Catalytic Asymmetric Cross-Dehydrogenative Coupling of 2H-Chromenes and Aldehydes

Article abstract of DOI:10.1002/cjoc.201800369

The first catalytic asymmetric cross-dehydrogenative coupling of 2H-chromenes with aldehydes using o-chloranil (3,4,5,6-tetrachloro-1,2- benzoquinone) as an oxidant has been described. The organocatalytic process is tolerated with a broad range of structurally and electronically varied 2H-chromenes and aldehydes with good yield and high enantiocontrol.

Full text of DOI:10.1002/cjoc.201800369

Catalytic Asymmetric Cross-Dehydrogenative Coupling of 2H-Chromenes
and Aldehydes
a,c,+
a,+
a
a
,a,b
Xinhui Pan, Xigong Liu, Shutao Sun, Zhilin Meng, and Lei Liu*
ABSTRACT
The first catalytic asymmetric cross-dehydrogenative coupling of 2H-chromenes with aldehydes using o-chloranil
(
3,4,5,6-tetrachloro-1,2-benzoquinone) as an oxidant has been described. The organocatalytic process is tolerated with a broad range of structurally and
electronically 2H-chromenes and aldehydes with good yield and high enantiocontrol.
KEYWORDS asymmetric catalysis, C–H functionalization, 2H-chromene, aldehyde, oxidation
Introduction
The cross-dehydrogenative coupling (CDC) reactions of two
readily available C−H substrates have been regarded as an
economic and straightforward strategy for the construction of
1
new C−C bonds whereby the only loss is H
2
formally. However,
the development of corresponding catalytic asymmetric variants
is challenging, mainly because of the incompatibility of the harsh
2
oxidative conditions with the chiral catalyst system. Since the
pioneering studies of the groups of Li and Cozzi, impressive
advances have been achieved for the asymmetric CDC of
electron-rich amines and diarylmethanes, especially N-arylated
3
,4
tetrahydroisoquinolines and xanthenes.
In contrast,
enantioselective CDC of corresponding ether substrates has
remained elusive, probably owning to their increased oxidation
potentials and lack of suitable sites on oxocarbenium ion
intermediates for coordination to chiral catalysts. To the best of
our knowledge, only two examples of enantioselective CDC of
5
,6
ethers have been reported to date. In 2014, our group disclosed
the first catalytic asymmetric bimolecular CDC of cyclic benzylic
5
ethers with aldehydes with excellent enantiocontrol (Figure 1a).
In 2018, Scheidt and co-workers described an elegant
Cu(OTf) -catalyzed enantioselective intramolecular CDC of allylic
2
ethers with appended β-ketoesters, furnishing substituted
Figure
1
Overview of catalytic asymmetric oxidative C−H
functionalization of ethers.
tetrahydropyrones with high yields and enantioselectivity (Figure
o-chloranil as the oxidant (Figure 1d). A broad range of
2H-chromene and aldehyde components were well tolerated with
the organocatalytic process with excellent enantiocontrol and
good functional group compatibility.
6
1
b). Therefore, developing a catalytic asymmetric CDC process of
other types of ether skeletons would still be an attractive project
to pursue.
