Cu(i)-Catalyzed asymmetric intramolecular addition of aryl pinacolboronic esters to unactivated ketones: Enantioselective synthesis of 2,3-dihydrobenzofuran-3-ol derivatives

Article abstract of DOI:10.1039/c9cc09653a

An (S,S)-QuinoxP?-supported Cu(i) catalyst has been disclosed for highly enantioselective intramolecular addition of aryl pinacolboronic esters to unactivated ketones under mild reaction conditions. This protocol showcases a broad substrate tolerance and allows access to various chiral 2,3-dihydrobenzofuran-3-ol derivatives in generally good yields with excellent enantioselectivities.

Full text of DOI:10.1039/c9cc09653a

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DOI: 10.1039/C9CC09653A
COMMUNICATION
Cu(I)-Catalyzed Asymmetric Intramolecular Addition of Aryl
Pinacolboronic Esters to Unactivated Ketones: Enantioselective
Synthesis of 2,3-Dihydrobenzofuran-3-ol Derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
ab
a
a
Chunjie Ni, Gihui Gao and Xianjie Fang*
A (S,S)-QuinoxP*-supported Cu(I) catalyst has been disclosed for ketones which are lack of electron-withdrawing groups. In
4
highly enantioselective intramolecular addition of aryl 2006, Lu and coworkers firstly realized the enantioselective
pinacolboronic esters to unactivated ketones under mild reaction intramolecular addition of aryl boronic acids onto ketones by
5
6
conditions. This protocol showcases a broad substrate tolerance using a chiral cationic Pd-Binap catalyst. Later, Sarpong, Lam,
7
and allows access to various chiral 2,3-dihydrobenzofuran-3-ol Xu independently described the Rh(I)-promoted asymmetric
derivatives in generally good yields with excellent intramolecular addition of arylboron reagents to unactivated
enantioselectivities.
ketones. Apart from these intramolecular examples, Tang and
Deng successfully realized intermolecular process in excellent
8
Functionalized chiral 2,3-dihydrobenzofuran-3-ol derivatives
are important moieties in natural and bioactive molecules
yields and enantioselectivities by using a Rh/(R,R,R,R)-
WingPhos catalyst system. Despite these advances in
asymmetric addition of arylboron reagents to unactivated
ketones, challenges remain. First, the aforementioned
contributions mainly depend on expensive Pd or Rh catalysts,
no examples employed earth-abundant transition metal
catalysts. Second, no substrates containing relatively hindered
ketones such as ortho-substituted aromatics were
(Figure 1), such as cancer chemotherapy translationinhibitor
rocaglamide, plant growth inhibitor vaginidiol and antibacterial
1
brosimacutin G. Because of the prevalence of chiral 2,3-
dihydrobenzofuran-3-ol skeletons in medicine and biologically
active compounds, it is necessary to develop efficient synthetic
methods to construct a wide array of important molecules
which contain these desired core scaffolds.
4,5,8
presented;
while heteroatom aromatic ketones were not
6
,7
described in other works. Relatively hindered ketones, alkyl
ketones and heteroatom aromatic ketones are yet to be
achieved in the same catalytic system. Therefore, there is still
a high demand for exploring the asymmetric addition of
arylboron reagents to various unactivated ketones, especially
by using earth-abundant transition metal catalysts.
HO
HO
MeO
CONMe2
Ph
O
O
OH
OH
O
OH
MeO
O
OH
OH HO
O
O
OMe
Rocaglamide
Vaginidiol
Brosimacutin G
Figure 1. Chiral 2,3-dihydrobenzofuran-3-ol skeletons in natural and bioactive
molecules.
