Catalytic asymmetric synthesis of chiral phenols in ethanol with recyclable rhodium catalyst

Article abstract of DOI:10.1039/c9gc02420d

A general method to access diverse chiral phenols by rhodium-catalyzed asymmetric conjugate arylation using hydroxylated arylboronic acids in ethanol was developed. Recycling of the rhodium catalyst by flash chromatography on silica gel was feasible in this system. The synthetic utility of the strategy was demonstrated by efficient synthesis of chiral drug tolterodine.

Full text of DOI:10.1039/c9gc02420d

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DOI: 10.1039/C9GC02420D
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Catalytic asymmetric synthesis of chiral phenols in ethanol with
recyclable rhodium catalyst
Jian Yao, Na Liu, Long Yin, Junhao Xing, Tao Lu and Xiaowei Dou*
Received 00th July 20xx,
Accepted 00th July 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A general method to access diverse chiral phenols by rhodium- in electrophilic aromatic substitution reactions, chiral phenols
catalyzed asymmetric conjugate arylation using hydroxylated can be directly generated by asymmetric Friedel–Crafts or oxa-
arylboronic acids in ethanol was developed. Recycling of the Pictet–Spengler reaction.3 Asymmetric conjugate addition to
rhodium catalyst by flash chromatography on silica gel was feasible para-quinone methides also led to the formation of chiral
in this system. The synthetic utility of the strategy was phenol derivatives.4 4-Hydroxylated phenylboronic acid was
demonstrated by efficient synthesis of chiral drug tolterodine.
compatible with the Pd-catalyzed enantioselective 1,1-
diarylation of acrylates, thus generating optically active
phenols.5 In spite of these significant advances, development of
a general and green strategy that features high reactivity,
excellent enantioselectivity, and broad substrate scope, which
are essential for practical applications, is still highly desirable.
The rhodium-catalyzed asymmetric conjugate arylation
reaction using arylboronic acids represents one of the most
reliable methods for synthesizing chiral molecules bearing a
benzylic stereogenic center.6,7 We envisioned that this catalytic
system might be applied to the effective synthesis of chiral
phenols, with the use of hydroxylated arylboronic acids.
However, early studies showed that the presence of phenol
would deactivate the rhodium catalyst,8 and there have been
rare examples using hydroxylated arylboronic acid/ester in
rhodium-catalyzed arylation reactions.9 Lautens and co-workers
Phenols have been regarded as an important class of organic
compounds because of their versatility in organic synthesis and
remarkable significance in medicinal chemistry.1 As a subset,
chiral phenols bearing a benzylic stereogenic center represent
an important class of structural motifs, which constitute the
framework of many natural products and active pharmaceutical
ingredients (APIs). Examples include cherylline isolated from
Crinum powellii,2a mimosifoliol from the rootwood of
Aeschynomene mimosifolia,2b lasofoxifene as
a selective
estrogen receptor modulator,2c and the blockbuster drug (R)-
tolterodine2d (Fig. 1). Therefore, asymmetric synthesis of chiral
phenols is of great synthetic interest, and considerable efforts
have been devoted to this goal. Derivatization of chiral
precursors provides a useful approach to chiral phenols,
however, it inevitably leads to compromised step and atom
economy. Taking advantage of the inherent reactivity of phenol
developed
an
elegant
approach
to
(di)aza-
dihydrodibenzoxepines by Rh/Pd domino catalysis,9a,b in which
ortho-hydroxylated arylboronic ester was used for the
conjugate addition step, with the need of stoichiometric
amount of base. Herein we report a new reaction system for
diverse hydroxylated arylboronic acids and phenolic substrates
under rhodium catalysis, providing an expeditious route to
various chiral phenols in a sustainable manner (Scheme 1). It is
OH
N
OMe
O
OH
MeO
OMe
N
Ph
N
OH
HO
HO
Ar2
OH
cherylline
(+)-mimosifoliol
lasofoxifene
(R)-tolterodine
EWG
+
[RhCl(L*)]2
B(OH)2
Fig. 1 Selected examples of natural products and APIs featuring the chiral phenolic motif.
