Copper-catalyzed tandem asymmetric borylation of β-chloroalkyl aryl ketones and related compounds

Article abstract of DOI:10.1002/cctc.201402823

The Cu-catalyzed, one-pot tandem (asymmetric) borylation of β-chloroalkyl aryl ketones via the in situ generated acyclic enones with bis(pinacolato)diboron was achieved efficiently to reach up to 97% yield and 99% enantioselectivity for the formal sp³ C-Cl borylation products. The present methodology provides an efficient alternative route to (chiral) alkylboron compounds. In situ generation works better! Copper-catalyzed (asymmetric) borylation of β-chloroalkyl aryl ketones via in situ generated enones has been realized with bis(pinacolato)diboron (B₂pin₂) to achieve up to 97% yield and 99% enantioselectivity. β-Chloroalkyl aryl ketones are a class of effective precursors to acyclic enones, and the present methodology provides an efficient alternative route to (chiral) organoboron compounds.

Full text of DOI:10.1002/cctc.201402823

DOI: 10.1002/cctc.201402823
Full Papers
Copper-Catalyzed Tandem Asymmetric Borylation of
b-Chloroalkyl Aryl Ketones and Related Compounds
Quanbin Jiang,[a] Tenglong Guo,[a] and Zhengkun Yu*[a, b]
The Cu-catalyzed, one-pot tandem (asymmetric) borylation of
b-chloroalkyl aryl ketones via the in situ generated acyclic
enones with bis(pinacolato)diboron was achieved efficiently to
reach up to 97% yield and 99% enantioselectivity for the
formal sp3 CÀCl borylation products. The present methodology
provides an efficient alternative route to (chiral) alkylboron
compounds.
Introduction
Organoboron compounds are among the most important re-
agents in organic synthesis,[1] and some of them can exhibit
biological activity.[2] Chiral organoboron derivatives have been
documented for the construction of CÀO, CÀN, and CÀC
bonds with the retention of the original enantioselectivity.[3]
The transition-metal-catalyzed conjugate addition of diboron
reagents to a,b-unsaturated compounds has been applied as
an efficient protocol to access organoboron compounds,[4,5]
and organocatalysts[6] are also known for the same purpose. In
this respect, Cu catalysts have been among the most effec-
tive.[7] As a result of the pioneering work of Lee and Yun on
the Cu-catalyzed enantioselective borylation of a,b-unsaturat-
ed esters and nitriles,[8] the asymmetric borylation of a,b-unsat-
urated compounds has been investigated recently.[7d,9] Howev-
er, the borylation of simple acyclic a,b-unsaturated compounds
has not been paid much attention[5b,9h] because they can easily
self-dimerize/polymerize or undergo unexpected side reactions
because of their susceptibility to heat and light during reaction
and storage.[10] Under elaborate conditions, enones such as aryl
vinyl ketones have been utilized as starting materials in organ-
ic synthesis.[11] Although the oxidation of a-vinyl benzyl alco-
hols and the Wittig reaction can be used to synthesize these
enones, time-consuming and inefficient procedures have to be
employed in the preparation.[12] Recently, the in situ generation
of enones has been considered as a solution to overcome the
drawbacks of the direct use of enones as the reactants.[13]
Very recently, we found that b-chloroalkyl aryl ketones could
be used as the enone precursors for both Rh-catalyzed 1,4-
conjugate addition with arylboronic acids[14] and Pd-mediated
annulation with indoles to form carbazoles.[15] Thus, we envi-
sioned that b-chloroalkyl aryl ketones might be applied for
(chiral) CÀB bond formation through 1,4-conjugate addition.
Herein, we report a one-pot, Cu-catalyzed tandem (asymmet-
ric) borylation of b-chloroalkyl aryl ketones with bis(pinacol-
ato)diboron (B2pin2; Scheme 1).
Scheme 1. One-pot borylation of b-chloroalkyl aryl ketones via in situ gener-
ated enones.