a) Previous work: highly activated ketoamides
CF3
Over the past decade, metal-catalyzed asymmetric
arylations of ketones has emerged as one of the simple and
powerful tool for the construction of these enantioenriched
F3C
HO
CuF 3PPh3 2EtOH
(10 mol%)
Bpin
Ar
O
O
Ar
L6 (14 mol%)
N
N
2
chiral benzylic alcohols. Particularly, the catalytic asymmetric
BOM O
BOM
up to 90% yield, 87% ee
addition of stable and nontoxic arylboron reagents to ketones
stand out to be more attractive. However, compared with the
transition-metal catalyzed asymmetric arylations of activated
b) This work: unactivated ketones
Bpin
HO
R1
R2
CuCl/L10
R1
3
R2
ketones with arylboron reagents, few successful works
O
NaOt-Bu, i-PrOH
THF
O
reported on the asymmetric addition of arylboron reagents to
O
R1 = aryl, alkyl
up to 87% yield, 99% ee
Scheme 1. Copper-catalyzed asymmetric 1,2-addition of arylboron reagents to
ketones.
a. Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of
Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800
Dongchuan Road, Shanghai 200240, China. Email: fangxj@sjtu.edu.cn.
To the best of our knowledge, copper catalyst can also
promote the asymmetric nucleophilic addition to ketones.
9
b.
School of Pharmacy, Yancheng Teachers University, Yancheng 224051, China.
Electronic Supplementary Information (ESI) available: [details of any However, the copper-catalyzed asymmetric addition of
supplementary information available should be included here]. See
arylboron reagents to ketones remain rare. Only one
DOI: 10.1039/x0xx00000x
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Journal Name
asymmetric version has been disclosed by Kanai, Shibasaki and the presence of CuCl (5.0 mol%) and (R)-Binap (5.5 mol%), no
View Article Online
co-workers.10 This cyclization are restricted to the use of highly desired product 2a was obtained and only compound 2a’ was
activated α-ketoamides (Scheme 1a). With regard to the high isolated with 17% yield (Table 1, entry 1). Unfortunately, other
significance of chiral 2,3-dihydrobenzofuran-3-ol derivatives, commonly used chiral diphosphine ligands, such as (R)-SegPhos, (R)-
DOI: 10.1039/C9CC09653A
we report herein
a
copper-catalyzed asymmetric SDP, (S,S)-DIOP, and (S,S)-ChiraPhos also showed no activity in the
intramolecular addition of aryl pinacolboronic esters to formation of desired product 2a (Table 1, entries 2-5). These results
unactivated ketones (Scheme 1b).
suggested that the aryl-Cu species could undergo protonation
easily in the presence of alcohol at room temperature, which
also has been confirmed by Brown’s work. Considering the
Table 1. Evaluation and optimization of reaction conditionsa
11
CuCl/Ligand
NaOt-Bu, Alcohol
HO
H
central role of ligand in the development of efficient metal-
catalyzed reactions, various selected electron-rich ligands
were screened. When (R,R)-Ph-BPE was used, we successfully
obtained the desired product 2a in 73% yield with 19% ee and
Bpin
O
Ph
12
+
Ph
Ph
THF
O
O
O
O
1a
2a
2a'
only trance 2a’ was observed (Table 1, entry 6). Then, the
O
i
(R,R)- Pr-DuPhos and (R,R)-Me-DuPhos ligands were tested,
PPh2
PPh2
O
O
PPh2
PPh2
but unsatisfied results were presented without both yield and
enantioselectivity improvement simultaneously (Table 1,
entries 7 and 8). Fortunately, (R,R)-BenzP* improved both the
yield and enantioselectivity (Table 1, entry 9, 75% yield and
PPh
2
PPh2
O
(
R)-Binap (L1)
(R)-SegPhos (L2)
(R)-SDP (L3)
9
5% ee). Further ligand investigations indicated that (S,S)-
QuinoxP* led to 79% yield and 96% ee (Table 1, entry 10). The
absolute configuration of product 2a was assigned as R by
comparison of the optical rotation with literature data.
