A practical synthetic approach to chiral (α-chloroalkyl)boronic esters via iridium-catalyzed chemoselective hydrogenation of chloro-substituted alkenyl boronates

Article abstract of DOI:10.1055/s-0033-1338512

Chiral (α-chloroalkyl)boronic esters are obtained by homogeneous asymmetric iridium-catalyzed chemoselective hydrogenation of (1-chloro-1-alkenyl)boronic esters. P,N-Iridium catalysis provides low level of dehalogenation during the hydrogenation, while th

Full text of DOI:10.1055/s-0033-1338512

2824▌
PRACTICAL SYNTHETIC PROCEDURES
pAracPticarlasycntthiecticaplroSceydunrets hetic Approach to Chiral (α-Chloroalkyl)boronic Esters via
Iridium-Catalyzed Chemoselective Hydrogenation of Chloro-Substituted
Alkenyl Boronates
Hydrogenation Approach to (α-Chloroalkyl)boronic Esters
Stephen J. Roseblade,a Eva Casas-Arcé,a Ulrike Nettekoven,b Ivana Gazić Smilović,c Antonio Zanotti-Gerosa,a
Zdenko Časar*c,d,e
a
Johnson Matthey, Catalysis and Chiral Technologies, Unit 28, Cambridge Science Park, Milton Road, Cambridge CB4 0FP, UK
b
Solvias AG, Business Unit Synthesis and Catalysis, Römerpark 2, 4303 Kaiseraugst, Switzerland
c
Lek Pharmaceuticals, d.d., Sandoz Development Center Slovenia, API Development, Organic Synthesis Department, Kolodvorska 27,
1234 Mengeš, Slovenia
d
PSP
Sandoz GmbH, Global Portfolio Management API, 6250 Kundl, Austria
Fax +43(5338)200418; E-mail: zdenko.casar@sandoz.com
e
Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia
Received: 26.06.2013; Accepted: 01.07.2013
No257
Dedicated to Prof. Dr. Dominique Lorcy (University of Rennes 1, France) on the occasion of her birthday
Abstract: Chiral (α-chloroalkyl)boronic esters are obtained by homogeneous asymmetric iridium-catalyzed chemoselective hydrogenation
of (1-chloro-1-alkenyl)boronic esters. P,N–Iridium catalysis provides low level of dehalogenation during the hydrogenation, while the cat-
alyst activity and enantioselectivity essentially depends on the applied P,N ligand features. Fine tuning of P,N ligand structures enables high
conversions, broad substrate acceptance, and high to excellent enantioselectivities with enantiomeric excess values up to 94% along with
low levels of dechlorination. Low catalyst loading with S/C = 200 can also be achieved for the preparation of an industrially important iso-
butyl derivative.
Key words: alkenes, alkyl halides, asymmetric synthesis, chemoselectivity, hydrogenation
Procedure 1:
PF6
H2 (10 bar), catalyst 4
N
O
O
O
Cl
B
B
Ir
B
+
Cl
Cy3P
S/C = 50
O
O
O
THF, 50 °C, 10 days
99% conversion
catalyst 4
2c
3c
1c
95% (GC yield)
3%
89% isolated yield
O
Procedure 2:
Ph
BArF
R
R
R
Ph
Ir
Ph
N
N
(S)
H2 (5–30 bar), catalyst 5
O
O
O
B
+
B
Cl
B
Cl
S/C = 7–25
P
O
O
O
Fe
Ph
Ph
CH2Cl2, 50 °C, 12–18 h
>99% conversion
3
2
1
catalyst 5
46–94% ee
R = alkyl, aryl
81–96% (GC yield)
65–91% isolated yield
3–19%
Procedure 3:
BArF
O
(S)
H
2 (60 bar), catalyst 6
O
O
O
N
Cl
B
Cl
B
+
B
S/C = 200
Ir
O
O
O
P
CH2Cl2, r.t. to 50 °C, 20 h
up to 99% conversion
Xyl
Xyl
catalyst 6
2c
3c
1c
84–85% ee
95–99% (GC yield)
0%
Scheme 1 Iridium-catalyzed chemoselective hydrogenation of chloro-substituted alkenyl boronates
SYNTHESIS 2013, 45, 2824–2831
Advanced online publication: 01.08.2013
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DOI: 10.1055/s-0033-1338512; Art ID: SS-2013-Z0439-PSP
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Introduction
Hydrogenation Approach to (α-Chloroalkyl)boronic Esters
2825
variant of the protocol. This confirmed the unique activity
of P,N–Ir catalysts, since among numerous combinations
of P,P; N,N; and P,N ligands with various Rh, Ru, and Ir
metal precursors only P,N–Ir based type catalysts assured
low levels of dechlorination.12a Indeed, P,N–Ir catalysts
with phosphinite-oxazoline ligands14 provided 46–63% ee
along with full conversion (S/C = 25) and no 3c pres-
ent.12a To follow up this lead, related catalyst structures of
PHOX,15 SimplePHOX,16 PyrPHOX,17 and ferrocenyl ox-
azolinylphosphine (phosferrox or Fc-PHOX)18 were test-
ed. They generally did not deliver improved performance
and either partial conversions or lower enantiomeric ex-
cesses were obtained, albeit accompanied by low levels of
dechlorination.
