Nickel-catalyzed annulation of donor-acceptor oxiranes with imines: Diastereoselective access to highly substituted 2,4-trans-oxazolidines

Article abstract of DOI:10.1002/adsc.201300449

An efficient approach for the synthesis of highly substituted 2,4-trans-oxazolidines has been achieved by means of nickel(II) chlorate hexahydrate [Ni (ClO₄)₂·6H₂O]-catalyzed [3+2] dipolar cycloaddition reactions of donor-

Full text of DOI:10.1002/adsc.201300449

COMMUNICATIONS
DOI: 10.1002/adsc.201300449
Nickel-Catalyzed Annulation of Donor–Acceptor Oxiranes with
Imines: Diastereoselective Access to Highly Substituted 2,4-trans-
Oxazolidines
Junqing Zhang,a Yuanjing Xiao,a and Junliang Zhanga,b,*
a
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal
University, 3663 N. Zhongshan Road, Shanghai 200062, Peopleꢀs Republic of China
Fax : (+86)-021-6223-5039; e-mail: jlzhang@chem.ecnu.edu.cn
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
b
Sciences, Shanghai 200032, Peopleꢀs Republic of China
Received: May 23, 2013; Published online: October 9, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300449.
Abstract: An efficient approach for the synthesis of
highly substituted 2,4-trans-oxazolidines has been
achieved by means of nickel(II) chlorate hexahy-
cleavage via gold- or rhodium-catalyzed activation[8]
of the alkyne or Lewis acid-catalyzed activation of
the carbonyl groups.[9] As part of our ongoing explo-
ration of this new chemistry of oxiranes as 1,3-dipoles,
herein we report an efficient Lewis acid-catalyzed
chemo-, regio- and diastereoselective 1,3-dipolar cy-
cloadditions of donor–acceptor oxiranes 1 with imines
2 via the carbonyl ylide intermediate under mild con-
ditions, leading to highly substituted 2,4-trans-oxazoli-
dines 3 bearing various N-aryl and alkyl groups in
good yields with high diastereoselectivity [Eq. (3)],
which are commonly utilized as prodrugs for improv-
ing the pharmacokinetic profile of certain b-amino al-
cohol pharmacophores[10] and as chiral auxiliaries.[11,12]
This 2,4-trans-selectivity is quite different from the re-
sults of our group and others [Eqs. (1) and (2)]. We
have recently demonstrated that 2,5-cis-oxazolidines
drate [NiACHTUNGTRENNUNG(ClO4)2·6H2O]-catalyzed [3+2]dipolar cy-
cloaddition reactions of donor–acceptor oxiranes
À
with imines via C C bond cleavage in good yields
with moderate to high diastereoselectivity. The ap-
propriate orientation of two activating ketones or
À
esters is crucial for this chemoselective C C bond
cleavage of the oxirane ring.
À
Keywords: C C bond cleavage; cycloaddition; dia-
stereoselectivity; nickel; oxazolidines
Carbonyl ylides as 1, 3-dipoles participating in [3+2]
cycloaddition processes represent one important strat-
egy for the preparation of 5-membered cyclic substan-
ces.[1] Therefore, remarkable attention has been paid
on how to generate various substituted carbonyl
À
ylides. Several methods are available including C C
bond heterolysis of oxiranes under photochemical or
thermal conditions,[2] thermal decomposition of oxa-
diazolines,[3] fluoride ion-promoted 1,3-elimination re-
actions of trimethylsilyl-substituted chloromethyl
ethers,[4] samarium or manganese-mediated genera-
tion of non-stabilized carbonyl ylides from iodometh-
yl silyl ethers and bis(chloroalkyl) ethers,[5] thermal
decomposition of organomercury compounds[6] and
transition metal-catalyzed decomposition of diazo
compounds in the presence of a carbonyl functionali-
ty.[7] Obviously, C C bond heterolysis of the oxirane
À
ring is the most economical and straightforward way
to generate a carbonyl ylide. Very recently, our group
À
developed two novel strategies to achieve C C bond
Adv. Synth. Catal. 2013, 355, 2793 – 2797
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2793

Junqing Zhang et al.
