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Metal-Catalyzed (4+3) Cyclization of Vinyl Aziridines with para-Quinone Methide Derivatives Fei Jiang, Fu-Ru Yuan, Li-Wen Jin, Guang-Jian Mei, and Feng Shi ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03410 • Publication Date (Web): 03 Oct 2018 Downloaded from http://pubs.acs.org on October 3, 2018
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ACS Catalysis
Metal-Catalyzed (4+3) Cyclization of Vinyl Aziridines with paraQuinone Methide Derivatives Fei Jiang, Fu-Ru Yuan, Li-Wen Jin, Guang-Jian Mei* and Feng Shi* School of Chemistry and Materials Science, Jiangsu Normal University, Xuzhou 221116, China ABSTRACT: The development of (4+3) cyclizations of vinyl aziridines, especially catalytic asymmetric versions, is needed in organic synthesis. This report describes an iridium-catalyzed (4+3) cyclization of vinyl aziridines with para-quinone methide (pQM) derivatives, and this reaction constructs a seven-membered benzoxazepine scaffold in moderate to high yields (40% to 96%) and considerable diastereoselectivities (70:30 dr to >95:5 dr). Moreover, the catalytic asymmetric version of this (4+3) cyclization is accomplished in the presence of a palladium catalyst and a chiral ligand, and this modification provides chiral benzoxazepine derivatives in generally moderate diastereoselectivities (73:27 dr to 91:9 dr) and high enantioselectivities (92:8 to 96:4 er). This approach delivers a scarcely reported catalytic enantioselective (4+3) cyclization of vinyl aziridines and offers a metal-catalyzed (4+3) cyclization of p-QM derivatives.
KEYWORDS: Asymmetric catalysis; Cyclization; Enantioselectivity; Metal catalysis; Vinyl aziridine; para-Quinone methide Vinyl aziridines belong to a class of important nitrogencarbon-carbon (NCC) synthetic blocks, and they are broadly applicable in cyclizations aiming at building up nitrogencontaining heterocyclic ring systems.1-4 As illustrated in Scheme 1, vinyl aziridines can form zwitterionic π-allyl metal intermediates under metal-catalysis, allowing them to act as NCC building blocks in cyclizations. However, most cyclizations involving vinyl aziridines are (3+2) cyclizations with electron-deficient alkenes or other two-carbon synthons, and these reactions construct five-membered nitrogenous frameworks (eq. 1).2-3 On the other hand, although (3+3) and (4+3) cyclizations of vinyl aziridines can construct six- and seven-membered nitrogen-containing rings, they are underdeveloped (eq. 2-3). Surveying previous reports revealed the examples of (3+3) cyclizations of vinyl aziridines with 1,3dipoles (eq. 2) are very limited,4 while (4+3) cyclizations of vinyl aziridines are scarcely described by chemists (eq. 3). It should be noted that (4+3) cyclizations and (5+2) cyclizations of vinyl aziridines3d,5 are powerful methods of synthesizing seven-membered nitrogenous heterocycles. Compared to (3+2) and (3+3) cyclizations leading to the building up of five- and six-membered scaffolds, (4+3) cyclizations for the construction of seven-membered skeletons are much more challenging due to unfavorable entropic factors and transannular interactions.6-7 Recently, Zhang, Feng and their co-workers established a (4+3) cyclization of chiral vinyl aziridines with dienes in the presence of a rhodium catalyst, which constructed an azepine scaffold in an enantioselective manner (eq. 4).8 Despite this elegant approach, (4+3) cyclizations of vinyl aziridines are still rather limited, and catalytic asymmetric versions in the presence of chiral catalysts are unknown. Therefore, the development of (4+3) cyclizations of vinyl aziridines, especially catalytic asymmetric versions of such transformations, is highly needed. To accomplish this task, the selection of suitable fouratom reaction partners and the specific design of the (4+3) cyclizations of vinyl aziridines are very important.
R EWG N
(3+2)
EWG
R
EWG
(1)
N
W ell-established GWE Vinyl aziridines MLn
R1
MLn GWE
N
R2 X
R3 Y
(3+3) Limited examples GWE
NCC building blocks
R5
R4
R2 X
R1
Y
R3 (2)
N
R5
R4
(4+3) N Scarcely reported GWE More challenging
(3)
Sole example of a (4+3) cyclization:
R7 R6
OSi N
EWG
+ 4
R
R7
5 mol% [Rh(NBD)Cl]2 10 mol% AgClO4 DCE, 0 oC
R6
OSi N
GWE
(4) R4
Scheme 1. Profile of vinyl aziridines-involved cyclizations acting as NCC synthons In this context, ortho-hydroxyphenyl-substituted paraquinone methides (p-QMs)9 are noticed by us because reactants of this type are competent four-atom reaction partners aiming at building up oxygenous heterocyclic motifs (Scheme 2).10-12 The Enders group pioneered the design and application of this class of substrates in (4+2) cyclizations.10 After that, a series of (4+2)11 and (4+1)12 cyclizations, which constructed six- and five-membered oxygenated heterocyclic skeletons, were established (eq. 5). In contrast, (4+3) cyclizations of this class of reactants have not yet been disclosed, and it remains unknown chemistry (eq. 6).13 Thus, the development of (4+3) cyclizations of such p-QM derivatives is highly attractive.
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ACS Catalysis OH
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
R1
R1
OH
R1
R1 (4+2), (4+1) O R1
R2 R
Known
R1
O HO R1
R OH
Nu
E
?