Ar1
(1 mol % Rh)
Ar2
HO
HO
EWG
EtOH
HO
Ar1
expeditious synthesis of diverse chiral phenols
ethanol as an effective and green solvent
recycling of the rhodium catalyst
35 examples
up to 99% yield, >99% ee
Department of Chemistry and State Key Laboratory of Natural Medicines,
China Pharmaceutical University, Nanjing 211198, China.
E-mail: dxw@cpu.edu.cn; Fax: +86-25-8618 5679
Scheme 1 Synthesis of chiral phenols by rhodium-catalyzed asymmetric addition.
Electronic Supplementary Information (ESI) available. See DOI: 10.1039/x0xx00000x
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noteworthy that the reaction proceeds in ethanol, which is one improved (entries 10–13). At last, acidic additives were
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of the recommended solvents for green synthesis.10 Moreover, investigated, and phenol (5 or 100 equiv.DtOoI:R1h0).1w03a9s/Cfo9uGnCd02t4o20bDe
the reaction employs a stable chiral diene–rhodium(I) -chloro fully compatible with the current reaction system (entries 14–
dimer as the catalyst under base-free conditions for most 15). Surprisingly, with stronger acids like acetic acid and benzoic
examples, and the catalyst can be recycled after easy separation acid as the additive (5 equiv. to Rh), the reaction still proceeded
by flash chromatography on silica gel.
well (entries 16–17), which represents the first example
As shown in Table 1, we commenced our investigation with showing the compatibility of rhodium-catalyzed arylation
a model reaction between two phenolic substrates, the reaction with Brønsted acid additives.15
phenolic enone 1aand 4-hydroxyphenylboronic acid 2a.
With the optimal conditions, the generality of the current
Initially, we tested the reaction using a chiral diene L1-ligated system was investigated. As summarized in Table 2, phenolic
rhodium catalyst (1 mol % Rh) in toluene/H2O.11 The reaction enones bearing diverse substitutions were found to be
was not fully suppressed (entry 1), and a higher yield was compatible with the current system (3b–3e). Notably, site-
obtained without base (entry 2). A significant solvent effect was selective mono-protected catechol derivatives can be readily
observed, and it is interesting to observe a general trend that obtained (3b–3c). Non-phenolic enones, including the aryl (3f–
the solvent with better water miscibility gave a higher yield 3i) and alkyl (3j–3k) ones, were well-tolerated. In addition to 4-
(entries 2–6), and ethanol was identified as the best solvent hydroxyphenylboronic acid, hydroxylated phenylboronic acids
(entry 6, 99% yield, 97% ee). Further studies revealed that water bearing different substitutions at different positions were also
was not essential (entries 7–8). The reaction also proceeded in
pure water, but a diminished yield was obtained (entry 9). Other
chiral ligands including dienes L2,12 L3,13 and (R,R)-Ph-bod,14 as
well as bisphosphine (R)-binap were also studied. All the
catalyst gave 3a in high yields, but the ee value was not further
Table 2 Substrate scopea
Ar2
(OH)
O
O
[RhCl(L1)]2
(1 mol % Rh)
B(OH)2
Ar1
+
(HO)
Ar2
(HO)
EtOH, 60 °C, 12 h
Ar1
(HO)
1
2
3
OH
Table 1 Rhodium-catalyzed asymmetric conjugate addition to phenolic enone 1a with 4-
hydroxyphenylboronic acid 2aa
OH
OH
OH
OH
O
O
O
O
Br
HO
MeO
Cl
O
[RhCl(L*)]2
(1 mol % Rh)