Chiral (α-chloroalkyl)boronic esters, initially discovered
by Matteson, represent an important class of chiral build-
ing blocks in organic synthesis.1 Moreover, (α-chloroal-
kyl)boronic esters proved to be key precursors of α-
aminoboronic acids, which attracted considerable interest
in recent years in the field of biology.2,3 Indeed, α-amino-
boronic acids constitute a fundamental structural unit in
proteasome inhibitors4 like Bortezomib (FDA ap-
proved),5,6 Ixazomib (Phase III studies),7 and Delanzomib
(Phase II studies)8 as well as in the dipeptidyl peptidase-4
(DPP-4) inhibitors such as Dutogliptin (Phase III studies)
for treatment of type 2 diabetes mellitus.9 Recently, α-
aminoboronic acid derivatives also proved to be useful
precursors for the synthesis of enantioenriched benzyl- More encouraging results were obtained with iridium cat-
amines in the Suzuki–Miyaura coupling reaction.10 De- alyst 6 bearing the t-Bu-Xyl-NeoPHOX ligand;19 at 50 °C
spite the fact that chiral (α-chloroalkyl)boronic esters and 20 bar of hydrogen pressure, full conversion and 86%
were discovered more than three decades ago and proved ee were achieved applying an S/C ratio of 50 in dichloro-
to be versatile synthetic tools, the only method for their ethane. Interestingly, the structurally related catalysts
preparation has been Matteson’s homologation. This bearing phenyl or o-tolyl moieties, respectively, instead of
stimulated us to consider a novel method for the prepara- the xylyl groups showed significantly worse performance.
tion of (α-chloroalkyl)boronic esters via chemoselective The comparably lower bulk of the phenyl substituents of
asymmetric hydrogenation of chloro-substituted alkenyl the catalyst gave rise to only 35% ee at full conversion,
boronates. However, we were faced with a severe chal- whereas the high steric demand of the o-tolyl substituents
lenge related to the possible C–Cl bond cleavage under likely disfavored substrate coordination and resulted in
the homogeneous hydrogenation reaction conditions.11 34% ee and only 50% conversion under otherwise identi-
Namely, there was no literature precedent for the homoge- cal conditions.
neous asymmetric hydrogenation of alkene substrates
With a focus on increasing enantioselectivity further, our
bearing directly bound chlorine functionality and nonpo-
attention was turned to imidazoline-type P,N–Ir catalysts.
lar groups that are incapable of coordination to catalyst.
To our delight, ferrocenyl-phosphinoimidazoline20 iridi-
To our delight, our initial screening for such a hydrogena-
um complexes demonstrated high chemo- and stereose-
tion approach revealed that chemoselective hydrogena-
lectivity.12a Our modification of the ligand structure by
tion of (1-chloro-1-alkenyl)boronic esters can be achieved
protection of the free imidazoline NH functionality by an
acyl moiety was the key to catalysts that also enabled high
with P,N–Ir complexes.12
Scope and Limitations
conversions along with excellent enantioselectivities and
low level of dehalogenation.12a Among these, P,N–Ir com-
plex 5 proved to be the most promising as evidenced by
highly enantioselective hydrogenation of 1c reaching full
conversion and giving the product 2c in 93% ee. The cat-
alyst loading (S/C = 25) was relatively high but a good
yield of 2c (85%) and low levels of the dechlorinated side-
product 3c (3% by GC area) were obtained, making this
reaction a useful method for the synthesis of 2c with high
enantiomeric excess (Table 1, entry 3). The scope of the
method was examined by testing asymmetric hydrogena-
tion on a range of aliphatic and aromatic substrates
(Scheme 1, procedure 2). Substrate 1a bearing a methyl
substituent on the double bond, instead of the larger iso-
propyl group present in 1c, reacted to give the desired
product 2a with a lower ee of 46%, while the amount of
dechlorinated side product 3a remained low (4%) (Table
1, entry 1). The related aliphatic substrate bearing an n-
propyl group on the double bond gave the hydrogenated
product 2b in 75% yield with 83% ee (Table 1, entry 2).
This increased ee in relation to the hydrogenation of 1a is
probably a result of the larger n-propyl substituent inter-
acting with the chiral P,N ligand to induce a higher level
of asymmetric induction. The higher ee obtained with 1c,
Due to the biological significance, 1c was chosen as the
model substrate for the initial investigation of the hydro-
genation of (1-chloro-1-alkenyl)boronic esters 1 under
homogeneous reaction conditions. During our initial reac-
tion screening,12a we surprisingly observed a significant
difference in catalytic performance between Crabtree’s
catalyst 4 and [Rh(cod)DiPFc]BF4 catalyst.13 Markedly,
while Crabtree’s catalyst afforded 99% conversion of 1c
giving 95% of 2c with less than 3% of 3c present in 10
days at 50 °C (THF, 10 bar H2) and substrate/catalyst
(S/C) = 50 (Scheme 1, procedure 1), the [Rh(cod)DiPFc]BF4
catalyst provided only 5% conversion of 1c giving 4% of
dehalogenated product 3c in 1 day at 50 °C (MeOH, 10
bar H2) and S/C = 50. Crabtree’s catalyst performed
equally well in CH2Cl2 (50 °C, 10–30 bar H2, 12–18 h)
when tested on other aliphatic substrates 1a (2a/3a
= 98:2), 1b (2b/3b = 95:5), 1e (2e/3e = 96:4) with some
reduction in chemoselectivity observed with substrate 1d
(2d/3d = 75:12, 87% GC conversion).
The striking result on the racemic version of the hydroge-
nation of 1c prompted us to perform an extended chiral
catalyst screening in order to elaborate the asymmetric
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2824–2831

