Basic CuCO3/ligand as a new catalyst for 'on water' borylation of Michael acceptors, alkenes and alkynes: Application to the efficient asymmetric synthesis of β-alcohol type sitagliptin side chain

Article abstract of DOI:10.1002/aoc.2957

The efficient 'on water' β-borylation using bis(pinacolato)diboron agent was achieved with a newly developed catalytic system based on basic copper carbonate and various ligands. The catalytic system was used for β-borylation of various Michael acceptors,

Full text of DOI:10.1002/aoc.2957

Full Paper
Received: 18 October 2012
Revised: 21 November 2012
Accepted: 2 December 2012
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.2957
Basic CuCO3/ligand as a new catalyst for ’on
water’ borylation of Michael acceptors, alkenes
and alkynes: application to the efficient
asymmetric synthesis of b-alcohol type
sitagliptin side chain
a
a,b,c
ꢀ
Gaj Stavber and Zdenko Casar
*
The efficient ’on water’ b-borylation using bis(pinacolato)diboron agent was achieved with a newly developed catalytic system
based on basic copper carbonate and various ligands. The catalytic system was used for b-borylation of various Michael acceptors,
alkenes and alkynes. The presented methodology was successfully applied to the novel synthesis of b-alcohol type sitagliptin side
chain precursor via water-based highly enantioselective b-borylation followed by an oxidation process. Copyright © 2013 John
Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: water; copper catalysis; boron; asymmetric synthesis; drugs
purpose we envisioned that basic copper carbonate [Cu2(OH)
Introduction
2CO3][13] could be used as an appropriate transition metal precur-
Introduction of a boron moiety into organic molecules constitu-
tes a central research interest in the field of modern organoboron
chemistry.[1] This is due to the immense synthetic versatility[2]
and unique biological activity[3] of organoboron compounds.
Besides hydroboration with R02BH,[4] diboron reactions[5] based
on bis(pinacolato)diboron (B2pin2) or bis(catecholato)diboron
(B2cat2) as boron source gained strong impetus in the last decade
as an attractive method for the introduction of boron into
organic frameworks via unsaturated precursors (Scheme 1). This
is due to the discovery of a catalytic version of the reaction
catalyzed by transition metal salts in the presence of additional
base additives and ligands, which also enables asymmetric
b-borylation.[6] Recent advances in the preparation process of
B2pin2 rendered this boron precursor easily and effectively
accessible, which should further extend its use as a prime boryla-
tion reagent.[7]
sor incorporating metal species as well as basic functionality.
Moreover, the recent discovery of some ’on water’ accelerated
reactions, which can be simply carried out by vigorous stirring
of the neat reactants in an aqueous suspension,[14] stimulated
us to investigate the proposed catalytic system in pure water†
in order to make the overall method more sustainable. It is worth
mentioning that in many cases the incompatibility of organic
substrates, intermediates and catalysts with water, which is a
result of hydrophobic interactions, represents a potential obstacle
to efficiently perform organic reactions in aqueous medium.[15] This
finally leads us to take up the challenge of discovery and develop-
ment of the water-compatible catalytic system based on basic cop-
per carbonate/ligand for efficient and (stereo)selective b-borylation
of a wide range of organic compounds.[16]
Therefore, there is a wide interest in further developing B2pin2-
based b-borylation methodology. Although Michael acceptors
have been widely studied as model compounds in catalytic
b-borylation reactions[8–10] and very recently the b-borylation of
alkynes was achieved,[11] catalytic systems with a broad substrate
acceptance are still scarce. Moreover, catalytic b-borylation is still
conducted in organic solvents such as CH2Cl2, THF and toluene in
the presence of a proton donor such as methanol.[12] Further-
more, the copper-catalyzed reactions are very often conducted
in the presence of additional base additives such as alkali metal
alkoxides (e.g. NaOtBu). Based on these facts we presumed that
existing catalytic systems based on copper species could be
simplified and become more economical by removing the alkali
metal alkoxide base additives from the catalytic system. For this
ꢀ
*
Correspondence to: Zdenko Casar, Sandoz GmbH, Global Portfolio Manage-
ment API, Biochemiestrasse 10, 6250 Kundl, Austria. E-mail: zdenko.casar@
sandoz.com
a Lek Pharmaceuticals d.d., Sandoz Development Center Slovenia, API Development,
Organic Synthesis Department1234 Menges, Slovenia
ꢀ
b Sandoz GmbH, Global Portfolio Management API, 6250Kundl, Austria
c
Faculty of Pharmacy, University of Ljubljana, 1000Ljubljana, Slovenia
†
During the preparation of this manuscript and corresponding patent appli-
cation (see reference 16) an amine base promoted b-borylation of Michael
acceptors in water was reported by Santos et al. (see reference 10) For a
detailed explanation of conceptual differences between this and Santos’s
reports see supporting information (S27).
