Allylic sp3 C-H borylation of alkenes via allyl-Pd intermediates: An efficient route to allylboronates

Article abstract of DOI:10.1039/c4cc04151h

Palladium catalyzed allylic C-H functionalization was performed using exocyclic alkene substrates. Multi-component synthesis of stereodefined homoallylic alcohols could be performed using a reaction sequence involving allylic C-H borylation and allylation

Full text of DOI:10.1039/c4cc04151h

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Allylic sp3 C–H borylation of alkenes via allyl-Pd
intermediates: an efficient route to
allylboronates†
Cite this: Chem. Commun., 2014,
50, 9207
Received 30th May 2014,
Accepted 26th June 2014
Hong-Ping Deng,a Lars Erikssonb and Kalman J. Szabo*a
´
´
´
DOI: 10.1039/c4cc04151h
www.rsc.org/chemcomm
Palladium catalyzed allylic C–H functionalization was performed
using exocyclic alkene substrates. Multi-component synthesis of
stereodefined homoallylic alcohols could be performed using a
reaction sequence involving allylic C–H borylation and allylation
of aldehydes.
Catalytic C–H borylation has become a practically useful synthetic
method for preparation of organoboronates.1 The main reason is that
these transition metal catalyzed C–H functionalization reactions can be
performed under relatively mild conditions with remarkably high
selectivity1b,c usually using B2Pin2 as a boronate source. The largest
efforts have been focused on sp2 C–H borylation of aromatic and
alkene substrates to obtain aryl/heteroaryl2 and vinyl3 boronates. How-
ever, in the last couple of years increased attention has been focused on
development of sp3 C–H functionalization methods.4 These studies
involved functionalization of aliphatic C–H bonds4d–h,l,m,o–q
usually directed by heteroatoms, benzylic C–H bonds4i–k and there
are a few examples of allylic C–H borylation4a–c as well. A selective
allylic C–H borylation4a–c is particularly challenging to achieve due to
two main reasons: (i) under catalytic conditions allylboronates very
easily rearrange to the more stable vinylboronates.3b,c,f,4c Thus, even
if the kinetic product is an allylboronate, the thermodynamic (final)
product of the C–H borylation of alkenes is vinylboronate; i.e. an
overall sp2 instead of sp3 C–H bond functionalization; and (ii) for
non-symmetrical organometallic intermediates (e.g. allyl or alkyl-
metal species) the regioselectivity of the borylation is difficult to
control. Therefore, only a very few transition metal catalyzed
methods are available for allylic C–H borylation of alkenes4a–c
and because of (i) and (ii) the substrate scope is also very narrow.
The previously developed procedures providing predominantly
allylboronate products are based on C–H functionalization of simple
cycloalkenes (Fig. 1). Sabo-Etienne and Caballero4a have shown that
Fig. 1 Overview of catalytic allylic C–H borylations.
cycloheptene undergoes hydroboration and allylic C–H borylation in
the presence of catalytic amounts of bis(dihydrogen)Ru complex. We
have shown4b,c that simple cycloalkenes can be reacted with B2pin2
in the presence of Ir-catalysts to give allyl-Bpin compounds.
Interestingly, other catalytic conditions with the above endo-cyclic
alkene substrates using rhodium3g or palladium3c,f catalysts also give
allyl-Bpin products in varying amounts. However, for substrates with
an exo-cyclic double bond allylic C–H borylation has never been
reported. This can probably be explained by the mechanistic features
of the currently available Ru, Rh, Ir and Pd catalyzed methods. In all
cases initial formation of an M–Bpin complex can be postulated
(eqn (1)), which undergoes a syn insertion into the double bond
followed by a syn selective b-hydride elimination. However, acyclic
compounds can undergo unhindered rotation of the s-bonds, and
therefore the b-hydride elimination may easily result in the thermo-
dynamically more stable vinyl–Bpin form.4c
(1)
a Department of Organic Chemistry, Stockholm University, Sweden
b Department of Inorganic and Structural Chemistry, Stockholm University, Sweden.
E-mail: kalman@organ.su.se; Web: http://www.organ.su.se/ks/;
Fax: +46-8-15 49 08
Therefore, we decided to develop a new sp3 allylic C–H borylation
reaction based on an alternative mechanistic concept. We hypo-
thesized that a Pd-catalyzed process based on initial formation of an
allyl-Pd complex followed by transmetallation5 with B2pin2 may
† CCDC 1000349. For crystallographic data in CIF or other electronic format see
DOI: 10.1039/c4cc04151h
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Table 1 Allylic C–H borylation of alkenesa
avoid the termination of the reaction with b-hydride elimination.
The realization of this idea is very challenging, as closing the catalytic
cycle (see bellow) requires use of oxidants, while B2pin2 is a reductant
and allylboronates are sensitive to oxidation.6
We directed the initial studies to C–H functionalization of
b-pinene 1a, as these compounds readily form7 (Z3-allyl)palladium
complexes with stoichiometric amounts of Pd-salts. Indeed, when
1a, 3a, an appropriate oxidant and catalytic amounts of Pd(TFA)2
were mixed in (CD3)2CO, formation of borylated b-pinene was
observed (Fig. 1c). Using deuterated acetone enabled us to follow
the reaction by 1H NMR. The 1H NMR of the reaction mixture
showed that the reaction was not completed, probably because of
product inhibition. When the allylboronate product was quenched
with nitro-benzaldehyde (2), the corresponding homoallylic alcohol
4a was formed selectively as a single, regio-stereoisomer.
Gratifyingly, the entire procedure with 1a, 2, 3a, the oxidant (BQ),
