A nickel(ii)-catalyzed asymmetric intramolecular Alder-ene reaction of 1,7-dienes

Article abstract of DOI:10.1039/c9cc01521c

A highly diastereo- and enantioselective intramolecular Alder-ene reaction with an alkene as the enophile has been developed by using a chiral N,N′-dioxide/nickel(ii) complex as the catalyst. This protocol provides a facile route towards the synthesis of diverse 3,4-disubstituted chroman, tetrahydroquinoline, piperidine and thiochroman derivatives in high yields with good to excellent diastereo- and enantioselectivities.

Full text of DOI:10.1039/c9cc01521c

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
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DOI: 10.1039/C9CC01521C
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Nickel(II)-catalyzed asymmetric intramolecular Alder-ene reaction
of 1,7-dienes
Wen Liu, Pengfei Zhou, Jiawen Lang, Shunxi Dong,* Xiaohua Liu and Xiaoming Feng*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A highly diastereo- and enantioselective intramolecular Alder-ene
reaction with alkene as the enophile has been developed by using
a chiral N,N-dioxide/nickel(II) complex as the catalyst. This
protocol provides a facile route towards the synthesis of diverse
3,4-disubstituted chroman, tetrahydroquinoline, piperidine and
thiochroman derivatives in high yields with good to excellent
diastereo- and enantioselectivities.
a) Stoichiometric chiral Lewis acid mediated intramolecular Alder-ene
reaction with alkenes as the enophiles (ref. 7)
EWG
100–200 mol%
chiral Lewis acid
EWG


b) Organocatalytic Alder-ene reaction with cinnamaldehydes as the enophiles
(ref. 8)
The ene reaction,1-2 as one of the most powerful methods for
C‒C bond formation, has been widely used in rapid synthesis of
complex molecules and natural products.3 In the past several
decades, remarkable progress has been made in the area of
asymmetric ene reactions with the enophiles bearing C=O,4
C=N,5 and C≡C6 bonds. In sharp contrast, the enantioselective
ene reactions using alkenes (C=C bond) as the enophiles are
rather limited.7,8 Restrained by the low reactivity of olefins
along with high activation energy of ene reactions,2c
stoichiometric chiral Lewis acid catalysts were usually necessary
to get satisfied outcomes (Scheme 1a).7 To date, the only
example of organocatalytic enantioselective intermolecular ene
reaction of ,-unsaturated enals (as the enophiles) was
realized by the Hayashi group utilizing diphenylprolinol silyl
ether as the catalyst, good yields and high enantioselectivities
could be obtained with focus on cyclopentadiene as the ene
component (Scheme 1b).8 Thus, discovery of new olefin-based
ene reactions is highly desirable but challenging.
10 mol% cat.,
20 mol%
p-nitrophenol
CHO
CHO
CHO
+
+
Ar
MeOH
Ar
Ar
OTBS
Ph
cat.:
N
H
Ph
c) Asymmetric catalytic intramolecular Alder-ene reaction of 1,7-dienes (this
work)
R'O2C
R'O2C
CO2R'
CO2R'
R
R
1–10 mol%
N,N'-dioxide/Ni(II)
X
X
2
1
 Atom-economical process
 Broad substrate scope
 Diverse chiral heterocycles
24 examples
up to 99% ee,
>19:1 d.r.
X= O, NTs, S
Scheme 1. Enantioselective intermolecular and intramolecular Alder-ene
reactions with alkenes as the enophiles. EWG = electron-withdrawing group.
The chemistry of heterocycles has attracted considerable
attention due to its increasing importance in the field of
pharmaceuticals and industrial chemicals. Among the vast array
of heterocycles, chroman and tetrahydroquinoline moieties are
of particular interest because of their frequent existence in
various biologically active molecules and natural products.9-10
Consequently, great endeavors have been devoted to develop
facile routes towards the synthesis of these highly valuable
chiral compounds. On the other hand, intramolecular Alder-ene
reactions provide efficient straightforward accesses to a variety
of chiral functionalized carbocyclic and heterocyclic
compounds. However, this strategies are seldomly used in the
construction of chiral chroman and tetrahydroquinoline
derivatives.7c In this regard, we designed a new type of 1,7-
dienes 1 in which a heteroatom containing tether was
introduced to connect ,-unsaturated ester and alkene
bearing an allylic hydrogen, and we envisioned that if
Key Laboratory of Green Chemistry & Technology, Ministry of Education,
College of Chemistry, Sichuan University, Chengdu 610064, P. R. China.
