Copper-Catalyzed Asymmetric Annulation Reactions of Carbenes with 2-Iminyl- or 2-Acyl-Substituted Phenols: Convenient Access to Enantioenriched 2,3-Dihydrobenzofurans

Article abstract of DOI:10.1002/anie.201907943

We have developed a method for the highly diastereo- and enantioselective construction of 2,3-dihydrobenzofurans bearing tetrasubstituted carbon stereocenters by means of annulation reactions between carbenes and 2-iminyl- or 2-acyl-substituted phenols through catalysis by readily accessible copper(I)/bisoxazoline catalysts under mild conditions. These reactions feature a unique mechanism in which the copper catalyst serves a dual function: first it reacts with the diazo compound to generate a metal carbene, and second, upon formation of an oxonium ylide, it acts as a Lewis acid to activate the imine or ketone for diastereo- and enantioselective cyclization.

Full text of DOI:10.1002/anie.201907943

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Copper-Catalyzed Asymmetric Annulation Reactions of Carbenes
with 2-Iminyl- or 2-Acyl-Substituted Phenols: Convenient Access
to Enantioenriched 2,3-Dihydrobenzofurans
Authors: Xin-Shen Liang, Rui-Dong Li, and Xiao-Chen Wang
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201907943
Angew. Chem. 10.1002/ange.201907943
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10.1002/anie.201907943
Angewandte Chemie International Edition
COMMUNICATION
Copper-Catalyzed Asymmetric Annulation Reactions of Carbenes
with 2-Iminyl- or 2-Acyl-Substituted Phenols: Convenient Access
to Enantioenriched 2,3-Dihydrobenzofurans
Xin-Shen Liang, Rui-Dong Li, and Xiao-Chen Wang*
Dedicated to the 100th anniversary of Nankai University
Abstract: We have developed a method for highly diastereo- and
enantioselective construction of 2,3-dihydrobenzofurans bearing
tetrasubstituted carbon stereocenters by means of annulation
reactions between carbenes and 2-iminyl- or 2-acyl-substituted
phenols with catalysis by readily accessible copper(I)/bisoxazoline
catalysts under mild conditions. These reactions feature a unique
mechanism in which the copper catalyst serves a dual function: first it
reacts with the diazo compound to generate a metal carbene, and
second, upon formation of an oxonium ylide, it acts as a Lewis acid to
activate the imine or ketone for diastereo- and enantioselective
cyclization.
oxonium ylides, probably because of the challenges presented by
the competing reaction pathways, such as O–H insertion[10] and
electrophilic substitution[13]. Furthermore, most of the asymmetric
ylide addition reactions reported to date rely on a Rh(II)/chiral
phosphoric acid (or chiral Lewis acid) cooperative catalytic
system: Rh(II) effects the formation of the metal carbene, and the
chiral acid activates the electrophile and is responsible for the
enantiocontrol.[11,12] There have been only a few cases in which
enantiocontrol was achieved with a single catalyst.[14,15] Although
Cu catalysts have long been known to induce carbene formation
and to function as Lewis acids to activate electrophiles, it was only
recently that Waser and co-workers achieved the first Cu-
catalyzed enantioselective ylide addition to an electrophile, via an
oxy-alkynylation reaction of diazo compounds.[15] Herein, we
disclose that readily available Cu(I)/bisoxazoline (BOX)
complexes can catalyze annulation reactions between
aryldiazoacetates and 2-iminyl- or 2-acyl-substituted phenols to
give 2,3-dihydrobenzofurans bearing tetrasubstituted carbon
stereocenters with excellent diastereomeric ratios and high
enantiomeric excesses (Scheme 1c).
2,3-Dihydrobenzofuran motifs are present in a number of
natural products and bioactive compounds,[1] many of which bear
a
tetrasubstituted carbon stereocenter or two contiguous
tetrasubstituted carbon stereocenters (e.g., furaquinocin A,[2]
phalarine,[3] and rocaglamide;[4] Scheme 1a). Therefore, the
development of methods for diastereo- and enantioselective
synthesis of these motifs is of great importance. There are several
known methods for asymmetric synthesis of 2,3-
dihydrobenzofurans, including [4+1] cycloaddition reactions of
a) Natural products containing 2,3-dihydrobenzofuran moieties:
quinone methides with
a
one-carbon synthon,[5] catalytic
OMe
HO
Me
OH
Me
O
asymmetric dearomatization reactions of benzofurans,[6]
intramolecular carbene C–H insertion reactions of alkylated
phenols,[7] and intramolecular Heck reactions of allyl phenyl
ethers.[8] However, the synthesis of molecules with
tetrasubstituted carbons remains challenging because their steric
bulk decreases their reactivity and enantiocontrol is difficult.