Enantiopure α-substituted 2H-chromenes and their analogs
are commonly encountered in numerous biologically active
natural products and synthetic pharmaceuticals exhibiting
antipsychotic, antibacterial, antifungal, antiviral, anticancer,
antioxidative, antidepressive, antihypertensive, and antidiabetic
Results and Discussion
Initially, the CDC of 2H-chromene 1a and pentanal 2a was
selected
as
the
model
reaction
using
DDQ
7
,8
activities. Direct and enantioselective C−H functionalization of
H-chromene skeletons with diverse carbon components
(2,3-dichloro-5,6-dicyano-1,4-benzoquinone) as an oxidant for the
search of a suitable chiral catalyst (Table 1). While chiral
imidazolidinone A failed to promote the CDC reaction, expected
3a was isolated in 40% yield and 25% ee when salt A·TFA was
employed as the catalyst (entries 1 and 2, Table 1). A systematic
investigation of the combination of chiral amine catalysts B-F and
Brønsted acids identified phenylalanine-derived catalyst B·TFA to
be optimal in terms of selectivities and yields (entries 2-12, Table
2
represents an ideal strategy that streamlines the synthetic
planning for both complex target molecules and their analogues
for lead discovery. In this context, the Floreancig group
9
documented the first and only example of enantioselective
oxidative C−H functionalization of 2H-chromene with allyl phenyl
dimethylsilane through asymmetric ion-pairing catalysis (Figure
1
0
1
c). Despite great innovation and good enantioselectivity, the
1). Next,
a
series of benzoquinone oxidants bearing
method suffered from high loading of chiral thiophosphoric acid
and limited scope of both 2H-chromene and allylsilane
components. As part of our ongoing interest in enantioselective
oxidative C−H functionalization, we herein communicate the first
catalytic asymmetric CDC of 2H-chromenes with aldehydes using
electron-withdrawing substitutions were evaluated. While the
CDC with p-chloranil (tetrachloro-1,4-benzoquinone) and fluoranil
(tetrafluoro-1,4-benzoquinone) did not provide any expected 3a,
o-chloranil proved to be an ideal oxidant for the process,
furnishing 3a in 80% yield and 61% ee (entries 3 and 13-15, Table
a
c
School of Pharmaceutical Sciences, Shandong University, Jinan 250012 China
Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of
E-mail: leiliu@sdu.edu.cn
School of Chemistry and Chemical Engineering, Shandong University, Jinan
Education, School of Pharmaceutical Sciences, Shihezi University, Shihezi
832002, China
b
250100, China
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.201800369
This article is protected by copyright. All rights reserved.

a
Table 1 Reaction condition optimization.
1). Synchronous presence of LiOTf and H
and 87% ee (entry 21, Table 1). The amount of H
the enantioselectivity, and increasing the H O additive from 1.5
2
O led to 3a in 80% yield
2
O was crucial to
2
equiv to 30 equiv afforded 3a in 78% yield and 94% ee (entries 22
and 23, Table 1).
b
c
d
Entry
Amine
A
Additive
d.r.
Yield (%)
< 5
ee (%)
n.d.
25
Scheme 1 The scope of aldehydes.
1
2
3
—
—
—
n.d.
1.7:1
1.9:1
A·TFA
B·TFA
40
80
52
4
5
6
7
8
9
C·TFA
D·TFA
E·TFA
F·TFA
F
—
—
—
—
—
—
—
—
—
—
—
—
—
1.2:1
1.5:1
1.4:1
n.d.
65
70
70
< 5
< 5
58
57
55
59
< 5
< 5
80
70
40
< 5
64
61
80
78
76
40
47
48
n.d.
n.d.
40
n.d.
B·HCl
B·DCA
B·HCOOH
B·AcOH
B·TFA
B·TFA
B·TFA
B·TFA
B·TFA
B·TFA
B·TFA
B·TFA
B·TFA
B·TFA
B·TFA
1.7:1
1.5:1
1.3:1
1.4:1
n.d.
10
11
12
46
40
45
e
13
n.d.
n.d.
61
f
14
n.d.
g
1
5
1.9:1
1.9:1
1.7:1
n.d.
g,h
g,h
g,h
g,h
g,h
g,h
1
6
7
8
9
0
1
66
1
1
1
2
2
LiClO
4
58
LiOAc
LiOTf
n.d.
77
1.9:1
1.9:1
1.9:1
1.9:1
1.9:1
H
2
O
76
LiOTf/H
LiOTf/H
LiOTf/H
2
2
2
O
O
O
87
With the optimized reaction conditions in hand, the scope of
aldehyde components was extensively examined (Scheme 1).
