Asymmetric synthesis of 2,3-dihydropyrroles by ring-opening/ cyclization of cyclopropyl ketones using primary amines

Article abstract of DOI:10.1002/anie.201407880

The asymmetric ring-opening/cyclization of cyclopropyl ketones with primary amine nucleophiles was catalyzed by a chiral N,N'-dioxide/scandium(III) complex through a kinetic resolution process. A broad range of cyclopropyl ketones and primary amines are suitable substrates of this reaction. The corresponding products were afforded in excellent enantioselectivities and yields (up to 97% ee and 98% yield) under mild reaction conditions. This method provides a promising access to chiral 2,3-dihydropyrroles as well as an effective procedure for the kinetic resolution of 2-substituted cyclopropyl ketones.

Full text of DOI:10.1002/anie.201407880

Angewandte
Chemie
DOI: 10.1002/anie.201407880
Asymmetric Catalysis
Asymmetric Synthesis of 2,3-Dihydropyrroles by Ring-Opening/
Cyclization of Cyclopropyl Ketones Using Primary Amines**
Yong Xia, Xiaohua Liu,* Haifeng Zheng, Lili Lin, and Xiaoming Feng*
Abstract: The asymmetric ring-opening/cyclization of cyclo-
propyl ketones with primary amine nucleophiles was catalyzed
by a chiral N,N’-dioxide/scandium(III) complex through
a kinetic resolution process. A broad range of cyclopropyl
ketones and primary amines are suitable substrates of this
reaction. The corresponding products were afforded in excel-
lent enantioselectivities and yields (up to 97% ee and 98%
yield) under mild reaction conditions. This method provides
a promising access to chiral 2,3-dihydropyrroles as well as an
effective procedure for the kinetic resolution of 2-substituted
cyclopropyl ketones.
1,1-dicarboxylates with enol silyl ethers,[9a–c] aldehydes,[9d–g]
aldimines,[9h,i] and indoles[9j–l] as well as the [3+3] cycloaddi-
tion of aromatic azomethine imines[10a,b] and nitrones[10c–g]
have been conducted by the groups of Tang, Johnson, Kerr,
and others. Furthermore, nucleophilic ring-opening reactions
of cyclopropane derivatives with indoles,[11a,b] amines,[11c–h] or
sodium azide[11i] were also reported to afford the correspond-
ing acyclic products. However, asymmetric variants are rare;
only one successful example on the use of secondary aliphatic
amines as the nucleophiles for the construction of chiral
g-substituted g-amino acid derivatives has been reported by
Tang and co-workers.[11f] The France group found that the
Lewis acid catalyzed ring-opening cyclization of cyclopropyl
ketones with primary amines provided a milder approach to
2,3-dihydropyrroles bearing electron-withdrawing groups at
the 4-position.[11g] Surprisingly, unlike for the reaction of
cyclopropyl esters,[9c,f,i,k,10b,e,11b,f] an asymmetric variant of the
reaction with cyclopropyl ketones has not been described.
The carbonyl group of cyclopropyl ketones can coordinate to
a chiral metal complex to enable enantioselective trans-
formations,[10b,e,11f] but also act as a functional group for
further intramolecular condensation reactions. As part of our
continuing work on exploring the use of metal complexes with
a chiral N,N’-dioxide ligand in asymmetric catalysis,[12] we
reported the [3+2] cycloaddition of aryl oxiranyl ketones with
C
hiral dihydropyrroles frameworks are a privileged struc-
tural unit in a number of natural compounds with important
biological activities and also a key building block in the
synthesis of complex molecules.[1,2] Versatile asymmetric
approaches have been reported towards substituted pyrroli-
dine derivatives. For instance, asymmetric [3+2] cycloaddi-
tions of imines with allenes[3a–c] and of ynones with azome-
thine ylides[3d,e] have been developed to efficiently construct
chiral 2,5-dihydropyrroles. Aside from the reactions starting
from 2-pyrroline[4] and pyrrole[5] precursors, asymmetric
[3+2] cycloadditions of 1-alkylallenylsilanes with a-imino
esters[6a] and of isocyanoesters with nitroolefins[6b] were useful
for the synthesis of chiral 2,3-dihydropyrroles. Tandem
Michael/cyclization reactions also provide an efficient
method to access such nitrogen heterocycles in an enantioen-
riched form.[7] Nevertheless, the development of an alterna-
tive method towards optically active 2,3-dihydropyrroles with
various functional groups remains appealing.