O
HO
MeO
HO
HO
HO
B(OH)2
+
Br
solvent, 60 °C, 2 h
3d
3e
3b
3c
OH
(87%, 95% ee)b
(85%, 95% ee)b
(99%, >99% ee)
(99%, 96% ee)
1a
2a
3a
OH
OH
OH
OH
OH
L1: R = OAr (Ar = 2-naphthyl)
L2: R = OAr (Ar = 2,6-iPr2-C6H3)
L3: R = NHtBu
O
R
Ph
O
O
PPh2
PPh2
O
O
Br
Ph
Me
(R,R)-Ph-bod
F3
C
Cl
3f
3g
3h
3i
(R)-binap
(99%, 97% ee)
(99%, 96% ee)
(99%, 97% ee)
(99%, 96% ee)
Entry
1
2
3
4
5
6
7
8
Ligand (L*)
Solvent/additive
toluene/H2Od
toluene/H2O
DCE/H2O
THF/H2O
dioxane/H2O
EtOH/H2O
EtOH
Yieldb (%)
25
eec (%)
OH
OH
OH
OH
L1
L1
L1
L1
L1
L1
L1
L1
95
95
97
97
97
97
97
97
94
92
97
53
8
Cl
31
29
68
74
99
99
99
48
99
99
99
83
99
99
90
99
O
OH
O
Me
O
O
O
HO
HO
3l
3m
3j
3k
(96%, 97% ee)b
(84%, >99% ee)b
(99%, 99% ee)
(99%, 97% ee)
F
OH
O
OH
O
EtOHe
O
O
9
L1
L2
L3
H2O
EtOH
EtOH
EtOH
10
11
12
13
14
15
16
17
HO
HO
ent-3a
(99%, 96% ee)b
3n
5a
3o
(R,R)-Ph-bod
(R)-binap
(82%, 94% ee)b
(99%, >99% ee)d
(99%)c
EtOH
OMe
Me
L1
L1
L1
L1
EtOH/PhOHf
EtOH/PhOHg
EtOH/AcOHf,h
EtOH/PhCO2Hf,h
97
97
96
97
O
O
O
HO
HO
HO
HO
3p
aReactions were performed with 1a (0.20 mmol), 2a (0.30 mmol), and Rh catalyst
(1 mol % Rh) in solvent (1.0 mL, 0.10 mL water was added if used) at 60 oC for 2 h.
bYield of the isolated 3a. cDetermined by HPLC analysis. dKOH (5 mol %) was added.
eAnhydrous solvent was used. fAcid (5 mol %, 5 equiv. to Rh) was added. g100
equiv. to Rh was added. h0.40 mmol of 2a, 12 h.
ent-3f
(99%, 94% ee)
3q
3r
(98%, 96% ee)b
(99%, 97% ee)
(99%, 97% ee)
a1 (0.20 mmol) and 2 (0.30 mmol). bat 80 oC. c0.40 mmol of 2 was used, and KOH (5
mol %) was added. dDehydration condition: TsOH·H2O (10 mol %), 4 Å MS, toluene,
100 oC, 3 h.
2 | Green Chem., 2019, 00, 1-5
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OH
Ph
suitable (3l–3n). The addition product from 2-
hydroxyphenylboronic acid readily cyclized to give a hemiacetal
product (3o), which was dehydrated to produce the chiral
chromene (5a). In addition, non-hydroxylated arylboronic acids
(ent-3f–3r) worked equally well, showing the broad scope of the
current system.
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DOI: 10.103O9E/tC9GC02420D
BF3 OEt2
Et3SiH, BF3
2
O
O
O
OH
PhMe, 50 °C
HO
CH2Cl2, -78 °C
Ph
Ph
Ph
7; 90%,
Ph
Cy
Ph
Cy
4m; 99% ee
4l; 97% ee
6; 90%, 97% ee
>20:1 d.r., 99% ee
OH
OH
OH
O
To further expand the scope of the current system, we next
examined the substrates bearing different functional groups,
and the results are summarized in Table 3. The substrates with
benzoyl (4a), ester (4b), amide (4c), and aldehyde (4c)
functional groups were all well-tolerated, and universal high
yields and excellent enantioselectivities were obtained. The
challenging ,-unsaturated nitrile also worked, although a
diminished yield and ee value was obtained (4e). The substrates
with -ketoester and -ketophosphonate groups also worked
well, producing valuable 1,3-dicarbonyl (4f) and Horner–
Wadworth–Emmons reagent (4g) bearing chiral phenol motifs.
Cyclic ketones and lactone were also suitable substrates (4h–
4j). In addition, meta- and ortho-hydroxylated phenylboronic
acids, as well as substrates with different substitutions were all
well-tolerated (4k–4o). Note that catalytic amount of base was
added to achieve a higher yield in several cases. The
extraordinary functional group compatibility distinguishes the
current method from other known.
