Org. Lett. 2017, 19, 6526-6529
Org. Lett. 2017, 19, 6526-6529
Org. Lett. 2017, 19, 6526-6529
pubs.acs.org/OrgLett
cyclization of aziridines with enolates for the synthesis of chiral γ- and aryl (1e−h) groups could be readily incorporated, and the
lactams.4a Unfortunately, there was only one example involving a reaction gave the corresponding 2-methylenepyrrolidines
vinylaziridine in Ghorai’s work and the corresponding γ-lactam bearing two adjacent stereocenters, one of which was a
product was obtained from SN2-type ring-opening at the C-2 quaternary carbon stereocenter, in moderate to good yield
position of the vinylaziridine followed by cyclization. Moreover, with high to excellent diastereoselectivity. The structure and
the SN2′ nucleophilic ring-opening product was also obtained as relative stereochemistry of 3ha were confirmed by X-ray
a side product (Scheme 1b). To the best of our knowledge, there crystallography. Of note, the substrate 1b possessing a CF3
is no report on the domino ring-opening at the C-3 position with group was found to be a suitable substrate, yielding the
attendant cyclization of vinylaziridines with α-substituted 1,3- corresponding product 3ba as a single diastereomer in 78%
dicarbonyls to provide products with quaternary centers. As a yield. We next turned our attention to examining the generality of
part of our program of development of new reactions of 1,3-diketones 2 in the presence of vinylaziridine 1a and the
vinylaziridines to synthesize nitrogen-containing heterocycles,8 iridium catalyst. Interestingly, compared to 1,3-diketone 2a,
herein we report a convenient preparation of 2-methylenepyrro- substrates with an ethyl and an n-butyl group at the α-position
lidines bearing two adjacent stereocenters, one of which is a deliver the corresponding products 3′ab and 3′ac as the major
quaternary carbon stereocenter and functionalized 2,3-dihydro- diastereomers, respectively (Scheme 3a). However, 3ab and 3ac
pyroles through an iridium-catalyzed domino ring-opening
cyclizations of vinylaziridines with β-ketocarbonyls (Scheme Scheme 3. Transformation from 3′ to 3
1c).8c,9
An initial scouting reaction was performed with vinylaziridine
1a and methylacetylacetone 2a in the presence of various
rhodium catalysts (see Table S1). After many attempts, we found
that the reaction afforded the desired 2-methylenepyrrolidine
3aa in 73% NMR yield with 7:1 dr when [Rh(NBD)Cl]2/
AgSbF6 was used as the catalyst. Next, other commonly used
transition-metal catalysts were tested. Compound 1a decom-
posed quickly under the catalysis of Pd(PPh3)47 and Cu(OTf)2.4a were obtained as the major diastereomers upon heating the crude
Gratifyingly, treatment of 1a and 2a with [Ir(COD)Cl]2/AgSbF6 product in CHCl3 (Scheme 2). To test whether 3 arose from
in DCE for 2 h at room temperature gave 3aa in 90% NMR yield isomerization of 3′, we subjected 3′ab and 3′ac in CHCl3 at
with 10:1 dr, while [Ir(COD)Cl]2 itself failed to catalyze this room temperature for 16 h in the absence of the Ir catalyst.
reaction. Compounds 3ab and 3ac were also obtained as the major
With optimal reaction conditions in hand, we set out to diastereomers (Scheme 3b,c). These results indicate that 3 is a
investigate the scope of the current reaction with respect to the thermally more stable diastereomer. Besides alkyl groups (3aa−
vinylaziridine. As depicted in Scheme 2, the R2 group of ac), allyl (3ad) and ester groups (3ae and 3af) were compatible
vinylaziridines 1 exhibited general tolerance. Both alkyl (1a−d) with the standard conditions. Notably, the reaction gave the 2-
methylenepyrrolidine product 3af rather than the corresponding
Scheme 2. Preparation of 2-Methylenepyrrolidinesa γ-lactam when 2f was used as the substrate, which is quite
different from Ghorai’s work.4a Unsymmetric 1,3-diketone 2g
was examined in the reaction and showed good reactivity,
yielding 3ag as a single diastereomer. The reaction of 4-
methylheptane-3,5-dione 2h gave a slightly lower yield of 3ah
and diastereoselectivity than that with 2a. Besides acyclic 1,3-
dicarbonyls, cyclic 1,3-diketone 2i also worked in the current
reaction but showed low activity and diastereoselectivity.
