Copper-Complex-Catalyzed Asymmetric Aerobic Oxidative Cross-Coupling of 2-Naphthols: Enantioselective Synthesis of 3,3′-Substituted C1-Symmetric BINOLs

Article abstract of DOI:10.1002/anie.201903435

A novel chiral 1,5-N,N-bidentate ligand based on a spirocyclic pyrrolidine oxazoline backbone was designed and prepared, and it coordinates CuBr in situ to form an unprecedented catalyst that enables efficient oxidative cross-coupling of 2-naphthols. Air serves as an external oxidant and generates a series of C₁-symmetric chiral BINOL derivatives with high enantioselectivity (up to 99 % ee) and good yield (up to 87 %). This approach is tolerant of a broader substrates scope, particularly substrates bearing various 3- and 3′-substituents. A preliminary investigation using one of the obtained C₁-symmetric BINOL products was used as an organocatalyst, exhibiting better enantioselectivity than the previously reported organocatalyst, for the asymmetric α-alkylation of amino esters.

Full text of DOI:10.1002/anie.201903435

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Accepted Article
Title: Cu-Complex Catalyzed Asymmetric Aerobic Oxidative Cross
Coupling of 2-Naphthols: Enantioselective Synthesis of C1-
symmetric BINOLs Bearing 3,3′-Disubstituents
Authors: Jin-Miao Tian, Ai-Fang Wang, Ju-Song Yang, Xiao-Jing Zhao,
Yongqiang Tu, Shu-Yu Zhang, and Zhi-Min Chen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201903435
Angew. Chem. 10.1002/ange.201903435
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Cu-Complex Catalyzed Asymmetric Aerobic Oxidative Cross Coupling of 2-Naphthols:
Enantioselective Synthesis of C1-symmetric BINOLs Bearing 3,3-Disubstituents
Jin-Miao Tian,1 Ai-Fang Wang,1 Ju-Song Yang,2 Xiao-Jing Zhao,1 Yong-Qiang Tu,1,2* Shu-Yu Zhang,1
Zhi-Min Chen1
Dedication ((optional))
two different 2-naphthols have much less been described, despite
Katsuki and Pappo groups have reported separately two approaches
with Fe-complexes to generate a limited number of C1-BINOLs with a
single or no 3-functional group (Scheme 1B).[3b,7] Therefore,
development of an effective catalytic system for affording a cross
coupling to generate the 3,3-disubstituted C1-symmetric BINOLs is
of particular demand.
Abstract: A novel chiral 1,5-N,N-bidentate ligand based on a
spirocyclic pyrrolidine oxazoline (SPDO) backbone has been
designed and prepared, which in situ coordinates with CuBr to form
an unprecedented catalyst that enables an efficient oxidative cross
coupling of 2-naphthols using air as external oxidant, generating a
series of C1-symmetric chiral BINOL derivatives in high
enantioselectivity (up to 99% ee) and good yield (up to 87%). This
approach could be nicely tolerant of much broader substrates scope,
particularly bearing bran-new various 3- and 3-substituents. A
preliminary investigation using a prepared C1-symmetric BINOL-
derived aldehyde organocatalyst exhibits better enantioselectivity
than the previously reported organocatalyst toward the asymmetric
α-alkylation of amino esters.
As a core structural element, the binaphthyl has been prevalently
found in numerous chiral ligands, functional materials, and
biologically active natural products.[1] During the past decades, the
C2-symmetrical chiral BINOL (binaphthol) and its derivatives have
exerted historical effect on asymmetric catalysis, particularly as
exemplified by BINAP,[1b] BINOL derived phosphoric acid,[1h] and so
on, that have been enabling a broad scope of enantioselective
transformations. In recent years, however, the C1-symmetric BINOL-
derived ligands and catalysts[2] bearing different functional groups at
the 3,3’-positions (e.g. PPh3 and Bn) have been found to exhibit
better enantio-induction toward some transformations than the
[2g]
corresponding C2-symmetric catalyst (e.g. Scheme 1A)
. This
observation indicates the C1-symmetric chiral binaphthyls, that bear
variable 3- and 3-disubstituents as a “two-arms” tool to improve the
stereo-controlling, would have great potential to prompt the future
asymmetric catalysis.
