Enantioselective iridium catalyzed α-alkylation of azlactones by a tandem asymmetric allylic alkylation/aza-Cope rearrangement

Article abstract of DOI:10.1039/c9cc01450k

The development of an iridium catalyzed enantioselective α-alkylation of azlactones has been described. The reaction provides rapid access to a wide range of enantio-enriched quaternary carbon center allylated 2,4-diaryloxazol-5(2H)-ones in excellent yiel

Full text of DOI:10.1039/c9cc01450k

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Enantioselective iridium catalyzed a-alkylation of
azlactones by a tandem asymmetric allylic
alkylation/aza-Cope rearrangement†
Cite this:DOI: 10.1039/c9cc01450k
Received 20th February 2019,
Accepted 10th April 2019
Xue-Dan Bai, Qing-Feng Zhang and Ying He
*
DOI: 10.1039/c9cc01450k
rsc.li/chemcomm
The development of an iridium catalyzed enantioselective a-alkylation
of azlactones has been described. The reaction provides rapid access
to a wide range of enantio-enriched quaternary carbon center allylated
2,4-diaryloxazol-5(2H)-ones in excellent yields with high enantio-
selectivities. The transformation was achieved through a tandem
allylic alkylation/aza-Cope rearrangement, affording the desired
products under mild conditions. Ultimately, the resulting products
could be readily converted into diverse enantio-enriched deriva-
tives which highlight the importance of the methodology.
Asymmetric allylic alkylation (AAA), which represents a powerful
strategy for C–C bond formation, is of great interest in recent
decades.1 Among other catalysts, the catalysts derived from
palladium2 and iridium3 are mainly used for this transformation
because of their promising regio- and enantioselective control
(Scheme 1a). Consequently, substantial efforts have been devoted
to find out a variety of nucleophiles for the diversification and
elaboration of allylic alkylated compounds. In these cases, sub-
stituted allylic carbonates, used as coupling partners, are usually
selected as electrophiles. Interestingly, using allylic carbonates
with one terminal substituent in the presence of palladium
Scheme 1 Transition metal catalyzed allylic alkylations.
catalysts usually yields achiral linear products. Whereas, iridium sites at the C2 and C4 positions are commonly functionalized to
catalyzed allylic substitution furnishes branched products, along generate a quaternary carbon center.8 For example, Jiang and
with excellent regio- and enantioselectivities when using chiral co-workers reported an asymmetric allylic alkylation of azlactones
¨
phosphoramidites as ligands (Scheme 1a). Correspondingly, at the C2 position by combining palladium and Bronsted acid
representative ligands such as Feringa ligand,4 Alexakis ligand5 catalysis (Scheme 1b).9 Very recently, Breit and co-workers developed
and Carreira ligand6 were developed which have been widely a Rh-catalyzed C4 position selective allylic alkylation (Scheme 1c).10
used in an iridium catalyzed allylic substitution.7
In this regard, the reaction proceeded via a domino azlactone-alkyne
Azlactones, which have emerged as ‘‘masked’’ acids, have coupling/aza-Cope rearrangement affording N,O-acetal derivatives.11
been involved in a number of syntheses of natural and synthetic Although this strategy has been established successfully, the
bioactive molecules.8 The electrophilic and nucleophilic sites in enantioselective transformation remains a big challenge. This
the azlactone scaffold have allowed its broad application in diverse challenge refers to the necessary requirements of a branched
organic syntheses. Regarding azlactones as nucleophiles, the reactive intermediate A with both high enantioselectivities and diastereo-
selectivities in the AAA step (Scheme 1d, intermediate A). Only
upon fulfilling this requirement, the aza-Cope rearrangement
could occur to generate the desired products in high enantio-
School of Chemical Engineering, Nanjing University of Science & Technology,
Nanjing, 210094, China. E-mail: yhe@njust.edu.cn
selectivities. Based on the analysis and inspired by previous
reports, we wondered whether we could rise to the challenge by
† Electronic supplementary information (ESI) available. CCDC 1887161. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c9cc01450k
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using iridium-catalyzed asymmetric allylic alkylation as a means entries 7–9), similar to that with the use of 1,2-DCE, 1,4-dioxane,
of achieving the enantioselective ‘‘palladium-like’’ a-alkylation of and toluene as the solvent (Table 1, entries 10—12). Moreover,
azlactones by a tandem asymmetric allylic alkylation/aza-Cope the leaving group of –OBz led to diminished enantioselectivity
rearrangement. On the basis of our proposal, we selected cinnamyl of 88% ee (Table 1, entry 13). A dramatically low ee of 7% and
carbonates as the electrophile and anticipated that our studies racemic products were obtained using –Cl and –OPO(OEt)2 as
would lead to the selective synthesis of C4 allylated 2,4-diaryl- the leaving group in substrate 1a (Table 1, entries 14 and 15).
