Asymmetric synthesis of cis-4-aminobenzopyran derivatives catalyzed by N,N′-Dioxide-Sc(OTf)3 complexes

Article abstract of DOI:10.1002/chem.201102058

The reactions of salicylaldimines with electron-rich alkenes (2,3-dihydro-2H-furan and 3,4-dihydro-2H-pyran) catalyzed by N,N′-dioxide-Sc(OTf)₃ complexes were investigated. The methodology was successfully applied to the asymmetric synthesis of

Full text of DOI:10.1002/chem.201102058

DOI: 10.1002/chem.201102058
Asymmetric Synthesis of cis-4-Aminobenzopyran Derivatives Catalyzed by
N,N’-Dioxide–ScACHTNUGRTENUNG(OTf)3 Complexes
Yulong Zhang, Shunxi Dong, Xiaohua Liu, Mingsheng Xie, Yin Zhu, Lili Lin, and
Xiaoming Feng*[a]
Table 1. Screening of the optimal reaction conditions.[a]
4-Aminobenzopyrans and related compounds are one of
the common subunits of natural products,[1] which could also
be used as drugs with antihypertensive and anti-ischemic
properties, and as modulators of calcium and potassium
channels, affecting the cardiac activity and blood pres-
sure.[2–4] Therefore, considerable attention has been devoted
to develop highly efficient methods for constructing this
fused, cyclic structure. The reaction between salicylaldi-
mines[5] and electron-rich alkenes has emerged as a powerful
tool for the synthesis of multifunctional 4-aminobenzopy-
Entry
Ligand
Metal
Sc(OTf)3
In(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
Yield [%][b]
d.r.[c]
ee [%][c]
1
2
3
4
5
6
7
8
L1
L1
L1
L2
L3
L4
L5
L6
L7
L6
L6
L6
L6
G
52
67
60:40
52:48
–
74:26
75:25
79:21
66:34
81:19
74:26
96:4
18
0
–
ACHTUNGTRENNUNG
Y
G
n.r.[d]
58
ACHTUNGTRENNUNGrans. Although diastereoselective reactions, catalyzed by var-
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
E
25
40
62
21
62
35
90
58
92
97
ious Lewis acids, have been widely developed,[6] catalytic
asymmetric reactions to obtain enantiopure 4-aminobenzo-
pyrans are relatively rare. Rueping and co-workers intro-
duced chiral N-triflylphosphoramide-catalyzed asymmetric
Mannich–ketalization reactions to access optically pure
(3a,4-trans-3a,9a-cis)-4-aminotetrahydro-2H-furobenzopyrans
and derivatives.[7,8] Recently, Fochi and co-workers used
chiral phosphoric acid catalysts to obtain the corresponding
(3a,4-cis-3a,9a-cis)-product with high diastereoselectivities,
but only moderate ee values.[9] The search for new catalytic
systems that achieve both excellent yields and stereoselec-
tivities is highly desirable. Herein, we present asymmetric
reactions of salicylaldimines with 2,3-dihydro-2H-furan
(DHF) or 3,4-dihydro-2H-pyran (DHP) catalyzed by a
E
65
86
75
86
79
92
83
77
R
R
N
9
N
10[e]
11[f]
12[e,g]
13[e,g,h]
R
E
85:15
97:3
97:3
T
A
97
[a] Unless otherwise noted, the reactions were performed with 1a
(0.1 mmol), 2 (12 mL, 1.2 equiv), ligand (5 mol%) and metal (5.5 mol%)
in CH2Cl2 (0.5 mL) under nitrogen at 08C for 48 h. [b] Isolated yield.
[c] The ee and the d.r. values were determined by HPLC analysis (chiral-
cel AS-H); the d.r. value refers to cis:trans. [d] n.r.=no reaction.