COMMUNICATIONS
were obtained via Ni(II)-catalyzed cycloadditions of catalysis of ScACTHNUGTRENUNG(OTf)3/1,10-phenanthroline (Table 1,
N-tosylaziridine-derived azomethine ylides with alde- entry 8). Various substituted 1,10-phenanthrolines
hydes [Eq. (1)].[13] Domingo, Mongin and co-workers were examined, but unfortunately failed to give
have shown that the cycloaddition of 3-aryloxirane- better results (entries 9–11). However, this ScACHTUNGTRENNUNG(OTf)3/
2,2-dicarbonitriles with imines affords also the 2,4-cis- 1,10-phenanthroline catalysis system cannot be ap-
cycloadduct under classical heating or microwave irra- plied to a general substrate scope according to further
diation conditions [Eq. (2)].[14]
investigations. For example, the reaction of oxirane 1f
Our investigation began with the 1,3-dipolar cyclo- with 2a under the catalysis of Sc(OTf)3/1,10-phenan-
AHCTUNGTRENNUNG
addition of oxirane 1a with imine 2a in DCE at room throline gives 3f in trace yield (see the Supporting In-
temperature in the presence of 4ꢂ MS under the cat- formation). We then focused our attention on the
alysis of 5 mol% YbACHTUNGRTENNUG CAHUTNGTREN(NUGN ClO4)2·6H2O and ligands, among
(OTf)3.[9a] Indeed the desired cy- combination of Ni
cloadduct 3a was obtained in good yield but as a mix- which 2,9-dimethyl-1,10-phenanthroline (L3) seems
ture of two diastereomers in a ratio 5:1 (Table 1, the best one (Table 1, entry 14).
entry 1). In order to improve the diastereoselectivity,
Under the optimal reaction conditions, the scope
various Lewis acids were tested (Table 1, entries 1–6), and limitations of this transformation were next ex-
[9b]
among them Sc
(OTf)3
gave the product in 75% plored by variation of substituents R1 and Ar of the
yield along with a 13:1 dr and Ni
(ClO4)2·6H2O[9c] oxirane component (Table 2). Acetyloxiranes (R1 =
ACHTUNGTRENNUNG
shows high efficiency in yield (97%) but with no dia- Me) were first examined, leading to the correspond-
stereoselectivity (Table 1, entry 5). A slight improve- ing products in 80–92% yields with up to 18:1 dr
ment in diastereoselectivity was observed when 2,2’- (Table 2, entries 1–6). For example, the annulation re-
bipyridine was used as ligand and ScACTHNURGTNEUNG(OTf)3 as catalyst action of oxirane 1b with 2a gave the corresponding
(Table 1, entry 7). To our delight, the reaction afford- highly substituted 2,4-trans-oxazolidine 3b in 84%
ed 90% isolated yield of 3a with a 30:1 dr under the with 18:1 dr (Table 2, entry 2). An 89% isolated yield
of 3c with 10:1 dr and 100% conversion can be ob-
tained under the catalysis of NiACTHUNGTRNEG(UN ClO4)2·6H2O/2,9-di-
methyl-1,10-phenanthroline (L3) (Table 2, entry 3),
Table 1. Screening of the reaction conditions.[a]
whereas >99:1 dr can be obtained but with only 74%
conversion under the catalysis of Sc
ACHTUNGRTEN(NGNU OTf)3/1,10-phen-
AHCTUNGTREGaNNNU nthroline (Table 2, entry 4), these results again indi-
Table 2. Study the reaction scope by variation of the oxirane
component.
Entry
Cat.
Yb(OTf)3
L
Yield[b] [%]
dr[c]
1
G
–
84
5:1
2
Y
G
–
90
7:1
3
4
5
N
–
–
–
41
41
97
9:1
9:1
1:1
Entry
R1/Ar (1)
Conv.
