Communication
Table 1. Optimization of reaction conditions.
Table 2. Scope of the asymmetric [3+2] cycloaddition to afford cycload-
ducts 3aa–3ak.
Entry[a] Cat.* Solvent
T
[8C]
Additive Yield[b] d.r.[c]
[%]
ee[d]
[%]
Entry[a]
2 (R1/R2)
Yield[b] [%]
d.r.[c]
ee[d] [%]
1[e]
2
3
4
5
6
7
8
–
toluene or DCM 25
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
1
2
3
4[e]
5
6
7
8
9
10
11[f]
2a: Bn/C6H5
2b: tBu/C6H5
2c: Me/C6H5
3aa: 81
3ab: 93
3ac: 78
3ad: 92 (64)
3ae: 90
3af: 78
3ag: 92
3ah: 62
3ai: 65
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
–
93
91
86
77 (80)
75
74
74
77
73
CP1
CP2
CP3
CP4
CP5
CP6
CP7
CP8
CP9
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
25
25
25
25
25
25
25
25
25
25
0
25
25
25
25
25
25
25
25
35
26
17
49
24
58
trace
78
75
48
30
79
70
50
86
62
81
42
48
>20:1 25
>20:1 21
>20:1
>20:1
>20:1
6
6
6
2d: CH2tBu/C6H5
2e: Bn/2-BrC6H4
2 f: Bn/3-BrC6H4
2g: Bn/4-BrC6H4
2h: Bn/4-FC6H4
2i: Bn/4-MeOC6H4
2j: Bn/CH2C6H5
2k: Bn/H
>20:1 22
–
–
9
>20:1 80
>20:1 87
>20:1 73
>20:1 85
>20:1 45
>20:1 62
>20:1 79
>20:1 80
>20:1 70
>20:1 93
>20:1 82
>20:1 82
10
11
12
13
14
15
16
17
18
19
20
3aj: 57
3ak: trace
68
–
CP10 toluene
CP9
CP9
CP9
CP9
CP9
CP9
CP9
CP9
CP9
toluene
DCM
[a] All reactions were carried out with 1a (0.1 mmol), 2a (0.15 mmol),
CP9 (10 mol%) in p-xylene (1.0 mL). [b] Isolated yield. [c] Determined by
1H NMR of crude product. [d] Determined by HPLC. [e] Neophenyl=
CH2tBu, the values in parentheses were obtained by catalyzing with CP8
(R)-SITCP. [f] The racemic product was obtained in 46% yield, but only
trace optical product catalyzed by CP8 or CP9.
THF
Et2O
benzene
fluorobenzene
p-xylene
p-xylene
p-xylene
–
–
4 A MS
H2O
in this reaction, but the desired product could not be ob-
tained.
[a] All reactions were carried out with 1a (0.1 mmol), 2a (0.15 mmol), cat-
alyst (10 mol%) in solvent (1.0 mL), Cat*=chiral phosphine. [b] Isolated
yield. [c] Determined by 1H NMR spectroscopy of crude product. [d] De-
termined by chiral HPLC. [e] The reaction was carried out with 1a
(0.1 mmol), 2a (0.15 mmol), toluene (1.0 mL) or DCM (1.0 mL) at room
temperature.
A plausible mechanism for this phosphine-catalyzed novel
[3+2] cycloaddition has been proposed in Scheme 5 on the
basis of our experiments and the previous literature.[10,16] The
reaction starts from the formation of a zwitterionic intermedi-
ate A between allenoate and phosphine, which would be
transformed to intermediate B via a proton transfer.[17] Inter-
mediate B acts as a 1,4-dipole and subsequently undergoes
a d-addition with C,N-cyclic azomethine imines 1 to give a zwit-
terionic intermediate C. Subsequently, a nucleophilic addition
reaction initiated by nitrogen ion yields the phosphorus ylide
D. Then an intramolecular [1,2] proton transfer is speculated to
convert the phosphorus ylide D to another zwitterionic inter-
mediate E, which, upon elimination of the phosphine catalyst,
gives rise to the final [3+2] cycloaddition product 3. A plausi-
ble transition state accounting for the stereochemical outcome
of this reaction is outlined in the Supporting Information.
The deuterium-labeling experiment was carried out under
standard conditions by adding D2O (10 equiv) into the reaction
of azomethine 1g and allenoate 2b in the presence of
10 mol% PPh3. As shown in Scheme 6, a partially deuterated
product 3gb’ was obtained in 40% yield and 10:1 d.r., along
with 41% deuterium incorporation at C4-position, 50% deute-
rium incorporation at C5-position and 56% deuterium incorpo-
ration at C6-position, further confirming the proton-transfer
process in the above proposed mechanism (Scheme 6).
corresponding product 3aj in 57% yield with 68% ee and
>20:1 diastereoselective ratio (Table 2, entry 10). When R2 is
hydrogen atom (R2 =H), the reaction could not proceed effi-
ciently to afford the corresponding product catalyzed by CP8
or CP9 (Table 2, entry 11). The absolute configuration of 3aa
was assigned by X-ray diffraction. The ORTEP drawing and the
CIF data are summarized in the Supporting Information.[15]
Recognized d-substituted allenoates 2a and 2b were more
suitable for this type of [3+2] cycloaddition. We next attempt-
ed to examine the asymmetric [3+2] cycloaddition from the re-
action of different azomethine imines 1 and allenoates 2a or
2b, and the results are summarized in Table 3. As for the sub-
stitution pattern of the C,N-cyclic azomethine imines, halogen
substituents (F, Cl, Br) were all tolerated, giving the corre-
sponding products 3bb–3 fb in moderate to excellent yields
(72–92%) and good ee (68–83%). For the substrate with no
substituent on their aromatic rings, tricyclic heterocyclic com-
pound 3gb was obtained in 72% yield with 82% ee. The sub-
strates 1h–1j with various electron-rich substituents on their
aromatic rings were more suitable for this reaction, affording
the corresponding cycloadducts 3ha–3ja in good yields with
90–93% ee. These results suggest that the electronic properties
of substituents of substrates 1 have an important influence on
the reaction outcomes, especially on the control of enantiose-
lectivity. Substrate 1 having an aliphatic group was also tested
We also tested N,N’-cyclic azomethine imine 4 or compound
5 in this reaction catalyzed by triphenylphosphine or CP9.
However, no desired products were obtained under the stan-
dard conditions [Scheme 7, Eqs. (1) and (2)]. Enlarging the reac-
tion scale to 264 mg (1.0 mmol) afforded 3aa in 380 mg, 72%
Chem. Eur. J. 2014, 20, 1 – 6
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