[e] CHCl3 (0.5 mL) was used as the solvent. [f] CH2ClCH2Cl (0.5 mL)
was used as the solvent. [g] Performed at À208C. [h] 5 ꢀMS (5.0 mg)
was added.
chiral Lewis acid. Chiral N,N’-dioxide–ScACTHNUGTRENUNG(OTf)3 com-
plexes[10,11] were found to be efficient catalysts for the ste-
reoselective synthesis of (3a,4-cis-3a,9a-cis)-4-aminobenzo-
pyran derivatives with up to 98% yield, >95:5 d.r., and
99% ee.
or no reaction, respectively (Table 1, entries 2 and 3). Then,
a series of N,N’- dioxides were synthesized by modifying the
subunits of the amide and the amino acid (L1–L7). The
Initially, the model reaction of salicylaldimine 1a with
DHF was performed by screening metal salts with the
ligand L1, derived from (S)-pipecolic acid (Table 1, en-
combination of N,N’-dioxide with ScACTHNGUTRENU(NG OTf)3 showed that the
amide moiety of the ligand had significant effect on both
the yield and the stereoselectivity of the reaction (Table 1,
tries 1–3). Sc
60:40 d.r., 18% ee, Table 1, entry 1), and other metal sour-
ces, like In(OTf)3 and Y(OTf)3, resulted in poor selectivity
ACHTUNGTRENNUNG(OTf)3 gave the best results (52% yield,
A
ACHTUNGTRENNUNG
[a] Y. Zhang, S. Dong, Prof. Dr. X. Liu, M. Xie, Y. Zhu, Dr. L. Lin,
Prof. Dr. X. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (P. R. China)
Fax : (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102058.
13684
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Chem. Eur. J. 2011, 17, 13684 – 13687

COMMUNICATION
Table 2. Scope of the substrates.[a,b]
entries 4–9). The introduction of diphenylmethyl groups into
the amide moieties increased the yield and the ee value
(86% yield with 62% ee; Table 1, entry 6). The reactivity
and enantioselectivity significantly decreased when using
N,N’-dioxides with larger or smaller sterically hindered
amide moieties (Table 1, entries 4–5 and 7). N,N’-Dioxides
derived from amino acids were also examined, and the
ligand L6, derived from l-proline acid, and the ligand L4,
derived from l-pipecolic acid, resulted in similar yield and
enantioselectivity, but with slightly higher diastereoselectiv-
ity for L6 (Table 1, entry 8 vs. 6). However, l-ramipril acid
derived L7 failed to control the enantioselectivity, giving a
low ee value (Table 1, entry 9). In all these cases, the tetra-
hydropyran and tetrahydrofuran rings of the product were
cis-fused, and (3a,4-cis-3a,9a-cis)-4-aminotetrahydrofuroben-
zopyran 3a was isolated as the major diastereoisomer. With
the best ligand L6 in hand, the effect of solvents was further
investigated (Table 1, entries 10–11). The results indicated
that the reaction solvents played an important role in adjust-
ing the enantioselectivity of the reaction. CHCl3 was found
to be the most suitable solvent for the reaction, affording
the adduct 3a in 92% yield and 96:4 d.r. with 90% ee
(Table 1, entry 10). Subsequently, with decreasing the reac-
tion temperature from 0 to À208C, the reaction proceeded
smoothly with a slight increase of enantioselectivity, whereas
the reactivity was lower (Table 1, entry 12). It is worth
noting that a significant increase of both the enantioselectiv-
ity and the yield was accomplished at À208C by adding 5 ꢀ
molecular sieves (Table 1, entry 13). Other reaction condi-
tions were also examined, but the results could not be im-
proved (for details, see Supporting Information).