2826
S. J. Roseblade et al.
PRACTICAL SYNTHETIC PROCEDURES
bearing a more bulky isopropyl group, is also in line with a cyclohexyl substituent gave the desired product 2e in
this trend. Hydrogenation of substrate 1d, bearing a tert- good yield (85%) with a high ee of 92% and only 5% of
butyl group, was possible but a high catalyst loading was the dechlorinated side-product 3e (Table 1, entry 5). The
needed in this case (S/C = 7). Nevertheless, high yield of aliphatic substrate that did not react well in the desired
the product 2d was obtained, with a high ee of 93% being way was the cyclopropyl-substituted derivative (Scheme
achieved (Table 1, entry 4). Hydrogenation of 1e bearing 1, compound 1, R = c-Pr; not shown in Table 1). This de-
Table 1 The Scope of Asymmetric Iridium-Catalyzed Chemoselective Hydrogenation of Chloro-Substituted Alkenyl Boronates with Catalyst 5a
Entry Alkene
S/C
25
Pressure Time
Product 2
3
2/3b
Yield
eeb
46
(bar)
(h)
(%) of 2c
Bpin
Bpin
Bpin
(S)
1
2
3
30
18
96:4
73
75
85
Cl
Cl
3a
1a
1b
2a
Bpin
Cl
Bpin
Bpin
(S)
25
25
5
5
12
12
96:3.5
95:3
83
93
Cl
3b
3c
2b
Bpin
Cl
Bpin
Bpin
Bpin
(S)
Cl
2c
2d
2e
1c
Bpin
Bpin
(S)
4
5
7
10
30
12
18
90:10
95:5
86
85
93
92
Cl
Cl
3d
3e
3f
1d
Bpin
Cl
Bpin
Bpin
(S)
25
Cl
1e
1f
Bpin
Cl
Bpin
Bpin
(S)
6
7
10
10
10
30
12
18
94:6
89
70
90
88
Cl
2f
Bpin
Cl
Bpin
Bpin
(S)
86:14
Cl
2g
3g
1g
F
F
F
Bpin
Cl
Bpin
(S)
Bpin
8
9
10
10
10
5
30
30
12
18
18
92:8
91
73
65
89
88
94
Cl
3h
1h
2h
MeO
MeO
MeO
Bpin
Cl
Bpin
(S)
Bpin
88:12
81:19
Cl
3i
1i
2i
F3C
F3C
F3C
Bpin
Cl
Bpin
Bpin
(S)
10
Cl
1j
3j
2j
a Conditions: substrate (0.18–0.22 mmol), catalyst 5, CH2Cl2 (2.5–3 mL), 0.066–0.087 M substrate concentration, 50 °C, full conversion.
b Conversions to 2 and 3 as well as enantiomeric excesses were calculated by GC analysis. When the sum of 2 and 3 does not correspond to
100% this is due to the presence of unidentified side products.
c Isolated yields.
Synthesis 2013, 45, 2824–2831
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Hydrogenation Approach to (α-Chloroalkyl)boronic Esters
2827
rivative gave low conversion of 34% within 12 hours (10 lyst 5, CH2Cl2, 30 bar H2, 50 °C, 18 h) a different result
bar H2, S/C = 10) and only 13% of the desired product was was obtained in comparison to the aliphatic substrates. A
obtained. This was probably due to side-reactions result- small, but noticeable increase in the amount of dehaloge-
ing from ring-opening of the vinylcyclopropane moiety as nated side-products 3g, 3i, and 3j (ranging from 4% on 2g
demonstrated by the presence of larger amounts of un- to 11–16% on 2i and 2j) was detected. The origin of this,
identified side-products in GC chromatograms. Interest- in some cases (e.g., 2g and 2i), can be ascribed to the ther-
ingly, when this substrate was hydrogenated under mal instability of products 2 as evidenced by detectable
identical conditions but in the presence of Crabtree’s cat- dechlorination in experiments without catalyst under the
alyst 4 in toluene, 86% conversion of the starting material identical conditions as described above. A moderate back-
was achieved giving 52% of desired racemic product.
ground dechlorination of the products, detectable irre-
spective of the electronic nature of the substituents on the
aromatic ring, would explain the observed trend for sub-
strates/products bearing aromatic substituents to give
slightly higher amounts of dechlorinated side products.
To examine the scope of the synthetic method further,
substrates bearing aromatic substituents of various types
were prepared and hydrogenated using catalyst 5.
Crabtree’s catalyst 4 was again used to prepare the race-
mic references (S/C = 10:1, CH2Cl2, 50 °C, 10–30 bar H2, In addition to optimizing catalyst selectivity, catalyst pro-
12–18 h). Phenyl-substituted 1f reacted under standard ductivity was also explored. Unfortunately, it was not pos-
conditions to give 70% conversion to products 2f and 3f sible to increase the activity of catalyst 5. The use of
in a 64:6 ratio. The presence of electron-withdrawing sub- different reaction temperatures and hydrogen pressures
stituents appeared to increase reactivity: substrates 1h and generally made little difference to the reaction outcome.
1j gave full conversion (2h/3h = 68:5 ratio and 2j/3j = Reactions in toluene at 80 °C provided an acceptable al-
49:37). The presence of electron-donating substituents ternative to reactions at 50 °C in CH2Cl2 but, in all cases,
caused instead a marked decrease in reactivity: substrates catalyst loadings lower than S/C = 25/1 caused a slight re-
1g and 1i gave respectively 35% conversion (2g/3g = duction in enantioselectivity and a significant drop in con-
16:19) and 21% conversion (2i/3i = 10:11). Comparable version. We therefore decided to reconsider the use of
substrate reactivity trends were observed using chiral cat- iridium catalyst 6, bearing the t-Bu-Xyl-NeoPHOX li-
alyst 5. Hydrogenation of the phenyl-substituted 1f could gand,19 which, during the catalyst optimization phase had
be achieved at increased catalyst loading (S/C = 10). given promising results in the hydrogenation of substrate
Good conversion to product 2f was obtained (89% yield) 1c (S/C = 50, 86% ee in dichloroethane, 50 °C, 20 bar). A
with 90% ee (Table 1, entry 6). The amount of dechlori- switch to dichloromethane as solvent brought noticeable
nated side-product 3f was still low at 6%. Even with this improvement in reactivity and S/C ratios of 100 were fea-
less reactive substrate the reaction was performed under sible. Alternative solvents and mixtures such as trifluoro-
mild conditions of temperature and pressure (50 °C, 10 ethanol or 2-methyltetrahydrofuran–dichloromethane
bar H2). The related substrate 1g bearing a p-tolyl substit- (1:1) proved counter-productive, as did the addition of 0.1
uent was hydrogenated to give the product 2g in 70% equivalent versus substrate of triethylamine or acetic acid.
