Pinacolyl boronic esters as components in the Petasis reaction

Article abstract of DOI:10.1016/S0040-4039(02)01265-0

The multicomponent reaction of boronic esters with imine or iminium species (generated in situ by reaction of amines with glyoxylic acid) has received little attention in the literature despite the current interest in the corresponding reactions of boronic acids (Petasis reaction). Moreover, the use of boronic esters in this reaction is particularly attractive since chiral esters could act as auxiliaries in a novel enantioselective process. We set out to establish whether boronic esters were general substrates in the Petasis reaction. Pinacolyl boronic esters were selected for study as a model substrate for more complex homochiral boronic esters because of their ease of synthesis and chemical stability. We found that pinacolyl boronic esters do not react with imines derived from primary amines and glyoxylic acid under standard conditions. By contrast, imines derived from secondary amines and glyoxylic acid react readily with vinylboronic esters but less readily with heteroaryl- or arylboronic esters.

Full text of DOI:10.1016/S0040-4039(02)01265-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5965–5968
Pinacolyl boronic esters as components in the Petasis reaction
Tobias Koolmeister, Mikael So¨dergren and Martin Scobie*
Biovitrum AB, Rapsgatan 7, SE-751 82 Uppsala, Sweden
Received 21 May 2002; revised 13 June 2002; accepted 27 June 2002
Abstract—The multicomponent reaction of boronic esters with imine or iminium species (generated in situ by reaction of amines
with glyoxylic acid) has received little attention in the literature despite the current interest in the corresponding reactions of
boronic acids (Petasis reaction). Moreover, the use of boronic esters in this reaction is particularly attractive since chiral esters
could act as auxiliaries in a novel enantioselective process. We set out to establish whether boronic esters were general substrates
in the Petasis reaction. Pinacolyl boronic esters were selected for study as a model substrate for more complex homochiral boronic
esters because of their ease of synthesis and chemical stability. We found that pinacolyl boronic esters do not react with imines
derived from primary amines and glyoxylic acid under standard conditions. By contrast, imines derived from secondary amines
and glyoxylic acid react readily with vinylboronic esters but less readily with heteroaryl- or arylboronic esters. © 2002 Elsevier
Science Ltd. All rights reserved.
The Petasis multicomponent reaction of aryl- and vinyl-
boronic acids with aldehydes and amines has recently
been the subject of considerable attention.1–3 Sometimes
referred to as the boronic acid Mannich reaction, it
provides a powerful and convenient method for the
one-pot formation of unnatural amino acid derivatives.
Thus (Scheme 1), simply stirring an aryl- (or
vinyl)boronic acid 1 together with glyoxylic acid 2 and
an amine in dichloromethane affords high yields of
amino acid derivatives 3. The reaction can also be used
for preparation of a,a-disubstituted amines when alde-
hydes other than glyoxylic acid are used.1 This
approach is often substrate specific with respect to the
aldehyde and appears to favour aldehydes containing
an adjacent heteroatom.
Both Petasis and Harwood have developed diastereose-
lective methodologies by employing either homochiral
aldehydes or amines as components in the reaction.4,5
These approaches have met with considerable success
but both suffer from the drawback that the chiral
centre, which is responsible for chiral induction in the
reaction, must also be present as a feature in the final
product.
We reasoned (Scheme 2) that if the reaction could be
extended to tolerate homochiral boronic esters (e.g. 4),
it should be possible to develop a generally enantiose-
lective process utilising a chiral auxiliary group which
Scheme 1.
Keywords: boronic ester; Petasis reaction; amino acid.
* Corresponding author. Tel.: +46 8 697 3863; fax: +46 8 697 3867;
e-mail: martin.scobie@biovitrum.com
Scheme 2.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01265-0