TsOH H2
O
CO2Et
-TFE
O
O
PhMe, 80 °C
F3CH2CO
Ph
Ph
OH
O
O
4o; 92% ee
8; 95%, 91% ee
10
81% for two steps, 96% ee
rt
TFE,
,
O
2
OH
OH
PhI(OAc)
OH
NaBH4, MeOH, 0 °C
CHO
Ph
PhI(OAc)2, solvents
O
Ph
Ph
11
4d; 96% ee
9
O
OH
OH
PhI(OAc)2, TFE, rt
LiOH, MeOH, 50 °C
CO2Me
Ph
O
COOH
Ph
Ph
O
4b; 99% ee
12
13
95% for two steps, 99% ee
OH
O
O
PhI(OAc)2
O
Pd(OAc)2, K2CO3
Br
Br
OMe
Bz
OMe
Bz
MeOH, 0 °C
Ph
TBAB, CH3CN, 80 °C
Table 3 Scope of substrates with different functional groupsa
15; 93% for two steps
19:1 d.r., 96% ee
4n; 95% ee
14
[RhCl(L1)]2
(1 mol % Rh)
OH
B(OH)2
EWG
+
HO
OH
R
EtOH, 60 °C, 12 h
EWG
Scheme 2 Synthetic transformations of the chiral phenol products.
R
1
2
4
As depicted in Scheme 2, several stereospecific
derivatizations of the chiral phenol products were conducted to
demonstrate their synthetic utility. An intramolecular Friedel–
Crafts type reaction of chiral phenol produced the chiral indene
product (4l to 6). The hemiacetal product can be directly
reduced to the corresponding chromane with excellent
diastereoselectivity (4m to 7, >20:1 d.r.).16 Chiral
dihydrocoumarin 8 was easily obtained by intramolecular
transesterification of 4o. Oxidative transformations of different
phenolic products with iodobenzene diacetate17 were
conducted to give diverse structures. For example, alcohol 9
underwent a formal dehydrogenation reaction under oxidative
conditions to give the chiral chromane 10. Spiro lactone 13 was
obtained from phenolic carboxylic acid 12. Oxidation of chiral
phenol 4n followed by an intramolecular Mizoroki–Heck
reaction provided a convenient way to the fused-ring structure
with excellent diastereocontrol (15).
OH
OH
OH
O
CO2Me
CONHBn
CHO
Ph
Ph
Ph
Ph
Ph
4d
(91%, 96% ee)b,c
4a
4b
(99%, 99% ee)c
4c
(99%, 95% ee)
(92%, 98% ee)
OH
OH
OH
O
O
O
O
CN
CO2Me
P(OMe)2
Ph
Ph
Ph
OH
4e
4h
4f
(99%, >99% ee)
4g
(96%, 96% ee)
(67%, 80% ee)c
(99%, 98% ee)c
O
O
HO
HO
O
O
O
Cy
Ph
Ph
Ph
OH
OH
4i
4j
4k
4l
(99%, 99% ee)c
(98%, 84% ee)c,d
(99%, 94% ee)e
(99%, 97% ee)d
The utility of the developed method was further
demonstrated through a highly efficient two-step asymmetric
synthesis of tolterodine,18 a blockbuster drug used to treat
overactive baldder to relieve urinary difficulties.2d As shown in
Scheme 3, either combination (hydroxylated cinnamaldehyde
with arylboronic acid or cinnamaldehyde with hydroxylated
arylboronic acid) worked well to produce the key hemiacetal
intermediate, which was directly converted to tolterodine by
reductive amination in high yields with >99%
enantioselectivities.
OH
OH
Br
O
O
O
CO2Et
OH
Ph
Ph
Ph
Ph
Ph
OH
4o
5b
(99%, 99% ee)g
4n
(99%, 95% ee)d
4m
(99%)d,f
(98%, 92% ee)
a1 (0.20 mmol) and 2 (0.30 mmol). bat 50 oC. cL3-ligated rhodium catalyst was used.
dKOH (5 mol %) was added. eat 80 oC. 0.40 mmol of 2 was used. fDehydration
f
condition: TsOH·H2O (10 mol %), 4 Å MS, toluene, 100 oC, 3 h.