E-mail: dongs@scu.edu.cn, xmfeng@scu.edu.cn; Fax: +86 28 85418249
†Electronic Supplementary Information (ESI) available. CCDC 1889731. For ESI and
crystallographic data in CIF or other electronic format see DOI:10.1039/x0xx00000x
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compound 1 could be activated by a Lewis acid and undergo an oxygen-incorporated tether was selected as VietwheArticlme Oondlineel
intramolecular Alder-ene reaction, chroman
and substrate to optimize the reaction condiDtiOoIn: 1s0(.1T0a3b9l/eC91C)C. 0In15t2h1Ce
tetrahydroquinoline could be readily obtained (Scheme 1c). presence of two equiv of ZnCl2 in CH2Cl2 at 30 °C, the reaction
Herein, we wish to report the results of this effort. Chiral N,N- occurred and the desired Alder-ene product 2a was isolated in
dioxide/Ni(NTf2)2 complex11 developed by our group was found 73% yield with 91:9 dr (entry 1). The initial attempt to promote
to be a suitable catalyst to promote the titled reaction, the reaction by using catalytic amount of chiral N,N-dioxide–
providing chroman and tetrahydroquinoline derivatives in good Sc(OTf)3 complex turned out to be unsuccessful (entry 2). Taking
yields with high diastereo- and enantioselectivities (up to 90% account into high activation energy of olefin-based ene
yield, >19:1 dr and 99% ee). In addition, optically active reaction, we performed the reaction at a higher temperature
piperidine and thiochroman could be synthesized as well by this (60 °C) in CH2ClCH2Cl (DCE), and product 2a could be afforded in
strategy.
In our preliminary investigation, 1,7-diene 1a bearing an
84% yield but as a racemic mixture (entry 3). Next, various
metal salts were screened by coordinating with L-pipecolic acid
derived N,N'-dioxide L-PiPr2 (entries 4–7). It was found that the
complex with Zn(OTf)2 didn’t show any activity toward 1a (entry
4) and the use of Cu(OTf)2 provided the product 2a in good yield
but with low ee value (entry 5). Pleasingly, the complexes with
Mg(OTf)2 or Ni(OTf)2 could promote the reaction smoothly,
providing the promising results (entries 6 and 7). And nickel-
based complex was a better choice since higher ee value was
provided (66% ee vs. 51% ee). The examination of the
counterions of the nickel salts suggested that Ni(NTf2)2 could
give better results (entry 9 vs. entries 7 and 8). Then further
investigations focused on the chiral backbone of the N,N-
dioxide ligands. L-Ramipril derived L-RaPr2 was superior to L-
PrPr2 derived from L-proline and L-PiPr2 in terms of ee value
(entry 11 vs. entries 9 and 10). Decreasing the steric hindrance
of the amide moiety in the ligand resulted in poor outcomes
(entries 11–13). Gratifyingly, the catalyst loading could be
reduced to 5 mol% without any detrimental influence on the
stereoselectivity and yield (entry 14).