Appl. Organometal. Chem. 2013, 27, 159–165
Copyright © 2013 John Wiley & Sons, Ltd.

ꢀ
G. Stavber and Z. Casar
B2pin2 or B2cat2
M salt /L/ base
solvent, MeOH
R'2BH
M salt /L/ base
solvent
be obtained by the reaction outcome in the absence of the
ligand. Encouragingly, when only basic CuCO3 was used, 30%
conversion to 2 was attained (entry 3). When a transition
metal free b-borylation was attempted in aqueous medium by
employing only B2pin2 and PPh3, no reaction took place
(entry 4). To our delight, combining both the basic CuCO3 and
PPh3 in aqueous solution of amphiphile resulted in a full conver-
sion of 1 to 2 at 60 ꢀC (entry 5). Lowering the temperature to
25 ꢀC at the same catalyst load did not affect the reaction out-
come and a complete conversion of 1 to 2 was obtained (entry
6). Lowering the catalyst load still provided a full conversion in a
TPGS micelle-based aqueous system (entries 7–8). This stimu-
lated us to test the efficiency and compatibility of the catalytic
system also with the pure aqueous medium, in which the
problematic hydrophobic character of a substrate and reagent
is even more expressed. We were delighted to find that full
conversion to 2 using B2pin2 (1.1 equiv.) in the presence of basic
CuCO3 (3.0 mol%) and PPh3 (3.5 mol%) was surprisingly estab-
lished (entry 9). By applying even lower catalyst load, 2 was
isolated in 92% yield (entry 10).
By identifying basic CuCO3 in combination with PPh3 as an
efficient catalytic system for ’on water’ b-borylation, we contin-
ued with exploration of its potential with other ligands (Scheme 2
and Table 2). Interestingly, P^P ligands like DPE-phos, Dppbz,
Dtpf and Dppf proved to be compatible with the established
method ’on water’ and afforded a full conversion of 1 to 2
(entries 2–6) as PPh3 (entry 1). Of note, Dppbz ligand provided
a full conversion to 2 in only 2 mol% load and in significantly
shorter time (entry 4). On the other hand, diamino-type ligand
tetramethylethylenediamine (TMEDA) performed poorly and
provided low 40% conversion to 2 (entry 7). Finally, to emphasize
the environmentally friendlier aspect of our water-based meth-
odology, application of naturally occurring sugar type ligands
were undertaken (entries 8–9). Interestingly, while D-glucose gave
65% conversion to 2 in 7 h, D-glucosamine ligand afforded a full
conversion to 2 after 20 h.
Having outlined the optimal reaction conditions and the
optimal ligand profile, we were intrigued to explore whether
the applied catalytic system actually reaches its full potential in
pure aqueous medium. For this purpose the efficiency of the
catalytic system for 1 to 2 was carefully tested in series of other
solvents such as acetonitrile, methanol, tetrahydrofuran, aqueous
tetrahydrofuran, methyl tert-butyl ether, toluene and chloroform.
All these solvents performed with significantly lower efficiency
compared to the pure aqueous system, demonstrating the
uniqueness of the selected catalytic system and the proof of
concept for water-accelerated reaction based on basic copper
carbonate. Moreover, the ’on water’ acceleration effect was
demonstrated and proved also with the influence of speed of
stirring on the outcome of the reaction.† It is well known that a
stirring effect plays an important role by ’on water’ accelerated
reactions.[14c–e,15f]
R
R
R
hydroboration
see ref. 4
diboron additions
see ref. 5, 8, 12
BR'2
M = Ni, Fe, Cu, Ir, Ru, Rh, Pt; L = PR3, NHCs, diamines
R = EWG, EDG, Ar; R' = cat, pin
base = LiO Bu, NaO Bu, KO Bu; solvent = CH2Cl2, PhMe, THF
t
t
t
Scheme 1. Main methodologies for introduction of a boron moiety into
unsaturated precursors.