[%]
Yield
[%]
dr[d]
G
N
6
7
8
9
10
11
12
13
14
15
16
Sc
Sc
Sc
Sc
Sc
Sc
Ni
Ni
Ni
Ni
Ni
N
–
75
86
95 (90)
96
100
98
100
100
100 (92)
100
100
13:1
18:1
30:1
12:1
16:1
23:1
2:1
8:1
14:1
8:1
1
2
Me/4-MeC6H4 (1a)
Me/Ph (1b)
Me/1-naphthyl (1c)
(1c)
Me/4-BrC6H4 (1d)
Me/3-BrC6H4 (1e)
Ph/Ph (1f)
Ph/2-furyl (1g)
Ph/4-MeOC6H4 (1h)
(1h)
100
100
100
74
100
77
100
100
100
100
85
3a (92)
3b (84)
3c (89)
3c (95)[e]
3d (83)
3e (80)[e]
3f (88)
3g (89)
3h (81)
3h (20)
3i (90)[e]
14:1
18:1
10:1
>99:1
13:1
13:1
16:1
15:1
8:1
L1
L2
L3
L4
L5
L1
L2
L3
L4
L5
3
4[a]
5
6[b]
7
N
E
N
T
8
9
10[a]
11[c]
>99:1
2:1
A
8:1
MeO/4-MeC6H4(1i)
[a]
[a]
1a (0.2 mmol) and 2a (0.34 mmol, 1.7 equiv.), 5 mol%
catalyst, and 120 mg 4ꢂ MS in 2 mL of DCE at room
temperature.
NMR yield (CH2Br2 as an internal standard). Numbers
in parentheses are isolated yield.
5 mol% of Sc
used.
10 mol% of catalyst, 608C.
Without ligand, 608C.
Determined by NMR analysis of the crude products.
Isolated yield based on oxirane consumed.
ACHTUNGRTEN(NUNG OTf)3, 6 mol% 1,10-phenanthroline were
[b]
[c]
[d]
[e]
[b]
[c]
Determined by NMR.
2794
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 2793 – 2797

Nickel-Catalyzed Annulation of Donor–Acceptor Oxiranes with Imines
cate that the former catalyst system has a more gener-
ACHTUNGTRENiNGNU mine 2h is also amenable to this transformation, af-
al substrate scope. The halogen on the aryl group fording a 70% isolated yield of trans-3p as the major
shows a different effect on the activity depending on diastereomer along with a 14% yield of 3p’ as a minor
its position. For example, the 4-bromophenyl-substi- cis-isomer with a removable N-benzyl group (Table 3,
tuted 1d afforded the desired cycloadduct 3d in 83% entry 7). The structure and the relative stereochemis-
yield under optimal conditions (Table 2, entry 5), in try of the products were established by X-ray crystal-
contrast, the reaction of 3-bromophenyl-substituted lography analysis of 3o as
1e requires higher catalyst loading and higher reac- (Figure 1).[15]
tion temperature to achieve a 77% conversion
a
2,4-trans-isomer
(Table 2, entry 6). Benzoyloxiranes 1f–1h with differ-
ent electronic natures of the substituents were then
investigated and the corresponding products 3f–3h
were obtained in 81–89% yields with 8:1–16:1 dr
(Table 2, entries 7–9). The quite low conversion of
entry 10 again indicates the limitation of the ScACTHNUTRGNEUNG(OTf)3
catalysis system. When the acceptor group was
switched to ester from ketone, the reaction could only
proceed with 85% conversion under optimal condi-
tions to give the corresponding product with 2:1 dr
(Table 2, entry 11).