oxazol-5(2H)-ones (Scheme 1d).
Finally, the screening of leaving group –OBoc in 1a revealed that
To this end, we commenced our studies by examining the 92% ee with 82% yield of the C4 product was obtained under the
model reaction of cinnamyl carbonate (1a) with 2,4-diphenyl- ‘‘standard conditions’’ (Table 1, entry 16).
oxazol-5(4H)-one (2a). The iridacycle catalyst was generated
With the optimized conditions in hand, we next explored
in situ by the treatment of [Ir(cod)Cl]2 and Feringa phosphor- substrate scope of the reaction (Table 2). In general, allylic sub-
amidites L1 with 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD).12 stitutions of a variety of substituted tert-butyl cinnamyl carbonates
Using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base, we are well tolerated under optimized conditions. Excellent ee
were pleased to find that the reaction proceeded smoothly to (84–92%) and good yields of the products were obtained using
afford the product with allylic alkylation at the C4 position a range of para-substituted tert-butyl cinnamyl carbonates
rather than the C2 position in 85% yield with 90% ee (Table 1, possessing electron-donating and electron-withdrawing groups
entry 1). To further improve the enantioselectivity of the (Table 2, compounds 3b–3f). Moreover, the functional group
product, various phosphoramidite ligands were examined for –OBoc at the para-position of 1 furnished the desired product in
the reaction. However, all the phosphoramidite ligands L2–L6 87% ee with a moderate yield. The tert-butyl cinnamyl carbonates
led to lower enantioselectivities in the range of 13% ee to containing the ortho- and meta-substituted, electron-poor and
81% ee (Table 1, entries 2–6). The use of other bases such as Et3N, electron-rich substituents gave us a good to excellent ee of
DABCO and TBD led to a diminished ee of the product (Table 1, 83–94%, albeit with a moderate yield of 3h and 3l (Table 2,
compounds 3h–3l). The R1 of substrate 1 was also amenable to
bulky groups, electron-poor and electron-rich heterocycles,
affording good to excellent ee of the a-alkylated C4 products
Table 1 Selected optimization of reaction conditionsa
(Table 2, compounds 3m–3q). It is worth noting that the
reaction was not limited to tert-butyl cinnamyl carbonates; a
vinylogous substrate also furnished the desired product in a
good ee of 78% (Table 2, compound 3r).
With respect to the azlactone scope, various substitutions of
Entry
Variation from ‘‘standard conditions’’
eeb (%) (yieldc)
R2 were investigated. Substrates bearing electron-withdrawing
and electron-donating groups, such as –Me, –CF3, –Cl and –Br,
at the para-position were compatible with the reaction, leading
to the C4 products in 84–91% ee (Table 2, compounds 3s–3v).
The reaction also tolerated substitution at both meta- and ortho-
positions on the phenyl ring of R2, producing the corres-
ponding C4 products in 91–92% ee (Table 2, compounds 3w–3z).