À
aldehydes and alkynes, which proceeds through the C C
bond cleavage of oxiranes.[12c,d] Herein, we describe a simple
and highly enantioselective ring-opening/cyclization reaction
of cyclopropyl ketones with primary amines that is catalyzed
by a chiral N,N’-dioxide/Sc(III) complex. This transformation
proceeds through a kinetic resolution process and generates
chiral 2,4,5-trisubstituted 2,3-dihydropyrrole derivatives in
good yields and enantioselectivities.
In recent years, donor–acceptor cyclopropanes, as a useful
class of building blocks, have been used as substrates in
a series of organic transformations.[8–11] Extensive studies
related to the formal [3+2] cycloaddition of cyclopropane-
Initially, the ring-opening/cyclization reaction of racemic
cyclopropyl ketone 1a with aniline (2a) was selected as the
model reaction. Several metal salts coordinated to N,N’-
dioxide L1, which is derived from (S)-pipecolic acid, were
tested in DCE at 358C. As shown in Table 1, Sc(OTf)3 was
able to accelerate this reaction, delivering the desired 2,3-
dihydropyrrole 3aa in promising enantioselectivity and
moderate yield (73% ee and 30% yield; entry 3). Other
metal salts, such as Ni(ClO4)2·6H2O, gave racemic product
albeit in good yield (entry 1). To further improve the
enantioselectivity of the reaction, a series of chiral N,N’-
dioxides were examined. It was found that both the bulky
amide subunits and the amino acid backbone of the ligands
were crucial for the enantiocontrol. Increasing the steric bulk
of the amide substituents benefited the enantioselectivity of
the reaction (entries 3–5). Changing the chiral backbone of
the ligand from (S)-pipecolic acid to (S)-proline and (S)-
[*] Y. Xia, Prof. Dr. X. H. Liu, H. F. Zheng, Dr. L. L. Lin,
Prof. Dr. X. M. Feng
Key Laboratory of Green Chemistry & Technology, Ministry of
Education, College of Chemistry, Sichuan University
Chengdu 610064 (China)
E-mail: liuxh@scu.edu.cn
xmfeng@scu.edu.cn
Prof. Dr. X. M. Feng
Collaborative Innovation Center of Chemical Science and Engi-
neering, Tianjin (China)
[**] We thank the National Natural Science Foundation of China
(21432006, 21321061, and 21172151), the National Basic Research
Program of China (973 Program: 2011CB808600), and the Ministry
of Education (NCET-11-0345) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407880.
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Table 1: Optimization of the reaction conditions.[a]
Table 2: Variation of the cyclopropyl ketone.[a]
R1, R2
Yield[b] [%]
ee[c] [%]
Entry
Metal salt
L
Solvent
Yield[b] [%]
ee[c] [%]
Entry
1
2
3
4
5
6
7
8
Ni(ClO4)2·6H2O
Yb(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
L1
L1
L1
L2
L3
L4
L5
L3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
71
60
30
49
41
39
39
51
40
39
82
0
58
73
63
87
73
76
84
87
89
91
1
2
3
4
5
6
7
8
Ph, Ph (1a)
82 (3aa)
95 (3ba)
96 (3ca)
94 (3da)
86 (3ea)
88 (3 fa)
96 (3ga)
81 (3ha)
67 (3ia)
71 (3ja)
92 (3ka)
95 (3la)
55 (3ma)
66 (3na)
76 (3oa)
98 (3pa)
98 (3qa)
97 (3ra)
43 (3sa)
63 (3ta)
93 (3ua)
59 (3va)
16 (3wa)
91
91
92
95
92
95
92
94
95
95
94
92
90
96
90
92
96
94
91
96
94
73
66
4-MeC6H4, Ph (1b)
4-MeOC6H4, Ph (1c)
4-FC6H4, Ph (1d)
4-ClC6H4, Ph (1e)
4-BrC6H4, Ph (1 f)
3-MeC6H4, Ph (1g)
3-MeOC6H4, Ph (1h)
3-ClC6H4, Ph (1i)
9
L3 THF
L3
L3
9
10
CHCl2CHCl2
CHCl2CHCl2
10
11
12
13
14
15
16
17
18
19
20
21
22
23[d]
3-BrC6H4, Ph (1j)
11[d,e]
2-MeC6H4, Ph (1k)
2-MeOC6H4, Ph (1l)
2,4-Cl2C6H3, Ph (1m)
3,4-Cl2C6H3, Ph (1n)
2,3-(MeO)2C6H3, Ph (1o)
3,4-(MeO)2C6H3, Ph (1p)
1-naphthyl, Ph (1q)
2-naphthyl, Ph (1r)
[a] Unless otherwise noted, all reactions were performed with metal salt
and ligand (10 mol%, 1:1), 1a (0.40 mmol), and 2a (0.10 mmol) in the
specified solvent (0.5 mL) under N2 atmosphere at 358C for 48 h.