yield with 88% ee (Table 1, entry 7). In this reaction a Reducing the reaction temperature to ambient did neither
higher level of dechlorinated side-product was formed significantly improve productivity, nor enantioselectivity.
than with the unsubstituted phenyl group and any of the An increase in pressure to 60 bar at ambient temperature,
aliphatic substrates. Substrate 1h bearing a p-fluoro aro- however, enabled 99% conversion and 85% ee of 1c at
matic ring was hydrogenated successfully using catalyst S/C = 200 (Scheme 1, procedure 3). Equivalent experi-
5. High product yield (91%), high ee (89%) and a low ment at 50 °C provided 95% conversion to 2c and 84% ee.
amount of dechlorinated side-product (8%) resulted (Ta- In all experiments, product selectivity proved excellent
ble 1, entry 8). The p-OMe analogue 1i gave 73% yield of with <1% of dehalogenated by-product 3c observed.
the desired product 2i with 88% ee and about 12% dechlo-
rinated side-product 3i (Table 1, entry 9). The p-CF3 ana-
logue 1j gave the highest ee observed at 94%, but more
In conclusion, we have developed a new catalytic and
asymmetric route to enantiomerically enriched (α-chloro-
alkyl)boronic esters. The methodology has been applied
to a variety of substrates bearing both alkyl and aryl sub-
dechlorination occurred in this case resulting in a reduc-
tion in the yield of product 2j (Table 1, entry 10).12a
stituents. While significant changes in reactivity have
In line with experiments conducted by others on fluoro been detected depending on the steric and electronic na-
derivatives,21 we established that pure, racemic 2c and 2e ture of the alkyl and aryl residues in substrates 1, it has
did not dechlorinate under the reaction conditions in the been proven that catalyst 5 provides high enantioselectiv-
presence of catalyst 5. While aromatic substrates 1f–j ity with reasonably broad substrate acceptance. In addi-
could be successfully hydrogenated using catalyst 5, they tion, catalyst 6 has proven its value in the hydrogenation
generally showed reduced reactivity and higher levels of of a key aliphatic substrate providing slightly reduced en-
dechlorination. Electronic factors related to the nature of antioselectivity but at significantly lower catalyst load-
the substituents on the aromatic rings appear to play a ings, which can make its use valuable from an applied
role. When samples of product mixtures of 2g, 2i, and 2j perspective.
were resubmitted to hydrogenation conditions (10% cata-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2824–2831

2828
S. J. Roseblade et al.
PRACTICAL SYNTHETIC PROCEDURES
Products 2a–j were characterized by 1H NMR, 13C NMR spectros-
(S)-2-(1-Chloro-2-ethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lane (2a)
Following the general procedure with catalyst 5 (S/C = 25) using 1a
(40 mg, 0.20 mmol) in anhyd CH2Cl2 (3 mL), 2a was obtained as a
colorless oil; yield: 30 mg (73%); 46% ee.
copy, and HRMS. NMR spectra were recorded on a Varian
1
VNMRS 400 spectrometer (400 MHz for H NMR and 100 MHz
for 13C NMR). Chemical shifts are reported in δ ppm referenced to
TMS as an internal standard. High-resolution mass spectra (HRMS)
were acquired on a Bruker BioApex II 4.7e FTICR mass spectrom-
eter. The chromatographic and optical purity of products 2a–j was
determined by gas chromatography on the following instruments: a)
Varian CP3800 Gas Chromatograph, b) Agilent 7890A Gas Chro-
matograph, and c) Agilent 6890N Gas Chromatograph. Gas chro-
matograph was equipped with a flame ionization detector on the
capillary column. Retention times for eluting peaks of compounds
1a–j, rac-2a–j, (R)-2a–j, (S)-2a–j, and 3a–j are reported. All chem-
icals and solvents were purchased from commercially sources and
were used without further purification. Anhyd THF and CH2Cl2
were obtained from Sigma-Aldrich. Starting materials 1a–j were
prepared according to the literature procedure as well as standards
of dechlorinated products 3a–j.12a Column chromatography was
performed with silica gel (Merck, type 60, 0.063–0.2 mm). Catalyst
4 was supplied by Johnson Matthey and stored under inert atmo-
sphere prior to use. Catalyst 5 was synthesized according to litera-
ture data.12a Catalyst 6 was supplied by Solvias and stored under
inert atmosphere prior to use.
GC: Both conversion and ee were established using chiral GC under
the following conditions: Column: Chrompack capillary column
CP-Chirasil-Dex CB, 25 m × 0.25 mm × 0.25 μm; Injector: split ra-
tio 30, T = 250 °C; Carrier gas: He, constant flow rate: 1.5 mL
min–1; Detector: T = 250 °C; Temperature: 100 °C for 30 min; Total
run time: 20 min; 1a = 8.4 min; 3a = 2.8 min; (R)-2a = 7.5 min; (S)-
2a = 7.7 min.
1H NMR (400 MHz, CDCl3): δ = 1.05 (t, J = 7.6 Hz, 3 H), 1.31 (12
H, s), 1.89 (m, 2 H), 3.39 (t, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 11.9, 24.6, 27.5, (C–B not ob-
served), 84.4.
HRMS-ESI+: m/z [M + Na]+ calcd for C9H18BClO2 + Na: 227.0981;
found: 227.0979.
(S)-2-(1-Chloropentyl)-4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lane (2b)
Following the general procedure with catalyst 5 (S/C = 25) using 1b
(50 mg, 0.22 mmol) in anhyd CH2Cl2 (2.5 mL), 2b was obtained as
a colorless oil; yield: 38 mg (75%); 83% ee.