(4+3) Unknown
R4 (5)
R
O
3
R
R5
R1
Nu
(6)
R O E
Scheme 2. Profile of reactions involving p-QM derivatives. To achieve the above-mentioned goals and as part of our ongoing efforts toward constructing heterocyclic scaffolds,14 we designed metal-catalyzed (4+3) cyclizations of vinyl aziridines with o-hydroxyphenyl-substituted p-QMs. As depicted in Scheme 3, the hydroxyl group of the ohydroxyphenyl-substituted p-QM would form an oxygen anion by the promotion of a base, which is highly nucleophilic. Simultaneously, under the promotion of a metal-catalyst, the vinyl aziridine would form zwitterionic π-allyl metal intermediate A, which could be attacked by the nucleophilic oxygen anion of the o-hydroxyphenyl-substituted p-QM to generate transient intermediate B. Then, an intramolecular aza1,6-addition would finish the (4+3) cyclization and to construct the seven-membered benzoxazepine scaffold, which constitutes the core structure of some bioactive compounds.15 In addition, if a suitable chiral ligand was employed in the reaction, a catalytic asymmetric version of this (4+3) cyclization could be realized. Therefore, the designed reaction would represent the first catalytic asymmetric (4+3) cyclization of vinyl aziridines and would establish the first metal-catalyzed (4+3) cyclization of p-QM derivatives. Herein, we report our investigations on this reaction. This work: 1st catalytic asymmetric (4+3) cyclization of vinyl aziridines 1st metal-catalyzed (4+3) cyclization of o-hydroxyphenyl-substituted p-QMs O R1
HO
R1
R1
R1 EWG N
+
R
EWG
R O
NCC building blocks
base
MLn
O R
N
(4+3) cyclization
OH four-atom synthons
1
MLn/base
O R
1
R1
R1 EWG
N
N R
EWG
R O A oxa-allylic alkylation
(4+3) cyclization in a better diastereoselectivity of 90:10 dr and a greatly improved yield of 75% (the details are in the SI). Therefore, [Ir(cod)Cl]2 was regarded as the best catalyst for this reaction. After that, other conditions for the reaction, such as the solvent, the base, the temperature for the reaction, the ratio of reagents and the amount of base, were carefully modulated (the details are in the SI), and the most suitable reaction conditions were ultimately determined (Scheme 4). Under these conditions, product (±)-3aa could be generated in a good diastereoselectivity of 93:7 dr and an excellent yield of 95%. HO
O t
t
Bu
t
Bu
+
1a
Ts N
t
Bu
5 mol% Cat., base
Bu
NTs
solvent, T oC O
OH 2a
(+)-3aa
Initial conditions: Pd2dba3 CHCl3, Cs2CO3 (1.2 equiv.), DCM, 20 oC, 1a:2a = 1:1.2 Optimal conditions: [Ir(cod)Cl]2, DMAP (1.5 equiv.), DCM, 20 oC, 1a:2a = 1:1.5
80:20 dr, 36% yield 93:7 dr, 95% yield
Scheme 4. Conditions elaboration for the designed (4+3) cyclization After we obtained the most suitable conditions for the reaction, we studied the applicability of the (4+3) cyclization (Table 1). First, we studied the generality of p-QM derivatives 1 in reactions with substrate 2a. As shown in entries 1-13, a wide range of substrates 1 with either electronically rich or electronically poor R1 substituents at different positions on the phenyl ring were able to undergo the (4+3) cyclization and generate products (±)-3 in acceptable to excellent chemical yields (45% to 96%) and generally pretty diastereoselectivities (75:25 to >95:5 dr). In most cases, it seemed that a methoxy group, a strong electron-donating substituent, was helpful for achieving a high yield, which was demonstrated by the reactions involving substrates 1b, 1f and 1i (entries 2, 6 and 9). Second, the generality of vinyl aziridines 2 was investigated by changing the substituents on the benzenesulfonyl group (entries 1 and 14-19). We discovered that both electron-rich (entries 1 and 14), electron-neutral (entry 15) and electron-poor substituents (entries 16-19) could be used for substrates 2, and they smoothly participated in the (4+3) cyclization to yield compounds (±)-3 with overall high diastereoselectivities (89:11 to 93:7 dr) and generally considerable yields (50% to 96%). Table 1. Applicability of the (4+3) cyclizationa
O
LnM
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O
B
t
aza-1,6-addition
Scheme 3. Design of (4+3) cyclizations of vinyl aziridines with p-QM derivatives As listed in Scheme 4, to test our hypothesis, the reaction of p-QM derivative 1a with vinyl aziridine 2a was selected as the model reaction. Initially, in the presence of a palladium catalyst and cesium carbonate as the base, the (4+3) cyclization took place and afforded product (±)-3aa in an acceptable diastereoselectivity of 80:20 dr, but the yield was just 36%. Therefore, this initial result illustrated that our design is feasible. Then, a series of metal catalysts were screened, and [Ir(cod)Cl]2 was found to be able to promote the
5
6
R1
HO t
Bu
Bu
1
+
2 4
3
t
SO2R N
t
Bu
5 mol% [Ir(cod)Cl]2 1.5 equiv. DMAP DCM, 20 oC
OH
N
SO2R
R1 O (+)-3
2
1
Bu
entry
R1 (1)
R (2)
(±)-3
drb
yield (%)c
1
H (1a)
p-MeC6H4 (2a)
(±)-3aa
93:7
95
2
3-OMe (1b)
p-MeC6H4 (2a)
(±)-3ba
>95:5
96
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ACS Catalysis 3-Cl (1c)
p-MeC6H4 (2a)
(±)-3ca
3-Br (1d)
p-MeC6H4 (2a)
(±)-3da
5
4-NEt2 (1e)
p-MeC6H4 (2a)
(±)-3ea
87:13
45
6
4-OMe (1f)
p-MeC6H4 (2a)
(±)-3fa
85:15
95
3 4
93:7 >95:5
5-Me (1h)
p-MeC6H4 (2a)
(±)-3ha