Results and Discussion
We started our investigation by screening reaction conditions on
(E)-ethyl crotonate 1 as a model substrate (Scheme 2 and Table 1).
First we tested the compatibility of some newly established cata-
lytic b-borylation methods with water, using an aqueous solution
of a-tocopheryl polyethylene glycol succinate (TPGS) amphiphile.
The recently described method of Bonet et al.[9f] provided a low
12% conversion to 2 (entry 1) also at an elevated temperature
of 60 ꢀC. Furthermore, the method of Mun et al.[12] resulted in
incomplete conversion of 1 to 2 (entry 2). Next, we were eager
to perform control experiments using the proposed catalytic
system based on basic CuCO3. The important information would
B2pin2
copper catalyst
phosphine ligand
O
Bpin O
Me
OEt
Me
OEt
aqueous medium
16 h, 800-900 rpm
1
2
Scheme 2. b-Borylation of (E)-ethyl crotonate 1 in aqueous medium.
Table 1. b-Borylation of (E)-ethyl crotonate 1 in aqueous mediuma
Entry
Catalyst
Ligand
T
Method Conv.
(%)
(load) (mol%)
(load) (mol%) (ꢀC)
1b
2c
3
Cs2CO3 (15)
Ph3P(20)
Ph3P(20)
—
60
60
60
60
60
25
25
25
25
30
A
A
A
A
A
A
A
A
B
B
12
63
30
CuCl/NaOtBu (15)
Basic CuCO3 (7.5)
—
d
4
Ph3P(10)
Ph3P(20)
Ph3P(20)
Ph3P(10)
Ph3P(5)
Ph3P(3.5)
Ph3P(2.5)
—
5
Basic CuCO3 (15)
Basic CuCO3 (15)
Basic CuCO3 (7.5)
Basic CuCO3 (4)
Basic CuCO3 (3)
Basic CuCO3 (2)
100
100
100
100
100
100e
6
7
8
9
10
aGeneral reaction conditions: 1 (1.00 mmol), B2pin2 (1.10 mmol),
basic CuCO3 (0.02–0.15 mmol), PPh3 (0.025–0.2 mmol), H2O (2.5 ml),
25–60 ꢀC, 16 h, 800–900 rpm. Method A: reaction was performed in
2 wt% aqueous solution of TPGS amphiphile (micelle-based
system). Method B: reaction was performed on pure H2O.
With established efficient reaction conditions for ’on water’
b-borylation of the model compound 1 we next investigated
the scope of the reaction by its application to a variety of struc-
turally diverse Michael acceptors (Scheme 3). Although several
ligands could be applied for this purpose, as demonstrated in
bAccording to method of Bonet et al.[9f]
cAccording to method of Mun et al.[12]
dNo reaction.
e92% isolated yield after column chromatography (see supporting
†For the effect of stirring speed on the efficiency of the ’on water’ accelerated
b-borylation see supporting information (S13).
information for further details and explanation).
wileyonlinelibrary.com/journal/aoc
Copyright © 2013 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2013, 27, 159–165

’On water’ borylation with basic copper carbonate/ligand catalyst
Table 2. Screening of various ligands for b-borylation of 1 to 2a
Table 2, we decided to utilize PPh3 since it represents a cost-
beneficial ligand alternative, which plays a significant factor in
industrial processes. To our delight the catalytic method proved
to be quite general with respect to the variation of structure of
R and EWG functionalities, providing good functional group toler-
ance and a diverse array of products. In most cases conversions
of over 90% were achieved under mild conditions: 27–60 ꢀC in
10–24 h. Indeed, cinnamic esters 3a and 3b gave 90–100%
conversion and 80–91% isolated yield of desired pinacol esters
4a and 4b. It is worth mentioning that in the case of 3b the reac-
tion was fully regioselective, giving rise only to the Michael b-
borylated product, while the vinyl alcohol moiety remained
unaffected. Similarly, variation of R substituent from aryl to alkyl
did not affect the efficacy of the catalyst, and 2-octenoic acid
methyl ester 3c gave 100% conversion and 76% isolated yield
of 4c. Further modification of substrate structure by the change
of R to H did not result in aggravation of the reaction outcome.