Procedure 1: Gram Scale Hydrogenation with Crabtree’s Cat-
alyst 4
GC: Both chromatographic purity and the ee were established using
a chiral GC under the following conditions: Column: Chrompack
capillary column CP-Chirasil-Dex CB, 25 m × 0.25 mm × 0.25 μm;
Injector: split ratio 30, T = 250 °C; Carrier gas: He, constant flow
rate 1.5 mL min–1; Detector: T = 250 °C; Temperature: 100 °C for
30 min; Total run time: 30 min; 1b = 20.3 min; (R)-2b = 21.9 min;
(S)-2b = 22.6 min; 3b = 6.7 min.
1H NMR (400 MHz, CDCl3): δ = 0.92 (t, J = 7.0 Hz, 3 H), 1.30 (s,
12 H), 1.36 (m, 3 H), 1.48 (m, 1 H), 1.83 (m, 2 H), 3.42 (dd, J = 6.8,
8.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.0, 22.2, 24.6, 29.5, 33.8, 43.5
(br), 84.3.
HRMS-ESI+: m/z [M – CH3]+ calcd for C10H19BClO2: 217.1167;
found: 217.1161.
The (1-chloro-1-alkenyl)boronic ester 1c (1.84 g, 8.0 mmol), (1,5-
cyclooctadiene)(pyridine)(tricyclohexylphosphine)iridium(I) hexa-
fluorophosphate (4; Crabtree’s catalyst, 129 mg, 0.16 mmol, S/C =
50) and anhyd THF (50 mL) were rapidly placed in the 75 mL stain-
less steel autoclave under N2 atmosphere. The autoclave was sealed
and pressurized/depressurized: first, three times with 6 bar of N2,
then three times with 6 bar of H2. The mixture was stirred for 10
days at 50 °C under 10 bar of H2. Once the autoclave had cooled to
r.t., the autoclave was carefully depressurized, and the solution was
poured into a round bottomed flask. The crude product analysis by
GC revealed the 99% conversion with 95% of 2c and 3% of 3c pres-
ent. The solvent was removed under the reduced pressure and the
residue was passed through a short column of silica gel (eluent: n-
hexane) to remove the catalyst. The racemic product 2c was isolated
in 89% (1.65 g) yield.
Procedure 2: Hydrogenation with Catalyst 5; (α-Chloroal-
kyl)boronic Esters 2a–j; General Procedure
(S)-2-(1-Chloro-3-methylbutyl)-4,4,5,5-tetramethyl-1,3,2-di-
oxaborolane (2c)
Following the general procedure with catalyst 5 (S/C = 25) using 1c
(50 mg, 0.22 mmol) in anhyd CH2Cl2 (2.5 mL), 2c was obtained as
a colorless oil; yield: 43 mg (85%); 93% ee.
The respective (1-chloro-1-alkenyl)boronic ester 1a–j was placed in
a vial suitable for the Biotage Endeavour and the P,N–Ir complex 5
was added. The vial was placed into the Endeavour and sealed. The
system was purged with N2 five times and then solvent was added.
The system was purged five more times with N2 and ten times with
H2. The reaction mixture was heated to adequate temperature and
pressurized with H2 for 12–18 hours. The system was vented and the
resulting reaction crude was purified by flash column chromatogra-
phy using as eluent a mixture of n-hexane and EtOAc (v/v).
GC: Chromatographic purity was determined by GC method under
the following conditions: Column: Chrompack capillary column
CP-Chirasil-Dex CB, 25 m × 0.25 mm × 0.25 μm; Injector: split ra-
tio 30, T = 250 °C; Carrier gas: He, constant flow rate 1.5 mL min–1;
Detector: T = 250 °C; Temperature: 120 °C for 8 min; Total run
time: 8 min; 1c = 6.6 min, 2c = 5.7 min, 3c = 2.8 min.
Procedure 3: Hydrogenation with Catalyst 6
The ee was established using a chiral GC under the following con-
ditions: Column: Chrompack capillary column CP-Chirasil-Dex
CB, 25 m × 0.25 mm × 0.25 μm; Injector: split ratio 30, T = 250 °C;
Carrier gas: He, constant flow rate 1.5 mL min–1; Detector: T = 250
°C; Temperature gradient: 60 °C for 40 min, increase 0.5 °C min–1
until 90 °C, hold 2 min, decrease 15 °C min–1 until 60 °C, hold 1
min; Total run time: 105 min; 1c = 83.8 min; (R)-2c = 94.5 min; (S)-
2c = 95.1 min.
1H NMR (400 MHz, CDCl3): δ = 0.82 (d, J = 6.8 Hz, 3 H), 0.85 (d,
J = 6.8 Hz, 3 H), 1.21 (s, 12 H), 1.52 (m, 1 H), 1.70 (m, 1 H), 1.79
(m, 1 H), 3.40 (dd, J = 6.0, 9.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.2, 22.9, 24.6, 25.6, 41.5 (br),
42.5, 84.3.
HRMS-ESI+: m/z [M – C3H6O]+ calcd for C8H16BClO: 174.0986;
found: 174.0977.
The (1-chloro-1-alkenyl)boronic ester 1c (115.2 mg, 0.5 mmol) was
placed in a Schlenk flask, set under argon by three vacuum/argon
cycles and dissolved in degassed CH2Cl2 (2 mL). (S)-Ir-t-Bu-Xyl-
NeoPHOX catalyst precursor 6 (2.5 μmol, 4.13 mg, S/C = 200) was
placed in a Schlenk flask, set under argon by three vacuum/argon
cycles and dissolved in degassed CH2Cl2 (1 mL). Both solutions
were stirred for 15 min at r.t. and subsequently transferred into an
inertized 50 mL stainless steel autoclave via syringe under a slight
overpressure of argon. The autoclave was closed, purged three
times with argon and three times with H2 and the pressure was set
to 60 bar. Heating and stirring was started and as soon as the tem-
perature of 50 °C was reached, the pressure was readjusted and the
reaction was stirred for 20 h. Afterwards, the autoclave was vented,
flushed with argon, unloaded, and the product solution was ana-
lyzed.