9
5-OMe (1i)
p-MeC6H4 (2a)
(±)-3ia
86:14
93
10
5-tBu (1j)
p-MeC6H4 (2a)
(±)-3ja
88:12
80
11
5-F (1k)
p-MeC6H4 (2a)
(±)-3ka
12
5-Cl (1l)
p-MeC6H4 (2a)
(±)-3la
83:17
45
13
5-Br (1m)
p-MeC6H4 (2a)
(±)-3ma
80:20
46
14
H (1a)
p-OMeC6H4 (2b)
(±)-3ab
92:8
66
H (1a)
Ph (2c)
t
Bu
N
DCM, 20 oC
OH
Bu
Ts (7)
O (+)-3na
2a
1n
t
Bu
5 mol% [Ir(cod)Cl]2 1.5 equiv. DMAP
Ts N
+
75:25
OH
O t
(±)-3ga
15
t
Bu
70:30 dr, 50% yield
p-MeC6H4 (2a)
8
t
75
4-Br (1g)
7
OH
O
50
t t
Bu
Bu
85
NTs
90
MeCN(0.1M), 20 oC O 2h
(+)-3ah >95:5 dr, 60% yield HO
O
91:9
t
Bu
t
Bu
93
89:11
Bu
NTs
DCM, 20oC
(9)
O
Me (+)-3ai
2i
1a
t
Bu
5 mol% [IrcodCl]2 1.5 equiv. DMAP
Ts N
+ OH
(±)-3ac
(8)
NTs
OH 1a
t
Bu
5 mol% Pd2dba3 CHCl3 1.2 equiv. Cs2CO3
+
90:10
t
Bu
Me
94:6 dr, 45% yield HO
O t
t
Bu
t
Bu
(10)
O
Ph 2j
1a
Bu
NTs
DCM, 20oC
OH
70
5 mol% [IrcodCl]2 1.5 equiv. DMAP
Ts N
+
t
Bu
(+)-3aj Ph 94:6 dr, 40% yield
16 17 18
p-FC6H4 (2d)
(±)-3ad
H (1a)
p-BrC6H4 (2e)
(±)-3ae
H (1a)
p-NO2C6H4 (2f)
H (1a)
(±)-3af
91:9 91:9 89:11
70
t
Bu
55
H (1a)
In addition, under the most suitable reaction conditions, pQM derivative 1n could be engaged in the (4+3) cyclization to yield product (±)-3na; however, the achieved diastereoselectivity and the yield were not satisfactory (Scheme 5, eq. 7). In addition, cyclic vinyl aziridine 2h could serve as a suitable substrate in the (4+3) cyclization using a palladium complex as the catalyst, and the reaction afforded product (±)-3ah in a satisfactory diastereoselectivity of >95:5 dr and a considerable yield of 60% (eq. 8). More importantly, some other vinylaziridines with different substituents on olefin moiety could be engaged in the (4+3) cyclization. For instance, methyl-substituted vinylaziridine 2i (eq. 9) and phenylsubstituted vinylaziridine 2j (eq. 10) smoothly underwent the (4+3) cyclization with 1a under the most suitable reaction conditions with high diastereoselectivities and acceptable yields. Notably, vinylaziridine 2k bearing an ester group was competent in performing the (4+3) cyclization, and the reaction offered product (±)-3ak with a high diastereoselectivity and a moderate yield (eq. 11).
HO
Bu
+
t
1a
t
Bu
5 mol% [IrcodCl]2 1.5 equiv. DMAP
Ts N
Bu
NTs
DCM, 20oC
CO2Et
OH
50
p-CF3C6H4 (±)-3ag 89:11 60 (2g) aThe reaction was conducted on the 0.1 mmol scale which was catalyzed by 5 mol% [Ir(cod)Cl]2 in DCM (1 mL) at 20°C for 24 h, and the molar ratio of 1:2 was 1:1.5. bThe dr value was assigned by 1H NMR spectroscopy. cIsolated yield. 19
O t
O (+)-3ak
2k
94:6 dr, 56% yield
(11)
CO2Et
Scheme 5. Further expansion of the substrate scope Then, to investigate whether this (4+3) cyclization can be scaled up or not, a one-mmol scale preparation of product (±)3aa was launched under the conditions similar to the model reaction (Scheme 6). Apparently, this one-mmol scale reaction could prepare product (±)-3aa with a good level of diastereoselectivity (95:5 dr) and a high level of yield (95%), which is similar to the 0.1 mmol scale reaction (Table 1, entry 1). This outcome convinced that the (4+3) cyclization could be utilized for a large-scale synthesis. The chemical structures of compounds (±)-3 have been identified by NMR spectroscopy, infra-red spectrum, and highresolution mass spectroscopy. In addition, the exact structure (including the relative configuration) of compound (±)-3aa was elucidated by single-crystal X-ray crystallography. As drawn in Scheme 6, the relative configuration of (±)-3aa was designated as cis.16 HO
O t
Bu
t
+ OH 1a 1 mmol
t
Bu Ts N
5 mol% [Ir(cod)Cl]2 1.5 equiv. DMAP DCM, 20 oC
2a 1.5 mmol
t
Bu
Bu
NTs O (+)-3aa
95:5 dr, 95% yield (508 mg)
Scheme 6. One-mmol scale preparation of (±)-3aa and its relative configuration
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Because the relative configuration of the major diastereomers of (±)-3aa was definitely assigned to be cis via its single-crystal X-ray crystallography, we can learn important information from the 1H NMR and NOESY spectra of (±)-3aa, which should be very helpful for determining the relative configurations of the major diastereomers of other products (±)-3. As shown in Scheme 7a, as exemplified by (±)-3aa, if the configuration of H1 and H2 is cis, they should have a NOE correlation with the same hydrogen (Ha); if the configuration of H1 and H2 is trans, they should not have a NOE correlation with the same hydrogen. Instead, they should have a NOE correlation with different hydrogens (Ha and Hb), respectively. As listed in Scheme 7b, in the 1H NMR spectrum of (±)-3aa, the chemical shift of H2 in cis-(±)-3aa (major diastereomer) is 4.02-4.12, while the chemical shift of H2 in trans-(±)-3aa (minor diastereomer) is 4.38-4.46. Thus, the chemical shift of H2 can also be used as an important information for assigning the relative configurations of the major diastereomers of other products (±)-3. So, based on the NOESY spectra and the chemical shift of H2, the relative configurations of the major diastereomers of all products (±)-3 were determined (the details are in the SI). Apart from (±)-3aj whose relative configuration of the major diastereomer was assigned to be trans, the relative configurations of the major diastereomers of all other products (±)-3 were determined to be cis.
