Study of chemoselective asymmetric hydrogenation of (1-bromo-1-alkenyl) boronic esters with iridium-P?N complexes

Article abstract of DOI:10.1016/j.tet.2014.02.065

In this paper we report the first chemoselective asymmetric hydrogenation of (1-bromo-1-alkenyl)boronic esters, which constitutes a new route to (α-bromoalkyl)boronic esters. The study demonstrates that excellent chemoselectivities along with full conversions can be obtained for hydrogenation of alkyl substituted derivatives with iridium-P?N complexes. Moreover, acyclic alkyl derivatives afford (α-bromoalkyl)boronic esters in good enantioselectivities ranging from 64 to 73% ee. A cyclic alkyl derivative was obtained only in a nearly racemic form. The (1-bromo-1-alkenyl)boronic esters appear to be less reactive towards homogenous hydrogenation conditions than their chloro analogues as demonstrated by the higher catalyst loadings required to achieve full conversions for alkyl derivatives and lower conversions observed for the aryl substituted derivatives.

Full text of DOI:10.1016/j.tet.2014.02.065

Tetrahedron 70 (2014) 2654e2660
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Study of chemoselective asymmetric hydrogenation of (1-bromo-1-
alkenyl)boronic esters with iridiumeP^N complexes
a
b,c,d,
ꢀ b
ꢁ
*
ꢀ
Stephen J. Roseblade , Ivana Gazic Smilovic , Zdenko Casar
a Johnson Matthey, Catalysis and Chiral Technologies, Unit 28, Cambridge Science Park, Milton Road, Cambridge CB4 0FP, UK
b
ꢁ
Lek Pharmaceuticals, d.d., Sandoz Development Center Slovenia, API Development, Organic Synthesis Department, Kolodvorska 27, SI-1234 Menges,
Slovenia
c Sandoz GmbH, Global Portfolio Management API, 6250 Kundl, Austria
d
ꢁ
ꢁ
Faculty of Pharmacy, University of Ljubljana, Askerceva cesta 7, SI-1000 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
In this paper we report the first chemoselective asymmetric hydrogenation of (1-bromo-1-alkenyl)bo-
Received 20 December 2013
Received in revised form 13 February 2014
Accepted 24 February 2014
Available online 3 March 2014
ronic esters, which constitutes a new route to (
excellent chemoselectivities along with full conversions can be obtained for hydrogenation of alkyl
substituted derivatives with iridiumeP N complexes. Moreover, acyclic alkyl derivatives afford ( -bro-
moalkyl)boronic esters in good enantioselectivities ranging from 64 to 73% ee. A cyclic alkyl derivative
was obtained only in a nearly racemic form. The (1-bromo-1-alkenyl)boronic esters appear to be less
reactive towards homogenous hydrogenation conditions than their chloro analogues as demonstrated by
the higher catalyst loadings required to achieve full conversions for alkyl derivatives and lower con-
versions observed for the aryl substituted derivatives.
a-bromoalkyl)boronic esters. The study demonstrates that
a
^
Keywords:
Hydrogenation
Catalysis
Chemoselectivity
Enantioselectivity
Ó 2014 Elsevier Ltd. All rights reserved.
P
N Ir complexes
^
Drugs
1. Introduction
(a-Haloalkyl)boronic esters represent an important class of
chiral building blocks useful for the synthesis of complex chiral
compounds.1 Their efficient asymmetric synthesis, via break-
through and unique homologation methodology, was elaborated in
the early 1980s by Matteson.1 Furthermore, beside their synthetic
value, these compounds proved to be ideal and till recently the only
precursors for the preparation of a
-amino boronic acids,2 which
were found to be the key constituent of some proteasome in-
hibitors.3,4 These active substances demonstrated a real therapeutic
potential as evidenced by marketing authorizations obtained for
bortezomib5,6 as an anti-cancer treatment both in US and EU at the
beginning of the last decade. This has triggered further interest in
these compounds and new refined drug candidates entered the
clinical studies among which ixazomib7 and delanzomibe8 are in
the most advanced stage. Moreover, a-amino boronic acid moiety
proved to be a key structural element in the dipeptidyl peptidase-4
(DPP-4) inhibitors, such as dutogliptin for treatment of type 2 di-
abetes mellitus (Fig. 1).9 Although, chiral (
a-chloroalkyl)boronic
Fig. 1. Structure of drugs and drug candidates containing a-amino boronic acid moiety.
* Corresponding author. Tel.: þ43 5338 200 3747; fax: þ43 5338 200 418; e-mail
ꢁ
address: zdenko.casar@sandoz.com (Z. Casar).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.065

S.J. Roseblade et al. / Tetrahedron 70 (2014) 2654e2660
2655
esters were extensively investigated by Matteson, preparation of
their bromo analogues is much less explored.1 Indeed, while the
were isolated in 32e67% yield for non-optimized conditions except
in the case of 2b, which was obtained as an inseparable 2:1 mixture
of regioisomers with 2-bromovinyl boronic ester and was used as
such in the hydrogenation experiments.