Results and Discussion
Initially, the reaction of 3-chloropropiophenone (1a) with
B2pin2 (2) was performed in THF at 608C in the presence of
methanol with 5.0 mol% CuI and K3PO4 (1.5 equiv.) as the cata-
lyst system. The target product 3a was formed in 20% yield
along with 4 generated in 16% yield (Table 1, entry 1). If the
solvent was changed to 1,4-dioxane, the yield of 3a increased
dramatically to 61% (Table 1, entry 2). All the simple alcohols,
that is, MeOH, EtOH, and iPrOH, as the sole solvents promoted
the borylation reaction to give both 3a (38–65%) and 4 (30–
56%; Table 1, entries 3–5). To our delight, bulkier t-amyl alcohol
(t-AmOH) as the solvent improved the selectivity remarkably to
afford 3a in 95% isolated yield with 4 (2%) as the minor prod-
uct (Table 1, entries 6 and 7). Both CuCl and CuBr are efficient
catalysts, although they exhibited a slightly lower efficiency
than CuI (Table 1, entries 8 and 9). If the CuI loading and the
reaction temperature were lowered to 2.5 mol% and 508C, re-
spectively, a slightly reduced yield of 3a was obtained (Table 1,
entries 10 and 11). If the temperature was elevated to 808C,
the reaction was not affected (Table 1, entries 7 and 12). The
optimized conditions were thus obtained as shown for entry 7
in Table 1. Such a process features a rare domino borylation of
[a] Q. B. Jiang, T. L. Guo, Prof. Dr. Z. K. Yu
Dalian Institute of Chemical Physics
Chinese Academic of Science
457 Zhongshan Road, Dalian, Liaoning 116023 (P.R. China)
Fax: (+86)411-8437-9227
E-mail: zkyu@dicp.ac.cn
[b] Prof. Dr. Z. K. Yu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (P.R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201402823.
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The reaction of 1a with 2 by was monitored by GC and
1H NMR spectroscopy to reveal the formation of phenyl vinyl
ketone (7a) during the borylation reaction. Upon heating, 7a
can be dimerized easily to 8a.[10c,d] Under the conditions stated
in Table 1, both 7a and 8a underwent the borylation reaction
with 2 to afford the corresponding 1,4-conjugate addition
products; compounds 3a (37%) and 4 (52%) were obtained
from the reaction of 7a with 2 [Eq. (1)], and 4 (67%) was
formed in the reaction of 8a with 2 [Eq. (2)]. These results
demonstrate that the present methodology that employs b-
chloroalkyl aryl ketones as the enone precursors is much more
efficient than the direct use of the corresponding enones as
substrates for borylation reactions. In situ generated phenyl
vinyl ketone (7a) is considered to be the reaction intermediate
that undergoes 1,4-conjugate addition with 2 to yield 3-bory-
lated propiophenone (3a) in the overall catalytic cycle.
Table 1. Screening of the reaction conditions.[a]
Entry
Catalyst/loading
[mol%]
Solvent
Yield
[%][b]
3a
4
1[c]
2[c]
3
4
5
6
7
8
9
CuI/5.0
CuI/5.0
CuI/5.0
CuI/5.0
CuI/5.0
CuI/5.0
CuI/5.0
CuCl/5.0
CuBr/5.0
CuI/2.5
CuI/5.0
CuI/5.0
THF
1,4-dioxane
MeOH
EtOH
iPrOH
20
61
65
38
52
85
96 (95)[d]
94
94
92
92
96
16
4
30
56 (50)[d]
45
14
2
4
5
tBuOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
10
11[e]
12[f]
3
4
2
[a] Reaction conditions: 1a (0.5 mmol), 2 (0.55 mmol), K3PO4 (0.75 mmol),
solvent (0.2 mL), 608C, 20 h, atmospheric N2. [b] 1H NMR spectroscopic
yield using CH2Br2 as the internal standard. [c] 2.0 equiv. MeOH was
added. [d] Isolated yield given in parentheses. [e] 508C. [f] 808C.