[b] Yield of isolated product. [c] Determined by HPLC analysis on a chiral
stationary phase. [d] The reaction was performed in 1.0 mL of
CHCl2CHCl2 for 96 h. [e] LiCl (1.0 equiv) was added. DCE=1,2-di-
chloroethane, DCM=dichloromethane, OTf=trifluoromethanesulfo-
nate.
=
H2C CH, Ph (1s)
Ph, 4-MeC6H4 (1t)
Ph, 4-FC6H4 (1u)
Ph, Me (1v)
Me, Ph (1w)
[a] Unless otherwise noted, all reactions were performed with L3/
Sc(OTf)3 (10 mol%, 1:1), LiCl (1.0 equiv), 1 (0.40 mmol), and 2a
(0.10 mmol) in CHCl2CHCl2 (1.0 mL) under N2 atmosphere at 358C for
96 h. [b] Yield of isolated product. [c] Determined by HPLC analysis on
a chiral stationary phase. [d] At 608C.
ramipril led to an obvious decrease in the enantioselectivity
(entries 5–7). Then we focused on the optimization of solvent
and additives. To our delight, when one equivalent of LiCl was
added and the solvent changed to CHCl2CHCl2, the outcome
of the reaction substantially improved, and the desired
product was isolated in 82% yield and 91% ee (entries 8–
11).[13] Therefore, the optimized conditions for the ring-
opening/cyclization reaction entail the use of the L3/ScIII
complex (10 mol%) as the catalyst and LiCl as an additive
in CHCl2CHCl2 at 358C for 96 hours (entry 11).
With the optimized reaction conditions in hand, the
substrate scope was investigated by varying the cyclopropyl
ketone partner. As shown in Table 2, a series of cyclopropyl
ketone derivatives reacted smoothly with 2a, providing the
corresponding products in good to excellent enantioselectiv-
ities and poor to excellent yields (66–96% ee, 16–98% yield).
Both electron-rich and electron-deficient aryl groups at the
2-position of the cyclopropyl ketones had a small effect on the
enantioselectivity (entries 1–12). Dichloride-substituted
ketones gave lower yields in comparison with dimethoxy-
substituted ones (entries 13–16). Naphthyl-substituted cyclo-
propyl ketones were suitable substrates for this reaction,
giving the desired products with excellent enantioselectivities
and yields (94–96% ee, 97–98% yield; entries 17–18).
Remarkably, a vinyl-substituted substrate was also compat-
ible with this catalytic system, and the product was obtained
with excellent enantioselectivity, albeit with moderate yield
(entry 19). Then the effect of the electronic nature of the
substituent at the para position of the benzoyl group of the
cyclopropyl ketone was investigated. An electron-donating
substituent decreased the reactivity, and a moderate yield was
obtained compared with the substrate with an electron-
withdrawing substituent (entries 20–21). When aliphatic
ketone 1v was used, the desired product was formed in
59% yield and 73% ee (entry 22). However, the reaction of
methyl-substituted cyclopropyl ketone 1w proceeded slug-
gishly even at elevated reaction temperatures (entry 23).