racemic (
a
-bromoalkyl)boronic esters were obtained by several
-unsaturated boronic
methods, such as addition of liquid HBr to
a,b
esters precursors,10 mercuration and bromination of 1,1-
bis(ethylenedioxyboryl)-2-phenylethane,11 racemic homologation
methodology with (dibromomethyl)lithium,12 hydrozirconation
and NBS bromination of alkenyl boronic esters,13 their chiral
counterparts were prepared infrequently only via Matteson’s
asymmetric homologation methodology using (dibromomethyl)
lithium in the presence of ZnCl2.14
With (1-bromo-1-alkenyl)boronic esters 2aeg in hand, we
continued our investigation with the screening for the best per-
forming hydrogenation catalyst. A variety of different catalysts
based on combinations of P P, N N and P N ligands with various
^
^
^
Rh, Ru and Ir metal precursors were screened for homogenous
hydrogenation using 2a as a model substrate. We investigated the
hydrogenation of 2a using a defined range of transition metal
complexes. Using Rh and Ru complexes low conversion was ob-
tained and in two cases using Ru-phosphine complexes the de-
bromination product 4a was formed. Interestingly, as in the case
Recently, in our preliminary communication we have elaborated
the first alternative route to (a-chloroalkyl)boronic esters via che-
moselective asymmetric hydrogenation of (1-chloro-1-alkenyl)bo-
ronic esters with iridiumeP N complexes.15 We were therefore
of chloro analogues,15 unique reactivity of P NeIr catalysts23 was
^
^
prompted to extend the scope of our method and to investigate the
homogenous hydrogenation of (1-bromo-1-alkenyl)boronic esters
with two clear objectives in mind. Firstly, it would be desirable to
observed regarding the chemoselectivity of C]C hydrogenation
versus CeBr hydrogenolysis. Indeed, the only useful results were
obtained with this class of catalysts based on pyridylphosphine li-
gands L2 and L3,24 phosphiniteeoxazoline ligands L4 (Simple
PHOX)25 and L8 (ThrePHOX),26 phosphanyl oxazolines L5 and L6,27
chiral spiro phosphineeoxazoline ligand L728 and NeoPHOX ligand
L929 (Scheme 2, Fig. 2, see Supplementary data for detailed
screening data).
have access to (a-bromoalkyl)boronic esters as a valuable alternative
to ( -chloroalkyl)boronic ester, since bromine is a significantly better
a
leaving group compared to chlorine, which provides an advanta-
geous option in the substitution reactions with poor and/or un-
charged nucleophiles. Namely, it is known that epimerization of the
a
-carbon in (a-haloalkyl)boronic ester occurs in the presence of free
halide ion.16 This is not problematic when substitution is carried out
with strong nucleophiles, which provide significantly higher sub-
stitution rate for the primary reaction compared to the reaction with
liberated free halide byproduct originating from the primary re-
action. However, when weak nucleophiles are used (e.g., azide ions)
the rate of the primary reaction is comparable to the rate of the re-
action with free halide byproduct originating from primary reaction,
which could lead to a significant extent of epimerization.16,17 More-
over, (a-bromoalkyl)boronic esters provided superior reactivity and
Scheme 2. Chemoselective asymmetric hydrogenation of (1-bromo-1-alkenyl)boronic
afforded better yields compared to their chloro analogues in reaction
with nucleophiles like enolates12 and alkoxides.18 Secondly, ho-
mogenous hydrogenation of (1-bromo-1-alkenyl)boronic esters
might provide additional insight into the unique nature of the ac-
esters with IreP N complexes.
^
tivity and selectivity of P NeIr complexes on halovinyl substrates
^
bearing a boron moiety. Therefore, it would be interesting to observe,
if the high chemoselectivity of C]C hydrogenation versus CeBr
hydrogenolysis could be preserved with bromo derivatives
where carbonehalogen bond strength is notably lower (for ca.
10e12 kcal/mol) compared to the chloro derivatives.19 Indeed, it is
perceived that the extent of dehalogenation in homogenously cata-
lyzed hydrogenation essentially depends on the strength of the CeX
bond.20
2. Results and discussion
Our investigation began with the preparation of suitable vinyl
bromide substrates bearing the boron moiety for the exploration of
homogenous hydrogenation reactions. The desired (1-bromo-1-
alkenyl)boronic esters 2aeg were readily prepared according to
Srebnik’s method21 by the treatment of easily accessible alky-
nylboronates 1aeg15a with Schwartz’s reagent (Cp2Zr(H)Cl),22 fol-
lowed by addition of NBS (Scheme 1). The pure boronic esters 2aeg
Scheme 1. Synthesis of (1-bromo-1-alkenyl)boronic esters 2. Reagents and conditions:
Fig. 2. Structure of the key ligands used in catalysts for asymmetric hydrogenation of
(i) Cp2Zr(H)Cl, THF, rt 1 h; (ii) NBS, rt, 1 h.
(1-bromo-1-alkenyl)boronic esters.

2656
S.J. Roseblade et al. / Tetrahedron 70 (2014) 2654e2660
Surprisingly, hydrogenation using Crabtree’s catalysts [Ir(P-
These results demonstrate the lower reactivity of (1-bromo-1-
Cy3)(Py)(COD)]PF6 gave very low conversion of 2a to the desired
reaction product 3a (see Supplementary data for detailed data).
This is in contrast to the analogous chloro derivative that gave good
conversion using Crabtree’s catalyst at extended reaction times.15
alkenyl)boronic ester 2a compared to its (1-chloro-1-alkenyl)bo-
ronic ester analogue.15 Gratifyingly, certain Ire(P N) complexes
^
identified in the screening process have given complete conversion
and high yield of the desired hydrogenation product 3a, with ex-
cellent chemoselectivity and relatively low levels of de-bromination
ranging from 3 to 10%. The enantioselectivities observed varied
widely from very low to quite good, with good enantioselectivities
obtained in range of 60e73% ee in two cases (Table 1, entries 8 and 9).
To evaluate the reaction scope, a variety of aliphatic derivatives
was also investigated (Table 2). The first scope extension substrate
was a vinylic derivative 2b (Table 2, entries 1e4). The Crabtree’s
catalyst gave modest conversion (see Supplementary data for de-
Following on from the successful application of IreP N complexes
^
to the asymmetric hydrogenation of (1-chloro-1-alkenyl)boronic
esters15 a wide range of IreP N complexes was tested in the hy-
^
drogenation of 2a. The complex bearing a ferrocenyl imidazoline
ligand L1a that proved to be reactive and highly enantioselective in
the hydrogenation of (1-chloro-1-alkenyl)boronic esters15 was
found to be quite unreactive and unselective in the hydrogenation
of 2a (Table 1, entry 1). A variety of related complexes was tested
and higher conversions were obtained using phosphiniteeoxazo-
tailed data), but three IreP N complexes bearing a phosphinite co-
^
ordinating group were found to give high conversion to the desired
product with a relatively low level of de-bromination (5e13% of
4b). The enantiomeric excesses for this substrate were similar to
those obtained with the initial substrate 2a: the complex bearing
ligand L8b gave 67% ee at full conversion and allowed us to isolate
3b in moderate 50% yield after flash chromatography over silica gel
(isohexane/EtOAc¼20:1), due to the high volatility of the product
(Table 2, entry 3). The pyridine phosphinite ligand L2 gave 40% ee
and the SimplePHOX ligand L4 gave 24% ee, respectively.