Generally, the organocatalytic enantioselective CDC of
g,h,i
2
2
94
g,h,j
2
3
94
2
H-chromene 1a with a wide range of aldehydes proceeded
smoothly, furnishing the corresponding expected α-alkylated
H-chromenes 3a-3j in good yields (60−95%) with excellent
enantioselectivities (92% ee on average) and moderate
2
diastereocontrol. Notably, the protocol showed excellent
functional group tolerance, with commonly encountered moieties
such as aryl (3d-3f), benzyl ethers (3g), silyl ethers (3h), and
alkenes (3i) tolerated, thus demonstrating the capacity in creating
diverse α-substituted 2H-chromenes.
Scheme 2 The scope of 2H-chromenes.
a
Reaction conditions, unless otherwise specified: a solution of 1a
0.2 mmol) and DDQ (0.19 mmol) in CH Cl (2.0 mL) was stirred at
(
2
2
rt for 0.5 h, followed by amine catalyst (0.04 mmol), 2a (0.8
b
mmol), and additive (1.5 equiv) at rt for 12-24 h. Determined by
1
c
d
H NMR spectroscopy. Isolated yield of the two diastereomers.
e
Determined by chiral HPLC analysis. p-Chloranil instead of DDQ
as an oxidant. Fluoranil instead of DDQ as an oxidant.
o-Chloranil instead of DDQ as an oxidant. Reaction at 0 °C. 30
2 2
equiv of H O added. 40 equiv of H O added. n.d. = not
f
g
h
i
j
determined, TFA = trifluoroacetic acid, DCA = dichloroacetic acid,
Ac = acyl, Tf = trifluoromethanesulfonyl, Bn = benzyl, TMS =
trimethylsilyl.
1
). The enantioselectivity was further increased to 66% by
lowering the temperature to 0 °C (entry 16, Table 1). A range of
additives were then introduced to the system, and either LiOTf or
2
H O was found to be beneficial for improving the enantiocontrol,
giving 3a in 77% ee and 76% ee, respectively (entries 17-20, Table
This article is protected by copyright. All rights reserved.

The scope of 2H-chromenes was next investigated (Scheme 2). We postulate that LiOTf should act as a Lewis acid to promote the
2
H-chromenes 1b and 1c bearing electron-donating substitutions
breakdown of the intermediate 5 into ion pair 8, which is a better
at the C6 position participated in the enantioselective CDC with
electrophile for subsequent nucleophilic attack in terms of
[
13]
2a efficiently, generating corresponding 4b and 4c with 91% and
enantiocontrol. In the predominant (E)-iminium ion 9,
the
9
2% ee, respectively. 2H-Chromenes bearing
benzyl group on the imidazolidinone ring shields the Re face of
the enamine (10), and the oxocarbenium ion will be attacked
from the Si face of 9 to give 11 with R configuration at the C2
electron-withdrawing moiety at C6 position were well tolerated
with the standard conditions, though slightly decreased efficiency
was observed, which might be ascribed to the increased oxidation
potential of 1d. 2H-Chromenes 1e and 1f bearing substitutions at
C5 and C7 positions were found to be competent substrates with
good enentiocontrol. 2H-Benzo[h]chromene 1g also proved to be
suitable component for the asymmetric coupling reaction, further
demonstrating the tolerance of diverse substituent patterns on
[
13b]
position.
The configuration at the C1’ position depends on
whether the attack occurs on the Si or Re face of the intermediate
8. The absolute and relative configurations of products were
determined by comparing the NMR spectra of CDC products with
8b
known compounds.
2
H-chromenes. The substitution effect on the dihydropyran ring
Conclusions
was next examined. The asymmetric CDC of C4-methyl
substituted 1h proceeded smoothly. The attempt to construct
quaternary carbon center from C2-methyl substituted 1i failed,
which might be ascribed to the increased steric hindrance on the
ether substrate.
In summary, we have developed the first catalytic asymmetric
CDC reaction of 2H-chromenes with aldehydes. The
organocatalytic process is tolerated with a broad range of
structurally and electronically 2H-chromenes and aldehydes with
good yield and high enantiocontrol. Instead of commonly adopted
DDQ, o-chloranil was used as the oxidant for the enantioselective
oxidative C−H functionalization for the first time. The study on the
catalytic asymmetric CDC of other types of ethers is being
pursued and will be reported in due course.
