Palladium-catalyzed synthesis and isolation of functionalized allylboronic acids: Selective, direct allylboration of ketones

Article abstract of DOI:10.1002/anie.201207951

Allyl boronates are very important reagents in advanced organic synthesis for the allylation of carbonyl compounds[1] and in cross-coupling[2] reactions. A practically unrivalled property of allylboronates is their highly regio- and stereoselective additi

Full text of DOI:10.1002/anie.201207951

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DOI: 10.1002/anie.201207951
Allylboration
Palladium-Catalyzed Synthesis and Isolation of Functionalized
Allylboronic Acids: Selective, Direct Allylboration of Ketones**
Mihai Raducan, Rauful Alam, and Kꢀlmꢀn J. Szabꢁ*
Allyl boronates are very important reagents in advanced
organic synthesis for the allylation of carbonyl compounds[1]
and in cross-coupling[2] reactions. A practically unrivalled
property of allylboronates is their highly regio- and stereo-
selective addition to carbonyl compounds to afford homo-
allylic alcohols.[1a–d,3] This high selectivity is mainly based on
two factors: 1) Allylboronates are configurationally stable,
and unlike many allyl metal compounds[4] (such as allyl-
Grignard reagents, allyl lithium compounds or allylboranes)
do not undergo metallotropic rearrangement and E/Z isomer-
ization at ambient conditions. 2) The six-membered ring
transition state (TS) of the allylboration of carbonyl com-
pounds is highly conformationally constrained, which leads to
a strong differentiation in the stereoselection process.[3a,5]
Method development for broadening the number of acces-
sible functionalized allyl boronates is one of the most
important challenges in organoboron chemistry.
In allylboration reactions with allylboronic esters, allyl
pinacolborate (allyl-Bpin) reagents are most frequently
applied as the allyl source,[1a–d] as allyl-Bpins can be easily
handled and the functionalized derivatives can be obtained by
metal-catalyzed borylation of the allyl precursors with
bis(pinacolato)diboron (B2pin2) as the boronate source.[6]
Problems in synthetic applications arise from the relatively
low reactivity of allyl-Bpin compounds towards most carbonyl
compounds. Although aldehydes easily react with allyl-Bpin
without catalysts, ketones do not. There are very few attempts
at the direct allylation of ketones by functionalized allyl-
Bpins or their ester analogues reported in the literature. The
reactions that have been successful require extreme condi-
tions (for example, 8000 bar and 3 days), which leads to an
unselective process;[7] therefore, a selective allylboration
requires catalytic conditions.[8] Some time ago we reported
the application of diboronic acid 1[9] (now commercially
available) as a boronate source[1e,10] for the Pd-catalyzed
borylation of allylic alcohols (3) to obtain allylboronic acids
(4; Scheme 1).[6c,d] However, owing to their instability, allyl-
boronic acids could not be isolated and studied in a pure form.
Therefore, the synthetic potential of pure allylboronic acids
remained unexploited.
Scheme 1. Synthesis and isolation of allylboronic acids.
We have now substantially modified the catalyst (2) and
the reaction conditions of the process, which allowed the
isolation of these extremely useful reagents (see Schemes 1
and 2, and Table 1). The outstanding synthetic utility of
allylboronic acids is demonstrated by their direct (uncata-
lyzed) reactions with ketones under mild conditions, which
proceeds with remarkably high regio- and stereoselectivity
(see Scheme 3 and Table 2). As we have previously noted,[6c,d]
allylboronic acids are fairly stable under ambient conditions,
as long as they are dissolved in coordinating solvents. When
these solvents are completely removed, rapid decomposition
occurs. Careful experiments under inert conditions have
shown that boroxine formation from 4 (which can be
1
observed by H NMR) leads to extreme oxygen sensitivity
(Scheme 2). Formation of boroxines from organoboronic
Scheme 2. Boroxine formation upon drying.
[*] Dr. M. Raducan, R. Alam, Prof. K. J. Szabꢀ
Department of Organic Chemistry, Stockholm University
Stockholm (Sweden)
acids is well known.[1b,11] However, in the case of arylboronic
acids the corresponding boroxine is usually still air stable. We
could not find any previous studies on boroxines formed from
allylboronic acids. We have found that all of the studied
allylboronic acids 4a–l become very oxygen sensitive after
drying, but they can be kept in a glove box for a couple of
weeks without extensive decomposition. The thermal stability
of the allylboronic acids is very high. For example, heating 4e
in dry degassed THF at 708C for 18 h does not lead to
borotropic rearrangement. After careful optimization, we
were able to find reaction conditions which are suitable for
the synthesis of a wide range of allylic boronic acids with
E-mail: kalman@organ.su.se
Homepage: http://www.organ.su.se/ks
[**] Support from the Swedish Research Council and the Knut och Alice
Wallenbergs Foundation through the Center of Molecular Catalysis
at Stockholm University, as well as a post-doctoral fellowship for
M.R. from the Wenner–Gren foundation is gratefully acknowledged.
