhCH=CH
93.5:6.5
93.5:6.5
93.5:6.5
95.5:4.5
92:8
92.5:7.5
93:7
92.5:7.5
97:3
91.5:8.5
98.5:1.5
97.5:2.5
97:3[b]
99:1
10
7.5
10
7.5
10
5
10
10
10
3
99
quant.
quant.
quant.
94
9
10
11
12
13
14
15[a]
16
17
97
99
85
92
87
64
66
ꢁ
C5H11C C
PhCH2CH2
PhCH2CH2
PhCH2CH2
3
10
7.5
G
99:1
[a] Compound ent-9 was used as a ligand. [b] The major isomer was the opposite enan-
tiomer of the product in entries 13 and 14.
action. In the presence of Zn(OH)2/9, the reaction of com-
pound 25 with a-chloroallylboronate 22 proceeded smoothly
to afford the desired adduct (26) in excellent yield with ex-
cellent diastereo- and enantioselectivities. The product (26)
stereoselectivities. In all cases, the a-addition products were
obtained and a wide substrate scope was tolerated. Further-
more, this reaction was applied to asymmetric catalysis by
using chiral ligand 9. Based on the X-ray structure of the
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Shu¯ Kobayashi et al.
Scheme 3. Synthesis of spirastrellolide A.
Scheme 6. Synthesis of RK-397, Mycoticin, and (À)-Madumycin II.
Scheme 7. Asymmetric alkoxyallylation reactions.
Scheme 4. Synthesis of (+)-disparlure.
Scheme 8. Assumed transition states.
vent that can form hydrogen-bonding interactions to pro-
mote the reactions; 2) as a ligand and solvent to create
Scheme 5. Synthesis of Botryolide B. DBU=1,8-diazabicyclo
7-ene, TBAF=tetra-n-butylammonium fluoride.
ACHTUNGTREN[NUNG 5.4.0]undec-
À
active zinc hydroxide species; 3) as a ligand on the B and
Zn atoms to control their Lewis acidity; 4) as a Lewis base
to promote B-to-Zn exchange; 5) as a ligand on the chiral
Zn atom to control its Lewis acidity and asymmetric envi-
ronment; 6) as a Brønsted acid to form the product from
Zn-9 complex, several nonsymmetrical chiral ligands were
also found to be effective. This reaction was further applied
to catalytic asymmetric alkylallylation, chloroallylation, and
alkoxyallylation processes and the synthetic utility of these
reactions was demonstrated. Through this work, the follow-
ing important roles of H2O were clarified: 1) as a polar sol-
À
the zinc alkoxide; and 7) as a Brønsted base to regenerate
Zn(OH)2.
Further investigations to develop other new reactions and
new systems in aqueous media are now underway.[52]
11
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Shu¯ Kobayashi et al.
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Acknowledgements
This work was supported by a Grant-in-Aid for Science Research from
the Global COE Program of the Japan Society for the Promotion of Sci-
ence (JSPS), the University of Tokyo, MEXT (Japan), the Japan Science
and Technology Agency (JST), and NEDO. We also thank Dr. Miyuki
Yamaguchi (University of Tokyo) for her assistance with the MS (ESI)
analysis.
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[32] For details of the kinetic studies see the Supporting Information.
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Received: March 30, 2013
Published online: && &&, 0000
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