To further extend the substrate scope, α-unsubstituted 1,3-
dicarbonyls 2 (R4 = H) were examined under the standard
conditions. However, a strikingly different reaction pattern was
observed when we applied α-unsubstituted 1,3-dicarbonyls as the
substrates. The reaction between 1a and 2j with [Ir(COD)Cl]2/
AgSbF6 in DCE for 2 h at room temperature proceeded smoothly
to furnish the 2,3-dihydropyrole 4aj rather than the correspond-
ing 2-methylenepyrrolidine product in 85% yield (Scheme 4).
The substrate scope was further investigated with respect to
variation of the vinylaziridine component. Varying the vinyl
moiety in 1 (bearing both alkyl and aryl subsitituents) was well
tolerated and produced 4aj−fj and 4hj in moderate to high yield.
The reactions of the N-tosyl 1i, N-nosyl 1j, and N-mesyl 1k
a proceeded smoothly, thus providing options for N-protection
Standard conditions: 1 (0.2 mmol), 2 (1.5 equiv), [Ir(COD)Cl]2 (5
mol %), AgSbF6 (10 mol %), DCE (2 mL), room temperature, 2 h.
and deprotection of the corresponding pyrrolines. The scope
Total isolated yield of two isomers and the dr value was determined by with regard to the β-ketocarbonyl component was also
H1 NMR of the crude product. bThe reaction was carried out under investigated. Both symmetric (2j−k) and unsymmetric (2l−n)
the standard conditions for 2 h, and then DCE was removed under 1,3-diketones delivered the corresponding 2,3-dihydropyroles
vacuum followed by heating the crude product at reflux in CHCl3 for (4aj−an) in 49−71% yield with excellent regioselectivity. We
12−18 h. also examined β-ketoester 2o as the nucleophile. The reaction
6527 DOI: 10.1021/acs.orglett.7b03232
Org. Lett. 2017, 19, 6526−6529
Organic Letters Letter
a
Standard conditions: 1 (0.2 mmol), 2 (1.5 equiv), [Ir(COD)Cl]2 (5
mol %), AgSbF6 (10 mol %), DCE (2 mL), room temperature, 2 h.
■
workup, which give the γ-lactam 6aa bearing a quaternary all-
carbon stereocenter in good yield and excellent diastereose-
ASSOCIATED CONTENT
lectivity. In addition, reduction of the carbonyl group with
DIBAL-H afforded 7aa in 90% yield with 3:1 dr. Finally, 2,3- *
S Supporting Information
dihydropyrole 8aa was obtained in high yield by treatment of 3aa The Supporting Information is available free of charge via the
with TsOH−H2O. Internet at . Experimental procedures, 1H and 13C NMR spectra
To gain insight into the reaction mechanism, we examined the and HPLC date for all new products (PDF) X-ray crystallo-
reaction of (R)-1a (98% ee) with 2a catalyzed by rhodium and graphic data for (R)-3ha(CIF) The Supporting Information is
iridium catalysts, respectively (Scheme 6a). The reaction available free of charge on the ACS Publications website at DOI:
catalyzed by [Rh(NBD)Cl]2/AgSbF6 gave (+)-3aa in 80% ee. 10.1021/acs.orglett.7b03232.