Acrylic acid derivatives 3d–g gave 90–100% conversions and
80–94% isolated yield of b-borylated products 4d–g. Interest-
ingly, methacrylic acid vinyl ester 3e reacted regioselectively,
giving only Michael addition product, while vinyl moiety remained
fully intact. Furthermore, this set of substrates revealed that the
method is not limited to acyclic substrates; moreover cyclic Michael
acceptors like 2-methylene-g-butyrolactone 3 h were prone to
undergo b-borylation and the corresponding pinacol ester 4 h
was isolated in excellent yield. Limitation of the method came to
light when formyl group was installed on the EWG position. Disap-
pointingly, when cinnamaldehyde 3i was reacted under similar
reaction conditions to other substrates, 30% conversion was
obtained with some impurities present, which did not allow us to
isolate a desired pure product. This is in contrast to results obtained
with the ester analogues 3a–b. Further variation of EWG led us to
explore the keto derivatives 3j–m. In sharp contrast to aldehyde
3i, the keto analogue methyl styryl ketone 3j enabled 95% conver-
sion and gave 86% isolated yield of 4j. An amazing result was
obtained also with a highly hydrophobic substrate 3 k. Further-
more, cyclic ketones like 2-cyclohexenone 3 l–m enabled full
conversion and excellent 92% isolated yields. Another interesting
modification of Michael substrates includes application of sulfone
functionality on the EWG position. Reactions of phenyl styryl sul-
fone 3n and phenyl vinyl sulfone 3o also gave excellent 90–100%
conversion and 71–86% isolated yields of products 4n–o. Finally,
reaction with b-phenylacrylonitrile 3p at 50 ꢀC provided 95% con-
version and the desired product 4p was isolated in 82% yield. A
preparative gram-scale model experiment featuring ’green’
isolation protocol after completion of the reaction by utilizing only
simple phase separation without using any organic solvents
provided pure 4p in 64% isolated yield (see supporting information
S16–S17).
Entrya
Ligand
t (h)
Conversion (%)b
1
2
3
4
5
6
7
8
9
Ph3P
7
7
100
100
100
100
100
100
40
DPE-phos
Dppbz
7
Dppbz (2 mol%)
Dtpf
3
7
Dppf
7
TMEDA
7
D-Glucose
D-Glucosamine
7
65
20
100
aStandard conditions: 1.1 equiv. B2pin2, 3 mol% basic CuCO3 and
3.5 mol% ligand unless otherwise stated, pure water (2.5 ml),
27–30 ꢀC, 800–900 rpm.
bConversion was determined from 1H NMR spectra of crude reaction
mixture.
Bpin
B2pin2, basic CuCO3/PPh3
EWG
EWG
R
R
H2O
T, t
3a-p
4a-p
O
O
O
Ph
O
Ph
OMe
OMe
4
3a: 30 °C, 20h,
90% conv.,
80% yield 4a
3b: 30 °C, 24h,
100% conv.,
91% yield 4b
3c: 30 °C, 24h,
100% conv.,
76% yield 4c
O
O
O
CF3
CF3
OMe
O
O
Me
3f: 27 °C, 24h,
90% conv.,
82% yield 4f
3e: 30 °C, 20h,
100% conv.,
94% yield 4e
3d: 27 °C, 10h,
100% conv.,
92% yield 4d
O
O
O
O
Ph
H
N(Me)2
3i: 27 °C, 24h,
30% conv.,
not isolated
3g: 27 °C, 20h,
90% conv.,
80% yield 4g
3h: 30 °C, 20h,
100% conv.,
93% yield 4h
O
O
Ph
O
Ph
Me
R = H, 3l
R = Me, 3m
R
Ph
3j: 27 °C, 24h,
95% conv.,
3k: 30 °C, 48h,
97% conv.,
3l-m: 27-30 °C, 10h,
100% conv.,
86% yield 4j
85% yield 4k
92% yield 4l-m
Ph
O
O
Ph
Encouraged by these results we wanted to further establish the
utility of the present catalytic system for ’on water’ b-borylation
and to explore its potential on model styrenes with different elec-
tronic properties (Scheme 4). Reaction with styrene 5a provided
full conversion and 92% isolated yield of 6a. The reaction is
marginally affected by the substituents on the aromatic rings.
Both electron-donating groups (e.g. 4-methoxystyrene 5b) and
electron-withdrawing groups (e.g. 4-trifluoromethylstyrene 5c)
on the phenyl ring performed well in this reaction, providing
95–100% conversion and 88–90% isolated yield of 6b–c.