Synthesis 2013, 45, 2824–2831
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Hydrogenation Approach to (α-Chloroalkyl)boronic Esters
2829
(S)-2-(1-Chloro-3,3-dimethylbutyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (2d)
Following the general procedure with catalyst 5 (S/C = 7) using 1d
(49 mg, 0.20 mmol) in anhyd CH2Cl2 (2.5 mL), 2d was obtained as
a colorless oil; yield: 44 mg (86%); 93% ee.
°C; Temperature 110 °C; Total run time: 120 min; (R)-2f = 104.5
min; (S)-2f = 106.0 min; 1f = 113.4 min.
1H NMR (400 MHz, CDCl3): δ = 1.25 (s, 6 H), 1.27 (s, 6 H), 3.12
(dd, J = 8.6, 13.9 Hz, 1 H), 3.21 (dd, J = 8.1, 13.9 Hz, 1 H), 3.63 (t,
J = 8.1 Hz, 1 H), 7.29 (m, 5 H).
GC: Chromatographic purity was determined by GC method under
the following conditions: Column: Chrompack capillary column
CP-Chirasil-Dex CB, 25 m × 0.25 mm × 0.25 μm; Injector: split ra-
tio 30, T = 250 °C; Carrier gas: He, constant flow rate 1.5 mL
min–1; Detector: T = 250 °C; Temperature: 120 °C for 12 min; Total
run time: 12 min; 2d = 8.4 min, 3d = 4.0 min.
13C NMR (100 MHz, CDCl3): δ = 24.5, 24.6, 40.3, 43.0 (br), 84.5,
126.8, 128.4, 129.2, 138.4.
HRMS-ESI+: m/z [M + Na]+ calcd for C14H20BClO2 + Na:
289.1134; found: 289.1137.
(S)-2-(1-Chloro-2-p-tolylethyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-
borolane (2g)
Following the general procedure with catalyst 5 (S/C = 10) using 1g
(55 mg, 0.20 mmol) in anhyd CH2Cl2 (3 mL), 2g was obtained as a
colorless oil; yield: 40 mg (70%); 88% ee.
The ee was established using a chiral GC under the following con-
ditions: Column: Chrompack capillary column CP-Chirasil-Dex
CB, 25 m × 0.25 mm × 0.25 μm; Injector: split ratio 30, T = 250 °C;
Carrier gas: He, constant flow rate 1.0 mL min–1; Detector: T =
90 °C; Temperature: 90 °C for 60 min; Total run time: 60 min;
(R)-2d = 52.7 min; (S)-2d = 53.3 min; 1d = 54.3 min.
1H NMR (400 MHz, CDCl3): δ = 0.95 (s, 9 H), 1.30 (s, 12 H), 1.77
(dd, J = 6.3, 13.7 Hz, 1 H), 1.98 (dd, J = 10.3, 13.7 Hz, 1 H), 3.47
(dd, J = 5.5, 9.7 Hz, 1 H).
GC: Chromatographic purity was determined by GC method under
the following conditions: Column: Chrompack capillary column
CP-Chirasil-Dex CB, 25 m × 0.25 mm × 0.25 μm; Injector: split ra-
tio 30, T = 250 °C; Carrier gas: He, constant flow rate 1.0 mL min–1;
Detector: T = 250 °C; Temperature 160 °C; Total run time: 20 min;
1g = 15.8 min, 2g = 13.7 min, 3g = 7.2 min.
13C NMR (100 MHz, CDCl3): δ = 24.5, 29.6, 31.3, (C–B not ob-
served), 48.0, 84.2.
HRMS-ESI+: m/z [M + Na]+ calcd for C12H24BClO2 + Na:
269.1456; found: 269.1450.
The ee was established using a chiral GC under the following con-
ditions: Column: Chrompack capillary column CP-Chirasil-Dex
CB, 25 m × 0.25 mm × 0.25 μm; Injector: split ratio 30, T = 250 °C;
Carrier gas: He, constant flow rate 1.5 mL min–1; Detector: T = 250
°C; Temperature 120 °C; Total run time: 120 min; (R)-2g = 75.6
min; (S)-2g = 77.3 min.
1H NMR (400 MHz, CDCl3): δ = 1.25 (s, 6 H), 1.27 (s, 6 H), 2.32
(s, 3 H), 3.06 (dd, J = 8.0, 13.6 Hz, 1 H), 3.16 (dd, J = 8.0, 13.6 Hz,
1 H), 3.59 (t, J = 8.0 Hz, 1 H), 7.11 (d, J = 8.0 Hz, 2 H), 7.17 (d,
J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.1, 24.5, 24.8, 39.8, 43.0 (br),
84.4, 128.9, 129.0, 135.3, 136.3.
HRMS-ESI+: m/z [M + H]+ calcd for C15H23BClO2: 281.1474;
found: 281.1460.
(S)-2-(1-Chloro-2-cyclohexylethyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (2e)
Following the general procedure with catalyst 5 (S/C = 25) using 1e
(54 mg, 0.20 mmol) in anhyd CH2Cl2 (3 mL), 2e was obtained as a
colorless oil; yield: 46 mg (85%); 92% ee.
GC: Chromatographic purity was determined by GC under the fol-
lowing conditions: Column: Chrompack capillary column CP-
Chirasil-Dex CB, 25 m × 0.25 mm × 0.25 μm; Injector: split ratio
30, T = 250 °C; Carrier gas: He, constant flow rate 1.0 mL min–1;
Detector: T = 250 °C; Temperature 160 °C; Total run time: 15 min;
1e = 8.4 min, 2e = 9.5 min, 3e = 4.8 min.