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Notes and references
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[RhCl(L3)]2
(1 mol % Rh)
(a) J. H. P. Tyman, Synthetic and NaturDaOl PI:h10e.n10o3ls9;/CIn9GStCu0d2i4e2s0iDn
iPr2NH
CHO
1
N
NaBH3CN
Ti(OiPr)4
conditions
PhB(OH)2
Organic Chemistry; Elsevier: Amsterdam, 1996; (b) The
Chemistry of Phenols; Z. Rappoport, Ed.; John Wiley & Sons:
Chichester, U. K., 2003; (c) S. Quideau, D. Deffieux, C. Douat-
Casassus and L. Pouységu, Angew. Chem. Int. Ed. 2011, 50,
586. (d) M. A. Rahim, S. L. Kristufek, S. Pan, J. J. Richardson
and F. Caruso, Angew. Chem. Int. Ed. 2019, 58, 1904; (e) Z.
Huang and J.-P. Lumb, ACS Catal. 2019, 9, 521.
OH
OH
O
OH
1p
(S)-Tolterodine
(97%, >99% ee)
[RhCl(L3)]2
(1 mol % Rh)
iPr2NH
CHO
N
NaBH3CN
Ti(OiPr)4
conditions
2-OH-5-Me-PhB(OH)2
OH
O
OH
1d
(R)-Tolterodine
(86%, 99% ee)
2
3
(a) A. Brossi, G. Grethe, S. Teitel, W. C. Wildman and D. T.
Bailey, J. Org. Chem. 1970, 35, 1100; (b) F. Fullas, L. J.
Kornberg, M. C. Wani and M. E. Wall, J. Nat. Prod. 1996, 59,
190; (c) L. Gennari, Expert. Opin. Pharmacother. 2009, 10,
2209; (d) D. Clemett and B. Jarvis, Drugs & Aging 2001, 18,
277.
(a) T.-Y. Liu, H.-L. Cui, Q. Chai, J. Long, B.-J. Li, Y. Wu, L.-S. Ding
and Y.-C. Chen, Chem. Commun. 2007, 2228; (b) J. Lv, X. Li, L.
Zhong, S. Luo and J.-P. Cheng, Org. Lett. 2010, 12, 1096; (c) S.
Das, L. Liu, Y. Zheng, M. W. Alachraf, W. Thiel, C. K. De and B.
List, J. Am. Chem. Soc. 2016, 138, 9429; (d) X. Han, C. Ye, F.
Chen, Q. Chen, Y. Wang and X. Zeng, Org. Biomol. Chem. 2017,
15, 3401.
For selected examples, see: (a) W.-D. Chu, L.-F. Zhang, X. Bao,
X.-H. Zhao, C. Zeng, J.-Y. Du, G.-B. Zhang, F.-X. Wang, X.-Y. Ma
and C.-A. Fan, Angew. Chem. Int. Ed. 2013, 52, 9229; (b) L.
Caruana, F. Kniep, T. K. Johansen, P. H. Poulsen and K. A.
Jørgensen, J. Am. Chem. Soc. 2014, 136, 15929; (c) Z. Wang, Y.
F. Wong and J. Sun, Angew. Chem. Int. Ed. 2015, 54, 13711;
(d) Y. Lou, P. Cao, T. Jia, Y. Zhang, M. Wang and J. Liao, Angew.
Chem. Int. Ed. 2015, 54, 12134; (e) X. Li, X. Xu, W. Wei, A. Lin
and H. Yao, Org. Lett. 2016, 18, 428; (f) S. Li, Y. Liu, B. Huang,
T. Zhou, H. Tao, Y. Xiao, L. Liu and J. Zhang, ACS Catal. 2017, 7,
2805.
Scheme 3 Application in two-step asymmetric synthesis of tolterodine.
As shown in Scheme 4, the model reaction was scaled up to
demonstrate the practicality of the current method (2 mmol
scale, 0.51 g of 3a, 99% yield, 96% ee). It is found that the chiral
diene–rhodium(I) -chloro dimer remained in the system after
completion of the reaction, and it can be easily recovered by
flash chromatography on silica gel. It should be noted that the
catalyst was recovered as a mixture with phenol (formed during
the reaction by protodeboronation of 2a), and the mixture was
directly used for the recycling.19 The catalyst was recycled for
4
additional
3 times, and no erosion of the yield and
enantioselectivity was observed. This recycling represents a
rare case for rhodium catalysis in a homogeneous system.20
OH
recyclable catalyst
[RhCl(L1)]2
(1 mol % Rh)
1a (2 mmol)
O
+
EtOH, 60 °C, 3 h
2a (3 mmol)
3a
(99%, 96% ee)
5
6
E. Yamamoto, M. J. Hilton, M. Orlandi, V. Saini, F. D. Toste and
M. S. Sigman, J. Am. Chem. Soc. 2016, 138, 15877.
OH
Scheme 4 Recycling of the catalyst.