When a-methylstyrene and b-methylstyrene were submitted to
b-borylation under similar reaction conditions as used in 5a–c,
no reaction took place.
S
Ph
S
O
Ph
CN
O
3p: 50 °C, 20h,
95% conv.,
82% yield 4p
3n: 60 °C, 20h,
90% conv.,
71% yield 4n
3o: 30 °C, 20h,
100% conv.,
86% yield 4o
Scheme 3. ’On water’ b-borylation of Michael acceptors (see supporting
information for further details and explanation). General reaction condi-
tions: 3 (1.00 mmol), B2pin2 (1.10 mmol), PPh3 (0.035–0.05 mmol), basic
CuCO3 (0.03–0.04 mmol), H2O (2.5 ml), 27–60 ꢀC, 800–900 rpm. Examples
3a, 3c–j, 3 l–m carried with 3 mol% of basic CuCO3 and 3.5 mol% PPh3.
Example 3n carried with 3.5 mol% of basic CuCO3 and 4 mol% PPh3.
Examples 3b, 3 k, 3o–p carried with 4 mol% of basic CuCO3 and 5 mol%
PPh3. Isolated yield after column chromatography.
Appl. Organometal. Chem. 2013, 27, 159–165
Copyright © 2013 John Wiley & Sons, Ltd.
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ꢀ
G. Stavber and Z. Casar
B2pin2
basic CuCO3/Ligand
(R,R)-DIOP ligand L1 afforded 80% conversion to 10 and promis-
ing enantiomeric excess (ee) of 22% (entry 1). Similar perfor-
mance was observed with (S,S)-Me-DUPHOS ligand L2 (entry 2).
(R)-P-Phos ligand L3 provided full conversion, while enantioselec-
tivity remained at the modest level of 35% ee (entry 3).
DuanPhos ligand L4 and (R,R)-Et-Ferrocelane ligand L5 performed
similarly in terms of enantioselectivity (40–41% ee) and provided
75–93% conversion (entries 4–5). N^N type ligand L6 afforded
the first efficient and optimistic result, with a full conversion
and good enantioselectivity of 62% ee (entry 6). Comparable per-
formance was also observed with (R)-BINAP ligand L7 and POX
ligand L8 (entries 7–8). High asymmetric induction but not quan-
titative conversion was obtained with Josiphos type ligand L9
(entry 9). Finally, we were delighted to find that Walphos type
ligand L10 in combination with basic CuCO3 afforded full conver-
sion and excellent enantioselectivity (95% ee) ’on water’ (entry
10). Subsequently, the optically active pinacol ester 10, which
was also isolated without the use of any organic solvents
(see supporting information S17-S18), was converted using a
newly developed environmentally benign oxidation method
based on NaOCl in AcOEt (see supporting information S15–S16)
to an b-alcohol type sitagliptin side chain 11, which can be easily
transformed to sitagliptin according to the known literature
procedures.[18]
Ar
Ar
H2O
T, t
pinB
5a-c
6a-c
Ph
C6H4-4-OMe
C6H4-4-CF3
5a:
5b:
ligand dppbz,
27 °C, 20h,
100% conv.,
92% yield 6a
ligand dppbz, 5c:
27 °C, 20h,
ligand PPh3,
60 °C, 20h,
100% conv.,
88% yield 6c
95% conv.,
90% yield 6b
Scheme 4. ’On water’ b-borylation of model alkenes (see supporting infor-
mation for further details and explanation). General reaction conditions: 5
(1.00mmol), B2pin2 (1.10 mmol), basic CuCO3 (0.05mmol), phosphine
(0.035mmol for dppbz and 0.065 mmol for PPh3), H2O (2.5ml),
800–900 rpm. Isolated yield after column chromatography.
Furthermore, we were interested in testing the ability of the
developed catalytic system on model phenyl-substituted alkynes
(Scheme 5), which have recently been successfully borylated
exclusively in organic solvents using well-known catalytic meth-
odologies.[11] We were pleased to observe that the full conver-
sion of 1-phenylethyne 7a was obtained ’on water’ under mild
conditions, which enabled isolation of 8a in high 92% isolated
yield. Changing the R to methyl and phenyl did not affect the
reaction significantly and methylphenylethyne 7b and dipheny-
lethyne 7c provided 93–100% conversion, giving 8b in 88% and
8c in 65% isolated yield respectively. Aromatic ring substitution
also a showed marginal difference in reactivity and p-methoxy-
phenylethyne 7d reached 95% conversion and afforded 8d in
85% isolated yield. It is worth mentioning that in all studied cases
the overall syn addition of (pinacolato)boron moiety and H across
the double bond was established and confirmed with NMR
NOESY experiments (see supporting information S25–S26).