We next investigated the scope of the imine compo-
nent briefly (Table 3). In general, various electron-do-
nating and electron-withdrawing groups can be well
introduced to the aryl moiety of imines and [3+2]cy-
cloadducts were obtained in good yields with satisfac-
tory diastereoselectivity. For example, the reactions of
imines 2b–f afforded the corresponding oxazolidines
Figure 1. X-ray crystal structure of compound 3o, the hydro-
gen atoms on the aromatic rings are omitted for clarity.
As the further illustration the synthetic application
3j–n in 77–95% yields with 11:1–40:1 dr (Table 3, en- of the product, one acetyl group of production was
tries 2–5). The reaction of 2d and 1b gave low conver- easily removed by treatment with K2CO3 (3 equiv.)
sion under the optimal conditions but proceeded with and MeOH (20 equiv.) in DCE at room temperature.
84% yield upon replacement of the ligand 2,9-dimeth- For example, the deacetylation reactions of product
yl-1,10-phenanthroline by 2, 2’-bipyridine (Table 3, 3b and 3o afforded the corresponding products 4c and
entry 3). The reaction of functionalized imine 2g with 4k in 90% and 88% yields with 1.4:1 and 2.5:1 dr, re-
1b could afford the desired product in 80% yield with spectively [Eq. (4)]. The reason for the low dr of
a 23:1 dr (Table 3, entry 6). Gratifying, (E)-N-benzyl- products 4c and 4k may be due to those two trans-
substituents at the 2- and 4-positions leading to an op-
posite stereoinduction.
Table 3. Variation of the imine component.
Entry R2/R3
Time 3
dr
[h]
ACHTUNGTRNE(NUNG Yield)
1
4-MeOC6H4/Ph (2b)
16
70
30
60
40
33
3j (80%)
3k (84%)
3l (84%)
3m (77%)
3n (95%)
3o (80%)
14:1
23:1
11:1
13:1
40:1
23:1
In order to study the role of two carbonyl groups
on the oxirane, two donor–acceptor oxiranes. 1m with
one acetyl group and 1k with two electron-withdraw-
ing groups in a rigid form which cannot bind to the
Lewis acid at the same time, were prepared according
to the literature methods.[16] When these two donor–
acceptor oxiranes were subjected to the reaction con-
ditions, no desired cycloadducts were detected [Eqs.
(5) and (6)]. These results indicate that only one elec-
tron-withdrawing group is not enough to weaken the
2
2-MeOC6H4/Ph (2c)
4-BrC6H4/Ph (2d)
4-ClC6H4/Ph (2e)
1-naphthyl/Ph (2f)
4-NCC6H4/4-MeOC6H4
(2g)
3[a]
4
5
6
7[b]
Ph/Bn (2h)
5
3p (70%)
+3p’
(14%)
5:1
[a]
[b]
2, 2’-Bipyridine was used.
Without ligand, 1f was used instead of 1b as starting ma-
terial.
Adv. Synth. Catal. 2013, 355, 2793 – 2797
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2795

Junqing Zhang et al.
COMMUNICATIONS
À
pressure, and the residue was purified by flash chromatogra-
phy (hexanes/DCM/EtOAc=90:9:1) to afford the pure
product 3a; yield: 73.4 mg (92%).
C C bond and two electron-withdrawing groups at an
appropriate orientation to enable two groups to bind
with the Lewis acid simultaneously are crucial to
À
achieve the C C bond cleavage under the catalysis of
Supporting Information
Lewis catalyst. Enantioenriched (S)-1f was prepared
and subjected to our optimal reaction conditions with
2g, affording the racemic cycloaddition product 3q
1
Experimental details and copies of H/13C NMR spectra of
all new compounds are available in the Supporting Informa-
and its diastereomer 3q’ [Eq. (7)], indicating that the tion.
reaction proceeds via the carbonyl ylide intermediate
reaction pathway.
Acknowledgements
We are grateful to the 973 program (2009CB825300), Nation-
al Natural Science Foundation of China (21172074), Fok
Ying Tung Education Foundation (121014), Shanghai Munic-
ipal Committee of Sciences and Technology (12XD1402300)
and the Program of Eastern Scholar at Shanghai Institutions
of Higher Learning for financial support.