Subsequently, a range of primary amines were employed
in this transformation. Substituted anilines with electron-rich
or electron-deficient substituents at the meta or para position
reacted smoothly with cyclopropyl ketone 1a, and excellent
results were achieved (85–96% ee, 85–98% yield; Table 3,
entries 1–11). 2-Chloroaniline showed lower reactivity but
higher enantioselectivity compared with 2-methoxyaniline
(entries 12–13). Notably, cyclopropylamine also underwent
the ring-opening reaction, affording the desired product with
good enantioselectivity and acceptable yield (87% ee, 43%
yield; entry 15). On the other hand, aliphatic amines, such as
cyclopentanamine, 2-methylpropan-2-amine, and phenylme-
thanamine, did not provide the desired dihydropyrrole
products. Furthermore, when the reaction of cyclopropyl
ketone 1a with aniline 2g was carried out on a gram scale with
10 mol% of the chiral L3/ScIII catalyst, good results were
obtained (95% ee, 96% yield; entry 6).
2
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Table 3: Variation of the primary amine.[a]
Table 4: Kinetic resolution of 2-substituted cyclopropanes with
anilines.[a]
Entry
R3
Yield[b] [%]
ee[c] [%]
1
2
3
4
4-MeC6H4 (2b)
4-MeOC6H4 (2c)
4-FC6H4 (2d)
86 (3ab)
89 (3ac)
95 (3ad)
89 (3ae)
85 (3af)
96 (3ag)
89 (3ah)
98 (3ai)
96 (3aj)
85 (3ak)
96 (3al)
70 (3am)
46 (3an)
81 (3ao)
41 (3ap)
92
85
90
91
96
95
87
90
96
94
95
90
97
92
87
Entry
1
2
T [h]
3
1
s[d]
Yield[b] [%] ee[c] [%] Yield[b] [%] ee[c] [%]
4-ClC6H4 (2e)
1
1a 2a 22
1c 2a
1d 2a 10
1a 2g 21
1a 2j 21
51
52
53
53
54
80
82
85
92
86
48
46
47
45
43
85
91
90
95
95
24
32
38
89
49
5[d]
6[e]
7
4-BrC6H4 (2 f)
4-O2NC6H4 (2g)
3-MeC6H4 (2h)
3-FC6H4 (2i)
2[e]
3
5
4
5
8
9
3-ClC6H4 (2j)
[a] Unless otherwise noted, all reactions were performed with L3/
Sc(OTf)3 (20 mol%, 1:1), LiCl (1.0 equiv), 1 (0.10 mmol), and 2
10
11
12
13
14
15[f]
3-BrC6H4 (2k)
3-F3CC6H4 (2l)
2-MeOC6H4 (2m)
2-ClC6H4 (2n)
3,4-(MeO)2C6H3 (2o)
cyclopropyl (2p)
(0.30 mmol) in CHCl2CHCl2 (0.5 mL) under N2 atmosphere at 358C.
[b] Yield of isolated product. [c] Determined by HPLC analysis on a chiral
stationary phase. [d] s=ln[(1ÀC)(1Àee1)]/ln[(1ÀC)(1+ee1)]; C=ee1/
(ee3 +ee1) where ee1 =ee of the recovered substrate, ee3 =ee of the
product. [e] 2a (0.075 mmol).
[a] Unless otherwise noted, all reactions were performed with L3/
Sc(OTf)3 (10 mol%, 1:1), LiCl (1.0 equiv), 1a (0.4 mmol), and 2
(0.1 mmol) in CHCl2CHCl2 (1.0 mL) under N2 atmosphere at 358C for
96 h. [b] Yield of isolated product. [c] Determined by HPLC analysis on
a chiral stationary phase. [d] The absolute configuration of 3af was
determined to be R by X-ray analysis.[14] [e] The reaction was scaled up
using 1a (12.0 mmol) and 2g (3.0 mmol) in 30.0 mL of CHCl2CHCl2.
[f] Reaction time: 168 h.
chiral Lewis acid catalyst. Then, the primary amine nucleo-
phile attacks at the 2-position of the cyclopropane, which is
followed by an intramolecular condensation to give the R-
configured product,[11c,g] leaving predominantly the (R)-cyclo-
propyl ketone behind. However, the slightly decreased
enantiopurity of the recovered cyclopropane indicates that
some dynamic kinetic resolution might accompany the
reaction.[9d,f,i,11b] Moreover, we can exclude that the reaction
occurs through imine formation followed by a Cloke rear-
rangement,[11h,15] as we did not detect any imine intermediate
under various conditions that generally benefit the generation
of imines.