Finally, we were intrigued to determine if an asymmetric
version of ’on water’ b-borylation methodology could be de-
veloped. It is worth mentioning that asymmetric induction in
aqueous medium is problematic due to sensitivity, solubility
and incompatibility of chiral metal catalysts and ligands with
water.[15f] Nevertheless, we decided to explore the possibility
of asymmetric ’on water’ b-borylation of olefinic precursor
9[17] to pinacol ester 10 and its subsequent oxidation to the
target alcohol 11,[18] which is a known key intermediate in
the synthesis of the antidiabetic drug sitagliptin.[19] Therefore,
basic CuCO3 as catalyst in combination with chiral P^P, N^N
and P^N ligands was investigated (Scheme 6, Fig. 1 and
Table 3). It was pleasing to find that application of
Conclusions
We have demonstrated that basic CuCO3 in combination with
appropriate ligands provides a simple and efficient catalytic sys-
tem for ’on water’ b-borylation.[20]{ We believe that our
discovery will open new perspectives towards environmentally
friendlier b-borylation methodologies. The discovered catalytic
system enables b-borylation of broad range of substrates
including Michael acceptors, alkenes and alkynes under mild
reaction conditions in high yields. Finally, we also successfully
established for the first time that a basic CuCO3/chiral ligand
catalytic system can be efficiently applied to asymmetric b-bory-
lation in aqueous medium, which has been demonstrated on a
model target system. This opens a very useful industrial synthetic
method to optical active precursors for target bioactive agents.
Indeed, b-borylation of the important alkene precursor of sita-
gliptin synthesis gave the corresponding boronic ester and its
further oxidative transformation afforded well-known alcohol
derivative of sitagliptin side chain in high yields and excellent
enantioselectivity.
B2pin2,
basic CuCO3/PPh3
pin
B
Experimental
R
Ar
H2O
T, t
R
Ar
General Remarks
7a-d
Ph
8a-d
Unless otherwise noted, all reactions were performed in dry,
two-necked, round-bottom flasks under a nitrogen atmosphere.
Reactions were conducted in deionized water. Starting materials
(Michael acceptors, alkenes and alkynes) were commercially
available and used as received. Bis(pinacolato)diboron (B2pin2)
and copper(II) carbonate basic (purity > 95%) were used as
purchased. N,O-containing ligand D-glucosamine hydrochloride
Me
Ph Ph
Ph
Ph-4-OMe
7a:27 °C, 20h,
100% conv.,
82% yield 8a
27 °C, 20h,
93% conv.,
88% yield 8b
27 °C, 24h, 7d: 27 °C, 24h,
7b:
7c:
100% conv.,
65% yield 8c
95% conv.,
85% yield 8d
Scheme 5. ’On water’ b-borylation of model alkynes (see supporting
information for further details and explanation). General reaction
conditions: 7 (1.00 mmol), B2pin2 (1.10 mmol), basic CuCO3 (0.05 mmol
for 7a–b,d and 0.075 mmol for 7c), PPh3 (0.065 mmol for 7a–b,d and
0.01 mmol for 7c), H2O (2.5 ml), 800–900 rpm. Isolated yield after column
chromatography.
{For additional information related to the efficiency of [Cu2(OH)2CO3] vs. Cu
(OH)2 and other catalytic systems see supporting information (S28).
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Appl. Organometal. Chem. 2013, 27, 159–165

’On water’ borylation with basic copper carbonate/ligand catalyst
CF3
N
F
F
N
F
F
F
B2pin2
basic CuCO3/chiral L
N
*
N
ref. 18a
CO2Me
CO2Me
NH2
O
R
"on water", 900 rpm
r.t., 20 h, 84% yield,
up to 95% ee
F
F
F
F
9
10 R = Bpin
11 R = OH
sitagliptin
NaOCl aq.,
EtOAc, 25 °C, 5 h,
94% yield
Scheme 6. Application of asymmetric ’on water’ b-borylation of olefin 9 to pinacol ester 10 and its subsequent oxidation to b-alcohol 11 precursor
of sitagliptin.