Notably, the R2 group was not limited to aryl moieties; it was
amenable to the heterocyclic rings, such as furan and thiophene,
which afforded the desired products in 89% ee and 86% ee,
respectively (Table 2, compounds 3a0–3b0). Finally, the reactions
of various azlactones derived from amino acids were studied. As
can be seen from Table 2, excellent enantioselectivities of the C4
products were obtained bearing para-, meta- and ortho-substituents
on the phenyl ring of R3 (Table 2, compounds 3c0–3e0).13
1
2
3
4
5
6
7
8
None
90 (85%c)
L2 instead of L1 as ligand
L3 instead of L1 as ligand
L4 instead of L1 as ligand
L5 instead of L1 as ligand
L6 instead of L1 as ligand
Et3N instead of DBU as base
DABCO instead of DBU as base
TBD instead of DBU as base
1,2-DCE instead of THF as solvent
1,4-Dioxane instead of THF as solvent
Toluene instead of THF as solvent
–OBz instead of –OCOOMe
–CI instead of –OCOOMe
ꢀ23
13
ꢀ36
81
15
54
53
85
64
3
54
88
9
10
11
12
13
14
15
16
7
0
–OPO(OEt)2 instead of –OCOOMe
–OBoc instead of –OCOOMe
92 (82%c)
In light of the desired C4 products obtained, we next examined
the possible intermediates of the aza-Cope rearrangement. Firstly,
the absolute configuration was assigned by analogy with that of 3j,
which was determined to be (S) by single-crystal X-ray diffraction
(CCDC 1887161†).14 The aza-Cope rearrangement, which is of high
practical importance in organic chemistry, arises from its high
preference for a chair transition state rather than a boat transition
state.15 Therefore, we assumed that two diastereoisomers of 4
(major) and 5 (minor) were formed during the reaction process,
which underwent preferential chair-like TS-1 and TS-2 to yield the
corresponding products (Scheme 2).16
a
Reaction conditions, 1a (0.1 mmol), 2a (0.2 mmol), [Ir(cod)Cl]2 (2 mol%),
L1 (4 mol%), TBD (10 mol%), DBU (0.3 mmol), THF (1.0 mL), and r.t. for
b
c
24 h. ee determined by chiral HPLC. Isolated yield in parentheses.
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Table 2 Substrate scope of the reactiona
a
Reaction conditions, 1 (0.1 mmol), 2 (0.2 mmol), [Ir(cod)Cl]2 (2 mol%), L1 (4 mol%), TBD (10 mol%), DBU (0.3 mmol), THF (1.0 mL), and r.t. for
b
c
24 h. ee determined by chiral HPLC. The reaction was proceeded at room temperature for 48 h. The reaction was proceeded at 30 1C.
Scheme 3 One-pot synthesis of 3a.
To explore the functionalization of the allylated 2,4-diaryl-
oxazol-5(2H)-one moiety, synthetic transformations were performed
(Scheme 4). The reduction of 3a was carried out to furnish product 7
in 90% yield with 91% ee by Pd/C-catalysis. Treatment of 3a with
Scheme 2 Proposed aza-Cope-rearrangement to generate E-3a and
ent-E-3a.
m-CPBA afforded the 3-phenyloxirane scaffold in 70% yield with a
To demonstrate the utility of the strategy to access allylated 1 : 1 diastereomeric ratio. The keto-ester moiety of 3a was readily
2,4-diaryloxazol-5(2H)-one, a one-pot synthesis has been carried converted to the corresponding alkene in 85% yield with 90% ee by
out involving the condensation of azlactone derived from an Tebbe-Petasis olefination. Moreover, the keto-ester moiety could
amino acid and a-alkylation of azlactone. To our delight, the also be functionalized using the Grignard reagent and organo-
reaction proceeded smoothly to generate the desired product in lithium reagent to generate the corresponding tertiary alcohols.
90% ee with a yield of 68% (Scheme 3). In addition, 3a was also The diene moiety of 3r could react with a dienophile, affording
isolated in 70% yield with 88% ee of a large scale experiment cycloadduct 12 in 71% yield with a moderate dr (1.3 : 1) by the
under optimized conditions (see ESI†).
Diels–Alder reaction. In addition, we also found the product 3a
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via a pathway in which aza-Cope rearrangement is the terminal
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iridium catalysis. The reaction provides an entry to a wide range of
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We gratefully acknowledge the Natural Science Foundation
of Jiangsu Province (BK20180447) and the Fundamental Research
Funds for the Central Universities (30918011313) for financial
support. We thank M.-F. Lv for assistance with the X-ray crystal-
lographic collection and analysis. We thank Prof. H.-M. Wu
from Nanjing Technology University for helpful discussions.
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There are no conflicts to declare.
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ent-E-3a and E-3a, respectively.
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