Given the versatility of metal carbenes,[9] we envisioned that
carbene annulation reactions of phenols bearing an ortho
electrophile might effectively provide access to 2,3-
dihydrobenzofurans (Scheme 1b). In particular, we speculated
that reaction of a phenol with a metal carbene would generate an
oxonium ylide, which would then intramolecularly attack the
electrophile to give a cyclized product, rather than undergoing
proton migration to give an O–H insertion product.[9,10]
Furthermore, we expected that the use of a chiral catalyst would
provide enantioenriched 2,3-dihydrobenzofurans. Although
addition of ylides (generated in situ from diazo compounds) to
electrophiles has been studied extensively, especially by the Hu
group,[11,12] this reaction has never been used for phenol-derived
N
OH
Me
OH
O
O
O
CONMe2
OMe
NH
Me
MeO
Me
OH
O
Ph
N
H
MeO
NMe2
OMe
rocaglamide
furaquinocin A
phalarine
b) Proposed carbene annulation for preparation of 2,3-dihydrobenzofurans:
H
R1
ylide
formation
OH
O
O
R1
R2
MLn
R2
MLn = metal catalyst
R2
cyclization
+
R1
MLn
E
H
E
E
E
= Electrophile
c) Asymmetric carbene annulations catalyzed by Cu(I)/BOX (this work):
OH
O
O
N2
O
Cu(I)/BOX
Ar
Ph
Ph
+
N
N
R
CO2Me
Ar
CO2Me
Cu
X
EH
R
Ph
Ph
E
single diastereomer
high ee
E = NPh or O
Cu(I)/BOX
Scheme 1. Syntheses of 2,3-dihydrobenzofurans
We began by investigating the reaction of phenyldiazoacetate
1a with 2-iminyl-substituted phenol 2a under various conditions
(Table 1). When a complex generated from Cu(CH3CN)4PF6 and
phenyl-BOX ligand L1 was used as the catalyst (5 mol %), the
desired annulation reaction occurred to give 2,3-
dihydrobenzofuran 3a as a single diastereomer in 30% yield with
11% ee (entry 1). Considering that the reaction involves a proton-
transfer step, we decided to add an organic base (10 mol %) to
serve as a proton shuttle. Although the addition of NEt3 shut down
the reaction (entry 2), presumably because of competitive
[a]
X.-S. Liang, R.-D. Li, Prof. Dr. X.-C. Wang
State Key Laboratory and Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University
94 Weijin Road, Tianjin 300071 (China)
E-mail: xcwang@nankai.edu.cn
Homepage: http://www.wangnankai.com/
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201907943
Angewandte Chemie International Edition
COMMUNICATION
by HPLC with a Chiralcel OD-H column; n.a., not applicable. [d] NaBARF
(6 mol %), 15-crown-5 (6 mol %), and activated 4Å molecular sieves (30
mg) were added.
coordination of the base to the Lewis acid catalyst, we were
surprised
to
find
that
bulkier
bases
(DIPEA
[diisopropylethylamine], DIPA [diisopropylamine], and PMP
[1,2,2,6,6-pentamethylpiperidine]) improved both the reactivity
and the enantioselectivity (entries 3–5). In fact, when DIPEA was
used, the ee reach 75% (entry 3). Next, various BOX ligands were
examined in the presence of DIPEA. Although tert-butyl-BOX L2,
indane-BOX L3, and diphenyl-BOX ligands L4 and L5 failed to
further improve the enantioselectivity (entries 6–9), cyclopropane-
derived diphenyl-BOX L6 increased the ee to 86% (entry 10).
Cyclobutane-derived analog L7 was less enantioselective than L6
(82% ee, entry 11). Gratifyingly, screening of various additives
With the optimal conditions for the annulation reaction in hand,
we explored its generality by first carrying out reactions of various
aryldiazoacetates with 2-iminyl-substituted phenol 2a (Table 2).
Phenyldiazoacetates with an electron-donating or electron-
withdrawing group at the para position of the phenyl ring were
tolerated, giving the corresponding products (3a–3h) in 31–94%
yields with 90–92% ee values. Meta- and ortho-substituted
phenyldiazoacetates also afforded the desired products (3i–3l)
with high ee values. Reactions of 1-napthyl- and 2-
naphyldiazoacetates and
a
benzodioxole-derived diazo
revealed that addition of
a catalytic amount of sodium
compound (3m–3o) proceeded in high yields with high
enantioselectivities. Furthermore, the methyl ester could be
changed to an ethyl ester (3p). Moreover, we performed the gram-
scale reaction of 1a with 2a (for details, see the supporting
information), and product 3a was obtained in 90% yield and 92%
ee. Therefore, this reaction can be scaled up.