in situ generated acyclic enones under ligand-free Cu cataly-
sis.[7e–g]
Under the optimal conditions, the protocol generality was
explored by the reaction of various substrates 1 with 2
(Scheme 2). The treatment of methyl- or methoxy-substituted
3-chloropropiophenones with 2 afforded the corresponding
target products 3b–3 f in excel-
lent yields (93–96%). However,
electron-withdrawing substitu-
ents such as chloro and fluoro
reduced the yields of 3g and 3h
to 87–88%, and bulky 2-naph-
thyl also lowered the product
yield (3i, 88%). 2-Thienyl-, 2-
furyl-, and 3-indolyl-propionones
underwent reaction to give 3j
(89%), 3k (70%), and 3l (89%),
respectively. The reaction of 1-
chloropentan-3-one with 2 oc-
curred smoothly to give 3m
(79%). 3-Chloropropionic acid
aryl esters were reacted with 2
to produce b-borylated esters,
that is, 3n (88%) and 3o (80%).
The use of b-chloro-b-methylpro-
piophenone (5a) as the sub-
strate led to the desired product
6a (94%), in which a prochiral
carbon center was established.
Notably, 3-bromopropiophenone
(1a’) could also be used as the
substrate to afford the corre-
sponding product 3a in 94%
Scheme 2. Borylation of b-chloroalkyl aryl ketones (1) with 2. Reaction conditions: 1a (0.5 mmol), 2 (0.55 mmol),
yield under the same conditions. K3PO4 (0.75 mmol), solvent (2 mL), 608C, 20 h, atmospheric N2. Yields refer to the isolated products.
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were achieved with excellent enantioselectivity (93–99%) for
the target chiral products 6 regardless of the alkyl chain length
and the substituent on the aryl group. Various substituents
were tolerated on the aryl rings. Substrate 5g, which bears
a naphthalene ring, reacted efficiently to give 6g (Table 3,
entry 7). b-Chloromethyl thienyl and furyl ketones 5h and 5i
underwent reactions to form (+)-6h in 97% yield with 98% ee
and (À)-6i, respectively (Table 3, entries 8 and 9). No clear sub-
stituent effect from the (hetero)aryl moieties was observed
except if 5i, 5j, 5l, 5m, and 5q were used (Table 3, entries 9,
10, 12, 13, and 17). The absolute configuration of the chiral
products was assigned to be S by comparison of the optical
rotation of 6b with reported data.[9e] However, the reactions of
aryl b-methyl-b-chloropropionates 9 with 2 under the same
conditions only gave very low yields and ee values for the
products 10 (Supporting Information). If the ligand was
changed from (S,S)-Taniaphos to (R,S)-Josiphos, the correspond-
ing products 10a (61%) and 10b (55%) with 72–82% ee were
obtained [Eq. (3)]. Similarly, the treatment of enone
7b with 2 resulted in (+)-6a in 90% yield with 93%
ee [Eq. (4)], which are lower than those (95% yield
and 96% ee) achieved using 1a as the substrate
(Table 3, entry 1). The in situ formation of the enone
provides both a high yield and ee value, which is at-
tributed to two reasons: (1) the enone intermediate
could be generated slowly so its effective concentra-
tion could be low, which leaves a higher relative con-
centration of the chiral catalyst and leads to reduced
competition from the racemic background and
(2) the dehydrochlorination gives proportions of al-
kene E/Z isomers that are different from the case if
pure (E)-alkene (enone) is used, and it is possible that
the (Z)-enone intermediate is preferable to afford the
enantioselective addition product.
Table 2. Screening of chiral ligands for the asymmetric conjugate addi-
tion of 2 to 5a.[a]
Entry
Ligand
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
92
88
70
74
95
79
96
62
28
À4
À89
0
48
96
[a] Reaction conditions: 5a (0.2 mmol), 2 (0.22 mmol), K3PO4 (0.3 mmol),
t-AmOH (2 mL), 608C, 20 h, atmospheric N2. [b] Determined by 1H NMR
spectroscopy using CH2Br2 as the internal standard. [c] Determined by
chiral HPLC analysis using an AD-H column.
Figure 1. Chiral ligands screened for the asymmetric reaction of 5a with 2.