Table 1
Hydrogenation of 2a with IreP N complexesa
^
The next example in this series was the substrate 2c (Table 2,
entries 5e10). The catalyst screening showed again that the complex
based on L1b has low reactivity. For this substrate full conversion
was obtained using the pyridineephosphinite ligand L2, which gave
89% of the desired product in 43% ee. Full conversion was also ob-
tained using ligand L8b, to give 3c with 64% ee and only 9% of the
de-brominated side-product 4c. In this case 3c was isolated in
65e70% yield in several repeated experiments (Table 2, entry 8).
Surprisingly, ligand L9 did not give high conversion in this case.
Substrate 2d (Table 2, entries 11e16), bearing an n-propyl sub-
stituent on the C]C double-bond was tested in the hydrogenation
Entry
Catalyst
Conv. (%)b
3a (%)b
4a (%)b
ee (%)b
1
2
3
4
5
6
7
8
9
[Ir(COD)(L1a)]BArF
[Ir(COD)(L2)]BArF
[Ir(COD)(L3)]BArF
[Ir(COD)(L4)]BArF
[Ir(COD)(L5)]BArF
[Ir(COD)(L6)]BArF
[Ir(COD)(L7)]BArF
[Ir(COD)(L8b)]BArF
[Ir(COD)(L9)]BArF
15
>99
>99
>99
>99
>99
>99
>99
97
5
94
94
92
95
95
97
10
6
6
7
5
5
3
8
8
nd
32 (e2, þ)
14 (e2, þ)
0
16 (e1, e)
10 (e1, e)
37 (e1, e)
60 (e1, e)
73 (e2, þ)
92 (70)c
89
nd¼not determined.
a
Standard reaction conditions: 10 mol % of catalyst, CH2Cl2, 50 ꢀC, 30 bar H2, 18 h.
Conversions, yields and enantiomeric excesses calculated by GC analysis
using IreP N complexes and gave similar results to substrate 2c:
b
^
the complex incorporating L2 gave full conversion to the desired
product with 40% ee. Complex based on L8b gave full conversion to
give the desired product 3d with 64% ee and the same isolated
yields as in the case of compound 3c (Table 2, entry 14). These
results show a consistency in the method and demonstrate that
acyclic aliphatic substrates are suitable for this transformation.
Substrate 2e (Table 2, entries 17e20), bearing a cyclohexyl
substituent was prepared and tested in the hydrogenation reaction.
on DexCB GC column (see Supplementary data for detailed screening data).
c
The highest isolated yield on 0.1 mmol scale.
line and phosphino-oxazoline complexes. Two complexes bearing
pyridineephosphinite ligands (L2 and L3)24 gave full conversion
with only 6% de-brominated side-product 4a formed (Table 1, en-
tries 2 and 3). The enantiomeric excess of the reaction product 3a
was low in both cases (14e32%). The phosphiniteeoxazoline
complex bearing a SimplePHOX ligand L4,25 also gave full conver-
sion with a low level of de-bromination, but the product formed
was racemic (Table 1, entry 4). Other complexes were tested in the
screening and a few gave high conversion to the desired product 3a.
The catalysts based on phosphino-oxazoline ligands L5 and L6,
developed by Mazet, Burgess and Pfaltz groups,27 were tested and
gave high conversion albeit with low enantiomeric excess (Table 1,
Although high conversion resulted using several of the IreP N
^
complexes to give the desired product 3e with good chemo-
selectivity, the product enantiomeric excesses were low in all cases
(see Supplementary data for additional examples). Nevertheless,
nearly racemic 3e was isolated reproducibly in 65e70% yield after
standard isolation procedure (Table 2, entry 17).
Aromatic substituents have also been screened to further probe
the scope of this hydrogenation reaction with IreP N catalysts.
^
entries
5 and 6). The catalyst incorporating the spirocyclic
Substrate 2f (Table 2, entry 21), bearing a phenyl group, was made
and tested in hydrogenations using a variety of complexes. It was
found to be very unreactive, giving<20% conversion in most cases
(10 mol %, 50 ꢀC, 30 bar H2, 18 h). The only catalyst to give >50%
conversion was that incorporating the pyridine phosphinite ligand
L2 that gave 64% conversion resulting in 34% hydrogenation
product 3f and 30 de-bromination side-product 4f according to GC
analysis and LC-HRMS analysis of the reaction mixture. The ee of
the product was 44%, in-line with previous results from hydroge-
nation of the acyclic aliphatic substrates using this catalyst. Sub-
strate 2g (Table 2, entry 22), bearing a p-F-phenyl substituent
gave a similar result: 56% conversion with the complex bearing
L2 to give 30% hydrogenation product and 26% de-brominated
side-product 4g. The ee of 3g was 34%. Other catalysts proved to
be much less reactive.
phosphino-oxazoline ligand L728 also gave high conversion to 3a,
with a low level of de-bromination (3% of 4a). Disappointingly, the
ee of the product was low (37%, Table 1, entry 7). Higher enantio-
selectivity was observed using the phosphiniteeoxazoline complex
L8b,26 bearing a PCy2 co-ordinating group. In this case, a full con-
version of starting 2a took place, with 92% conversion to the desired
product 3a, which was formed in 60% ee, along with 8% de-
brominated side-product 4a. After the filtration over silica gel
eluting with isohexane/EtOAc (20:1), 3a was isolated repeatedly in
65e70% yield (Table 1, entry 8). The catalyst based on phosphino-
oxazoline ligand L9, NeoPhox, developed by Pfaltz et al.,29 was
also tested and gave high (97%) conversion of 2a and 89% of desired
product 3a with a good ee of 73% and only 8% of 4a formed (Table 1,
entry 9).