In contrast, racemic 3aa was obtained when [Ir(COD)Cl]2/ Experimental procedures, 1H and 13C NMR spectra, and
AgSbF6 was used as the catalyst. Further control experiments HPLC data for all new products and X-ray data for 3ha
revealed that (R)-1a would undergo more rapid racemization in (PDF)
the presence of iridium catalyst than the reaction catalyzed by
rhodium catalyst (Scheme 6b). Moreover, the treatment of 1a Accession Codes
and 2a with [Ir(COD)Cl]2/AgSbF6 in the presence of 4 Å CCDC 1572755 contains the supplementary crystallographic
molecular sieves in DCE for 30 min provided the desired 9aa in data for this paper. These data can be obtained free of charge via
98% NMR yield (Scheme 6c). www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
On the basis of the above results, a plausible mechanism is request@ccdc.cam.ac.uk, or by contacting The Cambridge
proposed for the current reaction (Scheme 7). Coordination of Crystallographic Data Centre, 12 Union Road, Cambridge
vinylaziridine 1 to the iridium catalyst gives complex A, which CB2 1EZ, UK; fax: +44 1223 336033.
6528 DOI: 10.1021/acs.orglett.7b03232
Org. Lett. 2017, 19, 6526−6529
Organic Letters Letter
■ AUTHOR INFORMATION
Corresponding Authors
(8) (a) Feng, J.-J.; Lin, T.-Y.; Wu, H.-H.; Zhang, J. J. Am. Chem. Soc.
2015, 137, 3787. (b) Feng, J.-J.; Lin, T.-Y.; Wu, H.-H.; Zhang, J. Angew.
Chem., Int. Ed. 2015, 54, 15854. (c) Feng, J.-J.; Lin, T.-Y.; Zhu, C.-Z.;
*E-mail: jjfeng@chem.ecnu.edu.cn. Wang, H.; Wu, H.-H.; Zhang, J. J. Am. Chem. Soc. 2016, 138, 2178.
*E-mail: jlzhang@chem.ecnu.edu.cn. (d) Zhu, C.-Z.; Feng, J.-J.; Zhang, J. Angew. Chem., Int. Ed. 2017, 56,
1351. (e) Zhu, C.-Z.; Feng, J.-J.; Zhang, J. Chem. Commun. 2017, 53,
ORCID
4688.
Hai-Hong Wu: 0000-0001-6266-8290 (9) Representative examples for synthesis of 2-methylene-pyrrolidines
Jian-Jun Feng: 0000-0002-6094-3268 and 2-pyrrolines: (a) Liu, K.; Zhu, C.; Min, J.; Peng, S.; Xu, G.; Sun, J.
Junliang Zhang: 0000-0002-4636-2846 Angew. Chem., Int. Ed. 2015, 54, 12962. (b) Lin, T.-Y.; Zhu, C.-Z.;
Zhang, P.; Wang, Y.; Wu, H.-H.; Feng, J.-J.; Zhang, J. Angew. Chem., Int.
Notes Ed. 2016, 55, 10844. (c) Zhu, C.-Z.; Feng, J.-J.; Zhang, J. Youji Huaxue
The authors declare no competing financial interest. 2017, 37, 1165. (d) Jing, C.; Xing, D.; Qian, Y.; Shi, T.; Zhao, Y.; Hu, W.
■
Angew. Chem., Int. Ed. 2013, 52, 9289. (e) Jiang, H.; He, J.; Liu, T.; Yu, J.-
ACKNOWLEDGMENTS Q. J. Am. Chem. Soc. 2016, 138, 2055. (f) Ma, S.; Yu, F.; Li, J.; Gao, W.
Chem. - Eur. J. 2007, 13, 247. (g) Ma, S.; Gao, W. Org. Lett. 2002, 4, 2989.
We are grateful to the National Natural Science Foundation of (h) Walker, P. R.; Campbell, C. D.; Suleman, A.; Carr, G.; Anderson, E.
China (21373088, 21425205, 21602062), 973 Program A. Angew. Chem., Int. Ed. 2013, 52, 9139. (i) Larquetoux, L.; Kowalska, J.
(2015CB856600), and Innovative Research Team in University. A.; Six, Y. Eur. J. Org. Chem. 2004, 2004, 3517. (j) Mourad, A. K.;
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