Encouraged by the excellent reactivity of 5a with 2, the Cu-
catalyzed enantioselective addition of 2 to the enones generat-
ed in situ from b-chloroalkyl aryl ketones was conducted. A
range of chiral ligands was examined in the reaction of 5a
with 2 (Table 2). The reaction afforded product 6a in good to
excellent yields with the use of chiral ligands L1–L7 in various
enantioselectivities (Figure 1). In the presence of an axially
chiral bisphosphine ligand such as (S)-BINAP (L1), a moderate
enantioselectivity (62% ee) was obtained (Table 2, entry 1). The
use of (S,S)-Me-Duphos (L2) and (S,S,R,R)-Tangphos (L3) led to
poor ee values for the products (Table 2, entries 2 and 3). Chiral
ligands with a ferrocenyl backbone were also tested, among
which high enantiocontrol was observed for (R,S)-Josiphos
(L4), whereas (R)-(S)-NMe2-PPh2-Mandyphos (L5) and (R,R)-Wal-
phos (L6) did not work well (Table 2, entries 5 and 6). To our
delight, (S,S)-Taniaphos (L7) exhibited an excellent enantiose-
lectivity (96% ee; Table 2, entry 7).
The relevant substrate 5r, which bears an aryl group at the
b-position, was prepared to further test the substrate scope of
the synthetic methodology. If an aryl substituent is at the b-po-
sition, the corresponding b-chloroketone 5r was dehydro-
chlorinated readily to form the enone 5r’ during the prepara-
tion and work up. After repeated purification by column chro-
matography and recrystallization, a mixture of 5r and 5r’
(1.00:0.16) was obtained in 75% yield [Eq. (5)].[16] This mixture
was reacted under the conditions given in Table 3 to afford the
target product 6r[9e] in 60% yield and 76% ee, whereas the re-
Next, a variety of b-alkyl-b-chloroalkyl aryl ketones 5 were
applied in the reactions with 2 under the optimized conditions
(Table 3). The starting substrates 5 were prepared readily by
Friedel–Crafts reactions or through aldol/chlorination reaction
sequences (Supporting Information). Isolated yields of 72–97%
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Table 3. Asymmetric conjugate addition of 2 to b-alkyl-b-chloroalkyl aryl
ketones (5).[a]
Table 3. (Continued)
Entry
5
6
Yield [%][b]
ee [%][c]
16
95
75
98
5p
5q
(+)-6p
(+)-6q
Entry
1
5
6
Yield [%][b]
95
ee [%][c]
17
93
96
5a
5b
(+)-6a
(S)-6b
[a] 5 (0.2 mmol), 2 (0.22 mmol), K3PO4 (0.3 mmol), t-AmOH (2 mL), 608C,
20 h, atmospheric N2. [b] Isolated yield. [c] Determined by chiral HPLC
using an AD-H column.
2
3
95
92
96
96
5c
(+)-6c
4
96
99
5d
5e
5 f
(+)-6d
(+)-6e
(+)-6 f
5
6
7
88
95
93
96
95
97
Scheme 3. Asymmetric borylation of b-aryl-b-chloroalkyl aryl ketone 5r and
chalcone 5r’ with 2.
action of 5r’ gave 6r in 79% yield with 98% ee (Scheme 3). As
chalcones are stable and readily available, it is not necessary to
use their b-aryl-b-chloroketone precursors for organic transfor-
mations.
5g
5h
5i
(+)-6g
(+)-6h
(À)-6i
8
9
97
72
98
96
10
11
12
13
14
81
97
84
80
95
98
97
98
98
97
5j
(+)-6j
5k
5l
(+)-6k
(+)-6l
Conclusions
We have developed an efficient one-pot, Cu-catalyzed boryla-
tion process for b-chloroalkyl aryl ketones through the in situ
generation of enones as the reaction intermediate. In the pres-
ence of a chiral ligand, the corresponding asymmetric boryla-
tion occurs efficiently to afford the target chiral products. As
a result of the ready availability and easy manipulation of b-
chloroalkyl aryl ketones compared to the corresponding
enones, the present methodology provides an efficient alterna-
tive route to (chiral) organoboron compounds.