For reviews, see: (a) T. Jia, P. Cao and J. Liao, Chem. Sci. 2018,
9, 546; (b) W.-W. Chen and M.-H. Xu, Org. Biomol. Chem.
2017, 15, 1029; (c) M. M. Heravi, M. Dehghani and V.
Zadsirjan, Tetrahedron: Asymmetry 2016, 27, 513; (d) P. Tian,
H.-Q. Dong and G.-Q. Lin, ACS Catal. 2012, 2, 95; (e) H. J.
Edwards, J. D. Hargrave, S. D. Penrose and C. G. Frost, Chem.
Rev. 2010, 39, 2093; (f) T. Hayashi and K. Yamasaki, Chem. Rev.
2003, 103, 2829; (g) K. Fagnou and M. Lautens, Chem. Rev.
2003, 103, 169.
For selected examples, see: (a) M. Sakai, H. Hayashi and N.
Miyaura, Organometallics 1997, 16, 4229; (b) Y. Takaya, M.
Ogasawara, T. Hayashi, M. Sakai and N. Miyaura, J. Am. Chem.
Soc. 1998, 120, 5579; (c) T. Hayashi, M. Takahashi, Y. Takaya
and M. Ogasawara, J. Am. Chem. Soc. 2002, 124, 5052; (d) J.-
F. Paquin, C. Defieber, C. R. J. Stephenson and E. M. Carreira,
J. Am. Chem. Soc. 2005, 127, 10850; (e) Z.-Q. Wang, C.-G.
Feng, M.-H. Xu and G.-Q. Lin, J. Am. Chem. Soc. 2007, 129,
5336; (f) T. Gendrineau, O. Chuzel, H. Eijsberg, J.-P. Genet and
S. Darses, Angew. Chem. Int. Ed. 2008, 47, 7669; (g) Y. Luo and
A. J. Carnell, Angew. Chem. Int. Ed. 2010, 49, 2750; (h) G.-C.
Tsui and M. Lautens, Angew. Chem. Int. Ed. 2010, 49, 8938; (i)
G. Pattison, G. Piraux and H. W. Lam, J. Am. Chem. Soc. 2010,
132, 14373; (j) W.-T. Wei, J.-Y. Yeh, T.-S. Kuo and H.-L. Wu,
Chem. Eur. J. 2011, 17, 11405; (k) X. Feng, Y. Nie, J. Yang and
H. Du, Org. Lett. 2012, 14, 624; (l) H. Wang, T. Jiang and M-H.
Xu, J. Am. Chem. Soc. 2013, 135, 971; (m) J. Wang, M. Wang,
P. Cao, L. Jiang, G. Chen and J. Liao, Angew. Chem. Int. Ed.
2014, 53, 6673; (n) X. Dou, Y. Lu and T. Hayashi, Angew. Chem.
Int. Ed. 2016, 55, 6739.
In summary, we have developed a highly versatile method
for the synthesis of chiral phenols under rhodium catalysis. The
new method features low catalyst loading, high reactivity, and
excellent enantioselectivity aside from displaying a broad
substrate scope and functional group compatibility. The
synthetic utility of the new method was demonstrated through
useful synthetic transformations and synthesis of the chiral drug
tolterodine. In addition, the reported method employs ethanol
as the solvent with a recyclable catalyst, thus representing a
green and sustainable synthetic approach to chiral phenols.
7
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Financial support from the National Natural Science Foundation
of China (21602253), the Natural Science Foundation of Jiangsu
Province (BK20160749), the “Double First-Class” University
project (CPU2018GY35), and Young Teachers’ Research Funding
from the College of Science, China Pharmaceutical University
(2018CSYT001) are gratefully acknowledged. We thank Prof.
Tamio Hayashi for helpful comments.
8
9
F.-X. Chen, A. Kina and T. Hayashi, Org. Lett. 2006, 8, 341.
(a) A. A. Friedman, J. Panteleev, J. Tsoung, V. Huynh and M.