OMe
Table 3. Screening of various chiral ligands for borylation of 9 to 10
N
N
Entrya
Ligand
Conversion (%)b
ee (%)c
P(Ph)2
P(Ph)2
P
P
O
O
Me
Me
MeO
MeO
P(Ph)2
P(Ph)2
1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
80
70
22
25
35
40
41
62
70
77
86
95
2
3
100
75
4
OMe
L3
L1
L2
5
93
6
100
100
92
NHMe
7
H
H
Ph
P
Ph
8
Fe
L5
P
MeHN
P
P
9
90
tBu
tBu
10
100
L4
aStandard conditions: 1.1 equiv. B2pin2, 4 mol% basic CuCO3 and
5 mol% ligand.
bConversion was determined from H NMR spectra of crude reaction
L6
1
N
(Ph)2P
P(Ph)2
P(Ph)2
mixture.
Fe
L8
tBu
O
cEnantiomeric excess was measured by chiral HPLC analysis (see
supporting information for further details).
L7
F3C
atmosphere. Afterwards, 2.5 ml deionized water was added and
the reaction mixture was vigorously (800–900 rpm) stirred at am-
bient temperature for 15 min. The b-borylating reagent bis(pina-
colato)diboron (B2pin2; 1.1 equiv. according to starting material)
was added in one portion and the reaction mixture was stirred
at ambient temperature for another 30 min. Starting material
(1.0 mmol) was added to the reaction system and the reaction
mixture was intensively stirred at 27–60 ꢀC for 3–48 h (see
Schemes 2–6). The reaction mixture was diluted with brine
(5 ml) and extracted with EtOAc (2 ꢁ 35 ml). Combined organic
layers were again washed with brine (30 ml) and dried over
Na2SO4, and organic solvent was removed under reduced pres-
sure. The crude product was purified by column chromatography
using a Biotage SP4 flash purification system (SiO2; n-hexane:
EtOAc = 9:1) to obtain pure b-borylated product, which was
characterized by 1H, 11B and 13C NMR analysis.
CF3
P(Ph)2
P(tBu)2
Me
Fe
P
(Ph)2P
CF3
Fe
H
Me
CF3
L10
L9
Figure 1. Various chiral ligands screened for asymmetric b-borylation of
9 to 10.
(98% purity) and other phosphine type ligands including chiral
ones were used as purchased. NMR spectra were recorded on a
Bruker Avance III spectrometer: 500 MHz for 1H NMR; 160 MHz
for 11B NMR; 125 MHz for 13C NMR and 470 MHz for 19 F NMR.
Chemical shifts are reported in d ppm referenced to tetramethyl-
silane as an internal standard. High-resolution mass spectra
were acquired on an Agilent 6224 accurate mass TOF LC/MS
mass spectrometer. IR spectra were recorded on a Nicolet FTIR
Nexus spectrometer.
Representative Spectral and Analytical Data for some New
Borylated Compounds (see supporting information for
further details and explanation)
General Experimental Procedure for ’On Water’ b-Borylation
of Michael Acceptors, Alkenes and Alkynes (see supporting
information for further details and explanation)
Vinyl-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propanoate (4e)
Liquid; 11B (160 MHz, CDCl3, ppm) d = 33.3 (br); 1H NMR (500 MHz,
CDCl3, ppm)
d 7.26 (dd, J = 14.0 Hz, J = 6.3 Hz, 1Hc), 4.85
In a dry, two-necked, round-bottom flask were placed catalyst
CuCO3 basic (2–7.5 mol% according to starting material; see
Schemes 2–6) and ligand (2.5–10 mol%) under a nitrogen
(dd, J = 14.0 Hz, J = 1.5 Hz, 1Ha), 4.52 (dd, J = 6.3 Hz, J = 1.5 Hz,
1Hb), 2.68–2.79 (m, 1H), 1.24 (d, 3H), 1.21 (s, 6H), 1.18 (s, 6H),
1.15 (dd, J = 16.0 Hz, J = 7.4 Hz, 1H), 0.97 (dd, J = 16.0 Hz,
Appl. Organometal. Chem. 2013, 27, 159–165
Copyright © 2013 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

ꢀ
G. Stavber and Z. Casar
J = 7.5 Hz, 1H); 13C (125 MHz, CDCl3, ppm) d 174.3, 141.5, 97.2,
83.2, 35.14, 24.8, 24.7, 19.0, 15.9 (broad, C-B); IR (neat): n = 2979,
2935, 1753, 1646, 1372, 1322, 1143 cmꢂ1. Anal. Calcd for
C12H21BO4: C, 60.03; H, 8.82%. Found: C, 60.25; H, 9.03%.