S.J. Roseblade et al. / Tetrahedron 70 (2014) 2654e2660
2657
Table 2
Hydrogenation of (1-bromo-1-alkenyl)boronic esters 2beg with IreP N complexesa
^
Entry
Substrate 2
Catalyst
Conversion (%)b
Product 3
3 (%)b
ee (%)b
4
4 (%)b
1c
2c
3c
4c
5
6
7
8
9
10
11
12
13
14
15
16
17
19
19
20
21e
22e
2b (R3¼H)
[Ir(COD)(L2)]BArF
[Ir(COD)(L4)]BArF
[Ir(COD)(L8b)]BArF
[Ir(COD)(L8a)]BArF
[Ir(COD)(L1b)]BArF
[Ir(COD)(L2)]BArF
[Ir(COD)(L4)]BArF
[Ir(COD)(L8b)]BArF
[Ir(COD)(L8a)]BArF
[Ir(COD)(L9)]BArF
[Ir(COD)(L1b)]BArF
[Ir(COD)(L2)]BArF
[Ir(COD)(L4)]BArF
[Ir(COD)(L8b)]BArF
[Ir(COD)(L8a)]BArF
[Ir(COD)(L9)]BArF
[Ir(COD)(L2)]BArF
[Ir(COD)(L4)]BArF
[Ir(COD)(L8a)]BArF
[Ir(COD)(L8b)]BArF
[Ir(COD)(L2)]BArF
[Ir(COD)(L2)]BArF
>99
>99
>99
54
13
>99
40
>99
39
26
20
>99
30
>99
24
29
95
82
27
58
64
56
3b
3b
3b
3b
3c
3c
3c
3c
3c
3c
3d
3d
3d
3d
3d
3d
3e
3e
3e
3e
3f
78
40 (e2, þ)
24 (e1, e)
67 (e1, e)
29 (e1, e)
nd
43 (e2, þ)
48 (e1, e)
64 (e1, e)
30 (e1, e)
54 (e2, þ)
nd
4b
4b
4b
4b
4c
4c
4c
4c
4c
4c
4d
4d
4d
4d
4d
4d
4e
4e
4e
4e
4f
13
12
5
13
13
11
15
9
11
12
9
8
15
6
12
13
7
7
8
6
30
26
2b (R3¼H)
76
2b (R3¼H)
86 (50)d
2b (R3¼H)
38
0
89
22
2c (R3¼Me)
2c (R3¼Me)
2c (R3¼Me)
2c (R3¼Me)
2c (R3¼Me)
2c (R3¼Me)
2d (R3¼n-Pr)
2d (R3¼n-Pr)
2d (R3¼n-Pr)
2d (R3¼n-Pr)
2d (R3¼n-Pr)
2d (R3¼n-Pr)
2e (R3¼Cy)
2e (R3¼Cy)
2e (R3¼Cy)
2e (R3¼Cy)
2f (R3¼Ph)
2g (R3¼p-FePh)
91 (65-70)d
23
14
7
92
40 (e2, þ)
20 (e2, þ)
64 (e1, e)
nd
15
94 (65e70)d
12
16
nd
88 (65-70)d
2 (e1, þ)
6 (e2, e)
nd
75
15
52
34
30
0
44 (e2, þ)
3g
34 (e2, þ)
4g
nd¼not determined.
a
Standard reaction conditions: 10 mol % of catalyst, CH2Cl2, 50 ꢀC, 30 bar H2, 18 h.
Conversions, yields and enantiomeric excesses calculated by GC analysis. Reactions with 2beg analyzed on DexCB GC column for conversions and yields. Enantiomeric
b
excesses for 2b, 2c, 2d, 2f and 2g determined on DexCB GC column and for 2e on GammaDex 225 GC column (see Supplementary data for full details).
c
2:1 mixture of 2b and 2-bromovinyl boronic ester were used under the same conditions as noted above. Conversions, yields and enantiomeric excesses calculated by GC
analysis and are based on the content of the pure 2b in the substrate.
d
Range of isolated yields for several repeated experiments on 0.1 mmol scale.
Results determined based only on GC and HRMS analysis of the reaction mixture (see Supplementary data for full details).
e
These results clearly indicate that the hydrogenation of (1-
bromo-1-alkenyl)boronic esters 2 is more difficult than in the case
of their (1-chloro-1-alkenyl)boronic ester analogues,15 due to the
use of IreP N hydrogenation catalysts has allowed chemoselective
hydrogenation, giving low levels of de-halogenated side-products 4.
^
lower reactivity. Interestingly, based on the 13C NMR shifts for
b-
3. Conclusion
carbon atoms in compounds 2, the C]C bond appears to be more
polarized in the case of compounds 2 than in theirchloro analogues15
(see Supplementary data for detailed data), which demonstrates that
the presence of less electronegative bromine in the structure en-
hances the effect of C]C bond polarization in boronate esters due to
Our study demonstrates that homogenous asymmetric hydro-
genation of (1-bromo-1-alkenyl)boronic esters with selected
iridiumeP N complexes can be achieved with excellent chemo-
^
selectivity and full conversion for alkyl substituted derivatives.