Table 1 Optimization of the reaction conditionsa
EtO2C
CO2Et
H
EtO2C
Ligand/metal salt
(1:1, 10 mol%)
CO2Et
DCE, 60 °C, 24 h
O
O
2a
1a
n
n
N
N
N
N
O
O
O
O
O
O
O
O
N
N
N
N
H
H
H
H
Ar
Ar
Ar
Ar
L-RaPr2: Ar = 2,6-iPr2C6H3
L-RaEt2: Ar = 2,6-Et2C6H3
L-RaMe2: Ar = 2,6-Me2C6H3
L-PrPr2: Ar = 2,6-iPr2C6H3, n = 1
L-PiPr2: Ar = 2,6-iPr2C6H3, n = 2
Entry
Metal salt
Ligand
Yield
(%)b
drc
ee (%)c
Having identified optimal conditions for the intramolecular
Alder-ene reaction (Table 1, entry 14), we next explored the
substrate scope (Table 2). When the ethyl ester group of
alkylidene malonates was replaced by a methyl or iso-propyl
moiety, the enantioselectivity of products 2b and 2c remained
good (95% ee) and the diastereoselectivity gradually increased
along with increasing steric hindrance of the ester group
(9:1−12:1 dr). In addition, the ene unit can be modified with
various substituents that produce a wide range of chiral Alder-
ene products (2d−2h). For instance, substrates 1d−1f bearing 5-,
6-, and 7-membered rings underwent the reaction smoothly,
delivering the corresponding products 2d−2f in good yields and
stereoselectivities (77−90% yield, 11:1− >19:1 dr, 76−99% ee).
Applying 1-methyl-1-phenyl substituted olefins on the substrate
could afford the product 2g in good yield with excellent dr and
ee value (83% yield, >19:1 dr, 98% ee). Long chain olefin was
also compatible with the current system, and the reaction of
geranyl substituted substrate 1h provided the desired product
2h with 98% ee and 5:1 dr at higher catalyst loading (10 mol%).
Next, a wide range of alkylidene malonates with different
substituents on the phenyl group (1i−1q) were evaluated. It was
found that the position of substituents had a significant
influence on the reactivity and stereoselectivity. The reaction of
3- or 4-substituted ones delivered the chromans 2i−2l with
equally well results (76−90% yield, 7:1−12:1 dr, 96−98% ee).
However, lower yields and dr values (43−62% yield, 1.5:1−5:1
dr) were given with the substitutions at the 5- or 6-position of
1d
2e
3
ZnCl2
-
73
n.r.
84
n.r.
79
83
86
86
84
95
86
88
91:9
-
-
Sc(OTf)3
Sc(OTf)3
Zn(OTf)2
Cu(OTf)2
Mg(OTf)2
Ni(OTf)2
L-PiPr2
L-PiPr2
L-PiPr2
L-PiPr2
L-PiPr2
L-PiPr2
-
88:12
-
0
4
-
5
86:14
89:11
87:13
89:11
90:10
93:7
93:7
92:8
91:9
93:7
2
6
51
66
11
70
93
97
77
39
97
7
8
Ni(ClO4)2·6H2O L-PiPr2
9
Ni(NTf2)2
Ni(NTf2)2
Ni(NTf2)2
Ni(NTf2)2
Ni(NTf2)2
Ni(NTf2)2
L-PiPr2
L-PrPr2
L-RaPr2
L-RaEt2
10
11
12
13
14f
L-RaMe2 87
L-RaPr2 86
a
Unless otherwise stated, all reactions were performed with 1a (0.1 mmol) and
ligand/metal salt (1:1, 10 mol%) in DCE (1.0 mL) at 60 °C for 24 h. b Isolated yield of
two diastereomers. Determined by chiral HPLC analysis. Performed with ZnCl2
(2.0 equiv) in CH2Cl2 at 30 °C. Performed in CH2Cl2 at 30 °C. 5 mol% catalyst
loading.
c
d
e
f
2 | J. Name., 2012, 00, 1-3
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Table 2. Substrate scope of the reaction.a
MeO2
C
CO2Me
H
MeO2
C
a)
L-RaPr2/Ni(NTf2
(1:1, 5 mol%)
)
2
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CO2Me
DOI: 10.1039/C9CC01521C
R'O2C
R'O2C
6
DCE (0.1 M),
60 °C, 36 h
5
N
CO2R'
N
CO2R'
R
R
4
Ts
Ts
L-RaPr2/Ni(NTf2)2 (1:1, 5 mol%)
2s, 1.31 g, 95% yield
98% ee, 96:4 d.r.