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opening product (±)-4 (eq. 14). This reaction makes us understand why the detertbutylation reaction of products (±)-3 can hardly occur. As depicted in Scheme 8, Under the promotion of AlCl3 as a strong Lewis acid, compound (±)-3ak has a high tendency to undergo a retro-aza-1,6-addition, thus leading to the ring-opening of the aza-seven-membered ring and the formation of product (±)-4. So, the unsuccessful detertbutylation reaction of products (±)-3 should largely be ascribed to the instability of the aza-seven-membered ring under the acidic condition, which is inherent in the structures of products (±)-3. HO HO t
t
Bu
NTs NTs
OH
tBu
HO t
t
Bu
H1
O
O
HO
Ts N O
H2 cis-(+)-3aa Chemical shift of H2 is 4.02-4.12
CO2Et
(+)-4
(14)
CO2Et
43% yield
OH
Bu t
Ts N
tBu nOe
H1
Bu
NHTs
toluene, 0 oC, 48 h O
t
Bu
OH
tBu
t
Bu
AlCl3
b) Chemical shift of H in cis-(+)-3aa and trans-(+)-3aa
H1
O t
O (+)-3ak
t
tBu
(13)
10 equiv. AlCl3
H2 trans-(+)-3aa
OH
decompsed into a complex mixture
Bu
NTs
2
tBu
t
Bu
Ha Hb
O
H2 cis-(+)-3aa
60 oC,12 h
(+)-3aa
Ts N
Ha Hb
Tf2O/TfOH
NTs
tBu
Ts N
Bu
OH
tBu
O N.R. or decompsed (12) into a complex mixture
(+)-3aa
t
tBu H1
AlCl3 toluene, 12 h 0 oC to 80 oC
O
HO
a) NOE correlations in cis-(+)-3aa and trans-(+)-3aa
H
H
Bu
AlCl3
Bu
retro-aza-1,6-addtion NTs
O
O CO2Et
Ts
t
Bu
CO2Et
N O H2 trans-(+)-3aa Chemical shift of H2 is 4.38-4.46
Scheme 7. Determination of the relative configurations of the major diastereomers of products (±)-3 According to the literature methods,11c-d,17 we tried the detertbutylation reaction of product (±)-3aa in the presence of AlCl3 at different reaction temperatures (Scheme 8, eq. 12). However, no detertbutylation product was observed. Instead, no reaction (N.R.) occurred or compound (±)-3aa decomposed into a complex mixture, which had no main products and could not be identified (the details are in the SI). In addition, we also tried the detertbutylation reaction of product (±)-3aa by the promotion of Tf2O/TfOH according to the literature method.18 However, compound (±)-3aa still decomposed into a complex mixture, which could not be identified (eq. 13). Then, we tried the detertbutylation reaction of product (±)-3ak by the promotion of AlCl3. In this case, the reaction was clean and we got a main product, which was identified as ring-
Scheme 8. Attempts on detertbutylation of product (±)-3 After we accomplished the (4+3) cyclization of vinyl aziridines with o-hydroxyphenyl-substituted p-QMs, we tried to establish the catalytic asymmetric version of this reaction. However, initially, under the catalysis of [Ir(cod)Cl]2 and chiral ligand L1, the model reaction of 1a with 2a generated product 3aa in an almost racemic form (Scheme 9). It was found that changing the metal catalyst from the iridium complex to the palladium complex provided some enantioselectivity in the formation of product 3aa, although the yield fell down (the details are in the SI). The subsequent screening of chiral ligands revealed that L1 should be the optimal ligand in terms of controlling the enantioselectivity (the details are in the SI). To elevate the yield and enantioselectivity, a series of different reaction conditions, such as the solvent, the temperature of the reaction, the base, the catalyst loading, the concentration and the additives, were carefully investigated (the details are in the SI), and the most suitable reaction conditions were ultimately identified (in Scheme 9). Under these conditions, product 3aa could be
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ACS Catalysis obtained with a considerable yield (65%), a moderate diastereoselectivity ( 83:17 dr), and a high level of enantioselectivity (96:4 er). PPh2 O
O NH
PPh2
HN HO
O t
t
Bu
Ts N
t
Bu
metal/L* 1.2 equiv. base
+
1a
t
L1
Bu
O
2a
*
3aa
Initial conditions: 5 mol% [Ir(cod)Cl]2, 10 mol% L1, Cs2CO3, CH3CN (0.1 M), 30 oC, no additives
H (1a)
In addition, chiral product 3aa could undergo olefin metathesis, which gave chiral compound 3ak with retention of the diastereomeric ratio and enantiomeric ratio (Scheme 10).