Scheme 3 Control experiment.
Experimental
To a solution of 2H-chromene 1 (0.2 mmol, 1.0 equiv) in
CH Cl (2.0 mL) was added o-chloranil (0.19 mmol, 0.95 equiv) at
2 2
room temperature. The reaction was monitored by TLC and, upon
starting material consumption, LiOTf (0.3 mmol, 1.5 equiv), B·TFA
During the course of the enantioselective CDC process, TLC
analysis suggested the formation of a considerable amount of an
intermediate, which was verified to be hemiacetal 5 (Scheme 3).
Subjecting 5 to the standard CDC conditions in the absence of
oxidation elements afforded comparable ee and yield to those
starting from 2H-chromene 1a, thus implying the intermediacy of
(
(
0.04 mmol, 20 mol%), aldehyde 2 (0.8 mmol, 4.0 equiv), and H
2
O
6.0 mmol, 30 equiv) were successively added at 0 °C. The
reaction mixture was stirred at 0 °C until TLC analysis showed
complete starting material consumption. The reaction mixture
5
in the asymmetric CDC process.
was then poured into the suspension of excess NaBH
.0 equiv) in MeOH (1.0 mL) at 0 °C, and after stirring for 20 min,
the solution was treated with saturated aqueous NaHCO . The
mixture was extracted with Et O (10 mL × 3), and the combined
organic layer was dried over MgSO , filtered and the solvent was
4
(0.4 mmol,
2
3
2
4
evaporated under vacuum. The residue was purified by flash
chromatography to give the desired product.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement
We gratefully acknowledge the National Science Foundation
of China (21722204, 21472112) and the Fok Ying Tung Education
Foundation (151035) for support.
References
[
1] Selected reviews on CDC reactions: (a) Murahashi, S. I.; Komiya, N.;
Terai, H.; Nakae, T.; Komiya, N. J. Am. Chem. Soc. 2003, 125, 15312;
(b) Li, C.-J. Acc. Chem. Res. 2009, 42, 335; (c) Scheuermann, C. J.
Chem. Asian J. 2010, 45, 436; (d) Klussmann, M.; Sureshkumar, D.
Synthesis 2011, 353; (e) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011,
Figure 2 Stereochemical analysis.
1
11, 1215; (f) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111,
A plausible mechanism for the CDC process is shown in Figure
1780; (g) Rohlmann, R.; García Mancheño, O. Synlett 2013, 24, 6; (h)
2
. 2H-Chromene 1a was oxidized by o-chloranil in a reversible
[11]
Girard, S. A.; Knauber, T.; Li, C.-J. Angew. Chem. Int. Ed. 2014, 53, 74;
i) Miao, J.; Ge, H. Eur. J. Org. Chem. 2015, 7859; (j) Liu, C.; Yuan, J.;
Gao, M.; Tang, S.; Li, W.; Shi, R.; Lei, A. Chem. Rev. 2015, 115, 12138.
process to generate ion pair 7.
H
2
O and LiOTf are beneficial for
O is present in the
(
improving the enantioselectivity. When H
system, 7 might be captured by H O affording hemiacetal 5.
2
[
12]
2
This article is protected by copyright. All rights reserved.

[
[
2] (a) Zheng, C.; You, S.-L. RSC Adv. 2014, 4, 6173; (b) Qin, Y.; Lv, J.; Luo, [7] (a) Lu, Z.; Lin, Z.; Wang, W.; Du, L.; Zhu, T.; Fang, Y.; Gu, Q.; Zhu, W. J.
S. Tetrahedron Lett. 2014, 55, 551; (c) Zhao, Y.-L.; Wang, Y.; Luo,
Y.-C.; Fu, X.-Z.; Xu, P.-F. Tetrahedron Lett. 2015, 56, 3703.
Nat. Prod. 2008, 71, 543; (b) Pan, L.; Matthew, S.; Lantvit, D. D.;
Zhang, X.; Ninh, T. N.; Chai, H.; Carcache de Blanco, E. J.; Soejarto, D.