Good enantioselectivities ranging from 64 to 73% ee are obtained
for acyclic alkyl derivatives, while the cyclic alkyl derivative didn’t
allow any stereoselection and was obtained practically in a racemic
form only. Hydrogenation of aryl substituted (1-bromo-1-alkenyl)
boronic esters turned out to be a difficult task due to their low
reactivity in the hydrogenation reaction, which was evidenced by
the low conversions obtained in these examples. The presented
approach provides the only alternative to Matteson’s methodology
for the synthesis of this rarely described and useful class of com-
pounds, which represent inevitable alternative to well-known
chloro analogues when substitution reactions with weak nucleo-
BeC
p
-bonding.30 Furthermore, it is known that polarization of
double-bond can influence the outcome of the hydrogenation with
IreP N complexes.23k,31 Therefore, the electronic effects (e.g., en-
^
hanced bond polarization) as well as the steric effects (e.g., higher
bulk of bromine atom), can influence the energy of transition states
associated with hydride addition to C]C bond.23k,31 Evidently, the
interplay of steric and electronic effects in compounds 2 leads to
energetically less favourable transition states, which render these
compounds less reactive towards IreP N complexes catalyzed hy-
^
drogenation compared to their chloro analogues. Surprisingly, de-
spite a lower CeX bond strength in compounds 2 compared to their
chloro analogues, high chemoselectivities could be attained with
only 5e9% of 4 formed.20 Whilst the scope of the asymmetric hy-
drogenation reaction investigated is limited to aliphatic substituted
(1-bromo-1-alkenyl)boronic esters, the range of ligands that are
useful for this transformation is quite diverse. They include phos-
phiniteeoxazoline, phosphinite pyridine and phosphino-oxazoline
ligands. The highest activity has been observed with the phosphin-
ite pyridine ligand L2, but higher enantioselectivities have been ob-
tained using the phosphinite oxazoline L8b and phosphino-
oxazoline L9. Importantly, as in the case of chloro derivatives the
philes are conducted on
a-halo carbon of (a-haloalkyl)boronic es-
ters. Therefore, we believe that our study provides a valuable
contribution to the chemistry of (
4. Experimental section
4.1. General
a-haloalkyl)boronic esters.
Compounds 2aeg and 3aee were characterized by 1H NMR, 13
NMR spectroscopy and HRMS spectrometry (also for compounds
C

2658
S.J. Roseblade et al. / Tetrahedron 70 (2014) 2654e2660
3feg). NMR spectra were recorded on a Bruker Avance III 500
spectrometer and Varian VNMRS 400 spectrometer (500 or
400 MHz for 1H NMR and 125 or 100 MHz for 13C NMR). Chemical
1144, 1084, 845, 672 cmꢁ1; 1H NMR (500 MHz, CDCl3):
d 1.27 (12H,
s, 2b0), 1.32 (12H, s), 6.29 (1H, d, J¼15.1 Hz, 2b0), 6.40 (1H, s), 6.67
(1H, s), 7.17 (1H, d, J¼15.1 Hz, 2b0); 13C NMR (125 MHz, CDCl3):
shifts were reported in
d
parts per million referenced to TMS as an
-carbon atoms in
d
24.7, 83.7 (2b0), 85.1, 126.9 (2b0), 134.8; HRMS (ESI): [MþH]þ,
internal standard. 13C NMR chemical shifts of
b
found: 232.0379 C8H1410BBrO2 requires 232.0377.
compounds 2 [(Bpin)(Br)Ca]Cb(H)(R3)] were marked bold in the
characterization section for each compound. High-resolution mass
spectra (HRMS) were acquired on an Agilent 6224 accurate mass
TOF LC/MS system. The chromatographic and optical purity of
products 3aeg was determined by gas chromatography on an
Agilent 6890N with a flame ionisation detector. Retention times for
eluting peaks of compounds 2aeg, rac-3aeg, e1-3aeg, e2-3aeg
and 4aeg are reported. The sign of optical rotation was determined
on Perkin Elmer 341 series polarimeter. IR spectra were taken with
Thermo Nicolet Nexus FTIR spectrometer and only noteworthy
absorptions were listed. Melting points were determined with
Mettler Toledo DSC822e apparatus (heating rate 10 ꢀC/min) and
were referred to as onset values and peak values. Compounds 3aee
are stable, if kept in the freezer (below ꢁ10 ꢀC), for at least 4
months. At ambient temperature the compounds 3aee decom-
posed completely in approximately one year time.
All chemicals and solvents were purchased from commercial
sources and were used without further purification. Anhydrous THF
and CH2Cl2 were obtained from SigmaeAldrich. Starting material
1b was purchased from the commercial source. Other starting
materials 1a and 1ceg as well as standards of de-brominated
products 4aeg were prepared according to the literature
procedures.15a
4.2.3. 2-(1-Bromoprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (2c). The product was isolated as a greasy white
solid, yield 47%. Mp¼49.7 ꢀC (onset), 53.1 ꢀC (peak); nmax(KBr) 3439,
2979, 2934, 1616, 1323, 1255, 1145, 851, 675 cmꢁ1 1H NMR
;
(500 MHz, CDCl3):
d
1.32 (12H, s), 1.91 (3H, d, J¼7.4 Hz), 6.92 (1H, t,
J¼8.3 Hz); 13C NMR (125 MHz, CDCl3):
d 18.2, 24.7, 84.4, 149.8;
HRMS (ESI): [MþH]þ, found: 246.0529 C9H1710BBrO2 requires
246.0536.
4.2.4. 2-(1-Bromopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (2d). The product was isolated as light brown oil,
yield 56%. nmax(KBr) 2979, 2873, 1616, 1407, 1327, 1144, 966, 850,
676 cmꢁ1; 1H NMR (500 MHz, CDCl3):
d
0.91 (3H, t, J¼7.4 Hz), 1.31
(12H, s), 1.43 (2H, sext, J¼7.2 Hz), 2.32 (2H, q, J¼7.5 Hz), 6.84 (1H, t,
J¼8.2 Hz); 13C NMR (125 MHz, CDCl3):
d 13.5, 22.2, 24.7, 34.1, 84.4,
152.8; HRMS (ESI): [MþH]þ, found: 274.0848 C11H2110BBrO2 re-
quires 274.0849.