* NTs
solvent, T oC additives
OH
Bu
OMe 3ab 50 80:20 96:4 (2b) 8 H (1a) H (2c) 3ac 40 82:18 96:4 9 H (1a) CF3 (2g) 3ag 43 73:27 96:4 aThe reaction was conducted on the 0.1 mmol scale in acetonitrile (6 mL) for 12 h, and the molar ratio of 1:2 was 1:1.2. bIsolated yield. cThe dr value was assigned by 1H NMR spectroscopy. dThe er value was assigned by HPLC. 7
76%, 80:20 dr, 49:51 er
Optimal conditions: 10 mol%Pd2(dba)3 CHCl3, 30 mol% L1, Cs2CO3, 65%, 83:17 dr, 96:4 er CH3CN (0.017 M), 20 oC, 1 equiv. LiCl as additives
HO t
Bu
Table 2. Generaltiy of the catalytic enantioselective (4+3) cyclizationa O t
t
Bu
Bu
OH
R2
t
t
Bu
10 mol% Pd2(dba)3 CHCl3 5
6
1
+
1
R
4
3
2
OH
1
O S O N
* N
S
R2
O
O *
o
1 2
H (1a) 4-OMe (1f) 5-Me (1h) 5-OMe (1i) 5-F (1k) 5-Cl (1l)
t
* NTs
+
O *
t
Bu
Bu
5 mol% Grubbs II
*
o
DCM (0.1 M), 40 C 12 h
3aa 83:17 dr, 96:4 er
Ts N
* O 3ak 56% yield 84:16 dr, 95:5 er
CO2Et
Scheme 10. Preliminary derivatization of 3aa In conclusion, we have accomplished an iridium-catalyzed (4+3) cyclization of vinyl aziridines with o-hydroxyphenylsubstituted p-QMs for the building up of seven-membered benzoxazepine motifs in moderate to high yields (40% to 96%) and considerable diastereoselectivities (70:30 dr to >95:5 dr). Moreover, we have realized the catalytic asymmetric version of this (4+3) cyclization in the presence of a palladium catalyst and a chiral ligand, and the reaction afforded chiral benzoxazepine derivatives in generally moderate diastereoselectivities (73:27 dr to 91:9 dr) and high enantioselectivities (92:8 to 96:4 er). This approach delivers a scarcely reported catalytic enantioselective (4+3) cyclization of vinyl aziridines and offers a metal-catalyzed (4+3) cyclization of p-QM derivatives, which greatly enriches the chemistry of vinyl aziridines and p-QMs.
ASSOCIATED CONTENT Supporting Information. Screening of catalysts and condition optimization, experimental procedures, characterization data, NMR spectra for products (+)-3, (+)-4 and 3, HPLC spectra for products 3, NOESY spectra of products (+)-3, attempts on detertbutylation of product (+)-3aa and (+)-3ak, and crystallographic data (CIF) for compound (+)-3aa. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
3
R2 (2)
5 6
R
MeCN, 20 C
R1 (1)
4
Cs2CO3, LiCl
1
2
entr y
3
O
30 mol% L1
Bu
HO
Bu CO2Et
Scheme 9. Conditions elaboration for the catalytic asymmetric (4+3) cyclization After we obtained the most suitable reaction conditions, the generality for the catalytic enantioselective (4+3) cyclization was studied. As listed in Table 2, entries 1-6, a series of p-QM derivatives 1 bearing electronically distinct R1 groups at various positions proved to be suitable substrates for this catalytic asymmetric reaction, and they smoothly reacted with vinyl aziridine 2a to afford chiral products 3 in moderate to good diastereoselectivities (80:20 to 91:9 dr) and high enantioselectivities (92:8 to 96:4 er). In addition, several vinyl aziridines 2 with different R2 substituents could participate in the catalytic enantioselective (4+3) cyclization to yield corresponding products 3 in moderate diastereoselectivities (73:27 to 83:17 dr) and uniformly excellent enantioselectivities of 96:4 er (entries 1 and 7-9). We should admit that the chemical yields of chiral products 3 were only in a moderate level. This is because the reactivity of the two substrates was not very high under the catalysis of the palladium complex, and there were large amounts of substrates 1 and 2 remaining in the reaction mixture even with prolonged reaction time. Nevertheless, this reaction has accomplished the first catalytic asymmetric (4+3) cyclization of vinyl aziridines, and it is also the first metal-catalyzed asymmetric (4+3) cyclization of o-hydroxynaphthylsubstituted p-QMs.
t
3
yield (%)b
drc
erd
Me (2a) Me (2a)
3aa 3fa
65 40
83:17 80:20
96:4 94:6
*F.S.: email,
[email protected]. *G.-J.M.: email,
[email protected].
Me (2a)
3ha
40
91:9
92:8
Me (2a)
3ia
45
83:17
95:5
All authors have given approval to the final version of the manuscript.
Me (2a) Me (2a)
3ka 3la
50 42
83:17 82:18
96:4 93:7
Corresponding Authors
Author Contributions Notes The authors declare no competing financial interest.
ACKNOWLEDGMENT
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We are grateful for financial supports from NSFC (21772069), Natural Science Foundation of Jiangsu Province (BK20160003), Six Kinds of Talents Project of Jiangsu Province (SWYY-025), and Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX18_2107).