The ee was established using a chiral GC under the following con-
ditions: Column: Chrompack capillary column CP-Chirasil-Dex
CB, 25 m × 0.25 mm × 0.25 μm; Injector: split ratio 30, T = 250 °C;
Carrier gas: He, constant flow rate 1.5 mL min–1; Detector: T = 250
°C; Temperature 100 °C; Total run time: 180 min; (R)-2e = 165.9
min; (S)-2e = 166.9 min.
1H NMR (400 MHz, CDCl3): δ = 0.90 (m, 2 H), 1.20 (m, 15 H), 1.71
(m, 8 H), 3.55 (dd, J = 6.0, 9.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 24.5, 26.3, 26.5, 26.8, 32.0, 33.6,
(S)-2-[1-Chloro-2-(4-fluorophenyl)ethyl]-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (2h)
Following the general procedure with catalyst 5 (S/C = 10) using 1h
(50 mg, 0.18 mmol) in anhyd CH2Cl2 (2.5 mL), 2h was obtained as
a colorless oil; yield: 46 mg (91%); 89% ee.
GC: Chromatographic purity was determined by GC method under
the following conditions: Column: Chrompack capillary column
CP-Chirasil-Dex CB, 25 m × 0.25 mm × 0.25 μm; Injector: split ra-
tio 30, T = 250 °C; Carrier gas: He, constant flow rate 1.0 mL min–1;
Detector: T = 250 °C; Temperature 160 °C; Total run time: 15 min;
1h = 10.9 min, 2h = 10.7 min, 3h = 5.7 min.
35.1, 41.2, 84.3.
HRMS-ESI+: m/z [M + Na]+ calcd C14H26BClO2 + Na: 295.1607;
The ee was established using a chiral GC under the following con-
ditions: Column: Chrompack capillary column CP-Chirasil-Dex
CB, 25 m × 0.25 mm × 0.25 μm; Injector: split ratio 30, T = 250 °C;
Carrier gas: He, constant flow rate 1.5 mL min–1; Detector: T = 250
°C; Temperature 110 °C; Total run time: 120 min; 1h + (R)-2h =
109.5 min, (S)-2h = 111.6 min. Given the co-elution of 1h and (R)-
2h, the ee could be established only for the reactions that gave full
conversion.
1H NMR (400 MHz, CDCl3): δ = 1.25 (s, 6 H), 1.26 (s, 6 H), 3.08
(dd, J = 8.1, 14.3 Hz, 1 H), 3.16 (dd, J = 8.1, 14.3 Hz, 1 H), 3.58 (t,
J = 8.1 Hz, 1 H), 7.00 (t, J = 9.0 Hz, 2 H), 7.24 (dd, J = 5.6, 9.0 Hz,
2 H).
13C NMR (100 MHz, CDCl3): δ = 24.5, 24.6, 39.4, 43.0 (br), 84.6,
115.1 (2JC,F = 23.1 Hz), 130.7 (3JC,F = 8.0 Hz), 134.0 (4JC,F = 4.0
Hz), 161.9 (1JC,F = 243.5 Hz).
HRMS-ESI+: m/z [M + Na]+ calcd for C14H19BClFO2 + Na:
307.1053; found: 307.1043.
found: 295.1603.
(S)-2-(1-Chloro-2-phenylethyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-
borolane (2f)
Following the general procedure with catalyst 5 (S/C = 10) using 1f
(50 mg, 0.19 mmol) in anhyd CH2Cl2 (2.5 mL), 2f was obtained as
a colorless oil; yield: 45 mg (89%); 90% ee.
GC: Chromatographic purity was determined by GC method under
the following conditions: Column: Chrompack capillary column
CP-Chirasil-Dex CB, 25 m × 0.25 mm × 0.25 μm; Injector: split ra-
tio 30, T = 250 °C; Carrier gas: He, constant flow rate 1.0 mL min–1;
Detector: T = 250 °C; Temperature 160 °C; Total run time: 15 min;
1f = 11.6 min, 2f = 10.7 min, 3f = 5.4 min.
The ee was established using a chiral GC under the following con-
ditions: Column: Chrompack capillary column CP-Chirasil-Dex
CB, 25 m × 0.25 mm × 0.25 μm; Injector: split ratio 30, T = 250 °C;
Carrier gas: He, constant flow rate 1.5 mL min–1; Detector: T = 250
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2824–2831

2830
S. J. Roseblade et al.
PRACTICAL SYNTHETIC PROCEDURES
References
(S)-2-[1-Chloro-2-(4-methoxyphenyl)ethyl]-4,4,5,5-tetrameth-
yl-1,3,2-dioxaborolane (2i)
Following the general procedure with catalyst 5 (S/C = 10) using 1i
(58 mg, 0.20 mmol) in anhyd CH2Cl2 (3 mL), 2i was obtained as a
colorless oil; yield: 44 mg (73%); 88% ee.
(1) (a) Matteson, D. S. Chem. Rev. 1989, 89, 1535.
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GC: Chromatographic purity was determined by GC method under
the following conditions: Column: Chrompack capillary column
CP-Chirasil-Dex CB, 25 m × 0.25 mm × 0.25 μm; Injector: split
ratio 30, T = 250 °C; Carrier gas: He, constant flow rate 1.0 mL
min–1; Detector: T = 250 °C; Temperature 180 °C; Total run time:
20 min; 1i = 13.7 min, 2i = 11.6 min, 3i = 6.4 min.
The ee was established using a chiral GC under the following con-
ditions: Column: Chrompack capillary column CP-Chirasil-Dex
CB, 25 m × 0.25 mm × 0.25 μm; Injector: split ratio 30, T = 250 °C;
Carrier gas: He, constant flow rate 1.5 mL min–1; Detector: T = 250
°C; Temperature 130 °C; Total run time: 120 min; (R)-2i = 101.5
min; (S)-2i = 103.3 min.