Supporting information
Supporting information may be found in the online version of
this article, including characterization data of known and copies
of spectra for all new borylated compounds, specific procedures
and experimental protocols for gram-scale experiments empha-
sizing ’green’ isolation procedures. A study for development of
a new oxidation method and conceptual experiments showing
’on water’ accelerated borylation are also included.
4,4,5,5-Tetramethyl-2-(4-trifluoromethyl)phenethyl)-1,3,2-dioxoborolane (6c)
1
11B (160 MHz, CDCl3, ppm) d 33.7 (br); H NMR (500 MHz, CDCl3,
ppm) d 7.66–7.55 (m, 2H), 7.46–7.35 (m, 2H), 2.84 (t, J = 8.1 Hz,
2H), 1.26 (s, 12H), 1.16 (t, J = 8.1 Hz, 2H); 19 F (470 MHz, CDCl3,
ppm) d ꢂ63.2; 13C (125 MHz, CDCl3, ppm) d 148.5, 128.3, 128.2,
125.1, 125.0, 83.2, 29.8, 24.8, 12.5 (broad, C-B); IR (neat):
n = 2982, 2938, 1326, 1162, 1143, 1115 cm-1. Anal. Calcd for
C15H20BF3O2: C, 60.03; H 6.72%. Found: C, 59.92; H, 6.62%.
Acknowledgments
ꢀ
We thank A. Vesković for help with experimental work, S. Borisek
(E)-2-(4-Methoxystryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8d)
ꢀ
ꢀ
ꢀ
and Dr M. Crnugelj for NMR spectra, D. Orkic and M. Ustar for GC
1
ꢀ
Liquid; 11B (160 MHz, CDCl3, ppm) d 30.2 (br); H NMR (500 MHz,
and HPLC analysis, M. Borisek for IR spectra, Dr S. J. Roseblade
(Johnson Matthey) for chiral HPLC method development, Dr
D. Urankar and Prof. J. Kosmrlj (University of Ljubljana) for
CDCl3, ppm) d 7.45 (m, 2H), 7.36 (d, J = 18.4 Hz, 1H), 6.87
(m, 2H), 6.05 (d, J = 18.4 Hz, 1H), 3.82 (s, 3H), 1.30 (s, 12H); 13C
(125 MHz, CDCl3, ppm) d 160.3, 149.0, 130.4, 128.9, 128.4, 113.9,
113.6, 83.1, 55.2, 24.7; IR (neat): n = 2977, 2934, 1625, 1605,
1511, 1421, 1356, 1143, 1035, 996, 970, 815 cmꢂ1. Anal Calcd for
C15H21BO3: C, 69.26; H, 8.14%. Found: C, 69.41; H, 8.02%.
ꢀ
HRMS analysis.
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Protocol for ’On Water’ Asymmetric b-Borylation of Sitagliptin Intermediate
(9) to Corresponding b-Boronic Ester (10) (see supporting information for
further details and explanation)
In a dry, two-necked, round-bottom flask were placed catalyst
CuCO3 basic (0.02 mmol, 4 mol% according to starting material 9)
and Walphos ligand (0.025 mmol, 5 mol%; see Table 3 and
Scheme 6) under a nitrogen atmosphere. Afterwards, 2.5ml
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system and stirred for an hour. Finally, a,b-unsaturated ester (E)-
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mixture was diluted with brine (5ml) and extracted with EtOAc
(2 ꢁ 40 ml). Combined organic layers were again washed with brine
(30 ml) and dried over Na2SO4, and organic solvent was removed
under reduced pressure. The crude product was simply purified
by flash chromatography (silica; EtOAc) to obtain the final product
1
(10; 150 mg; 84% yield) as determined by H, 11B, 13C NMR and
high-resolution mass spectrometry (HRMS) analysis. Enantiomeric
purity (95% ee) was determined using high-performance liquid
chromatography (HPLC) chiral analysis.
Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(2,4,5-trifluorophenyl)-
butanoate (10)
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