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Am. Chem. Soc. 2016, 138, 2178-2181. (e) Lin, T.-Y.; Zhu, C.-Z.; Zhang, P.; Wang, Y.; Wu, H.-H.; Feng, J.-J.; Zhang, J. Regiodivergent Intermolecular [3+2] Cycloadditions of Vinyl Aziridines and Allenes: Stereospecific Synthesis of Chiral Pyrrolidines. Angew. Chem. Int. Ed. 2016, 55, 10844-10848. (f) Yuan, Z.; Wei, W.; Lin, A.; Yao, H. Bifunctional Organo/Metal Cooperatively Catalyzed [3+2] Annulation of para-Quinone Methides with Vinylcyclopropanes: Approach to Spiro [4.5] Deca6, 9-Diene-8-Ones. Org. Lett. 2016, 18, 3370-3373. (g) Lin, T.-Y.; Wu, H.-H.; Feng, J.-J.; Zhang, J. Divergent Access to Functionalized Pyrrolidines and Pyrrolines via Iridium-Catalyzed Domino-Ring-Opening Cyclization of Vinyl Aziridines with βKetocarbonyls. Org. Lett. 2017, 19, 6526-6529. (h) Kaicharla, T.; Jacob, A.; Gonnade, R. G.; Biju, A. T. AgOTf-Catalyzed Dehydrative [3+2] Annulation of Aziridines with 2-Naphthols. Chem. Commun. 2017, 53, 8219-8222. (i) Rivinoja, D. J.; Gee, Y. S.; Gardiner, M. G.; Ryan, J. H.; Hyland, C. J. T. The Diastereoselective Synthesis of Pyrroloindolines by Pd-Catalyzed Dearomative Cycloaddition of 1-Tosyl-2-Vinylaziridine to 3Nitroindoles. ACS Catal. 2017, 7, 1053-1056. (j) Zhu, C.-Z.; Feng, J.-J.; Zhang, J. Divergent Synthesis of Functionalized Pyrrolidines and γ-Amino Ketones via Rhodium-Catalyzed Switchable Reactions of Vinyl Aziridines and Silyl Enol Ethers. Chem. Commun. 2018, 54, 2401-2404. (4) For (3+3) cyclizations of vinyl aziridines: (a) Zhu, C.-Z.; Feng, J.J.; Zhang, J. Rhodium-Catalyzed Intermolecular [3+3] Cycloaddition of Vinyl Aziridines with C, N-Cyclic Azomethine Imines: Stereospecific Synthesis of Chiral Fused Tricyclic 1, 2, 4Hexahydrotriazines. Chem. Commun. 2017, 53, 4688-4691. (b) Wani, I. A.; Sayyad, M.; Ghorai, M. K. Domino Ring-Opening Cyclization (DROC) of Activated Aziridines and Epoxides with Nitrones via Dual-catalysis “On Water”. Chem. Commun. 2017, 53, 4386-4389. (c) Sayyad, M.; Wani, I. A.; Babu, R.; Nanaji, Y.; Ghorai, M. K. A Synthetic Route to Chiral 1,4-Disubstituted Tetrahydro-β-Carbolines via Domino Ring-Opening Cyclization of Activated Aziridines with 2-Vinylindoles. J. Org. Chem. 2017, 82, 2364-2374. (5) For some examples on (5+2) cyclizations of vinyl aziridines: (a) Feng, J.-J.; Lin, T.-Y.; Wu, H.-H.; Zhang, J. Transfer of Chirality in the Rhodium-Catalyzed Intramolecular Formal Hetero-[5+2] Cycloaddition of Vinyl Aziridines and Alkynes: Stereoselective Synthesis of Fused Azepine Derivatives. J. Am. Chem. Soc. 2015, 137, 3787−3790. (b) Feng, J.-J.; Lin, T.-Y.; Wu, H.-H.; Zhang, J. Modular Access to the Stereoisomers of Fused Bicyclic Azepines: Rhodium-Catalyzed Intramolecular Stereospecific hetero-[5+2] Cycloaddition of Vinyl Aziridines and Alkenes. Angew. Chem. Int. Ed. 2015, 54, 15854 -15858. (6) For some reviews on (4+3) cycloadditions: (a) Cha, J. K.; Oh, J. [4+3] Cycloaddition Reactions of Cyclic Oxyallyls in Natural Product Synthesis. Curr. Org. Chem. 1998, 2, 217-232. (b) Hartung, I. V.; Hoffmann, H. M. R. 8‐Oxabicyclo [3.2.1] Oct‐6‐En‐3‐Ones: Application to the Asymmetric Synthesis of Polyoxygenated Building Blocks. Angew. Chem. Int. Ed. 2004, 43, 1934-1949. (c) Battiste, M. A.; Pelphrey, P. M.; Wright, D. L. The Cycloaddition Strategy for the Synthesis of Natural Products Containing Carbocyclic Seven‐Membered Rings. Chem. Eur. J. 2006, 12, 3438-3447. (d) Harmata, M. The (4+3)-Cycloaddition Reaction: Heteroatom-Substituted Allylic Cations as Dienophiles. Chem. Commun. 2010, 46, 8904-8922. (e) Harmata, M. The (4+3)Cycloaddition Reaction: Simple Allylic Cations as Dienophiles. Chem. Commun. 2010, 46, 8886-8903. (f) Lohse, A. G.; Hsung, R.
