Highly enantioselective [3+3] cycloaddition of aromatic azomethine imines with cyclopropanes directed by π-π Stacking interactions

Article abstract of DOI:10.1002/anie.201207576

Designing armory: The side-arm-modified In-TOX/Ni^II complex was identified as a highly efficient and stereoselective catalyst for the [3+3] cycloaddition of aromatic azomethine imines with cyclopropanes (see picture). Density functional calculations and control experiments revealed that the directing effect of the side arm through π interactions is crucial to the stereochemical control. Copyright

Full text of DOI:10.1002/anie.201207576

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DOI: 10.1002/anie.201207576
Asymmetric Catalysis
Highly Enantioselective [3+3] Cycloaddition of Aromatic Azomethine
Imines with Cyclopropanes Directed by p–p Stacking Interactions**
You-Yun Zhou, Jun Li, Lin Ling, Sai-Hu Liao, Xiu-Li Sun,* Yu-Xue Li,* Li-Jia Wang, and
Yong Tang*
The development of efficient and highly stereoselective
catalysts is of central importance in asymmetric catalysis.
Typically, new catalysts can be generated from new chiral
scaffolds or through the modification of existing catalysts. The
latter becomes especially attractive and of practical use if
a simple manipulation of these readily available catalysts
results in significantly improved efficiency and selectivity.
Bisoxazoline (BOX) is an established privileged ligand in
modern asymmetric catalysis, and the corresponding metal
complexes have been applied to a wide variety of asymmetric
transformations.[1] To improve the efficiency and selectivity of
the BOX ligands in specific reactions, we recently introduced
a sidearm strategy which allows the modification of the
ligands in a three-dimensional manner and has been success-
fully applied to several types of reactions.[2,3] Metal catalysts
based on these sidearm-modified BOX ligands usually
exhibited higher efficiency and improved diastereo- and
enantioselectivity, together with much higher stability and
tolerance to impurities than the parent BOX ligands.[2a] The
role of the “sidearm” group was found to depend on the
functionality of the sidearm.[2,3] For example, sidearms con-
taining a ligating donor function (D) would bind to the metal
and modulate both the electronic properties and the micro-
environment of the catalytic center (Figure 1a), and make it
possible to tune the reaction efficiency and selectivity.[3p] The
sidearm group is also found to mainly exert a steric effect by
virtue of its steric demand (Figure 1b).[3f] Recently, we
observed a new role of the sidearm group in a nickel-
catalyzed [3+3] cycloaddition reaction of isoquinoline azo-
methine imines with cyclopropanes, in which a prominent p—
p stack-directing effect of the sidearm proved to be crucial to
the stereochemical control (Figure 1c).
Figure 1. Roles of sidearms in metal/BOX complexes.
Tetrahydroisoquinoline, dihydroisoquinoline, and related
polycyclic skeletons are widely present as core structures in
a large number of natural products, bioactive molecules, and
pharmaceuticals,[4] and extensive efforts have been directed to
the asymmetric construction of these structures in the last
decades.[4d,5–8] Recently, Charette and co-workers[9] reported
a non-asymmetric example of the [3+3] cycloaddition reac-
tion of isoquinoline azomethine imines with donor–acceptor
(D-A)-subtituted cyclopropanes. Though the product was
obtained in only 21% yield, this reaction represents a facile
and direct approach for the construction of 6,6,6-tricyclic
dihydroisoquinoline derivatives. Inspired by this pioneering
work, we wish to report here our efforts toward the
realization of the first highly enantioselective version of this
reaction and our understanding of the role of the sidearm
group.
Initially, the reaction of isoquinoline azomethine imine
1a[7] with cyclopropane 2a was examined under several sets of
conditions previously reported for the asymmetric cyclo-
addition of cyclopropanes.[10,11] Using DBFOX/NiII[10a] the
desired product 3aa was obtained in 83% yield and 30% ee.
While under the conditions for the asymmetric cycloaddition
with aldehydes,[10c] the reaction did not proceed even when
the reaction time was extended to 2 days. We then moved on
to evaluate a variety of BOX ligands;[12a] selected results are
tabulated in Table 1. In-BOX L1a provided a smooth reac-
tion, and full conversion was achieved in 19 h, but the product
was nearly racemic (2% ee; Table 1, entry 1). L1b with
a cyclopropylidene spacer gave 35% ee (Table 1, entry 2).