Undoubtedly asymmetric oxidative coupling of 2-naphthol
derivatives is the most straightforward approach to build up the
binaphthyl chirality.[1e] And the homocoupling versions have already
received a great success by use of chiral copper,[3] vanadium,[4] iron[5]
and other metal catalysts.[6] In sharp contrast, the cross coupling of
Scheme 1. C1-symmetric BINOLs Catalysis and their Construction
An ideal asymmetric catalytic system for efficient oxidative cross
coupling of 2-naphthol should reach not only high enantioselectivity
as well as chemoselectivity, but also a wide substrate toleration
especially with the 3,3-disubstitution. To date, however, there is still
lack of sufficient knowledge documented to guide such a catalytic
system design. Fortunately, a homocoupling catalyst developed by
Kozlowski group, the Cu-1,5-diazadecalin affording the 3,3-homo-
disubstitution, shows the unique high efficiency toward the homo-
coupling of 2-naphthol with 3-EWG (electron-withdrawing group),[3b]
which gives a clue for seeking this type of catalyst. In connection with
our recent effort toward this subject, two novel SPD (spirocyclic
pyrrolidine) and SPA (spirocyclic amide) -type organocatalysts have
successfully facilitated several asymmetric transformations,[8]
suggesting that these backbones would be possibly a privileged
structure for further building up new effective ligands. Herein we
[a]
J.-M. Tian, A.-F. Wang, X.-J. Zhao, Prof. Y.-Q. Tu, Prof. S.-Y.
Zhang, Prof. Z.-M. Chen
School of Chemistry and Chemical Engineering and Shanghai Key
Laboratory for Molecular Engineering of Chiral Drugs,
Shanghai Jiao Tong University
Shanghai 200240, P. R. China
E-mail: tuyq@sjtu.edu.cn, tuyq@lzu.edu.cn
J.S. Yang, Prof. Y.-Q. Tu
[b]
State Key Laboratory of Applied Organic Chemistry and
College of Chemistry and Chemical Engineering, Lanzhou University
Lanzhou 730000 (P. R. China)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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hypothesize that the 1,5-N,N-bidentate ligands SPDO (SPD-oxazoline) process only when two coupling partners have large enough redox
and SPAO (SPA-oxazoline) would be designed and made into Cu-
SPDO or Cu-SPAO complexes, that would enable the catalytic
asymmetric oxidative cross coupling as above (Scheme 1C).
potential difference (RPD) orΔN values (N = theoretical global
nucleophilicity).[2a,7,10]
Thus the electron-deficient 3-
phenyloxycarbonyl-2-naphthol (1a) and electron-rich 3-benzyloxy-2-
naphthol (2a) were selected to search for the coupling conditions.
Pleasingly as indicated in Table 2 (entry 1), when CuBr/L1 (1:1, 10
mol %) in THF was used, the desired product 3aa could be obtained
with 81% yield and 78% ee.[11] Then the ligands L2-L4 were further
investigated, showing the alkyl-substituted L2 and L3 gave slightly
poor results (entries 2-3 vs 1). And the SPAO ligand L4 gave even the
worst result (entry 4). Subsequently, Cu(I) salts (entries 5-6) and
solvents (entries 7-9) were screened, indicating the system CuBr/ L1
in iPrOH could give the remarkably high 85% yield and 96% ee
(entries 5-8 vs 9). However, a lower loading of L1 (5 mol %) would
Our investigation began with the preparation of our newly
designed SPDO and SPAO ligands L1-L4 easily in gram-scale from
SPD and SPA backbones, respectively (for details, please see
supporting information). Then the asymmetric homocoupling of the
3-methyloxycarbonyl-2-naphthol using in situ prepared Cu-L1-L4
complexes as catalyst was initially examined. To our delight, after
screening of Cu(I) salts, ligands and solvents, the complex CuBr/L1 in
MeOH could catalyze the homocoupling to generate desired product
in remarkably high 84% yield and 94% ee.[9] Under this conditions,
other esters (with Bn and Ph) of 3-carbonyl-2-naphthols could also be
readily coupled to give the satisfying results (Table 1), demonstrating
the efficiency of Cu(I)-L1 system toward the oxidative homocoupling
of 2-naphthol.
decrease the yield and ee (entry 10). Fortunately, this result could be
[3g]
further improved by adding the 4Å molecular sieves
and feeding
1a in two batches [7d] (entries 11- 12).
Table 3 Scope of electron-rich 2-naphthol patners 2 [a]
Table 1 Prelimary test of L1-L4 toward homocoupling of 2-naphthol [a]
[a] Reactions conditions: CuBr (0.05 equiv), L1 (0.05 equiv), 2-naphthols (0.1
mmol) in MeOH (1 mL) at rt for 24 h.