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ACS Catalysis P. (4+ 3)-Cycloaddition Reactions of Nitrogen‐Stabilized Oxyallyl Cations. Chem. Eur. J. 2011, 17, 3812-3822. (7) For some recent examples on (4+3) cycloadditions: (a) Shang, H.; Wang, Y.; Tian, Y.; Fang, J.; Tang, Y. The Divergent Synthesis of Nitrogen Heterocycles by Rhodium (II)‐Catalyzed Cycloadditions of 1‐Sulfonyl 1, 2, 3‐Triazoles with 1, 3‐Dienes. Angew. Chem. Int. Ed. 2014, 53, 5662-5772. (b) Liu, K.; Teng, H.-L.; Wang, C.-J. Et3N-Catalyzed Tandem Formal [4+3] Annulation/Decarboxylation/Isomerization of Methyl Coumalate with Imine Esters: Access to Functionalized Azepine Derivatives. Org. Lett. 2014, 16, 4508-4511. (c) Xu, H.; Hu, J.-L.; Wang, L.; Liao, S.; Tang, Y. Asymmetric Annulation of Donor–Acceptor Cyclopropanes with Dienes. J. Am. Chem. Soc. 2015, 137, 80068009. (d) Zhan, G.; Shi, M.-L.; He, Q.; Du, W.; Chen, Y.-C. [4+3] Cycloadditions with Bromo-Substituted Morita–Baylis–Hillman Adducts of Isatins and N-(ortho-Chloromethyl) Aryl Amides. Org. Lett. 2015, 17, 4750-4753. (e) Tian, Y.; Wang, Y.; Shang, H.; Xu, X.; Tang, Y. Rhodium (II)-Catalyzed Intramolecular Formal [4+3] Cycloadditions of Dienyltriazoles: Rapid Access to Fused 2,5Dihydroazepines. Org. Biomol. Chem. 2015, 13, 612-619. (f) Wei, L.; Wang, Z.-F.; Yao, L.; Qiu, G.; Tao, H.; Li, H.; Wang, C.-J. Copper (II)‐Catalyzed Asymmetric 1, 3‐Dipolar [3+4] Cycloaddition and Kinetic Resolution of Azomethine Imines with Azoalkenes. Adv. Synth. Catal. 2016, 358, 3955-3959. (8) For sole example of a (4+3) cyclization of vinyl aziridines: Zhu, C.-Z.; Feng, J.-J.; Zhang, J. Rhodium (I)‐Catalyzed Intermolecular Aza‐[4+ 3] Cycloaddition of Vinyl Aziridines and Dienes: Atom‐Economical Synthesis of Enantiomerically Enriched Functionalized Azepines. Angew. Chem. Int. Ed. 2017, 56, 13511355. (9) For some examples on p-QMs: (a) Chu, W.-D.; Zhang, L.-F.; Bao, X.; Zhao, X.-H.; Zeng, C.; Du, J.-Y.; Zhang, G.-B.; Wang, F.-X.; Ma, X.-Y.; Fan, C.-A. Asymmetric Catalytic 1,6-Conjugate Addition/Aromatization of para-Quinone Methides: Enantioselective Introduction of Functionalized Diarylmethine Stereogenic Centers. Angew. Chem. Int. Ed. 2013, 52, 9229-9233. (b) Wang, Z.-B.; Wong, Y.-F.; Sun, J.-W. Catalytic Asymmetric 1,6-Conjugate Addition of para-Quinone Methides: Formation of All-Carbon Quaternary Stereocenters. Angew. Chem. Int. Ed. 2015, 54, 13711-13714. (c) He, F.-S.; Jin, J.-H.; Yang, Z.-T.; Yu, X.; Fossey, J. S.; Deng, W.-P. Direct Asymmetric Synthesis of β-BisAryl-α-Amino Acid Esters via Enantioselective Copper-Catalyzed Addition of p-Quinone Methides. ACS Catal. 2016, 6, 652-656. (d) Ma, C.; Huang, Y.; Zhao, Y. Stereoselective 1,6-Conjugate Addition/Annulation of para-Quinone Methides with Vinyl Epoxides/Cyclopropanes. ACS Catal. 2016, 6, 6408-6412. (d) Li, S.; Liu, Y.; Huang, B.; Zhou, T.; Tao, H.; Xiao, Y.; Liu, L.; Zhang, J. Phosphine-Catalyzed Asymmetric Intermolecular CrossVinylogous Rauhut–Currier Reactions of Vinyl Ketones with paraQuinone Methides. ACS Catal. 2017, 7, 2805-2809. (10) For a pioneering work on o-hydroxyphenyl substituted p-QMs: Zhao, K.; Zhi, Y.; Shu, T.; Valkonen, A.; Rissanen, K.; Enders, D. Organocatalytic Domino Oxa‐Michael/1,6‐Addition Reactions: Asymmetric Synthesis of Chromans Bearing Oxindole Scaffolds. Angew. Chem. Int. Ed. 2016, 55, 12104-12108. (11) For examples on (4+2) cyclizations of o-hydroxyphenyl substituted p-QMs: (a) Liu, S.; Lan, X.-C.; Chen, K.; Hao, W.-J.; Li, G.-G.; Tu, S.-J.; Jiang, B. Ag/Brønsted Acid Co-Catalyzed Spiroketalization of β-Alkynyl Ketones toward Spiro [chromane2,1′-isochromene] Derivatives. Org. Lett. 2017, 19, 3831-3834. (b) Zhang, L.-L.; Liu, Y.; Liu, K.; Liu, Z.-T.; He, N.-N.; Li, W.-J. Asymmetric Synthesis of Dihydrocoumarins via the