Introduction of a benzyl sidearm group provided no enhance-
ment of the enantioselectivity (L1c; Table 1, entry 3). How-
ever, to our delight, the pseudo-C3-symmetric trisoxazoline
(TOX) ligand L1d containing an indane-derived oxazoline
sidearm group delivered significantly improved enantioselec-
tivity, notably with an inversed sense of asymmetric induction
(Table 1, entry 4). The corresponding isopropyl-substituted
ligand L2d[10b] was equally efficient but less enantioselective
(Table 1, entry 5).
[*] Y.-Y. Zhou,[+] J. Li,[+] L. Ling,[++] Dr. S.-H. Liao, Dr. X.-L. Sun,
Prof. Dr. Y.-X. Li, Dr. L.-J. Wang, Prof. Dr. Y. Tang
State Key Laboratory of Organometallic Chemistry
Chinese Academy of Sciences, Shanghai Institute of Organic
Chemistry
345 Lingling Lu, Shanghai 200032 (P.R. China)
liyuxue@ sioc.ac.cn
tangy@sioc.ac.cn
E-mail: xlsun@mail.sioc.ac.cn
[+] These authors contributed equally to this work.
[
++] L. Ling conducted the calculation.
[**] We are grateful for the financial support from the National Natural
Sciences Foundation of China (nos. 20932008, 21072207, and
21121062), the Major State Basic Research Development Program
(grant no. 2009CB825300), and the Chinese Academy of Sciences.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207576.
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Table 1: Optimization study.[a]
Table 2: Scope of cyclopropane and azomethine imine substrates.[a]
Entry
1
R2
t [h] Yield [%][b]
d.r.[c] ee [%][d]
Entry
1
R2
L
t [h]
Conv. [%][b]
ee [%][c]
1
2
3
4
1b Ph (2d)
35
34
31
92
24
7
31
74
1.5 92
2.0 97
1.5 99
1.5 93
98
99
98
95
98
91
97
95
>20:1 94
>20:1 97
>20:1 98[e]
>20:1 97
>20:1 96
>20:1 96
>20:1 96
>20:1 95
13:1 95
1b p-ClC6H4(2e)
1b p-BrC6H4(2 f)
1b p-NO2C6H4 (2g)
1b p-MeC6H4 (2h)
1b p-MeOC6H4 (2i)
1b m-MeC6H4 (2j)
1b 3,4-Cl2C6H3 (2k)
1b 3,4-(MeO)2C6H3 (2l)
1b 2-furyl (2m)
1[d]
2[d]
3[d]
4
5
6
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Et (2b)
iBu (2c)
tBuCH2 (2d)
tBuCH2 (2d)
tBuCH2 (2d)
L1a
L1b
L1c
L1d
L2d
L1d
L1d
L1d
L1d
L1d
19
11
65
20
19
96
>99
97
>99
>99
70
(À)2
(À)35
(À)31
56
34
65
72
79
95
94
5
6[f]
7
54
8
7
8
120
120
42
26
9[f]
10[f]
11[f]
12[f]
13[f]
14[g]
15
>20:1 92
>20:1 94
15:1 87
9[e]
10[d,e]
99[f]
98[f]
1b 2-thienyl (2n)
35
=
1b PhCH CH (2o)
[a] Reaction conditions are described in the Supporting Information.
[b] Determined by 1H NMR analysis. [c] Determined by HPLC on a chiral
stationary phase. [d] With 10 mol% catalyst, 408C. [e] [1b]0 =0.05m and
4 ꢀ MS (200 mg). [f] Yield of isolated product based on 1b.
1b CH2 =CH (2p)
1b H (2q)
50
92
92
87
94
85
81
>20:1 89
47
25
9
9
9
–
0
15[f,h] 1b p-MeOC6H4 (2i)
>20:1 95
>20:1 95
11:1 86
3:1 88
16[f]
17[f]
18[f]
1c p-MeOC6H4 (2i)
1d p-MeOC6H4 (2i)
1e p-MeOC6H4 (2i)
It was envisioned that the steric interaction of the two
ester groups of the cyclopropane with the catalyst could
interfere with the stereochemical control. Thus, the ester
group was varied systematically in reactions with ligand L1d.