4.2.5. 2-(1-Bromo-2-cyclohexylvinyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (2e). The product was isolated as a light brown solid,
yield 53%. Mp¼58.0 ꢀC (onset), 61.3 ꢀC (peak); nmax(KBr) 3439, 2974,
2920, 2844, 1612, 1452, 1140, 885, 698 cmꢁ1 1H NMR (500 MHz,
;
Flash chromatography was performed using Biotage SP1Ô sys-
CDCl3): d 1.13 (4H, m), 1.30 (12H, s), 1.67 (6H, m), 2.66 (1H, m), 6.68
tem on BiotageÒ SNAP Cartridges.
(1H, d, J¼10.2 Hz); 13C NMR (125 MHz, CDCl3):
d 24.7, 25.6, 25.8,
Research samples of ligands L2eL3 were supplied by prof. Pfaltz,
ligands L5eL6 by prof. Mazet, ligands L7eL8 were procured at
Strem Chemicals Inc. and ligand L9 was purchased at Solvias. Other
ligands and catalyst precursors were supplied by Johnson Matthey.
All the ligands and catalyst precursors were stored under inert
atmosphere prior to use.
32.9, 41.2, 84.4, 157.7; HRMS (ESI): [MþH]þ, found: 314.1161
C
14H2510BBrO2 requires 314.1162.
4.2.6. 2-(1-Bromo-2-phenylvinyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (2f). The product was isolated as a light brown oil,
yield 43%. nmax(KBr) 3059, 2979, 1617, 1390, 1327, 1242, 1140, 967,
852, 695 cmꢁ1; 1H NMR (500 MHz, CDCl3):
d 1.32 (12H, s), 7.31 (3H,
4.2. General procedure for the preparation of (1-bromo-1-
alkenyl)boronic esters 2aeg
m), 7.35 (2H, m), 7.65 (1H, s); 13C NMR (125 MHz, CDCl3):
d 24.4,
84.7, 127.7, 128.25, 128.3, 136.8, 145.6; HRMS (ESI): [MþH]þ, found:
308.0692 C14H1910BBrO2 requires 308.0692.
A suspension of Cp2Zr(H)Cl (1.1 equiv) in dry THF was stirred
at room temperature under argon atmosphere followed by ad-
dition of 0.5 M solution of 1aeg (1.0 equiv) in dry THF. The re-
action mixture was stirred for 1 h, resulting in a clear coloured
solution. Addition of N-bromosuccinimide (1.1 equiv) in situ led
to the alternation of the colour of the solution. The obtained
mixture was stirred further at room temperature for 1 h. After-
wards, the solvent was removed under reduced pressure, and the
product was extracted from the residue with n-hexane
(5ꢂ20 mL). After removal of solvent under reduced pressure, the
residue was purified by Kugelrohr distillation and if needed fur-
ther by flash chromatography (silica gel, n-hexane/MTBE, MTBE
gradient 2e10%).
4.2.7. 2-(1-Bromo-2-(4-fluorophenyl)vinyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (2g). The product was isolated as a slightly
yellow solid, yield 32%. Mp¼66.6 ꢀC (onset), 72.7 ꢀC (peak);
nmax(KBr) 3439, 2980, 1600, 1508, 1242, 1139, 838, 663 cmꢁ1 1H
;
NMR (500 MHz, CDCl3):
d
1.30 (12H, s), 6.99 (2H, m), 7.34 (2H, m),
24.4, 84.8, 115.1
7.61 (1H, s); 13C NMR (125 MHz, CDCl3):
d
(JCF¼19.2 Hz), 129.6 (JCF¼8.3 Hz), 133.0, 144.7, 161.7 (JCF¼247.2 Hz);
HRMS (ESI): [MþH]þ, found: 326.0600 C14H1810BBrO2 requires
326.0598.
4.3. Hydrogenation of (1-bromo-1-alkenyl)boronic esters
2aee to (a-bromoalkyl)boronic esters 3aee
4.2.1. 2-(1-Bromo-3-methylbut-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (2a). The product was isolated as a light brown oil,
yield 67%. nmax(KBr) 2978, 2869, 1614, 1408, 1333, 1321, 1141, 971,
4.3.1. 2-(1-Bromo-3-methylbutyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (3a). Substrate 2a (28 mg, 0.1 mmol) and
[Ir(COD)(L8b)]BArF (17 mg, 0.01 mmol) were weighed into a glass vial
and purged with nitrogen. Dichloromethane (3 mL) was added by
injection and the reaction mixture was purged with nitrogen and
hydrogen (five times) with slow stirring. The reaction was heated to
50 ꢀC under 30 bar of hydrogen with stirring for 18 h. The system was
vented. The reaction crude was analyzed by GC, showing full con-
version to give 8% of 4a and 92% of 3a (60% ee). Catalyst residue was
removed by rapid filtration of the crude reaction mixture through
a pipette full of silica gel, eluting with 20:1 isohexane/EtOAc. The
product was isolated as a colourless oil in 65e70% yield, with 5% of 4a.
854, 699 cmꢁ1; 1H NMR (500 MHz, CDCl3):
d
0.99 (6H, d, J¼7.4 Hz),
1.30 (12H, s), 2.99 (1H, m), 6.65 (1H, d, J¼10.2 Hz); 13C NMR
(125 MHz, CDCl3):
d 22.6, 24.7, 31.7, 84.4, 159.3; HRMS (ESI):
[MþH]þ, found: 274.0845 C11H2110BBrO2 requires 274.0849.