With the optimal conditions established (Table 1,
entry 13), various salicylaldimines 1a–1h, substituted at the
N-aryl ring, were examined, giving a wide range of cis-4-
aminobenzopyrans in up to 98% yield with >95:5 d.r. and
up to 99% ee. As shown in Table 2, the position of the sub-
stituent on the N-aryl ring of salicylaldimines had an evident
effect on the enantioselectivities. Substrates with the sub-
stituent on the para-position afforded better results than
those with the substituent on the ortho- or meta-position
(Table 2, entries 2 and 3 vs. 4–8). The electronic effect of the
substituent on the N-aryl ring of salicylaldimines had no evi-
dent influence on the stereoselectivities (Table 2, entries 4–
8), and the best outcome of 99% ee with 94% yield was ob-
tained for substrate 3h with a 4-MeO substituent on the N-
aryl ring (Table 2, entry 8). However, a dramatic decrease in
enantioselectivities was observed for the salicylaldimines de-
rived from substituted salicylaldehydes (for details, see Sup-
porting Information). The only exception was substrate 1i
with a 4’-MeO substituent on the salicylaldehyde, giving the
corresponding product 3i in 85% yield with 91% ee
(Table 2, entry 9). It is possible that the cause is the steric
hindrance between the substrates and the ligand of the cata-
lyst. We reasoned that chiral ligands with relative small
steric hindrance might be suitable for these substrates. A
series of chiral N,N’-dioxides with different amide subunits
were then screened for the purpose of improving the out-
Entry
R1
R2
Ligand
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
L6
L6
L6
L6
L6
L6
L6
L6
L6
97 (3a)
97 (3b)
85 (3c)
83 (3d)
87 (3e)
87 (3 f)
98 (3g)
94 (3h)
85 (3i)
97
82
85
97
97
91
95
99
93
2-Cl
3-Cl
4-Cl
4-F
4-CF3
4-Me
4-MeO
H
4-MeO
10
5-Cl
5-Br
5-Me
5-MeO
H
H
H
H
L3
L3
L3
L3
83 (3j)
81 (3k)
92 (3l)
84 (3m)
92
91
90
92
11
12[e]
13
14
15
5-Cl
5-Br
5-Me
5-MeO
4-MeO
4-MeO
4-MeO
4-MeO
L3
L3
L3
L3
86 (3n)
95 (3o)
97 (3p)
96 (3q)
92
93
91
91
16[e,f]
17[e,f]
18
19
5-Cl
5-Me
4-F
4-F
L3
L3
96 (3r)
87 (3s)
92
90
[a] Unless otherwise noted, the reactions were performed with
1
(0.1 mmol), 2 (for details, see Supporting Information), 5 mol% of L6–
or L3–ScIII complex (1:1.1) and 5 ꢀMS (5.0 mg) in CHCl3 (0.5 mL) under
nitrogen at À208C for 3–5 d. [b] The diastereomeric ratio was analyzed
by 1H NMR spectroscopy and all the values were >95:5. [c] Isolated
yield. [d] Determined by HPLC analysis. [e] Performed at 08C. [f] 20
Mol% of L3–ScIII complex was used.
come. Fortunately, the ligand L3, derived from l-pipecolic
acid and (S)-2-phenylethanamine, was found suitable for
substrates substituted on the salicylaldehyde moiety
(Table 2, entries 10–13). The reactions of salicylaldimines
1j–1m afforded the corresponding products smoothly with
good enantioselectivities catalyzed by the N,N’-dioxide L3–
ScACTHNUGTRENNG(U OTf)3 complex, although substrates with an electron-do-
nating substituent were less reactive and larger amounts of
DHF and longer reaction times were needed (Table 2, en-
tries 12 and 13 vs. 10 and 11). It is worth pointing out that
chiral match between the chiral amino acid backbone and
phenylethanamine is crucial for the enantiodifferentiation in
the process. The scandium complex of the ligand derived
from d-pipecolic acid and (S)-2- phenylethanamine sharply
decreased the enantioselectivity of the reactions. cis-4-Ami-
nobenzpyran 3j was obtained with only 10% ee (see Sup-
porting Information). Moreover, to expand the synthetic
utility of the reaction, various salicylaldimines with different
N-aryl groups, such as a 4-methoxyphenyl (PMP) and a 4-
fluorophenyl group, were subjected to the optimized reac-
tion conditions (Table 2, entries 14–19). Pleasingly, excellent
enantioselectivities were also observed for those salicylaldi-
Chem. Eur. J. 2011, 17, 13684 – 13687
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13685

X. Feng et al.
mines 1n–1s. Generally, electron-withdrawing substituents,
such as a Cl or Br group, slightly enhanced the reactivity,
while electron-donating substituents, such as a MeO or a
Me group, diminished the reactivity (Table 2 entries 16 and
17 vs. 14 and 15, entry 19 vs. 18).[12]
The absolute configuration of the major product 3j was
unambiguously determined to be (3aS, 4R, 9aR) by a single-
crystal X-ray diffraction study (Figure 1).[13]
In connection with the N-triflylphosphoramide catalyzed
reaction,[7] the difference in stereoselectivity might be due
to the activation model of the catalysts. Often, the cis-prod-
uct was obtained as the major product in the presence of a
Lewis acid, such as LiBF4,[6b] InCl3,[6d] and I2.[6 g] The model
C1 (Figure 2) could help to explain the mechanism. A six-
Figure 1. X-ray structure of the product 3j.