Meanwhile, N-methylaniline (2q) was also subjected to
this catalytic system, and the direct ring-opening product 4aq
was obtained with excellent enantioselectivity (97% ee) and
yield (97%), which indicates that secondary anilines are also
suitable nucleophiles (Scheme 1a).
To gain insight into the origin of the enantioselectivity of
the ring-opening reaction, we investigated the reaction of
aniline (2a) and (R)-cyclopropane 1a[14] with both enantio-
meric forms of the N,N’-dioxide/ScIII complex; the reactions
were run for the same period of time. The matched reaction of
(R)-1a and 2a catalyzed by ent-L3 derived from (R)-pipecolic
acid provided the optically pure product (S)-3aa (> 99% ee)
in 40% yield. On the contrary, the reaction catalyzed by L3
derived from (S)-pipecolic acid was unmatched, giving (S)-
3aa in 82% ee and 9% yield. Therefore, a kinetic resolution
process has occurred, and the reaction of (S)-1a proceeded
significantly faster under the standard conditions with the L3/
ScIII complex catalyst. The S enantiomer is activated by the
Consequently, the kinetic resolution of cyclopropyl
ketones with amines was studied. When the catalyst loading
was increased to 20 mol% and the amount of aniline was
varied, the ring-opening/cyclization products 3 were obtained
in 80–92% ee and 51–54% yield (Table 4, entries 1–5).
Meanwhile, the cyclopropyl ketones 1 were recovered in
85–95% ee and 43–48 yield. Therefore, this method provides
an easy access to both 2,3-dihydropyrroles and cyclopropyl
ketones with high enantiopurities.
In conclusion, we have developed an asymmetric catalytic
synthesis of chiral 2,4,5-trisubstituted 2,3-dihydropyrroles
that proceeds through a ring-opening/cyclization reaction of
cyclopropyl ketones with primary amine nucleophiles through
a kinetic resolution process. With a chiral N,N’-dioxide/
scandium(III) complex, the reaction provided the desired 2,3-
dihydropyrroles in excellent enantioselectivities (up to 97%
ee) and moderate to excellent yields (up to 98%). This
method provides a promising access to chiral 2,3-dihydropyr-
roles as well as an effective kinetic resolution of 2-substituted
cyclopropyl ketones. Further studies will focus on enantiose-
lective ring-opening reactions with other nucleophiles.
Experimental Section
Typical procedure: N,N’-dioxide L3 (0.01 mmol, 10 mol%), Sc(OTf)3
(0.01 mmol, 10 mol%), and LiCl (0.10 mmol) were stirred in
Scheme 1. a) Using a secondary amine as the substrate. b) Control
experiments.
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CHCl2CHCl2 (1.0 mL) at 358C under N2 atmosphere for 0.5 h; then
2a (0.10 mmol) was added. The solution was stirred for 10 min at the
same temperature, and then 1a (0.4 mmol) was added. The mixture
was stirred at 358C for 96 h. The reaction mixture was purified by
flash column chromatography (petroleum ether/ethyl acetate = 4:1)
on silica gel to afford the desired product as a yellow solid.
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Pohlhaus, S. D. Sanders, A. T. Parsons, W. Li, J. S. Johnson, J.
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Received: August 2, 2014
Revised: September 8, 2014
Published online: && &&, &&&&
Keywords: cyclization · kinetic resolution · N,N’-dioxides ·
.
ring opening · scandium
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4
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Asymmetric Catalysis
Y. Xia, X. H. Liu,* H. F. Zheng, L. L. Lin,
X. M. Feng*
&&&& — &&&&
Asymmetric Synthesis of 2,3-
Dihydropyrroles by Ring-Opening/
Cyclization of Cyclopropyl Ketones Using
Primary Amines
2,3-Dihydropyrroles are obtained in high
yields and enantioselectivities through an
enantioselective ring-opening/cyclization
reaction of substituted cyclopropyl
under mild reaction conditions. This
method also provides an effective proce-
dure for the kinetic resolution of2-sub-
stituted cyclopropyl ketones.
ketones with primary amine nucleophiles
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!