References
[1] a) 1,3-Dipolar Cycloaddition Chemistry, (Ed.: A.
Padwa), Wiley-VCH, New York, 1984, Vol. 1; b) 1,3-
Dipolar Cycloaddition Chemistry, (Ed.: A. Padwa),
Wiley-VCH, New York, 1984, Vol. 2; c) R. Huisgen, in:
Advances in Cycloaddition, Vol. 1, (Ed.: D. P. Curran),
JAI Press Inc., Greenwich, 1988, pp 1–32; d) P. De-
shong, S. W. Lander, J. M. Leginus Jr, C. M. Dicken,
in: Advances in Cycloaddition, Vol. 1, (Ed.: D. P.
Curran), JAI Press, Inc., Greenwich, 1988, pp 87–128;
e) K. V. Gothelf, K. A. Jørgensen, Chem. Rev. 1998, 98,
863; f) S. Kanemasa, Synlett 2002, 1371; g) Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products, in: The
Chemistry of Heterocyclic Compounds, (Eds.: A.
Padwa, W. H. Pearson), Wiley and Sons, New York,
2002; Vol. 59; h) Synthesis of Heterocycles via Cycload-
ditions I, in: Topics in Heterocyclic Chemistry, (Ed.: A.
Hassner), Springer-Verlag, Berlin, Heidelberg, 2008,
Vol. 12.
In summary, we have developed an efficient formal
[3+2]cycloaddition of imines and carbonyl ylides in
À
situ generated from the Lewis acid-catalyzed C C
bond cleavage of donor–acceptor oxiranes under mild
conditions, providing highly substituted 2,4-trans-oxa-
zolidines in high yields with moderate to high dr. Ad-
dition of ligand could tune the selectivity and the cat-
alytic activity of the Lewis acid. The control experi-
ments indicate that two activating groups in an appro-
priate orientation to bind to the Lewis acid simultane-
[2] a) R. Huisgen, Angew. Chem. 1977, 89, 589; Angew.
Chem. Int. Ed. Engl. 1977, 16, 572, and references cited
therein; b) C. Bernaus, J. Font, P. de March, Tetrahe-
dron 1991, 47, 7713; c) G.-W. Wang, H.-T. Yang, P. Wu,
C.-B. Miao, Y. Xu, J. Org. Chem. 2006, 71, 4346.
À
ously are crucial for achieving chemoselective C C
bond cleavage of the oxirane ring.
[3] a) N. Shimizu, P. D. Bartlett, J. Am. Chem. Soc. 1978,
100, 4260; b) M. Bꢃkhazi, J. Warkentin, J. Am. Chem.
Soc. 1983, 105, 1289; c) M. Bꢃkhazi, P. A. Risbood, J.
Warkentin, J. Am. Chem. Soc. 1983, 105, 5675; d) P.
Couture, J. K. Terlouw, J. Warkentin, J. Am. Chem. Soc.
1996, 118, 4214; e) J. Warkentin, J. Chem. Soc. Perkin
Trans. 1 2000, 2161.
Experimental Section
Typical Procedure
Under N2, a flame-dried vial with a magnetic stir bar was
charged with activated 4 ꢂ molecular sieves powder (MS)
and charged with Ni
ACHTUNGTRENNUNG
5 mol%), 2,9-dimethyl-1,10-phenanthroline
[4] M. Hojo, M. Ohkuma, N. Ishibashi, A. Hosomi, Tetra-
0.012 mmol, 6 mol%) and 2 mL DCE, after stirring for
40 min, oxirane 1a (43.6 mg, 0.2 mmol) and imine 2a ( 61.6,
0.34 mmol) were added at room temperature. When the re-
action had gone to completion as determined by TLC analy-
sis the reaction mixture was passed over a plug of silica with
30 mL of EtOAc. The solvent was removed under reduced
hedron Lett. 1993, 34, 5943.