5m
(+)-6m
5n
5o
(+)-6n
(+)-6o
15
97
98
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Experimental Section
General
The solvents were dried and distilled before use according to liter-
ature methods. 1H and 13C{1H} NMR spectra were recorded by
using a Bruker DRX-400 spectrometer, and all chemical shift values
refer to CDCl3 [d(1H), 7.26 ppm; d(13C), 77.16 ppm]. HRMS data
were obtained by using a Waters GC-TOF CA156 mass spectrome-
ter. Analytical TLC plates, Sigma–Aldrich silica gel 60F200 were
viewed by UV light (254 nm). Column chromatographic purifica-
tions were performed by using SDZF silica gel 160. Enantiomeric
excess was determined by HPLC analysis by using an Ad-H chiral
column. Optical rotations were measured by using a polarimeter.
All the chemical reagents were purchased from commercial sour-
ces and used as received unless otherwise indicated.
Typical procedure for the borylation of b-chloroalkyl aryl
ketones 1 with 2: Synthesis of 3a
Under a N2 atmosphere, a mixture of CuI (4.8 mg, 0.025 mmol), 2
(140 mg, 0.55 mmol), and K3PO4 (159 mg, 0.75 mmol) in t-AmOH
(1.5 mL) was stirred at RT for 30 min, followed by the addition of 3-
chloropropiophenone (1a; 84 mg, 0.5 mmol) in t-AmOH (0.5 mL).
The resultant mixture was stirred at 608C for 20 h. After it was
cooled to RT, the reaction mixture was filtered through a short pad
of Celite and rinsed with EtOAc (20 mL). The volatiles were re-
moved under reduced pressure, and the resulting residue was puri-
fied by silica gel column chromatography (eluent: petroleum ether
(60–908C)/EtOAc=60:1, v/v) to afford 3a as a colorless liquid
(124 mg, 95%).
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Typical procedure for the asymmetric borylation of b-alkyl-
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2012, 18, 12202–12206.
Under a N2 atmosphere, a mixture of CuI (1.9 mg, 0.01 mmol), (S,S)-
Taniaphos (10.3 mg, 0.015 mmol), and K3PO4 (64 mg, 0.3 mmol) in
t-AmOH (1.0 mL) was stirred at RT for 30 min, followed by addition
of 2 (56 mg, 0.22 mmol) in t-AmOH (0.5 mL). The mixture was
stirred at RT for 10 min, and 3-chloro-1-(p-tolyl)butan-1-one (5a;
39 mg, 0.2 mmol) in t-AmOH (0.5 mL) was added. The resultant
mixture was stirred at 608C for 20 h. After it was cooled to RT, the
reaction mixture was filtered through a short pad of Celite and
rinsed with EtOAc (20 mL). The volatiles were removed under re-
duced pressure, the resulting residue was purified by silica gel
column chromatography (eluent: petroleum ether (60–908C)/
EtOAc=60:1, v/v) to afford 6a as a white solid (55 mg, 97%).
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (21272232) for financial support for this research.
Keywords: asymmetric catalysis
homogeneous catalysis · ketones
·
copper
·
enones
·
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Received: October 15, 2014
Published online on && &&, 0000
&
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FULL PAPERS
In situ generation works better!
Copper-catalyzed (asymmetric) boryla-
tion of b-chloroalkyl aryl ketones via
in situ generated enones has been real-
ized with bis(pinacolato)diboron (B2pin2)
to achieve up to 97% yield and 99%
enantioselectivity. b-Chloroalkyl aryl ke-
tones are a class of effective precursors
to acyclic enones, and the present
methodology provides an efficient alter-
native route to (chiral) organoboron
compounds.
Q. B. Jiang, T. L. Guo, Z. K. Yu*
&& – &&
Copper-Catalyzed Tandem Asymmetric
Borylation of
b-Chloroalkyl Aryl Ketones and
Related Compounds
ChemCatChem 0000, 00, 0 – 0
www.chemcatchem.org
7
ꢀ 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