We also thank BASFand Allychem for the generous gifts of diboronic
acid.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207951.
Re-use of this article is permitted in accordance with the Terms and
Conditions set out at http://angewandte.org/open.
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aromatic (4a–e) and aliphatic (4 f–l) substituents, including
both acyclic (4a–g and 4j–k) and cyclic (4h–i, 4l) products.
The allylboronic acids are formed with remarkably high regio-
and stereoselectivity. We get perfect stereoselectivity, with the
exception of 4d, which was formed as a 5:1 (E/Z) mixture.
Notably, both geraniol 3j and nerol 3k underwent reaction
without E/Z isomerization (Table 1, entries 10 and 11), with
the double bond geometry remaining unchanged under the
borylation conditions.
proceeded rapidly with low catalyst loadings (0.2–
0.5 mol%). However, for sterically crowded substrates the
borylation process was relatively slow, resulting in the
decomposition of 1, and the reduction of the allylic alcohols.
In these cases, we replaced MeOH with a DMSO/H2O
mixture, which always led to a slower reaction, but suppressed
these undesired side reactions. The addition of DMSO was
also useful for stabilizing the forming Pd0 species, and thus
reducing the rate of deactivation of the Pd-catalyst. For some
relatively unreactive substrates we used a combination of
catalyst 2b and DMSO/H2O (entries 9 and 12) to optimize the
borylation rate and reduce the formation of by-products. The
concentration of the substrate was also an important factor. In
some reactions the products underwent protodeborylation
when the concentration was too high (see the molarity data in
Table 1). Furthermore, precipitation of the products was
initiated by the addition of brine, and thus the yield of isolated
product was also dependent on the ratio of the
We used two different catalysts, 2a and 2b. Catalyst 2a[12]
was simply prepared by dissolving PdCl2 in aq. HCl, whereas
2b is commercially available and was previously applied[13] in
the synthesis of allylsilanes and allyl-Bpin derivatives. Cata-
lyst 2a was less active, but more stable than 2b. Catalysts with
phosphine ligands and Pd2(dba)3 (dba = dibenzylideneace-
tone) were ineffective under the applied conditions. Reac-
tions in neat MeOH (Table 1, entries 1–3, 5–7) usually
organic solvent to water during the purifica-
tion stage. Geranyl 4j and neryl 4k boronic
Table 1: Synthesis and isolation of allylboronic acids.[a]
acids could not be forced to precipitate, and
therefore these compounds were separated by
extraction into chloroform. Boronic acid 4l
had similar solubility in both of the applied
organic solvents (MeOH and DMSO) and in
water. In this case (entry 12) the yield of the
pure isolated product was poor, even though
the borylation reaction was very selective. The
reaction is easily scalable; the synthesis of
cinnamylboronic acid 4a was repeated on
a gram (6 mmol) scale without a significant
change in the yield of isolated product
(entry 1).
To demonstrate the synthetic utility of the
functionalized boronic acids, we performed
the allylation of ketones 5a–c (Table 2). These
reactions were conducted either in dry THF or
chloroform without any additives. As men-
tioned above, allyl-Bpin or other allylboronic
esters are inefficient for the direct allylation of
ketones. However, allylboronic acids 4a and
4j–k reacted with amazingly high stereoselec-
tivity. The geranyl 4j and neryl 4k boronic
acids very cleanly afforded the epimeric prod-
ucts 6 f and 6g with the acetophenone deriv-
ative 5c (entries 6–7). Most of the reactions
were conducted at room temperature, only the
allylation of sterically crowded ketone 5d
required elevated temperature (entry 4). As
expected, the pinacolester of 4a (cinnamyl-
Bpin) does not react at all with ketones under
the above reaction conditions. Some of the
above reactions have been performed using
allylboronic esters[14] or allyl stannanes[15] in
the presence of catalysts, allylaluminum,[16] or
titanocene[17] compounds. However, the
reported selectivities were the same as, or in
several cases even lower than, with allylbor-
onic acids. For example, the reactions of 5b–d
Entry Substrate
Cat.[b]
Solvent[c]
t
Product
Yield[d]
[%]
(mol%) (molarity) [h]
2a
(0.5)
MeOH
(1.0)
1
2
18
61[e]
80
2a
(0.5)
MeOH
(1.0)
0.2
2a
(0.2)
MeOH
(1.0)
3
2
71
DMSO/
H2O
3:2 (1.0)
DMSO/
H2O
4:1 (1.0)
MeOH
(1.0)
2a
(0.2)
4
5
14
13
55
71
2a
(2.0)
2a
(0.2)
6
7
1[g]
1[g]
51
50
2a
(0.3)
MeOH
(1.0)
DMSO/
H2O
3:1 (1.0)
DMSO/
H2O
9:1 (0.4)
DMSO/
H2O
2a
(0.5)
8
18
0.2
18
68
2b
(5.0)
9
67
2a
(5.0)
10
77[h]
4:1 (0.5)
DMSO/
H2O
4:1 (0.5)
2a
(5.0)
11
12
18
1
79[h]
25
DMSO/
H2O
9:1 (1.0)
2b
(5.0)
[a] Unless otherwise stated, Pd-catalyst 2a or 2b (0.2–5 mol%) and diboronic acid
1 (2.4 mmol) were added to allylic alcohol 3 (2 mmol) in the given solvent. After filtration,
4 was precipitated with degassed brine. [b] Catalyst loading (mol%) is given in
parentheses. [c] The molar concentration of 3 in the given solvent is in parenthesis.