(R, R)-2s
CCDC 1889731
1s, 3.0 mmol, 1.37 g
DCE, 60 °C
3
X
X
1a–1x
2a–2x
MeO2
C
OH
b)
EtO2C
MeO2C
iPrO2C
MeO2C
H
CO2Me
CO2Me
CO2Et
CO2Me
CO2iPr
CO2Me
H
O
I
3
1
2
N
N
N
N
Ts
Ts
3s, 94% yield, 98% ee
Ts
Ts
O
2a, 24 h
O
O
O
4s, 90% yield, 98% ee
5s, 75% yield, 98% ee
2b, 24 h
89% yield, 95% ee,
9:1 d.r.
2c, 24 h
2d, 1 mol% cat., 48 h
77% yield, 76% ee,
11:1 d.r.
2s, 98% ee
80% yield, 97% ee,
11:1 d.r.
84% yield, 95% ee,
12:1 d.r.
OH
MeO2
C
c)
H
CO2Me
CO2Me
MeO2C
CO2Me
MeO2C
MeO2C
CO2Me
MeO2C
CO2Me
H
O
I
1
2
3
CO2Me
O
O
O
2b, 95% ee
O
5b, 75% yield, 97% ee,
3b, 96% yield, 95% ee
4b, 93% yield, 95% ee
Ph
O
O
O
O
79:21 d.r.
2h, 10 mol% cat., 48 h
72% yield, 98% ee,
5:1 d.r.
2e, 16 h
89% yield, 98% ee,
>19:1 d.r.
2f, 20 h
90% yield, 99% ee,
16:1 d.r.
2g, 16 h
83% yield, 98% ee,
>19:1 d.r.
Scheme 2. a) Gram-scale version of the reaction. b) Transformation of 2s. c)
Transformation of 2b. Conditions: 1) LiCl, H2O, DMSO, 130 °C; 2) iBu2AlH, CH2Cl2,
40 °C; 3) NIS, CH2Cl2, r.t..
MeO2C
MeO2C
CO2Me
MeO2C
MeO2C
CO2Me
CO2Me
Me
CO2Me
Cl
1w was also a viable substrate, forming the corresponding
piperidine 2w in 80% yield with 6:1 dr and 81% ee. When sulfur
atom was incorporated into the tethering moiety, longer
reaction time and higher temperature with 10 mol% catalyst
were needed to get the thiochroman derivative 2x with good
results (71% yield, 80% ee, 4:1 dr).
F
O
MeO
O
O
O
2i, 8 h
76% yield, 96% ee,
7:1 d.r.
2j, 36 h
83% yield, 98% ee,
7.5:1 d.r.
2k, 24 h
90% yield, 96% ee,
9:1 d.r.
2l, 36 h
85% yield, 97% ee,
12:1 d.r.
Cl
MeO2C
Br
MeO2C
Me
MeO2C
MeO
MeO2C
CO2Me
CO2Me
CO2Me
CO2Me
O
O
O
O
To show the utility of the reaction, a gram-scale synthesis of
2s was carried out (Scheme 2a). Under the optimized
conditions, 1s (3.0 mmol) reacted smoothly to afford the
product 2s with comparable results and the absolute
configuration of 2s was determined to be (R,R) by X-ray
crystallography.12 Next, transformations of the product were
conducted (Scheme 2b). An initial decarboxylation of 2s gave
the monoester product 3s in 94% yield with 98% ee. Reduction
of 3s with iBu2AlH generated the 4s in 90% yield. Furthermore,
the iodocyclization of 4s with NIS was completely
diastereoselective and yielded the polycyclic compound 5s as a
single diastereomer in 75% yield. Then we applied the same
reaction conditions into the transformation of 2b to provide the
product 5b containing a tricyclic compound with chroman units
(Scheme 2c). This tetrahydropyranochromene skeleton exists in
2m, 10 mol% cat., 68 h
62% yield, 90% ee,
17% yield, 75% ee,b
3:1 d.r.
2n, 10 mol% cat., 96 h
61% yield, 90% ee,
27% yield, 75% ee,b
2.5:1 d.r.
2p, 10 mol% cat., 120 h
58% yield, 92% ee,
15% yield, 80% ee,b
4:1 d.r.
2o, 10 mol% cat., 72 h
60% yield, 91% ee,
5:1 d.r.