Table 2 Optimization of asymmetric oxidative cross coupling [a]
[a] Unless otherwise noted, reactions were performed (for detail, see
entry
Cu(I) /L (mol %)
CuBr/L1 (10)
CuBr/L2 (10)
CuBr/L3 (10)
CuBr/L4 (10)
CuCl/L1 (10)
CuI/L1 (10)
solvent
THF
t (h)
10
24
24
48
24
24
10
16
16
36
36
30
Yield (%) [b]
Ee (%) [c]
78
supporting information) using 1 (0.1 mmol), CuBr (0.05 equiv) and L1 (0.05
i
equiv), 2 (1.5 equiv) and 4Å molecular sieves (30 mg) in PrOH (1 mL) at rt for
1
2
81
70
51
20
80
72
78
75
85
83
86
86
30 h. [b] CuBr (0.1 equiv) and L1 (0.1 equiv) were used. [c] BQ (0.1 mmol)
was extra used. [d] 2j (1 mmol), 2l (0.5 mmol) and BQ (0.5 mmol) were used,
and 99% ee, 34% yield were obtained after recrystallization.
THF
36
3
THF
54
4-
THF
24
After identifying the optimal catalyst CuBr/L1 and experimental
procedures for the cross coupling (Table 2, entry 12), then a wide
range of electron-rich or deficient 2-naphthols 2a-2m with varying R5
and R6 were investigated with the electron-deficient partners 1a and
1f. The results (Table 3) showed that most examples could work well
symme
5
THF
67
6
THF
56
7
CuBr/L1 (10)
CuBr/L1 (10)
CuBr/L1 (10)
CuBr/L1 (5)
CuBr/L1 (5)
CuBr/L1 (5)
MeOH
EtOH
iPrOH
iPrOH
iPrOH
iPrOH
20
8
82
to generate the expected C1-symmetric BINOLs
3 with high
9
96
enantioselectivity (up to 99% ee) and good yield (up to 86% yield).
Just as we assumed in the first group of examples 2a-2h with varying
electron-rich 3-benzyloxyl, the coupling with 1a gave dominantly the
C1-symmetric BINOLs 3aa-3ah with up to 86% yield and 99% ee
because the bigger difference of 1 and 2. Notably, 2h with 3,5-
di(trifluro)methyl- 3-benzyloxyl gave the best 99% ee of 3ah.
Secondly, substrate 2i with 6-OMe rather than 3-substituent could
still couple well with 1a and 1f to furnish 3ai in good 84% ee and 3fi in
high 92% ee, respectively, which provided further possibility to
modify the ligand/catalyst.[2] In third group of examples with both
partners being the electron-deficient, however, cross coupling often
led to the lower yields (40-65%) and/or ee (74%) of the products 3aj-
10
11 [d]
12 [d,e]
85
94
96
[a] Unless otherwise noted, reactions were performed (for detail, see
supporting information) using: CuBr (0.1 equiv), ligand (0.1 equiv), 1a (0.1
mmol), and 2a (1.5 equiv) in solvent (1 mL) at rt. [b] Isolated yield. [c]
Determined by chiral HPLC. [d] 4Å molecular sieves (30 mg) was used. [e] 1a
was added in two batches over 3 h.
Subsequently, the more challenging oxidative cross coupling[10]
process with two different 3-substituted-2-naphthol partners was
investigated. Based on literature information, the oxidative cross
coupling could preferentially occur through radical-anion coupling
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10.1002/anie.201903435
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3al and 3jl due to the minor difference between two partners.[12,13]
Importantly for the product 3jl, its low enantio-purity (74% ee) could
be improved to 99% ee after recrystallization, which presented good
enatio-induction in an aldehyde catalysis[14] bellow (Scheme 3B). In
most examples (3aa-3ai, 3fi) of Table 3 unless those noticed (3aj-3al,
3jl), the homocoupling byproducts of 2 were not up to 10% yield, and
no homocoupling byproduct of 1a or 1f was isolable.
coordinated with 1a to form species A, which subsequently coupled
with the radical species B (generated from 2a through an outer
sphere electron transfer with another Cu(II) complex), to form the
intermediate C via TS (transition states). The chiral coupling product
(S)-3aa was afforded after tautomerization of C. Noticeable was that
during this coupling process as shown in TS, species B tended to
attack from Si-face of species A to give the (S)-3aa, which was
consistent with our observed experiment results. While a Re-face
attack forming (R)-3aa was disfavored because of the bigger steric
hindrance effect between species B and A.
Table 4 Scope of electron-deficient 2-naphthol partners 1 [a]
Scheme 2. The postulated TS for explaining the stereoinduction.