4.2.2. 2-(1-Bromovinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(2b). The product was isolated in a mixture with 2-(2-bromovinyl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2b0) in ratio 2b:2b0¼2:1
as a colourless oil, yield 33%. nmax(KBr) 2980, 1610, 1586, 1406, 1341,

S.J. Roseblade et al. / Tetrahedron 70 (2014) 2654e2660
2659
Chromatographic purity was determined by GC method under the
following conditions: Chrompack Capillary Column CP-Chirasil-Dex
CDCl3):
d
13.4, 24.5, 27.5, 84.2; HRMS (ESI): [MþH]þ, found:
248.0699 C9H1811BBrO2 requires 248.0692.
CB, 25 mꢂ0.25 mmꢂ0.25
m
m; detector, 250 ꢀC; injection, 250 ꢀC;
carriergas, helium; carrier gasrate:1.5 mL/min;columntemperature:
120 ꢀCfor20min;totalruntime20min. Retentiontimes:2a¼7.3 min;
3a¼8.0 min; 4a¼2.9 min. Chiral purity wasdetermined by GC method
under the following conditions: Chrompack Capillary Column CP-
4.3.4. 2-(1-Bromopentyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(3d). Substrate 2d (28 mg, 0.1 mmol) and [Ir(COD)(L8b)]BArF
(17 mg, 0.01 mmol) were weighed into a glass vial and purged with
nitrogen. Dichloromethane (3 mL) was added by injection and the
reaction mixture was purged with nitrogen and hydrogen (five
times) with slow stirring. The reaction was heated to 50 ꢀC under
30 bar of hydrogenwith stirring for 18 h. The systemwas vented. The
reaction crude was analyzed by GC, showing full conversion to give
6% of 4d and 94% of 3d (64% ee). Catalyst residue was removed by
rapid filtration of the crude reaction mixture through a pipette full of
silica gel, eluting with 20:1 isohexane/EtOAc. The product was iso-
lated as a colourless oil in 65e70% yield, with 7% of 4d. Chromato-
graphic purity was determined by GC method under the following
Chirasil-Dex CB, 25 mꢂ0.25 mmꢂ0.25
m
m; detector, 250 ꢀC; in-
jection, 250 ꢀC; carrier gas, helium; carrier gas rate: 1.5 mL/min;
column temperature: 80 ꢀC for 80 min; total run time 80 min. Re-
tention times: e1-3a¼61.9 min; e2-3b¼63.3 min. nmax(KBr) 3439,
2958, 2870, 1731, 1616, 1382, 1215, 1139, 968, 728 cmꢁ1 1H NMR
;
(400 MHz, CDCl3): 0.91 (3H, d, J¼6.4 Hz), 0.94 (3H, d, J¼6.4 Hz), 1.30
(12H, s), 1.70 (1H, m), 1.85 (2H, m), 3.40 (1H, t, J¼8.0 Hz); 13C NMR
(100 MHz, CDCl3):
d 21.4, 22.6, 24.4, 27.2, 42.6, 84.1; HRMS (ESI):
[MþH]þ, found: 276.1001 C11H2211BBrO2 requires 276.1005.
conditions:
25 mꢂ0.25 mmꢂ0.25
Chrompack
Capillary
Column
FS-Lipodex-E,
4.3.2. 2-(1-Bromoethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(3b). A mixture of 2b and 2-bromovinyl boronic ester¼2:1 (23 mg,
0.1 mmol) and [Ir(COD)(L8b)]BArF (17 mg, 0.01 mmol) were
weighed into a glass reaction vial, placed in a Biotage Endeavour,
and purged with nitrogen. Dichloromethane (3 mL) was added by
injection and the reaction mixture was purged with nitrogen and
hydrogen (five times) with slow stirring. The reaction was heated
to 50 ꢀC under 30 bar of hydrogen with stirring for 18 h. The
system was vented. The reaction crude was analyzed by GC,
showing full conversion to give 5% of 4b, 86% of 3b (67% ee) and 9%
of other side-products. Catalyst residue was removed by rapid
filtration of the crude reaction mixture through a pipette full of
silica gel, eluting with 20:1 isohexane/EtOAc. The product was
isolated as a colourless oil in 50% yield, with 5% of 4b. Chromato-
graphic and chiral purity were determined by GC method under
the following conditions: Chrompack Capillary Column CP-
m
m; detector, 250 ꢀC; injection, 250 ꢀC; car-
rier gas, helium; carrier gas rate: 1.5 mL/min; column temperature:
110 ꢀC for 10 min; total run time 10 min. Retention times:
2d¼7.7 min; 3d¼7.0 min; 4d¼1.9 min. Chiral purity was determined
by GC method under the following conditions: Chrompack Capillary
Column CP-Chirasil-Dex CB, 25 mꢂ0.25 mmꢂ0.25
mm; detector,
250 ꢀC; injection, 250 ꢀC; carrier gas, helium; carrier gas rate: 1.5 mL/
min; column temperature: 100 ꢀC for 40 min; total run time 40 min.
Retention times: e1-3d¼25.9 min; e2-3d¼26.9 min. 1H NMR
(400 MHz, CDCl3): 0.92 (3H, t, J¼7.2 Hz), 1.30 (12H, s), 1.35 (4H, m),
1.92 (2H, q, J¼7.2 Hz), 3.33 (1H, t, J¼8.0 Hz); 13C NMR (100 MHz,
CDCl3): d 14.0, 22.2, 24.5, 31.0, 33.8, 84.2; This is a known compound
with spectroscopic and physical properties consistent with those
reported in the literature.14a
4.3.5. 2-(1-Bromo2-cyclohexylethyl)-4,4,5,5-tetramethyl-1,3,2-diox-
aborolane (3e). Substrate 2e (31 mg, 0.1 mmol) and [Ir(COD)(L2)]
BArF (15 mg, 0.01 mmol) were weighed into a glass vial and purged
with nitrogen. Dichloromethane (3 mL) was added by injection and
the reaction mixture was purged with nitrogen and hydrogen (five
times) with slow stirring. The reaction was heated to 50 ꢀC under
30 bar of hydrogen with stirring for 18 h. The system was vented.