Ph
Ph
PPh2
P
O
O
PPh2
5
PPh2
PPh2
P
Ph
Ph
Temperature increase caused decrease in both yield and
enantioselectivity (Table 1, entry 11), which is probably due to
the dehydration of the cyclic compound 2a at higher
temperature. Then, alcohols of different acidity were
submitted to the reaction conditions, but inferior yields and ee
values were presented (Table 1, entries 12-15). If the more
acidic alcohol was used, the more compound 2a’ was
obtained. Other solvents and bases were also investigated, but
no further improvement was noted. As a result, the optimal
(
S,S)-DIOP (L4)
(S,S)-ChiraPhos (L5) (R,R)-Ph-BPE (L6)
Me t-Bu
R
P
R
P
N
P
t-Bu
Me
Me
R
P
t-Bu
P
N
P
t-Bu
Me
R
i
(
R,R)- Pr-DuPhos (L7)
(
R,R)-BenzP* (L9) (S,S)-QuinoxP* (L10)
(
R,R)-Me-DuPhos (L8)
b
c
entry
ligand
alcohol
2a/yield (ee )
2a’/yield
reaction
conditions
were
established
as
room
1
2
3
4
5
6
7
8
9
L1
L2
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
MeOH
EtOH
trace (/)
trace (/)
17%
8%
temperature/CuCl/(S,S)-QuinoxP*/NaOt-Bu/i-PrOH/THF.
With the optimal reaction conditions in hand (Table 1, entry
0), a variety of arylpinacolboronic esters tethered to various
L3
trace (/)
10%
21%
trace
trace
6%
1
L4
trace (/)
unactivated ketones were prepared and applied to this
copper-catalyzed asymmetric transformation. As shown in
Scheme 2, a range of chiral 2,3-dihydrobenzofurans bearing
tertiary alcohols were prepared with excellent ee values (85-
L5
trace (/)
L6
73% (19%)
57% (48%)
65% (11%)
75% (95%)
79% (96%)
71% (92%)
55% (84%)
58% (86%)
67% (92%)
51% (68%)
L7
L8
10%
trace
trace
trace
12%
11%
trace
19%
9
8%), regardless of the electronic properties and substitution
patterns of arylketones 1a-1j. Notably, the sterically hindered
-naphthyl ketone and ortho-substituted aryl ketone
L9
1
1
1
1
1
1
0
1d
L10
L10
L10
L10
L10
L10
1
substrates proceeded smoothly in this transformation,
providing the corresponding product 2h and 2i in good yield
with excellent enantioselectivity. It is worth mentioning that
the heteroatom aromatic ketone was also tolerated, such as
thiophene, affording product 2j in 56% yield with 98% ee.
2
3
4
t-BuOH
HFIPe
5
aUnless otherwise mentioned, the reactions were carried out at room
temperature for 16 h with 1 (0.10 mmol), NaOt-Bu (10 mol%), alcohol (0.20 Besides aromatic ketones, the aliphatic ketones including one
mmol) and THF (0.5 mL) in the presence of CuCl (5.0 mol%) and ligand (5.5
with highly sterically hindered tert-butyl were also tested.
They afforded 2k and 2l with high enantioselectivity, albeit in
moderate yield. Moreover, the α,α-disubstituted ketone can
mol%). bIsolated yield. Determined by chiral HPLC analysis. The reaction was
c
d
o
e
performed at 60 C. HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol.
Initially, we chose substrate 1a containing an also be suitable for the reaction, affording cycloadduct 2m in
arylpinacolboronic ester tethered to a phenyl ketone via an 78% yield with 94% ee. We then investigated the effect of
oxygen linkage for preliminary attempt. When the reaction substituent on the benzene ring with the 2-Bpinphenol moiety.
was performed in THF under argon for 16 hours with 1a (0.1 They all delivered the corresponding products 2n-2p in good
mmol), NaOt-Bu (10 mol%) as base, and i-PrOH as H-source in yields with high ee values.