As outlined in Table 1, when the R group of the ester was
enlarged from methyl to neopentyl, the enantioselectivity of
the reaction gradually improved from 56% to 79% ee in the
order methyl < ethyl < isobutyl < neopentyl, but this was
accompanied by severely decreased reactivity (Table 1,
entries 4 and 6–8). To our delight, when an ortho-CF3 group
was introduced on the benzoyl ring of the azomethine imine,
the reactivity issue was resolved, the reaction time was
shortened from 120 h to 42 h, and the selectivitiy was also
further improved; the cycloaddition product was obtained in
99% yield and 95% ee (Table 1, entry 9). Moreover, at
a slightly elevated temperature (408C), the catalyst loading
could be reduced to 10 mol% with the preservation of both
stereoselectivity and yield (Table 1, entry 10).
Under optimized reaction conditions, a variety of cyclo-
propane diesters were then examined. As shown in Table 2,
the steric and electronic properties of para and meta
substituents on the phenyl group of D–A-substituted cyclo-
propane diesters had a slight influence on the yields (91–
99%) and stereoselectivities (94–98% ee and d.r. > 20:1). D–
A-substituted cyclopropane substrates with an electron-rich
donor moiety exhibited apparently higher reactivities
(Table 2, entries 2–4 vs. 5 and 6). D–A-substituted cyclo-
propanes having disubstituted aryl groups also reacted well
(Table 2, entries 8 and 9). Notably, the reaction could be
extended to substrates with heterocyclic, styryl, and vinyl
donor groups with high diastereo- and enantioselectivities
(Table 2, entries 10–13). It is worth mentioning that the
[a] Reaction conditions are described in the Supporting Information.
[b] Yield of isolated product based on 1. [c] cis/trans, determined by
1H NMR spectroscopy. [d] Determined by HPLC on a chiral stationary
phase. [e] The absolute configuration was determined by X-ray analy-
sis.[12c] [f] Room temperature. [g] Catalyst loading=20 mol%. [h] Cata-
lyst loading=5 mol% and [1b]0 =0.10m in DME (20 mL).
simple cyclopropane diester 2q also reacted smoothly with
isoquinoline azomethine imine 1b, but the product was
racemic (Table 2, entry 14). This result indicates that the
enantioselectivity was established in the first step—the
nucleophilic attack and the simultaneous opening of the
cyclopropane ring. In addition, the reaction can be scaled up
to the gram scale with high enantioselectivity and only
5 mol% catalyst was required (Table 2, entry 15). The scope
of the aromatic azomethine imines was also investigated
(Table 2, entries 16–18). The position of a methyl substituent
on the isoquinoline ring slightly influences the stereoselec-
tivity, but high d.r. and excellent ee values could be
maintained (85–94% yield, d.r. > 11:1, and 86–95% ee;
Table 2, entries 16 and 17).
To understand the synergistic effects between the sidearm,
diester groups, and the benzoyl group of the azomethine
imine, density functional theory (DFT)[13] studies were
performed using the M06[14] method, which was successfully
employed for the nickel(II)-catalyzed reactions.[15] The tri-
soxazoline ligand L1d and substrates 1b and 2d, which lead to
the best enantioselectivity, were employed in the calculation.
After an extensive computational study, the optimized model
of TOX/NiII coordination was obtained, which is a six-
coordinate NiII complex[16] with one molecule of isoquinoline
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cycloaddition product and the unreacted (R)-cyclopropane
were isolated in nearly quantitative yields with high enantio-
selectivities. The relative rate constant was determined with
an S-value of 45. This experiment strongly supports the
calculated results.[12b]
This calculation can also well explain the origin of the
enantioselectivity. As shown in Figure 3b, the coordination of
Figure 2. The coordination model of TOX/NiII complex.
azomethine imine 1b coordinating to the nickel center (L =
1b, Figure 2).[12b] This model is consistent with the X-ray
crystal structure analysis in our previous study[3p] and was
used here for explaining the stereochemistry. The calculated
results show that the chiral NiII complex recognized the (S)-
cyclopropane selectively. Complex S is favored by 1.7 kcal
molÀ1 over Complex R. And transition state TS1-S is also
more stable than TS1-R (Scheme 1). This effective discrim-
Figure 3. a) Side view and b) back view of the optimized structures of
Complex S and Complex R. The relative free energies in solvent DGsol
are in kcalmolÀ1; calculated at UM06/6-31G*/LanL2DZ level.