The reaction crude was analyzed by GC, showing 95% conversion,
7% of 4e and 88% of 3e (2% ee). Catalyst residue was removed by
rapid filtration of the crude reaction mixture through a pipette full
of silica gel, eluting with 20:1 isohexane/EtOAc. The product 3e was
isolated as a colourless oil in 65e70% yield, with 5% of 4e. Chro-
matographic purity was determined by GC method under the fol-
lowing conditions: Chrompack Capillary Column CP-Chirasil-Dex
Chirasil-Dex CB, 25 mꢂ0.25 mmꢂ0.25
m
m; detector, 250 ꢀC; in-
jection, 250 ꢀC; carrier gas, helium; carrier gas rate: 2.0 mL/min;
column temperature: 85 ꢀC for 20 min; total run time 20 min.
Retention times: 2b¼6.6 min; e1-3b¼6.5 min; e2-3b¼6.9 min;
4b¼2.3 min 1H NMR (400 MHz, CDCl3): 1.34 (12H, s), 1.72 (3H, d,
J¼8.0 Hz), 3.45 (1H, q, J¼8.0 Hz); 13C NMR (100 MHz, CDCl3):
d
20.6, 24.5, 84.3; HRMS (ESI): [MþH]þ, found: 236.1281
C8H1611BBrO2 requires 236.1281. This is a known compound with
spectroscopic and physical properties consistent with those re-
ported in the literature.12
4.3.3. 2-(1-Bromopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(3c). Substrate 2c (12 mg, 0.05 mmol) and [Ir(COD)(L8b)]BArF
(9 mg, 0.005 mmol) were weighed into a glass vial and purged
with nitrogen. Dichloromethane (3 mL) was added by injection
and the reaction mixture was purged with nitrogen and hydrogen
(five times) with slow stirring. The reaction was heated to 50 ꢀC
under 30 bar of hydrogen with stirring for 18 h. The system was
vented. The reaction crude was analyzed by GC, showing full
conversion to give 9% of 4c and 91% of 3c (64% ee). Catalyst residue
was removed by rapid filtration of the crude reaction mixture
through a pipette full of silica gel, eluting with 20:1 isohexane/
EtOAc. The product was isolated as a colourless oil in 65e70%
yield, with 5% of 4c. Chromatographic and chiral purity were
determined by GC method under the following conditions:
CB, 25 mꢂ0.25 mmꢂ0.25
m
m; detector, 250 ꢀC; injection, 250 ꢀC;
carrier gas, helium; carrier gas rate: 2.0 mL/min; column temper-
ature: 160 ꢀC for 20 min; total run time 20 min. Retention times:
2e¼6.5 min; 3e¼7.1 min; 4e¼2.9 min. Chiral purity was de-
termined by GC method under the following conditions: Chrom-
pack
Capillary
Column
m
CP-Chirasil-GammaDex
225,
25 mꢂ0.25 mmꢂ0.25
m; detector, 250 ꢀC; injection, 250 ꢀC; car-
rier gas, helium; carrier gas rate: 2.0 mL/min; column temperature:
120 ꢀC for 150 min; total run time 150 min. Retention times: e1-
3e¼127.3 min; e2-3e¼128.8 min. nmax(KBr) 3439, 2924, 2852, 1725,
1581, 1385, 1246, 1139, 849, 681 cm-1 1H NMR (400 MHz, CDCl3):
;
0.87 (3H, m), 1.10e1.35 (15H, m), 1.65 (8H, m), 3.44 (1H, t, J¼8.0 Hz);
Chrompack
25 mꢂ0.25 mmꢂ0.25
Capillary
Column
CP-Chirasil-Dex
CB,
13C NMR (100 MHz, CDCl3):
d 24.4, 26.1, 26.5, 26.8, 32.2, 33.9, 36.7,
m
m; detector, 250 ꢀC; injection, 250 ꢀC;
41.2, 84.1; HRMS (ESI): [MþH]þ, found: 316.1307 C14H2710BBrO2
carrier gas, helium; carrier gas rate: 1.5 mL/min; column tem-
perature: 100 ꢀC for 20 min; total run time 20 min. Retention
times: 2c¼12.1 min; e1-3c¼10.0 min; e2-3c¼10.4 min;
4c¼2.6 min nmax(KBr) 2978, 2876, 1611, 1373, 1278, 1130, 968,
requires 316.1318.
Acknowledgements
668 cm-1
;
1H NMR (400 MHz, CDCl3): 1.04 (3H, t, J¼7.2 Hz), 1.30
We thank A. Veskovic, S. Borisek and D. Orkic for the technical
assistance in some experimental work; P. Skelton (Univ. of
ꢀ
ꢁ
ꢁ
(12H, s), 1.95 (2H, m), 3.29 (1H, t, J¼7.6 Hz); 13C NMR (100 MHz,

2660
S.J. Roseblade et al. / Tetrahedron 70 (2014) 2654e2660
ꢀ
ꢀ
ꢁ
ꢀ
ꢀ
15. (a) Gazic Smilovic, I.; Casas-Arce, E.; Roseblade, S. J.; Nettekoven, U.; Zanotti-
ꢁ
Cambridge), Dr. D. Urankar and Prof. dr. J. Kosmrlj (Univ. of Ljuljana)
ꢁ
ꢁ
Gerosa, A.; Kovacevic, M.; Casar, Z. Angew. Chem., Int. Ed. 2012, 51, 1014e1018;
ꢁ
for HRMS analysis; Dr. M. Crnugelj for the acquisition of some NMR
spectra, J. Fabris for acquisition of optical rotation data, IR and DSC
spectra and P. Drnovsek as well as A. Zanotti-Gerosa for the given
support. We also thank Prof. A. Pfaltz and Prof. C. Mazet who sup-
plied some of the catalyst samples.
ꢁ
ꢀ
(b) Gazic Smilovic, I.; Casar, Z. PCT Pat. Appl. WO2010146172, 2010; Chem. Abstr.
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2010, 154, 88353; (c) Gazic Smilovic, I.; Casar, Z. PCT Pat. Appl. WO2010146176,
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Supplementary data contains full catalyst screening details,
copies of 1H NMR spectra, 13C NMR spectra and GC chromatograms.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.02.065.
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