MeO2C
CO2Me
MeO2C
F
CO2Me
O
CO2Me
MeO
CO2Me
CO2Me
O
N
N
CO2Me
Ts
Ts
2q, 10 mol% cat., 80 °C, 48 h,
43% yield, 95% ee,
32% yield, 81% ee,b
1.5:1 d.r.
2r, 10 mol% cat.,
80 °C, 48 h,
49% yield, 20% ee,
6:1 d.r.
2s, 36 h
89% yield, 98% ee,
> 19:1 d.r.
2t, 10 mol% cat., 96 h
75% yield, 90% ee,
>19:1 d.r.
Cl
MeO2C
MeO2C
MeO2C
CO2Me
CO2Me
CO2Me
CO2Me
Ts
N
CO2Me
N
N
S
Ts
Ts
2x, 10 mol% cat.,
80 °C,10 d,
71% yield, 80% ee,
4:1 d.r.
2v, 72 h
2w, 16 h
80% yield, 81% ee,
6:1 d.r.
2u, 10 mol% cat., 72 h
76% yield, 94% ee,
6:1 d.r.
44% yield, 85% ee,
43% yield, 78% ee,
1:1 d.r.
a
number of potentially antiproliferative, polyphenolic
compounds which were isolated from the seeds of Alpinia
blepharocalyx. However, few methods were described for the
syntheses of the core tricyclic framework.13
In summary, we have successfully realized the highly
enantioselective intramolecular ene reactions with alkenes as
a Unless otherwise stated, all reactions were performed with 1 (0.1 mmol) and L-
RaPr2/Ni(NTf2)2 (1:1, 5 mol%) in DCE (1.0 mL) at 60 °C. Isolated yield of the major
diastereomer. The ee values were determined by chiral HPLC analysis and the dr
b
were determined by 1H NMR analysis of crude products. Isolated yield and ee
value of the minor diastereomer.
the enophiles by using
a catalytic amount of the L-
the phenyl group (2m−2q), especially for the electron-
withdrawing substituted ones (2m, 2n and 2q), but good
enantioselectivities were retained (90−95% ee). The
dramatically decreased stereoselectivity might be caused by the
steric hindrance of the substituents (see stereocontrol model in
ESI for details). Changing the phenyl to naphthyl led to the poor
reactivity and enantioselectivity (2r, 49% yield, 20% ee, 6:1 dr).
Finally, we examined the scope of the reaction with respect to
the tethering moiety. With N-containing linkers, the
RaPr2/Ni(NTf2)2 complex as the catalyst. This protocol presents
a potentially general approach toward the synthesis of diverse
chroman, tetrahydroquinoline, piperidine and thiochroman
derivatives in good yields with good to excellent diastereo- and
enantioselectivities from achiral precursors under mild
conditions. Further exploration of the application and extension
of this methodology are currently in progress in our laboratory.
We acknowledge the National Natural Science Foundation of
China (No. 21432006 and 21772127) for financial support.
intramolecular
ene
reactions
could
generate
tetrahydroquinolines (2s−2v) with high enantioselectivities
(85−98% ee), while the diasteroselectivities were highly
depended on the positions of substituents. Notably, compound
Conflicts of interest
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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(b) S. Yao, X. Fang and K. A. Jørgensen, Chem. Commun., 1998,
There are no conflicts to declare.
View Article Online
0, 2547; (c) N. A. Caplan, F. E. HancockD, OP.I:C10. .B10. 3P9a/gCe9CaCn0d15G2.1CJ.
Hutchings, Angew. Chem. Int. Ed., 2004, 43, 1685; (d) P. S.
Aburel, W. Zhuang, R. G. Hazell and K. A. Jørgensen, Org.
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Notes and references
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9CC01521C
R'O2C
R'O2C
CO2R'
CO2R'
R
R
1–10 mol%
N,N'-dioxide/Ni(II)
X
X
X= O, NTs, S
24 examples
up to 99% ee,
up to >19:1 dr
 Atom-economical process
 Broad substrate scope
 Diverse chiral heterocycles
An asymmetric intramolecular Alder-ene reaction has been developed to synthesize diverse 3,4-
disubstituted chroman, tetrahydroquinoline, piperidine and thiochroman derivatives.