1b to the bottom of the L1d/Ni complex creates a confined
chiral cavity which accommodates cyclopropane 2d with its
phenyl group pointing up to avoid the steric interaction with
ligated 1b. In Complex S, the phenyl group points towards the
right side, and the right neopentyl ester group twists down to
avoid interaction with the phenyl group (2.367 ꢀ). In Com-
plex R, however, the phenyl group is pointing to the left side,
the coordination of 1b hinders the left neopentyl ester group
rotating down to release the strain, and the presence of the
ortho-CF3 group[17] of azomethine imine 1b further aggravates
the steric repulsion between the ester group and the phenyl
group (2.084 ꢀ). As a consequence, the dihedral angle C2-C3-
Ni-O1 in Complex R is À103.38 and the deviation is up to
Scheme 1. The calculated pathway of the first step of the reaction.
Bond lengths are in ꢀ and the relative free energies in solvent DGsol
are in kcalmolÀ1; calculated at UM06/6-31G*/LanL2DZ level.
ination between the two enantiomers of the D–A-substituted
cyclopropanes suggests kinetic resolution of the cyclopro-
panes during the reaction. In fact, as shown in Scheme 2,
when 2.0 equivalents of racemic 2d were used under the
standard reaction conditions, at 50% conversion both the
13.38 from perpendicular, indicating
a large repulsion
between the phenyl group and the ester group. In contrast,
the plane of the cyclopropane in Complex S is nearly
perpendicular to the main coordination plane and the
dihedral angle C2-C3-Ni-O2 is 88.38, only 1.78 from perpen-
dicular. These results are in agreement with the observed
effects of the esters on the enantioselectivity (Table 1,
entries 4, 6–8). Apart from these steric considerations,
a remarkable p–p directing effect[18] was revealed by calcu-
lation, which makes Complex S more favored over Com-
plex R. As shown in Figure 3a, the indane group of the
sidearm of L1d and the phenyl group of the cyclopropane in
Scheme 2. Kinetic resolution experiments of cyclopropane 2d.
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Complex S are on the same side and parallel to each other.
The distance between these two rings is about 3.4 ꢀ. This
beneficial p–p directing effect of the indane sidearm is
distinct from other sidearm oxazolines lacking such an
aromatic moiety. In fact, the beneficial effect of the indane-
derived oxazoline sidearm was consistently observed in the
ligand screening.[12a] In the transition states of the azomethine
imine attack and the simultaneous ring-opening step
(Scheme 1), since the N1–C2 distances are rather long
(2.312 ꢀ in TS1-S, 2.395 ꢀ in TS1-R), the factors that
makes Complex S more stable than Complex R are also in
effect in TS1-S and TS1-R.[12a] Thus, in both coordination–
activation (Complex S) and nucleophilic attack (TS1-S)
processes, the (S)-cyclopropane substrate reacts preferably;
this accounts for the high enantioselectivity and is consistent
with the experimental results.[12a]
functional theory (DFT) study indicate that the p–p inter-
action between the indane group of the ligated sidearm and
the phenyl group of the cyclopropane plays a key role in the
control of enantioselectivity, which would provide an inspira-
tion for the design of novel bifunctional catalysts. Further
investigation on the working model and extensions of the
current approach are ongoing in our laboratory.
Received: September 19, 2012
Published online: December 20, 2012
Keywords: [3+3] cycloaddition · dihydroisoquinolines · nickel ·
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Scheme 3. Control experiments.
replaced with an isopropyloxazoline group (L1e) which lacks
such an aromatic moiety, dramatically decreased enantiose-
lectivity was observed (42% ee vs. 94% ee). On the other
hand, a drop in enantioselectivity was also observed in the
reaction of cyclopropane 2r which contains an ortho methoxy
substituent on the phenyl group which can weaken the p–p
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aliphatic-substituted cyclopropane 2s reacted with signifi-
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reaction system.
In summary, we have developed an highly enantioselec-
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cyclopropane diesters with aromatic azomethine imines
catalyzed by In-TOX L1d/NiII; this reaction provides a variety
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