D.; Swanso, S. M.; Kinghorn, A. D. J. Nat. Prod. 2011, 74, 2193; (c)
Maneerat, W.; Ritthiwigrom, T.; Cheenpracha, S.; Promgool, T.;
Yossathera, K.; Deachathai, S.; Phakhodee, W.; Laphookhieo, S. J.
Nat. Prod. 2012, 75, 741; (d) TenBrink, R. E.; Bergh, C. L.; Duncan, J.
N.; Harris, D. W.; Huff, R. M.; Lahti, R. A.; Lawson, C. F.; Lutzke, B. S.;
Martin, I. J.; Rees, S. A.; Schlachter, S. K.; Sih, J. C.; Smith, M. W. J.
Med. Chem. 1996, 39, 2435; (e) Clarke, R. L.; Harris, L. S. J. Med.
Chem. 1962, 5, 77; (f) Bauer, D. J.; Selway, J. W. T.; Batchelor, J. F.;
Tisdale, M.; Caldwell, I. C.; Young, D. A. B. Nature 1981, 292, 369.
[8] (a) Moquist, P. N.; Kodama, T.; Schaus, S. E. Angew. Chem. Int. Ed.
2010, 49, 7096; (b) Rueping, M.; Volla, C. M. R.; Atodiresei, L. Org.
Lett. 2012, 14, 4642; (c) Maity, P.; Srinivas, H. D.; Watson, M. P. J. Am.
Chem. Soc. 2011, 133, 17142; (d) Srinivas, H. D.; Maity, P.; Yap, G. P.
A.; Watson, M. P. J. Org. Chem. 2015, 80, 4003.
3] (a) Benfatti, F.; Guiteras Capdevila, M.; Zoli, L.; Benedetto, E.; Cozzi,
P. G. Chem. Commun. 2009, 45, 5919; (b) Guo, C.; Song, J.; Luo,
S.-W.; Gong, L.-Z. Angew. Chem. Int. Ed. 2010, 49, 5558; (c) Zhang,
B.; Xiang, S.-K.; Zhang, L.-H.; Cui, Y.; Jiao, N. Org. Lett. 2011, 13, 5212;
(d) Zhao, Y.-L.; Wang, Y.; Hu, X.-Q.; Xu, P.-F. Chem. Commun. 2013,
49, 7555; (e) Larionov, E.; Mastandrea, M. M.; Pericàs, M. A. ACS
Catal. 2017, 7, 7008.
[
4] (a) Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997; (b) Li, Z.; MacLeod, P. D.; Li,
C.-J. Tetrahedron: Asymmetry 2006, 17, 590; (c) Zhang, G.; Zhang, Y.;
Wang, R. Angew. Chem. Int. Ed. 2011, 50, 10429; (d) Zhang, J.;
Tiwari, B.; Xing, C.; Chen, X.; Chi, Y. R. Angew. Chem. Int. Ed. 2012,
51, 3649; (e) Zhang, G.; Ma, Y.; Wang, S.; Zhang, Y.; Wang, R. J. Am.
Chem. Soc. 2012, 134, 12334; (f) D. A. DiRocco, T. Rovis, J. Am. Chem.
Soc. 2012, 134, 8094; (g) Zhang, G.; Ma, Y.; Wang, S.; Kong, W.;
Wang, R. Chem. Sci. 2013, 4, 2645; (h) Neel, A. J.; Hehn, J. P.; Tripet,
P. F.; Toste, F. D. J. Am. Chem. Soc. 2013, 135, 14044; (i) Bergonzini,
G.; Schindler, C. S.; Wallentin, C.-J.; Jacobsen, E. N.; Stephenson, C. R.
J. Chem. Sci. 2014, 5, 112; (j) Tan, Y.; Yuan, W.; Gong, L.; Meggers, E.
[9] (a) Wu, Z.-J.; Qian, J.; Wang, T.-T.; Huang, Z.-Z. Synlett. 2014, 25, 2072;
(b) Li, F.; Meng, Z.; Hua, J.; Li, W.; Lou, H.; Liu, L. Org. Biomol. Chem.