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Organometallics 1983, 2, 1543. (c) Adams, J.; Behnke, M.;
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1H NMR (400 MHz, CDCl3): δ = 1.25 (s, 6 H), 1.26 (s, 6 H), 3.06
(dd, J = 8.0, 13.6 Hz, 1 H), 3.14 (dd, J = 8.0, 13.6 Hz, 1 H), 3.56 (t,
J = 8.0 Hz, 1 H), 3.80 (s, 3 H), 6.85 (d, J = 8.0 Hz, 2 H), 7.20 (d,
J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 24.5, 24.6, 24.8, 39.4, 43.0 (br),
55.2, 84.4, 113.7, 130.3, 130.4, 158.5.
HRMS-ESI+: m/z [M + H]+ calcd for C15H23BClO3: 297.1423;
found: 297.1414.
(S)-2-[1-Chloro-2-(4-trifluoromethyl)phenylethyl]-4,4,5,5-tet-
ramethyl-1,3,2-dioxaborolane (2j)
Following the general procedure with catalyst 5 (S/C = 10) using 1j
(66 mg, 0.20 mmol) in anhyd CH2Cl2 (3 mL), 2j was obtained as a
colorless oil; yield: 43 mg (65%); 94% ee.
GC: Chromatographic purity was determined by GC method under
the following conditions: Column: Chrompack capillary column
CP-Chirasil-Dex CB, 25 m × 0.25 mm × 0.25 μm; Injector: split
ratio 30, T = 250 °C; Carrier gas: He, constant flow rate 1.0 mL
min–1; Detector: T = 250 °C; Temperature 160 °C; Total run time:
15 min; 1j = 8.6 min and 8.8 min, 2j = 9.4 min, 3j = 5.1 min.
The ee was established using a chiral GC under the following con-
ditions: Column: Chrompack capillary column CP-Chirasil-Dex
CB, 25 m × 0.25 mm × 0.25 μm; Injector: split ratio 30, T = 250 °C;
Carrier gas: He, constant flow rate 1.5 mL min–1; Detector: T = 250
°C; Temperature 120 °C; Total run time: 60 min; 3j = 37.1 min, (R)-
2j = 48.9 min; (S)-2j = 50.1 min.
1H NMR (400 MHz, CDCl3): δ = 1.25 (s, 6 H), 1.26 (s, 6 H), 3.15
(dd, J = 8.8, 14.0 Hz, 1 H), 3.26 (dd, J = 7.2, 14.0 Hz, 1 H), 3.62 (dd,
J = 7.2, 8.8 Hz, 1 H), 7.39 (d, J = 8.0 Hz, 2 H), 7.55 (d, J = 8.0 Hz,
2 H).
13C NMR (100 MHz, CDCl3): δ = 24.5, 24.6, 39.8, (C–B not ob-
served), 84.7, 125.1, 128.3, 129.6, 142.5.
HRMS-ESI+: m/z [M + H]+ calcd for C15H20BClF3O2: 335.1190;
found: 335.1191.
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Acknowledgment
We thank A. Vesković, S. Borišek, S. Omovšek, D. Orkič, Dr. F.
Nerozzi, and Dr. D. Grainger for the technical assistance in some
experimental work; P. Skelton (Univ. of Cambridge) for HRMS
analysis, Dr. M. Črnugelj for the acquisition of some NMR spectra
and Dr. M. Kovačevič for the contribution in primary GC method
development; Prof. A. Pfaltz for valuable discussions as well as for
the initial gift of NeoPHOX catalysts and P. Drnovšek for the given
support.
Synthesis 2013, 45, 2824–2831
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Hydrogenation Approach to (α-Chloroalkyl)boronic Esters
2831
(12) (a) Gazić Smilović, I.; Casas-Arcé, E.; Roseblade, S. J.;
Nettekoven, U.; Zanotti-Gerosa, A.; Kovačevič, M.; Časar,
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(15) For the preparation and use of PHOX ligands, see:
Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336.
(16) For the preparation and application of SimplePHOX ligands,
see: Smidt, S. P.; Menges, F.; Pfaltz, A. Org. Lett. 2004, 6,
2023.
(17) For the preparation and use of PyrPHOX ligands, see: Cozzi,
P. G.; Zimmermann, N.; Hilgraf, R.; Schaffner, S.; Pfaltz, A.
Adv. Synth. Catal. 2001, 343, 450.
(18) For the preparation of phosferrox (Fc-PHOX) type ligands,
see: (a) Richards, C. J.; Mulvaney, A. W. Tetrahedron:
Asymmetry 1996, 7, 1419. (b) Ahn, K. H.; Cho, C.-W.; Baek,
H.-H.; Park, J.; Lee, S. J. Org. Chem. 1996, 61, 4937.
(19) For the synthesis and application of NeoPHOX ligands, see:
Schrems, M. G.; Pfaltz, A. Chem. Commun. 2009, 41, 6210.
(20) For the preparation and application of ferrocenyl-
phosphinoimidazoline ligands, see: Boaz, N. W.; Ponasik, J.
A. Jr. US Patent Appl. US20070244319, 2007; Chem. Abstr.
2007, 147, 448932.
(13) For the preparation of [Rh(cod)DiPFc]BF4, see: (a) Tararov,
V. I.; Kadyrov, R.; Riermeier, T. H.; Holz, J.; Borner, A.
Tetrahedron: Asymmetry 1999, 10, 4009. (b) Nedden, H. G.
PCT Pat. Appl WO2008084258, 2008; Chem. Abstr. 2008,
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(14) For the synthesis and application of phosphinite-oxazoline
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Int. Ed. 2001, 40, 4445. (b) Menges, F.; Pfaltz, A. Adv.
Synth. Catal. 2002, 344, 40.
(21) Engman, M.; Diesen, J. S.; Paptchikhine, A.; Andersson, P.
G. J. Am. Chem. Soc. 2007, 129, 4536.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2824–2831