Table 2. Scope of the annulation reaction with respect to the diazo
compound[a]
tetrakis[(3,5-trifluoromethyl)phenyl]borate (NaBARF, 6 mol %)
markedly improved the yield (to 70%) and the enantioselectivity
(to 92% ee) (entry 12). Because NaBARF is very hygroscopic, we
added activated 4Å molecular sieves to scavenge water; and we
added 15-crown-5 to help solubilize the sodium salt in the organic
phase.[16] Finally, evaluation of different Cu sources revealed
CuCl to be optimal: under these conditions, 3a was obtained in
94% yield with 92% ee (entry 15). It is worth mentioning that we
separately prepared the product of an O–H insertion reaction
between 1a and 2a and subjected it to the optimal conditions for
the annulation reaction, but no formation of 3a was observed (See
the supporting information). This result rules out the possibility
that our reaction occurred via a cascade process involving O–H
O
Ar
OH
CuCl (5 mol %)
L6
N2
(6 mol %)
CO2R
H
+
Ar
CO2R
DIPEA, NaBARF
4Å MS, 15-crown-5
m-xylene, 35 °C
24 h
NH
N
Ph
Ph
1a–1p
2a
3a–3p
t
R1 = Bu ( ), 94% (90%[b]), 92% ee
3a
insertion and a Mannich reaction.
R1 = H ( ), 81%, 93% ee
R1 = Me (3c), 89%, 91% ee
O
R1
3b
Table 1. Optimization of reaction conditions[a]
R2
CO2Me
NH
O
R
R
R
1 = F (3d), 93%, 91% ee
1 = Cl (3e), 92%, 90% ee
1 = Br (3f), 71%, 90% ee
3g
tBu
CO2Me
Ph
NH
N2
OH
R1 = Ph ( ), 50%, 91% ee
R2 = OMe (3i), 80%, 93% ee
O
Ph
L
)
[Cu]/ (5 mol %
R1 = OAc ( ),[c] 31%, 90% ee
R2 = Br ( ), 43%, 93% ee
CO2Me
H
3h
3j
+
CO2Me
base, additive
m-xylene, 35 °C
tBu
N
NH
Ph
Ph
24 h
R3
1a
Me Me
2a
3a
O
O
Me
N
Me
N
O
Me Me
CO2Me
O
O
O
O
CO2Me
O
O
CO2Me
NH
NH
Ph
N
N
Ph
Ph
N
N
Ph
NH
Ph
R
R
Ph
Ph
L1
R = Ph (
)
R3 = F (3k), 58%, 93% ee
3m[c]
86%, 94% ee
3n[c]
81%, 94% ee
t
L2
R = Bu (
L3
L4
)
R3 = Me ( ), 67%, 93% ee
3l
Bn Bn
tBu
O
O
O
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
O
N
N
O
N
N
N
N
Ph
Ph
CO2Me
Ph
Ph
CO2Et
Ph
Ph
L5
L6
L7
NH
NH
Ph
Ph
3p
82%, 90% ee
entry
[Cu]
L
base
additive
yield
ee
3o[c]
82%, 90% ee
(%)[b]
30
(%)[c]
11
n.a.
75
52
53
0
1
2
3
4
5
6
7
8
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
CuOTf
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L6
L6
L6
L6
none
NEt3
DIPEA
DIPA
none
none
none
none
none
none
none
none
none
none
none
trace
47
45
52
20
17
27
32
37
40
70
77
70
[a] Unless otherwise specified, all reactions were performed with 0.15 mmol of
the diazo compound, 0.1 mmol of 2a, 5 mol % of CuCl, 6 mol % of L6, 10 mol %
of DIPEA, 6 mol % of NaBARF, 6 mol % of 15-crown-5, and 30 mg of activated
4Å molecular sieves in 1 mL of m-xylene. [b] Performed at gram-scale. [c]
Performed at 20 °C.