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would be eliminated during the course of the reaction
and therefore need not be present in the final product 5.
secondary amines. Initially we elected to study some
non-chiral pinacolyl boronic esters 11 since these
provide a good model system endowed with both chem-
ical stability and steric bulk. These are properties which
would ultimately be required if a suitable chiral auxil-
iary 4 were to be developed.
To our knowledge the literature contains only two
isolated examples of boronic esters participating in this
process. Thus, the non-chiral bis(isopropyl) bromo-
vinylboronic ester 6 is reported to react smoothly with
the primary amine 1,1-diphenylmethylamine 13 and
glyoxylic acid at room temperature to afford the corre-
sponding racemic amino acid derivative 7 in high yield
(80%).6 In a second, very recent example which
appeared in the literature during preparation of this
manuscript a resin tethered boronic ester 8 was shown
to react with a solution of glyoxylic acid in THF/EtOH
and a resin bound secondary amine 9. This is a rather
novel resin-to-resin transfer process involving deliberate
disproportionation of the polymer supported boronic
ester into a bis(ethyl) arylboronic ester which is released
into solution to react further with a second resin bound
species 9.7
Formation (Scheme 3) of the required pinacolyl
boronic esters 11 was extremely straightforward;8 the
results are summarised in Table 1. Reaction of the
boronic acids 1a–e with pinacol in ether afforded the
requisite aryl- or vinylboronic esters 11a–e directly. We
found that simply washing the crude ether reaction
mixture with water followed by evaporation of the
solvent led to isolation of the pure product in high
yields (76–100%).
Having found a reliable synthesis of pinacolyl boronic
esters, we then set out to study their reactivities with
amines and glyoxylic acid under standard Petasis condi-
tions (Table 3). Surprisingly, treatment of boronic
esters 11a–e with glyoxylic acid and the primary amines
12–14 in DCM as solvent produced no observable
reaction. This apparent lack of reactivity was quite
unexpected and in contrast to prior literature prece-
dents. We therefore carried out a study to determine if
the corresponding reactions of the boronic acids 1a–e
would work (Scheme 4). When we treated 4-methylben-
zeneboronic acid 1a with benzylamine 12 and glyoxylic
acid in dichloromethane at room temperature, the
expected product 18 was formed in good yield (67%).
We then evaluated the reaction of the corresponding
pinacolyl ester derivative 11a using a range of different
solvents (DCM, THF, dioxane, toluene or DMF) and
reaction temperatures. Conditions including both Lewis
acid catalysis and microwave heating were also evalu-
ated but in all cases studied, no product formation was
observed. The results are summarised in Table 2.
In view of the relative shortage of literature precedents
concerning participation of boronic esters in the Petasis
reaction, we set out to investigate whether boronic
esters were general substrates with both primary and
Scheme 3.
Table 1. Formation of pinacolyl boronic esters from
boronic acids
Scheme 4.
Table 2. Attempted reactions of 11a with benzylamine
and glyoxylic acid
DCM, rt
DCM, Yb(OTf)3, rt
THF, reflux
Dioxane, reflux
Toluene, reflux
DMF, 250°C (microwave)
No reaction
No reaction
No reaction
No reaction
No reaction
No reaction

T. Koolmeister et al. / Tetrahedron Letters 43 (2002) 5965–5968
5967
Table 3. Formation of amino acids 3 by reaction of pinacolyl boronic esters 11a–e with glyoxylic acid 2 and amines 12–17
By contrast, the reactions of boronic esters 11a–e with
secondary amines 15–17 and glyoxylic acid gave the
expected products 33–47 (Table 3). In these cases we
observed a striking reactivity pattern which was depen-
dent on the nature of the boronic ester substrate. Under
standard conditions the vinylic substrates 11c and 11d
gave high yields (70–82%) of the expected amino-acid
products with all secondary amines 15, 16 and 17. The
heterocyclic thien-3-yl substrate 11e gave only modest
(25–28%) yields of products while aryl substituted
boronic esters 11a and 11b were rather unreactive at
room temperature and only low yields (5–12%) of
products could be isolated by preparative HPLC. We
believe that it will be possible to optimise these low
yielding reactions but have not attempted this in the
present study.
could be explained by slow disproportionation of the
bis(isopropyl) ester under the reaction conditions (gly-
oxylic acid monohydrate). Certainly the stability of
isopropyl boronic esters to traces of aqueous acid is
expected to be much lower than their pinacolyl
analogues.
In any case there are still facets to this reaction which
are not well understood and these will doubtless
become the subjects of future investigations in the
literature. Our current focus is on developing the Peta-
sis reaction to include chiral boronic esters so that their
use as auxiliaries in this process can be evaluated. The
results of our initial studies in this area are presented in
the following communication.9
In summary we have demonstrated that pinacolyl
boronic esters participate in the Petasis reaction with
secondary amines but not with primary amines. The
reasons for the failure of primary amines to take part in
these reactions even under forcing conditions is not
clear to us at present. We speculate that the previous
literature example shown in Scheme 2 in which bis(iso-
propyl) vinylboronic ester 6 reacts with a primary
amine (1,1-diphenylmethylamine) might involve the
intermediacy of the corresponding boronic acid (6; H
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