To support the utility of our asymmetric catalytic protocol, a gram-
scale experiment was carried out in Scheme 3A, and the desired 3aa
could be obtained in 1.47 g (72% yield) with ideal 95% ee under
standard conditions. In addition, the chiral C1-symmetric BINOL
product 3jl obtained above was also used as an aldehyde-activating
catalyst toward a direct enantioselective α-alkylation of amino esters
(Scheme 3B). Compared with a reported result (81% ee) with catalyst
9, 3jl could yield product 8 with a much better enantioselectivity (94%
ee). [14b]
[a] Unless otherwise noted, reactions were performed (for detail, see
supporting information) using 1 (0.1 mmol), CuBr (0.05 equiv) and L1 (0.05
i
equiv), 2 (1.5 equiv) and 4Å molecular sieves (30 mg) in PrOH (1 mL) at rt for
30 h.
Subsequently, the cross coupling scope was further expanded by
using a series of the electron-deficient partners 1b-1p varying the 3-
ester group to couple with 2a. As summarized in Table 4, most
examples could also work well to give high enantioselectivity and
yield. Generally, the aromatic esters 1b-1n gave better ee values than
that of the aliphatic 1o and 1p (3ba-3na vs 3oa-3pa), although the
yield maintained the same level. Further detailed inspection showed
that in the first group of examples 1b-1k with mono, di and tri-
substitutents at the aromatic ring, the EWG and ENG (electron-
neutral group) substitutions gave better results than the EDG (3ba-
3ha and 3ka vs 3ia), with the 3,5-difluoro-phenyl ester 1h giving
the best ee (99%) of 3ha. An additional reason for the poor result (70
ee% and 72% yield) of 3ja was possibly the presence of highly steric
bulky t-butyl. The second group of examples (1l-1n) indicated that
this method could even be tolerant of the 6-substitution of the
naphthyl framework. And either electron-rich 6-MeO, or electron-
deficient 6-Br substitution could afford 3la-3na in high ee (92-96%)
and yield (75-84%), which provided additional chances to modify C1-
symmetric BINOL-derived ligand/catalyst. In the third group (1o-1p),
however, both alkyl esters 1o-1p gave poor enantioselectivity of 3oa-
3pa (20-61% ee), possibly due to the lack of aromatic π-π stacking
between 1o-1p and L1. The same as Table 3, in all cases of Table 4, no
homocoupling byproduct of 1 was observed, and just less than 10%
yield of the self-coupling byproduct of 2a was isolable.
Scheme 3. Synthetic applicability.
In summary, we have successfully developed a novel Cu-SPDO
complex catalytic system (Cu-L1), using which a catalytic asymmetric
aerobic oxidative cross coupling approach of 2-naphthols has been
explored, generating a series of chiral C1-symmetric BINOLs. This
convergent approach allows the rapid construction of various 3,3-
disubstitued axially chiral BINOLs, including 3-carboxylic ester, 3-
Based on the experimental results above and the literature reports
on the aerobic oxidative coupling,[3b,7]
a possible radical-anion
coupling process was proposed (Scheme 2). Initially, the Cu(II)/L1
complex was formed from Cu(I) and L1 under air. Then this complex
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oxylbenzyl, aldehyde, halides, and so on, featuring high
enantioselectivity, good chemoselectivity (homocoupling byproducts
10% in most cases), and particularly a bran-new and broad substrate
scope. We believe this methodology and the BINOL products
obtained would find potential utility in asymmetric catalysis in future.
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Acknowledgements
Financial support for this work was provided by NSFC
(21702136, 21871117, 21672145). National Science and
Technology Major project of the Ministry of Science and
Technology of China (2018ZX09711001-005-002).
[8]
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Conflict of interest
The authors declare no conflict of interest.
Keywords: aerobic oxidative cross coupling • SPDO • C1-
symmetric BINOL • 3,3-disubstituents • aldehyde catalysis
The absolute stereochemistry of homocoupling products was assigned
as S by comparison of the optical rotation with the literature 3b and 3f.
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And the absolute stereochemistry of cross-coupled product was
assigned as S by comparison of the optical rotation of 3aa and 3oa with
the literature 7b.
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COMMUNICATION
Jin-Miao Tian, Ai-Fang Wang, Ju-Song
Yang, Xiao-Jing Zhao, Yong-Qiang Tu, *
Shu-Yu Zhang, Zhi-Min Chen
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Cu-Complex Catalyzed Asymmetric
Aerobic Oxidative Cross Coupling of
2-Naphthols: Enantioselective
Synthesis of C1-symmetric BINOLs
Bearing 3,3-Disubstituents
Asymmetric aerobic oxidative cross coupling of 2-naphthols enabled by a novel Cu-
SPDO complex catalytic system was developed, generating a series of chiral C1-
symmetric BINOLs bearing 3,3-disubstituents. This method features high
enantioselectivity, good chemoselectivity, bran-new and broad substrate scope. A
preliminary investigation using a prepared C1-symmetric BINOL-derived aldehyde
organocatalyst exhibits better enantioselectivity than the previously reported
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