2015, 13, 5710; (c) Yang, F.; Li, Y.; Floreancig, P. E.; Li, X.; Liu, L. Org.
Biomol. Chem. 2018, 16, 5144.
Angew. Chem. Int. Ed. 2015, 54, 13045; (k) Wei, X.-H.; Wang, G.-W.; [10] Cui, Y.; Villafane, L. A.; Clausen, D. J.; Floreancig, P. E. Tetrahedron
Yang, S.-D. Chem. Commun. 2015, 51, 832; (l) Liu, X.; Meng, Z.; Li, C.; 2013, 69, 7618.
Lou, H.; Liu, L. Angew. Chem. Int. Ed. 2015, 54, 6012; (m) Liu, X.; Sun, [11] Jung, H. H.; Floreancig, P. E. Tetrahedron 2009, 65, 10830.
S.; Meng, Z.; Lou, H.; Liu, L. Org. Lett. 2015, 17, 2396; (n) Sun, S.; Li, [12] (a) Lakhdar, S.; Maji, B.; Mayr, H. Angew. Chem. Int. Ed. 2012, 51,
C.; Floreancig, P. E.; Lou, H.; Liu, L. Org. Lett. 2015, 17, 1684; (o) Xie,
Z.; Liu, X.; Liu, L. Org. Lett. 2016, 18, 2982; (p) Xie, Z.; Zan, X.; Sun, S.;
5739; (b) Cozzi, P. G.; Benfatti, F. Angew. Chem. Int. Ed. 2010, 49,
256.
Pan, X.; Liu, L. Org. Lett. 2016, 18, 3944; (q) Wei, G.; Zhang, C.; Bureš, [13] (a) Peelen, T. J.; Shi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2005, 127,
F.; Ye, X.; Tan, C.-H.; Jiang, Z. ACS Catal. 2016, 6, 3708; (r) Yang, Q.;
Zhang, L.; Ye, C.; Luo, S.; Wu, L.-Z.; Tung, C.-H. Angew. Chem. Int. Ed.
11598; (b) Mangion, I. K.; Northrup, A. B.; MacMillan, D. W. C.
Angew. Chem. Int. Ed. 2004, 43, 6722.
2
017, 56, 3694; (i) Fu, N.; Li, L.; Yang, Q.; Luo, S. Org. Lett. 2017, 19,
(
The following will be filled in by the editorial staff)
2122.
Manuscript received: XXXX, 2017
[
[
5] Meng, Z.; Sun, S.; Yuan, H.; Lou, H.; Liu, L. Angew. Chem. Int. Ed.
014, 53, 543.
6] Lee, A.; Betori, R. C.; Crane, E. A.; Scheidt, K. A. J. Am. Chem. Soc.
Revised manuscript received: XXXX, 2017
Accepted manuscript online: XXXX, 2017
Version of record online: XXXX, 2017
2
2018, 140, 6212.
This article is protected by copyright. All rights reserved.

Entry for the Table of Contents
Page No.
Catalytic
Cross-Dehydrogenative
Asymmetric
Coupling of
2
H-Chromenes and Aldehydes
The first catalytic asymmetric cross-dehydrogenative coupling of 2H-chromenes with aldehydes
using o-chloranil as an oxidant has been described. The organocatalytic process is tolerated with a
broad range of structurally and electronically 2H-chromenes and aldehydes with good yield and
high enantiocontrol.
a,c,+
a
Xigong Liu, Shutao Sun,a
Zhilin Meng, and Lei Liu
a,+
Xinhui Pan,
*,a,b
a
c
School of Pharmaceutical Sciences, Shandong University, Jinan 250012 China
E-mail: leiliu@sdu.edu.cn
School of Chemistry and Chemical Engineering, Shandong University, Jinan
Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of
Education, School of Pharmaceutical Sciences, Shihezi University, Shihezi
832002, China
b
250100, China
This article is protected by copyright. All rights reserved.