2
| J. Name., 2012, 00, 1-3
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COMMUNICATION
All of these primary attempts indicated that the linkage has a
strong impact on the corresponding reaction performances
likely the the presence of the oxygen atom facilitates the
View Article Online
DOI: 10.1039/C9CC09653A
Bpin
CuCl (5.0 mol%)
(S,S)-QuinoxP*(5.5 mol%)
HO
R1
R2
R1
O
R2
NaOt-Bu (10 mol%)
i-PrOH (2.0 equiv.)
THF
O
O
desired
nucleophilic
addition
and
enhances
the
1
2
enantioinduction. However, the exact reason for the slightly
higher reactivity and much better enantioselectivity of the
ether linked substrate is not fully understood. To demonstrate
the scalability of this method, the reaction of 1a was
conducted on 5.0 mmol scale under standard conditions
2
a: R = H
79% yield, 96% ee
80% yield, 96% ee
71% yield, 96% ee
70% yield, 95% ee
56% yield, 96% ee
62% yield, 97% ee
69% yield, 97% ee
R
2b: R = F
2c: R = Cl
HO
2
2
d: R = CF3
e: R = Me
O
2f: R = OMe
g: R = Ph
2
(Scheme 4). To our delight, 0.78 gram of product 2a could be
HO
S
isolated with 94% ee.
HO
HO
O
CuCl (5.0 mol%)
(S,S)-QuinoxP*(5.5 mol%)
OMe
HO
O
O
O
Ph
O
Ph
2j
2
h
2i
NaOt-Bu (10 mol%)
i-PrOH (2.0 equiv.)
THF, RT
5
6% yield, 98% ee
d87% yield, 97% ee
O
7
2% yield, 97% ee
d56% yield, 85% ee
Bpin
1
a (5.0 mmol)
2a, 0.78 g, 94% ee
HO
HO
Scheme 4. Gram-scale synthesis
HO
Although the detailed mechanism of the copper-catalyzed
intramolecular 1,2-addition of aryl pinacolboronic esters to
unactivated ketones is still under investigation, we suggest the
following catalytic cycle based on the known work on Rh or Pd-
catalyzed intramolecular addition of arylboron reagents to
ketones (Scheme 5). Initially, the active diphosphine ligated
CuOt-Bu or CuOi-Pr species A should be formed in situ from
O
O
O
2
k
2
l
2m
3
8% yield, 98% ee
d52% yield, 97% ee
6
4% yield, 94% ee
78% yield, 94% ee
HO
Ph
HO
Ph
HO
Ph
Cl
O
O
MeO
O
1
3
the reaction of CuCl/(S,S)-QuinoxP*, i-PrOH and NaOt-Bu.
Next, transmetalation of the arylboronic ester with the species
2n
2o
2p
6
6% yield, 99% ee
e71% yield, 86% ee
e63% yield, 99% ee
aUnless otherwise mentioned, the reactions were carried out at room
A provides the aryl–Cu species B. Subsequently, the insertion
temperature for 16 h with 1 (0.10 mmol), NaOt-Bu (10 mol%), i-PrOH (0.20 of carbonyl group into aryl–Cu bond should afford the species
mmol) and THF (0.5 mL) in the presence of CuCl (5.0 mol%) and (S,S)-QuinoxP*
D. Based on the stereochemical outcome of this reaction,
b
c
d
(
L10, 5.5 mol%). Isolated yield. Determined by chiral HPLC analysis. Reactions
1
4
o
e
o
transition state C was proposed. Key to this model is the
orientation of the OCH -substituent toward the smaller Me
were performed at 60 C. Reactions were performed at 80 C.
Scheme 2. Reaction Scopea
2
group (compared to t-Bu) of the ligand, and the Ph group
should be away from the bulky t-Bu group of the ligand.
Finally, protonolysis leads to the desired product 2a and
regenerates the Cu–oxide species A.