TFA and the Pd-catalyst could be performed as a multi-component8
(or genuine one-pot) reaction (Table 1, entry 1). As we used optically
active b-pinene, the multicomponent C–H borylation–allylation
sequence gave an enantiomerically pure product (4a). The structure
of 4a was assigned on the basis of single crystal X-ray diffraction.
Subsequently, we studied the synthetic scope of the reaction. We
have found that cyclic substrates with an exocyclic double bond give
synthetically useful yields in the C–H borylation based allylation of
aldehydes (Table 1). In most cases (except 1a) we obtained complex
mixtures and low yields, when we used BQ as an oxidant. However,
2,6-dimethyl BQ (DMBQ) successfully replaced BQ. Deuterated
acetone proved to be an ideal solvent in most cases as it allowed
us to study the crude mixtures by 1H NMR. In some cases, the
process was slow in acetone (e.g. entries 4–6 and 10) and therefore
the solvent was changed to trifluoro toluene, which gave a higher
reaction rate.
Entry Alkene
1
Temp. (1C)/solvent Yieldb (%)
B : L
rt/(CD3)2CO
rt/(CD3)2CO
rt/(CD3)2CO
40/PhCF3
450 : 1
2
3
4
1a
1a
426 : 1
450 : 1
450 : 1
5
6
40/PhCF3
40/PhCF3
450 : 1
450d : 1
7e
8
rt/(CD3)2CO
40/(CD3)2CO
450 : 1
8 : 1
Nitro-benzaldehyde 2 could be replaced by benzaldehyde or
aliphatic aldehyde (entries 2 and 3). The multicomponent reaction
is still very selective but the yield was dropped (cf. entries 1–3). The
reaction with six-membered ring based substrates 1b–d gave
exclusively the branched allylic products 4d–e (entries 4 and 5).
There are three stereogenic carbons in product 4f, thus statistically
four diastereomers could be formed. However, the reaction pro-
ceeds with a remarkably high stereoselectivity, as only two diaster-
eomers were obtained in a ratio of 9 : 1 (entry 6). The reactions for
the five membered ring based substrate 1e proceeded faster than
for the six membered ring analogs, and therefore the reactions
could be conducted at rt. The best yield and selectivity were
obtained, when DMBQ was replaced by tetramethyl BQ as an
oxidant (entry 7). The seven membered ring based substrate 1f
reacted with high yield (entry 8) but the regioselectivity was also
lower than for the six-membered ring based substrates. In the case
of 1g containing an eight-membered ring the regioselectivity drops
to 2.5 : 1 (entry 9). We had a limited success with borylation of
heterocyclic substrates, such as 1h (entry 10). This compound can
also be transformed into 4j with high selectivity but the yield is
poor and we could not improve it by extensive optimization.
9
40/(CD3)2CO
2.5 : 1
10 f
40/PhCF3
450 : 1
11
40/(CD3)2CO
15g : 1
a
Unless otherwise stated the reactions were carried out with
1
(0.1 mmol), 2, nitro-benzaldehyde (0.2 mmol), 3a (0.2 mmol),
Pd(TFA)2 (0.01 mmol), DMBQ (0.2 mmol) and TFA (0.05 mmol) in
solvent (0.2–0.5 mL) for 24 h. Isolated yields for the linear (L) and
branched (B) products together. Unless otherwise stated the branched
product was isolated as a single diastereomer. PhCHO (entry 2) and
n-C6H13CHO (entry 3) were used instead of nitro-benzaldehyde. d.r. =
9 : 1. Tetramethyl-benzoquinone instead of DMBQ. Reaction was
carried out with 1h (0.2 mmol) and 2 (0.1 mmol). d.r. = 3 : 2. Ar =
b
c
d
e
f
g
4-NO2C6H4, DMBQ = 2,6-dimethylbenzoquinone.
For acyclic analogs the yield and the selectivity drop dramatically the reaction can be performed with diboronic acid (3b) instead of
(entry 11). For example 1i reacts very slowly and with low conver- B2pin2 with a slight alteration of the reaction conditions (eqn (2)).
sion probably because of inhibition of the Pd-catalyst. Interestingly, This is a remarkable result, as it shows that highly oxidation
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sensitive allylboronic acids6 can also be reaction intermediates
under oxidative allylic C–H borylation conditions.
Support from the Swedish Research Council and the Knut
och Alice Wallenbergs Foundation, as well as a post-doctoral
fellowship for H.-P. Deng from the Wenner-Green foundation,
is gratefully acknowledged. The generous gift of B2pin2 from
Allychem is appreciated.
(2)
Notes and references
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We suggest that the first step of the process is formation of
allyl-palladium complex 5 by deprotonation and palladation of
the allylic position of the substrate, such as 1b (Fig. 2).7 The
subsequent step is transmetallation by B2pin2. It was shown5
that these reactions proceed easily, when weakly coordinating
ligands are on Pd. This could explain that Pd(TFA)2 is an
excellent catalyst for the process, while Pd(OAc)2 with the
chelating acetate group is inefficient. Iwasawa and co-workers9
have recently shown that Pd–Bpin complexes are stable species.
The reductive elimination of the Bpin group in 6 is supposed to
be fast5 due to the strong trans influence of the Bpin ligand.10 It
proceeds with a very high regioselectivity leading to the linear
allylboronate product. This high regioselectivity is a prerequisite
of the high selectivity of the allylation of aldehyde 2 affording the
branched homoallylic product 4d. The reductive elimination
involves formation of Pd(0), which has to be reoxidized at the
closing of the catalytic cycle. The main role of the used quinone
is reoxidation of Pd(0) to Pd(II). Added trifluoroacetic acid
increases the oxidation potential of the quinones and also
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Fig. 2 Suggested catalytic cycle exemplified by substrate 1b.
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