[5] a) M. Hojo, H. Aihara, A. Hosomi, J. Am. Chem. Soc.
1996, 118, 3533; b) M. Hojo, H. Aihara, Y. Suginohara,
K. Sakata, S.-Y. Nakamura, C. Murakami, A. Hosomi,
J. Org. Chem. 1997, 62, 8610; c) K. Takai, H. Kaihara,
K. Higashiura, N. Ikeda, J. Org. Chem. 1997, 62, 8612.
2796
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 2793 – 2797

Nickel-Catalyzed Annulation of Donor–Acceptor Oxiranes with Imines
[6] a) H. S. Gill, J. A. Landgrebe, Tetrahedron Lett. 1982,
23, 5099; b) H. S. Gill, J. A. Landgrebe, J. Org. Chem.
1983, 48, 1051.
47, 12870; c) J. Zhang, Z. Chen, H.-H. Wu, J. Zhang,
Chem. Commun. 2012, 48, 1817; d) Z. Chen, Z. Tian, J.
Zhang, J. Ma, J. Zhang, Chem. Eur. J. 2012, 18, 8591.
[10] G. P. Moloney, D. J. Craik, M. N. Iskander, T. L. Nero,
J. Chem. Soc. Perkin Trans. 2 1998, 199.
[11] C. Scolastico, Pure Appl. Chem. 1988, 60, 1689.
[12] I. Hoppe, H. Hoffmann, I. Gꢄrtner, T. Krettek, D.
Hoppe, Synthesis 1991, 1157.
[13] X. Wu, L. Li, J. Zhang, Chem. Commun. 2011, 47,
7824.
[14] G. Bentabed-Ababsa, A. Derdour, T. Roisnel, J. A.
Sꢅez, P. Pꢃrez, E. Chamorro, L. R. Domingo, F.
Mongin, J. Org. Chem. 2009, 74, 2120.
[15] CCDC 940034 (3o) contains the supplementary crystal-
lographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
[16] C. Yoakim, N. Goudreau, G. A. McGibbon, J.
OꢀMeara, P. W. White, W. W. Ogilvie, Helv. Chim. Acta
2003, 86, 3427.
[7] For reviews, please see: a) A. Padwa, M. D. Weingart-
en, Chem. Rev. 1996, 96, 223; b) G. Mehta, S. Muthusa-
my, Tetrahedron 2002, 58, 9477. For recent examples,
please see: c) B. Jiang, X.-B. Zhang, Z.-H. Luo, Org.
Lett. 2002, 4, 2453; d) C.-D. Lu, Z.-Y. Chen, H. Liu, W.-
H. Hu, A.-Q. Mi, J. Org. Chem. 2004, 69, 4856; e) A. E.
Russell, J. Brekan, L. Gronenberg, M. P. Doyle, J. Org.
Chem. 2004, 69, 5269; f) H. Suga, Y. Ebiura, K. Fu-
kushima, A. Kakehi, T. Baba, J. Org. Chem. 2005, 70,
10782; g) A. Padwa, Helv. Chim. Acta 2005, 88, 1357;
h) S. Torssell, P. Somfai, Adv. Synth. Catal. 2006, 348,
2421; i) S. Son, G. C. Fu, J. Am. Chem. Soc. 2007, 129,
1046; j) A. DeAngelis, M. T. Taylor, J. M. Fox, J. Am.
Chem. Soc. 2009, 131, 1101.
[8] a) T. Wang, J. Zhang, Chem. Eur. J. 2011, 17, 86; b) T.
Wang, C.-H. Wang, J. Zhang, Chem. Commun. 2011,
47, 5578.
[9] a) Z. Chen, L. Wei, J. Zhang, Org. Lett. 2011, 13, 1170;
b) R. Liu, M. Zhang, J. Zhang, Chem. Commun. 2011,
Adv. Synth. Catal. 2013, 355, 2793 – 2797
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2797