PMP
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
13
74
50
86
82
92
90
92
92
Next we evaluated the scope of the reaction with respect to the
phenol (Table 3). First, we explored the effect of the substituent
on the phenolic ring. Electron-donating and electron-withdrawing
groups were tolerated at the para position (4b–4g) and the meta
position (4h–4j); yields were moderate to high, and ee values
ranged from 88% to 96%. Reactions of substrates with electron-
rich heteroaromatic substituents (3-furyl [4k] and 2-thienyl [4l])
proceeded via the same pathway despite the possibility of side
9
10
11
12[d]
13[d]
14[d]
15[d]
NaBARF
NaBARF
NaBARF
NaBARF
Cu(OTf)2
CuCl
94
[a] Unless otherwise specified, all reactions were performed with 0.15
mmol of 1a, 0.1 mmol of 2a, 0.005 mmol of [Cu], 0.006 mmol of L, and
0.01 mmol of a base in 1 mL of m-xylene. [b] Isolated yields. [c] Determined
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10.1002/anie.201907943
Angewandte Chemie International Edition
COMMUNICATION
[a] Unless otherwise specified, all reactions were performed with 0.15 mmol of
the diazo compound, 0.1 mmol of 2a, 5 mol % of CuCl, 6 mol % of L6, 10 mol %
of DIPEA, 6 mol % of NaBARF, 6 mol % of 15-crown-5, and 30 mg of activated
4Å molecular sieves in 1 mL of m-xylene. [b] Performed at 20 °C. [c] Performed
at 30 °C.
reactions between the heteroarene and the diazo compound,
such as Friedel–Crafts or cyclopropanation reactions.
Furthermore, alkene or alkyne substituents on the phenolic ring
(4m–4p) did not undergo cyclopropanation or cyclopropenation
reactions. The tolerance for these functional groups clearly
indicates that this annulation protocol offers opportunities for
preparing compounds that can be elaborated further. Iminyl
substituents were subsequently examined. Again, electron-
donating and electron-withdrawing groups on the N-phenyl ring
were compatible with the reaction conditions, providing products
4q–4w with high enantioselectivities. Notably, this process was
not limited to 2-iminyl phenols. Ketones could also be used as
electrophiles; these reactions produced highly enantioenriched 3-
hydroxy-substituted 2,3-dihydrobenzofurans (4x–4z) bearing two
contiguous tetrasubstituted carbon stereocenters. The absolute
configurations of products 4d and 4y were determined to be
Notably, even though all these reactions formed two
stereocenters, they exclusively gave a single diastereomer with
the ester and the amine (or the hydroxy group) on the same face
of the dihydrobenzofuran ring. To account for the excellent
diastereoselectivity of the cyclization step, we propose the
transition-state model shown in Scheme 2. Because previous
computational studies have demonstrated that Cu(I) catalysts
bind to oxonium ylides more strongly than Rh(II) catalysts, thus
favoring reactions via a metal-associated ylide rather than via a
free ylide,[18] in this model, the Cu catalyst coordinates to both the
oxygen atom of the enolate and the nitrogen atom of the imine;
and the complex adopts a pseudo chair conformation in which
steric repulsion is minimized because all the aryl groups are at
equatorial positions. The excellent activity and stereoselectivity
showcases the power of the bifunctional Cu/BOX catalyst, which
not only reacts with the diazo compound for carbene formation,
but also acts as a Lewis acid to activate the electrophile and
govern the stereoselectivity.
(2S,3R) by X-ray analysis of single crystals.[17]
Table 3. Scope of the annulation reaction with respect to the phenol[a]
CuCl (5 mol %)
OH
O
Ar
N2
L6
(6 mol %)
R
R
+
R'
CO2Me
EH
DIPEA, NaBARF
4Å MS, 15-crown-5
m-xylene, 35 °C
24 h
Ar
CO2Me
R'
E
1a
2b–2z
4b–4z
OMe
Ar = 4-tBuC6H4
E = NAr or O
H
H
OMe
CuLn
Ph
R2
O
Ar
O
Ar
Ar
CO2Me
CuLn
Ph
O
N
N
R1 = Me ( ), 87%, 91% ee
4b
O
Ar
CO2Me
O
R
1 = Ph (4c), 71%, 90% ee
1 = OMe (4d),[b] 94%, 90% ee
4e
O
NH
R1
R
Ph
R2 = Me (4h), 98%, 96% ee
4i
R1 = F ( ),[c] 74%, 91% ee
NH
Ph
1 = Cl (4f),[b] 40%, 89% ee
1 = Br (4g),[b] 46%, 88% ee
R2 = Ph ( ),[c] 86%, 95% ee
4j
R
R
Scheme 2. Proposed transition state for the cyclization step
R2 = OMe ( ), 84%, 94% ee
To further demonstrate the utility of this annulation method, we
carried out several transformations of cyclization product 3a
(Scheme 3). Treatment with NaBH4 reduced the ester group to a
hydroxyl group, yielding product 5. Hydrolysis of the ester with
LiOH as the base gave carboxylic acid 6. Finally, addition of a
methyl Grignard reagent as a base delivered azetidinone-fused
dihydrobenzofuran 7. Notably, all these reactions occurred in high
yields with retention of the enantiomeric purity.