Lautens, Angew. Chem. Int. Ed. 2013, 52, 9755; (b) J. M.
4 | Green Chem., 2019, 00, 1-5
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Green Chemistry
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Journal Name
COMMUNICATION
Rebelo, S. Kress, A. A. Friedman and M. Lautens, Synthesis
2016, 48, 3155. 4-Hydroxylated phenylboronic acid was used
for a single entry, see: (c) S. W. Youn, J.-H. Song, D.-I. Jung, J.
Org. Chem. 2008, 73, 5658; (d) N. A. Anderson, B. J. Fallon, E.
Valverde, S. J. F. MacDonald, J. M. Pritchard, C. J. Suckling, A.
J. B. Watson, Synlett 2012, 23, 2817.
View Article Online
DOI: 10.1039/C9GC02420D
10 D. Prat, A. Wells, J. Hayler, H. Sneddon, C. R. McElroy, A. Abou-
Shehada and P. J. Dunn, Green Chem. 2016, 18, 288.
11 (a) L. Yin, J. Xing, Y. Wang, Y. Shen, T. Lu, T. Hayashi and X. Dou,
Angew. Chem. Int. Ed. 2019, 58, 2474; (b) J. Yao, L. Yin, Y. Shen,
T. Lu, T. Hayashi and X. Dou, Org. Lett. 2018, 20, 6882.
12 (a) K. Okamoto, T. Hayashi and V. H. Rawal, Org. Lett. 2008,
10, 4387; (b) K. Okamoto, T. Hayashi and V. H. Rawal, Chem.
Commun. 2009, 4815.
13 (a) T. Yasukawa, A. Suzuki, H. Miyamura, K. Nishino and S.
Kobayashi, J. Am. Chem. Soc. 2015, 137, 6616; (b) M. Hatano
and T. Nishimura, Angew. Chem. Int. Ed. 2015, 54, 10949; (c)
F. Xue and T. Hayashi, Angew. Chem. Int. Ed. 2018, 57, 10368.
14 N. Tokunaga, Y. Otomaru, K. Okamoto, K. Ueyama, R. Shintani
and T. Hayashi, J. Am. Chem. Soc. 2004, 126, 13584.
15 The rhodium-catalyzed arylation reaction typically proceeds
under basic conditions or neutral conditions. Addition of
catalytic amount of acid completely inhibited the reaction,
see: S. Sakuma, M. Sakai, R. Itooka and N. Miyaura, J. Org.
Chem. 2000, 65, 5951.
16 K. Li, K. Vanka, W. H. Thompson and J. A. Tunge, Org. Lett.
2006, 8, 4711.
17 Y. Tamura, T. Yakura, J. Haruta and Y. Kita, J. Org. Chem. 1987,
52, 3927.
18 (a) Z. Wu, S. D. Laffoon and K. L. Hull, Nat. Commun. 2018, 9,
1185; (b) T. Korenaga, R. Sasaki, T. Takemoto, T. Yasuda and
M. Watanabe, Adv. Synth. Catal. 2018, 360, 322; (c) S.
Guduguntla, V. Hornillos, R. Tessier, M. Fañanás-Mastral and
B. L. Feringa, Org. Lett. 2016, 18, 252; (d) D. A. Barancelli, A.
G. Salles Jr., J. G. Taylor and C. R. D. Correia, Org. Lett. 2012,
14, 6036; (e) S. Sörgel, N. Tokunaga, K. Sasaki, K. Okamoto and
T. Hayashi, Org. Lett. 2008, 10, 589; (f) G. Chen, N. Tokunaga
and T. Hayashi, Org. Lett. 2005, 7, 2285.
19 The rhodium catalyst and phenol share the similar polarity on
silica gel, thus they were recovered as a mixture. The recycled
catalyst remains mainly as the chiral diene–rhodium(I) -
chloro dimer, as detected by 1H NMR.
20 Recyclable heterogeneous rhodium catalyst has been
developed for asymmetric conjugate addition, see: (a) T.
Yasukawa, A. Suzuki, H. Miyamura, K. Nishino and S.
Kobayashi, J. Am. Chem. Soc. 2015, 137, 6616; (b) T.
Yasukawa, H. Miyamura and S. Kobayashi, J. Am. Chem. Soc.
2012, 134, 16963.
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