To further evaluate the synthetic potential of this catalyst
system, the reaction between salicylaldimine 1a and 3,4-di-
hydro-2H-pyran (DHP) was examined (Scheme 1). DHP
was tolerated in terms of yield and enantioselectivity, pro-
viding the corresponding (4a,5-cis-4a,9a-cis)-adduct as major
isomer in 82% yield, 85:15 d.r., and 85% ee under mild con-
ditions.
Figure 2. Proposed catalytic model.
membered ring, formed with a Lewis acid and including
both the nitrogen and oxygen of the salicylaldimine, leads to
the formation of (3a,4-cis-3a,9a-cis)-3. However, an arrange-
ment as shown in C2 is more likely to proceed through a
single hydrogen activation of the imine in Ruepingꢂs report
to yield (3a,4-trans-3a,9a-cis)-3.
The enantiodiscrimination of salicylaldimine in the reac-
tion process can be rationalized according to Figure 2. In
the presence of the scandium catalyst, the salicylaldimine
coordinates to the central metal in a bidentate manner. In
combination with the absolute configuration of the product
3j, we postulate that the steric hindrance between the N-
aryl group of the imine and one azacycle of the ligand
makes intermediate B unfavorable. It would thus appear
that DHF readily attacks the Re-face of the imine, followed
by a fast ketalization step to afford the (3aS, 4R, 9aR)-prod-
uct (Figure 2, A). It can also be seen that when substrates
substituted on the salicylaldehyde moiety were used, the use
of less sterically hindered ligand L3 (R=Me) is sufficient to
give good selectivity.
Scheme 1. The reaction of salicylaldimine 1a with DHP.
A sub-gram synthesis of cis-4-aminobenzopyran derivative
3h was carried out with 1h and DHF (Scheme 2). The reac-
tion proceeded smoothly to give the product 3h in 95%
yield, >95:5 d.r. and 96% ee with 5 mol% catalyst loading.
In conclusion, we have developed chiral N,N’-dioxide–Sc-
AHCTUNGRTEG(NNUN OTf)3 complexes for the asymmetric reactions of DHF and
DHP with salicylaldimine derivatives. This method enables
efficient access to a variety of optically pure cis-4-aminoben-
zopyrans in excellent outcomes (up to 98% yield,
>95:5 d.r., up to 99% ee). Moreover, the broad substrate
scope and the facile procedure demonstrated the potential
of the catalytic system. Further application of the catalyst in
other reactions is currently underway.
Scheme 2. Scaled-up version of the reaction.
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Asymmetric Synthesis of 4-Aminobenzopyranes
COMMUNICATION
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Experimental Section
Typical experimental procedure: N,N’-Dioxide L6 (3.2 mg, 0.005 mmol),
scandium triflate (2.6 mg, 0.0055 mmol), salicylaldimine 1a (19.7 mg,
0.1 mmol) and 5 ꢀ molecular sieves (5.0 mg) were stirred in a dry reac-
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was stirred for 3 d. The process was monitored by TLC. After salicylaldi-
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the desired product 3a as white solid (27.0 mg, 97% yield).
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Acknowledgements
We appreciate the National Natural Science Foundation of China (Nos.
20732003, 21021001 and 20872097), and the National Basic Research Pro-
gram of China (973 Program: 2010CB833300) for financial support. We
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Keywords: aminobenzopyrans
·
dioxides
·
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[13] CCDC 831655 (3j) contains the supplementary crystallographic data
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Received: July 5, 2011
Published online: November 3, 2011
Chem. Eur. J. 2011, 17, 13684 – 13687
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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