Organocatalytic Hetero-Diels–Alder Reaction of Ortho-quinone Methides. Org. Biomol. Chem. 2017, 15, 8743-8747. (c) Zhang, L.L.; Zhou, X.; Li, P.-F.; Liu, Z.-T.; Liu, Y.; Sun, Y.; Li, W.-J. Asymmetric Synthesis of Chromene Skeletons via Organocatalytic Domino Reactions of In Situ Generated ortho-Quinone Methide with Malononitrile and β-Functionalized Ketone. RSC Adv. 2017, 7, 39216-39220. (d) Zhang, Z.-P.; Xie, K.-X.; Yang, C.; Li, M.; Li, X. Asymmetric Synthesis of Dihydrocoumarins through Chiral Phosphoric Acid-Catalyzed Cycloannulation of para-Quinone Methides and Azlactones. J. Org. Chem., 2018, 83, 364-373. (e) Mei, G.-J.; Xu, S.-L.; Zheng, W.-Q.; Bian, C.-Y.; Shi, F. [4+2] Cyclization of para-Quinone Methide Derivatives with Alkynes. J. Org. Chem. 2018, 83, 1414-1421. (12) For examples on (4+1) cyclizations of o-hydroxyphenyl substituted p-QMs: (a) Liu, L.; Yuan, Z.; Pan, R.; Zeng, Y.; Lin, A.; Yao, H.; Huang, Y. 1,6-Conjugated Addition-Mediated [4+1] Annulation: An Approach to 2, 3-Dihydrobenzofurans. Org. Chem. Front. 2018, 5, 623-628. (b) Zhou, J.; Liang, G.; Hu, X.; Zhou, L.; Zhou, H. Facile Synthesis of 3-aryl-2,3-Dihydrobenzofurans via Novel Domino 1,6-Addition/O-Alkylation Reactions of paraQuinone Methides. Tetrahedron 2018, 74, 1492-1496. (c) Zhi, Y.; Zhao, K.; Essen, C.; Rissanen, K.; Enders, D. Synthesis of transDisubstituted-2,3-Dihydrobenzofurans by a Formal [4+1] Annulation Between para-Quinone Methides and Sulfonium Salts. Org. Chem. Front. 2018, 5, 1348-1351. (13) During our preparation of this manuscript, two groups reported an organocatalytic (4+3) cyclization of o-hydroxyphenyl substituted p-QMs with isatin-derived enals: (a) Li, W.-J.; Yuan, H.-J.; Liu, Z.-T.; Zhang, Z.-Y.; Cheng, Y.-Y.; Li, P.-F. NHCCatalyzed Enantioselective [4+3] Cycloaddition of orthoHydroxyphenyl Substituted para-Quinone Methides with IsatinDerived Enals. Adv. Synth. Catal. 2018, 360, 2460-2464. (b) Liu, Q.; Li, S.; Chen, X.-Y.; Rissanen, K.; Enders, D. Asymmetric Synthesis of Spiro-oxindole-ε-Lactones through N-Heterocyclic Carbene Catalysis. Org. Lett. 2018, 20, 3622-3626. (14) (a) Zhang, Y.-C.; Zhao, J.-J.; Jiang, F.; Sun, S.-B.; Shi, F. Organocatalytic Asymmetric Arylative Dearomatization of 2, 3‐Disubstituted Indoles Enabled by Tandem Reactions. Angew. Chem. Int. Ed. 2014, 53, 13912-13915. (b) Zhao, J.-J.; Sun, S.-B.; He, S.-H.; Wu, Q.; Shi, F. Catalytic Asymmetric Inverse-ElectronDemand Oxa-Diels-Alder Reaction of In Situ Generated orthoQuinone Methides with 3-Methyl-2-Vinylindoles. Angew. Chem. Int. Ed. 2015, 54, 5460-5464. (c) Zhang, H.-H.; Wang, C.-S.; Li, C.; Mei, G.-J.; Li, Y.; Shi, F. Design and Enantioselective Construction of Axially Chiral Naphthyl‐Indole Skeletons. Angew. Chem. Int. Ed. 2017, 56, 116-121. (15) (a) Effland, Richard C.; Kapples, Kevin J. U. S. 1988, US 4794110 A 19881227. (b) Chandrasekhar, S.; Seenaiah, M.; Kumar, A.; Reddy, C. R.; Mamidyala, S. K.; Kumar, C. G.; Balasubramanian, S. Intramolecular Copper (I)-Catalyzed 1,3Dipolar Cycloaddition of Azido-Alkynes: Synthesis of Triazolobenzoxazepine Derivatives and Their Biological Evaluation. Tetrahedron Lett. 2011, 52, 806-808. (16) CCDC 1843266 for compound (+)-3aa, see SI for details. (17) Li, W.; Xu, X.; Liu, Y.; Gao, H.; Cheng, Y.; Li, P. Enantioselective Organocatalytic 1,6-Addition of Azlactones to para-Quinone Methides: An Access to α,α-Disubstituted and β,βDiaryl-α-amino acid Esters. Org. Lett. 2018, 20, 1142-1145. (18) Zhang, Z.-P.; Chen, L.; Li, X.; Cheng, J.-P. Organocatalytic Asymmetric Sequential 1,6-Addition/Acetalization of 1‑Oxotetralin-2-carbaldehyde to ortho-Hydroxyphenyl-Substituted
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para-Quinone Methides for Synthesis of Spiro-3,4dihydrocoumarins, J. Org. Chem. 2018, 83, 2714-2724.
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ACS Catalysis
1st catalytic asymmetric (4+3) cyclization of vinyl aziridines 1st metal-catalyzed (4+3) cyclization of o-hydroxyphenyl-substituted p-QMs O
OH t
R1
t
Bu
* N O *
up to 91:9 dr up to 96:4 er
t
Bu
SO2R
t
Bu
HO
Bu t
Pd2(dba)3 CHCl3/L* 9 examples
R1
[Ir(cod)Cl]2 OH + SO2R N
24 examples
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t
Bu
Bu
N
SO2R
R1 O up to 96% yield up to >95:5 dr
9