TMS
O
O
O
O
S
Ar
Ar
Ar
CO2Me
CO2Me
CO2Me
NH
NH
NH
Ph
4m[c]
Ph
4k
Ph
4l[c]
80%, 94% ee
46%, 89% ee
75%, 97% ee
Ph
O
O
O
Ar
Ar
CO2Me
Ar
O
CO2Me
Ar
CO2Me
NH
NaBH4
NH
NH
5, 87% yield (92% ee)
CH2OH
TMS
MeOH, 0 °C
Ph
Ph
Ph
Ph
4n
NH
O
4o
76%, 87% ee
4p[c]
Ph
74%, 94% ee
70%, 92% ee
O
Ar
Ar
LiOH
CO2Me
O
CO2H
Ar
O
6, 84% yield (92% ee)
Ar
MeOH/H2O/THF
rt
NH
R3 = Me ( ), 89%, 94% ee
R3 = F ( ),[c] 60%, 91% ee
R3 = Br (4s),[b] 50%, 89% ee
R3 = Ph (4t), 59%, 92% ee
CO2Me
NH
NH
4q
CO2Me
NH
Ph
3a
Ph
4r
(92% ee)
Ar = 4-tBuC6H4
Br
Ar
H
O
MeMgBr
O
R3
7, 81% yield (92% ee)
4u
N
THF, 0 °C
Ph
75%, 90% ee
O
O
Ar
Scheme 3. Transformations of 3a.
Ar
CO2Me
NH
O
CO2Me
Ph
In conclusion, we have developed a protocol for asymmetric
annulation reactions of aryldiazoacetates with 2-iminyl or 2-acyl-
substituted phenols catalyzed by Cu/BOX complexes to afford
enantioenriched 2,3-dihydrobenzofurans bearing tetrasubstituted
carbon stereocenters. This reaction uses readily available
catalysts and mild conditions and shows broad functional group
tolerance and excellent diastereo- and enantioselectivities.
Furthermore, the bifunctional Cu/BOX catalysts are
complementary to the existing cooperative catalytic systems
comprising Rh(II) and a chiral phosphoric acid (or a chiral Lewis
acid) for asymmetric ylide addition reactions. Currently, we are
NH
CO2Me
OH
Me
MeO
Ph
Me
4v[c]
51%, 90% ee
4w
4x[b]
87%, 92% ee
65%, 93% ee
O
O
Ph
CO2Me
OH
Ph
CO2Me
OH
Cl
p-MeC6H4
4z[b]
97%, 90% ee
Ph
4y[b]
68%, 92% ee
This article is protected by copyright. All rights reserved.

10.1002/anie.201907943
Angewandte Chemie International Edition
COMMUNICATION
Z.-Y. Zhang, W. Hu, J. Am. Chem. Soc. 2011, 133, 8428; b) J. Jiang, X.
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investigating new asymmetric ylide transformations with the
catalytic system reported herein.
Acknowledgements
[13] a) Z. Yu, B. Ma, M. Chen, H.-H. Wu, L. Liu, J. Zhang, J. Am. Chem. Soc.
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[14] For the examples of the use of a chiral Rh catalyst as the sole catalyst,
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Chem. 2014, 126, 13352; c) G. Xu, P. Chen, P. Liu, S. Tang, X. Zhang,
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Chem. 2019, 131, 2002.
We thank financial support from the National Natural Science
Foundation of China (21602114 and 21871147), the Natural
Science Foundation of Tianjin (16JCYBJC42500), and the
Fundamental Research Funds for Central Universities.
Keywords: carbene • asymmetric catalysis • cyclization •
oxonium ylide • dihydrobenzofuran
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10.1002/anie.201907943
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Xin-Shen Liang, Rui-Dong Li, Xiao-Chen
Wang*
Page No. – Page No.
Copper-Catalyzed Asymmetric
Annulation Reactions of Carbenes
with 2-Iminyl- or 2-Acyl-Substituted
Phenols: Convenient Access to
Enantioenriched 2,3-
A Cu-catalyzed enantioselective annulation reaction of aryldiazoacetates with 2-
iminyl- or 2-acyl-substituted phenols has been developed to prepare enantioenriched
2,3-dihydrobenzofurans. In this reaction, the Cu catalyst first induces carbene
formation, and then functions as a Lewis acid to activate the electrophile and control
the diastereo- and enantioselectivity.
Dihydrobenzofurans
This article is protected by copyright. All rights reserved.