Bpin
HO
Ph
CuCl (5.0 mol%)
Ph
(a)
N
NaOt-Bu (10 mol%)
i-PrOH (2.0 equiv.)
Toluene, RT
Bn
N
O
Bn
3
(0.1 mmol)
4
Without Ligand, 64% yield
With L10, 61% yield, 0% ee
HO
Ph
CuCl
NaOt-Bu
i-PrOH
O
O
CuCl (5.0 mol%)
(S,S)-QuinoxP*
Ph
L
Bpin
HO
Ph
O
Bpin 1a
(
L10, 5.5 mol%)
2a
t
L
Cu O Bu
or
Ph
(b)
X
NaOt-Bu (10 mol%)
tBuO-Bpin
i
X
L
Cu O Pr
O
i-PrOH (2.0 equiv.)
Toluene, 120 oC, 48 h
6
or
alcohol
A
5
1
, X = C (0.1 mmol)
6, 44% yield, 7% ee
iPrO-Bpin
a, X = O (0.1 mmol)
2a, 69% yield, 83% ee
Scheme 3. Effect of linkage
Ph
O
Cu
L
Ph
O
L = (S,S)-QuinoxP*
O
After
successfully
realizing
this
copper-catalyzed
O
D
Cu L
intramolecular addition of aryl pinacolboronic esters to
unactivated ketones, the linkage between arylpinacolboronic
ester and ketone was examined. Although substrate 3 with
NBn-linkage gave the corresponding desired product 4 in good
yield even in the absence of ligand, no ee was observed
B
tBu
Me
P
N
Cu
O
N
P
Me tBu
O
Ph
(
Scheme 3a). When switching the O-linkage for the C-linkage,
C
dramatic decrease in both yield and enantioselectivity was
observed in toluene at 120 C (Scheme 3b, 44% yield and 7%
Scheme 5. Proposed mechanism
o
ee). Given the same conditions to substrate 1a, the desired
product 2a was obtained in 69% yield and 83% ee (Scheme 3b).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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7
8
9
D.-X. Zhu, W.-W. Chen, and M.-H. Xu, TetrahedrVoienw,A2rt0ic1le6O,n7lin2e,
637.
L. Huang, J. Zhu, G. Jiao, Z. Wang, X. Yu, W.-P. Deng, and W.
Tang, Angew. Chem., Int. Ed., 2016, 55, 4527.
In summary, an efficient enantioselective intramolecular
,2-addition of arylboron reagents to unactivated ketones via
the complex of CuCl and chiral diphosphine ligand (S,S)-
QuinoxP* has been established. This method showcases a
broad substrate tolerance and provides a straightforward
approach to construct important chiral 2,3-dihydrobenzofuran-
2
DOI: 10.1039/C9CC09653A
1
For selected examples, see: (a) Y. Yang, I. B. Perry, G. Lu, P.
Liu, and S. L. Buchwald, Science, 2016, 353, 144; (b) E. Y. Tsai,
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1
40, 2007; (c) C. Li, R. Y. Liu, L. T. Jesikiewicz, Y. Yang, P. Liu,
3
-ol
derivatives
in
good
yields
with
excellent
and S. L. Buchwald, J. Am. Chem. Soc., 2019, 141, 5062; (d)
X.-F. Wei, X.-W. Xie, Y. Shimizu, and M. Kanai, J. Am. Chem.
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enantioselectivities. Further applications of this methodology
for natural product or drug synthesis will be carried out and
reported in due course.
This work was financially supported by the Recruitment
Program of Global Experts, the startup funding from Shanghai
Jiao Tong University and the China Postdoctoral Science
Foundation (2018M641996). We thank Dr. Bastien Cacherat
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There are no conflicts to declare.
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DOI: 10.1039/C9CC09653A
COMMUNICATION
TOC
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CuCl (5.0 mol%)
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R1
R2
R2
up to 99% ee
NaOt-Bu (10 mol%)
i-PrOH (2.0 equiv.)
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