[d] Yield of isolated product. [e] 65 % yield was obtained when the reaction was performed
on a gram scale using 6 mmol of 3a. [f] 5:1 E/Z ratio. [g] The reactions were performed at
1
08C. [h] The product was isolated by extraction. The yield was determined by H NMR
spectroscopy using naphthalene as an internal standard.
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Table 2: Reaction of allylboronic acids with ketones.[a]
allylation reaction. We have noticed that in the presence of
water or MeOH the allylboration of ketones with 4 is strongly
inhibited. That was the reason[6d] for the failure of previous
attempts to react allylboronic acids with ketones in a one-pot
sequence with the borylation reaction (which requires the
presence of either water or MeOH). Solvents may coordinate
to the empty pp orbital of B(OH)2 and thus compete with the
oxygen of the carbonyl group in the TS (Scheme 3). An
alternative explanation for the remarkably high reactivity of
4a–k with ketones could be that boroxine is formed prior to
the allylation (Scheme 2), and the boroxine is more reactive
than the allylboronic acid itself. In a boroxine the B/O ratio is
1:1, whereas in B(OH)2 this ratio is 1:2. Accordingly, the
empty pp orbital of the boron atom in a B(OH)2 group
receives more electron density from the adjacent oxygen
atoms than the corresponding boron atom in a boroxine. As
a consequence, the Lewis acidity of a boroxine is higher than
that of the corresponding allylboronic acid or allyl-Bpin
derivative.
In summary, we have described a synthetically useful
method for the preparation and isolation of functionalized
allylboronic acids. In this Pd-catalyzed method, allylic alco-
hols are used as substrates and commercially available
diboronic acid as B(OH)2 source. The products were usually
isolated by precipitation under inert conditions. For the first
time we have demonstrated that functionalized allylboronic
acids react directly with ketones under mild conditions with
an amazingly high regio- and stereoselectivity. Our method
will hopefully open new synthetic routes in advanced organic
synthesis and natural product synthesis,[18] where highly
selective allylation reactions without interference from
strong Lewis acids are of paramount importance.
Entry Boronic Ketone
acid
Solvent
t
[h]
Product
Yield
[%][b]
1
2
4a
4a
THF
THF
1
86
89
24
3
4
4a
4a
THF
14
22
91
90
THF[c]
[d]
5
6
7
4j
4j
4k
5a
5c
5c
CHCl3 18
96
CHCl3 18
94[e]
76[f]
[d]
[d]
CHCl3 18
[a] Unless otherwise stated, allyl boronic acid 4 (0.24–0.8 mmol) was
reacted with ketone 5 (0.2–0.4 mmol) at RT in THF or CHCl3 for the
allotted reaction time, affording a single diastereomer. [b] Yield of isolated
product. [c] The reaction was performed at 608C. [d] Performed in the
presence of 4 ꢁ molecular sieves. [e] d.r.=98:2. [f] d.r.=99:1.
with 4a (entries 2–4) resulted in a single diasteromer, whereas
in analogous reactions using other allylating methods, the Experimental Section
In a typical reaction, Pd-catalyst 2a or 2b (0.2–5 mol%) and
formation of small amounts of the other diastereomers was
also reported. It can be concluded that the legendary high
selectivity of the direct allylation of aldehydes with allyl-Bpin
derivatives is also inherited by the direct allylboration of
ketones by allylboronic acids. The mechanism of the allylbo-
ration of carbonyl compounds with allyl-Bpin and allylbor-
onic acids most probably takes place through similar stereo-
chemistry, as the stereochemistry in 6b–d and 6 f–g is in line
with formation via a Type I TS (Scheme 3).
diboronic acid 1 (2.4 mmol) were added to an allylic alcohol
(2.0 mmol) dissolved in the appropriate solvent and stirred at room
temperature for the allotted reaction time (see Table 1). After
filtration of the reaction mixture, degassed brine was added under Ar;
after stirring for 18 h, the precipitated solid was filtered off. The
resulting boronic acid was washed with degassed water, dried, and
stored under Ar.
Received: October 2, 2012
Published online: November 19, 2012
The much higher reactivity of allylboronic acids toward
ketones (vs. allyl-Bpin derivatives) can be explained by the
sterically less demanding nature of the B(OH)2 group relative
Keywords: allylic compounds · boron · homogeneous catalysis ·
.
ketones · palladium
= À
to the Bpin group. Considering the close C O B contact in
the TS[5b] (which is probably important for the very high
stereoselectivity) the steric demand of the groups attached to
the boron atom is probably essential for the success of the
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