Nickel(II)-catalyzed diastereoselective [3+2] cycloaddition of N-tosyl-aziridines and aldehydes via selective carbon-carbon bond cleavage

Article abstract of DOI:10.1039/c1cc12189h

An efficient and mild Ni(ClO₄)₂-catalyzed [3+2] cycloaddition of N-tosylaziridines and aldehydes via C-C bond cleavage was developed. The cycloaddition reaction proceeds with high diastereoselectivity and regioselectivity leading to

Full text of DOI:10.1039/c1cc12189h

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COMMUNICATION
Nickel(II)-catalyzed diastereoselective [3+2] cycloaddition of
N-tosyl-aziridines and aldehydes via selective carbon–carbon
bond cleavagew
Xingxing Wu,a Lei Lia and Junliang Zhang*ab
Received 16th April 2011, Accepted 11th May 2011
DOI: 10.1039/c1cc12189h
An efficient and mild Ni(ClO4)2-catalyzed [3+2] cycloaddition
of N-tosylaziridines and aldehydes via C–C bond cleavage
was developed. The cycloaddition reaction proceeds with high
diastereoselectivity and regioselectivity leading to highly sub-
stituted 1,3-oxazolidines. Notably, this novel reaction can be
easily expanded to gram level scale and the thermal conditions
cannot achieve the same transformation.
substituted pyrrolidines by reaction with electron-rich alkenes.6c
Inspired by this, we wish to document a novel and efficient
synthesis of 1,3-oxazolidines with highly diastereoselectivity
by the formal [3+2] cycloaddition of aldehydes with AMYs7
generated from N-tosylaziridine dicarboxylates via C–C bond
cleavage under mild conditions.8 1,3-oxazolidines are common
structural units in many natural products,9a designed medicinal
agents,9b chiral auxiliaries,9c–e and precursors of a-amino-b-
hydroxyl compounds in organic synthesis.3o,7i,9f,g
Among the charming panorama of ylides, azomethine ylides
(AMY) represent a particular case of useful intermediates,1
providing general and direct access to five-membered hetero-
cycles. As a highly strained cyclic amine, aziridines can easily
undergo C–N bond cleavage to work as a masked 1C,3N-ylide,
which has been extensively exploited in organic synthesis.2
However, aziridines are also known to react by thermal or
photochemical electrocyclic ring-opening at the carbon–carbon
bond to give azomethine ylides, as useful reactive species for a
wide range of synthetic applications.3 For example, Schirmeister3k
has confirmed the formation of ylide species of the aziridine-
2,2-dicarboxylates by the photochromism and reactions with
dipolarophiles (alkenes or aldehydes) under thermal conditions.
A few cases of Lewis acids favoring the C–C bond heterolysis
of donor–acceptor aziridines under mild conditions, leading to
the corresponding N-arylated azomethine ylides were reported
in the past years.4 Engels5 has investigated the C–N vs. C–C
bond breakages of the aziridine derivates through computation,
and yet recently Johnson4b has achieved the first productive
[3+2] or [4+2] cycloadditions of N-phenyl aziridine
dicarboxylates with electron-rich olefins mediated by ZnCl2
(1.2 equiv). We have been engaged in the selective carbon–
carbon bond cleavage of heterocycle motifs for a while,6 and
very recently, we have expanded this conversion to related
N-tosylaziridines with their facile conversion to highly
Our studies in this area began by choosing N-tosylaziridine
1a10 and 3,4,5-trimethoxybenzaldehyde 2a as the model sub-
strates to test the possibility of formal [3+2] cycloaddition
under the catalysis of a Lewis acid. A representative selection
of Lewis acids including Sc(OTf)3, Mg(OTf)2, MgI2, Fe(OTf)3,
Cu(OTf)2, In(OTf)3, Sn(OTf)2, Yb(OTf)3, and Ni(ClO4)2ꢀ6H2O
in various solvents at room temperature were tested (see
Supporting Informationw). To our delight, the reaction
worked very well in toluene at room temperature with 4 A
molecular sieves as an additive by using 1.5 equiv of 2a in the
presence of 5 mol% of Ni(ClO4)2ꢀ6H2O catalyst, which
provides the highly substituted oxazolidine 3 in 87% isolated
yield as a single cis-isomer [eqn (1)]. Without 4 A molecular
sieves, the starting material easily undergoes decomposition
by reacting with trace amount of water in the system under
the reaction conditions. Yb(OTf)3 is another effective and
potential catalyst to give 3 in 84% yield. Other tested catalysts
or solvents failed to improve the yields. The structure and
relative stereochemistry of 3 (racemic) were established by
X-ray crystallography analysis.w11 Surprisingly, when the
reaction was run at 90 1C in toluene without the catalyst, no
desired product was observed, but instead, an unexpected
oxazole 412 was isolated in 57% yield [eqn (2)], indicating
the reaction proceeds through a different reaction pathway
under thermal conditions with those under the catalysis of
Lewis acid.
a Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry, East China Normal University,
3663 N. Zhongshan Road, Shanghai 200062, China.
E-mail: jlzhang@chem.ecnu.edu.cn
b State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
w Electronic supplementary information (ESI) available: Complete
experimental procedures and characterization data for all new com-
pounds. CCDC 795474. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1cc12189h
ð1Þ
c
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Table 1 Study of the reaction scope by variation of aldehyde componenta,c
Table 2 Study of the reaction scope by variation of aziridine componenta
Entry R1CHO 2
Time (h) Isolated yield (%)
Aziridine 1
1
2
3
4
PhCHO (2b)
2
1
1
1
1
3
3
1
2
1
8
5 (67)
6 (64)
7 (72)
8 (92)
9 (55)
10 (50)
11 (55)
12 (80)
13 (70)
14 (87)
3 (89)
Ar
R
Entry
R1CHO 2
Isolated yield (%)
3-MeC6H4CHO (2c)
4-iPrC6H4CHO (2d)
4-MeOC6H4CHO (2e)
2-MeOC6H4CHO (2f)
4-ClC6H4CHO (2g)
4-BrC6H4CHO (2h)
Furan-2-carbaldehyde (2i)
1-Naphthaldehyde (2j)
E-Styryl (2k)
1
2
3
4
5
6
7
8
4-NO2C6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-iPrC6H4
3-MeC6H4
2-BrC6H4
Ph
Me (1b)
Me (1c)
Me (1d)
Me (1e)
Me (1f)
Me (1g)
Me (1h)
Et (1i)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2e
2g
2a
15 (99)
16 (83)
17 (97)
18 (84)
19 (84)
20 (88)
21 (90)
22 (82)
23 (90)
24 (90)
25 (84)
26 (96)
27 (70)
28 (82)
5
6b
7b
8
9b
10
11d
3,4,5-(MeO)C6H2CHO (2a)
9
Ph
iPr (1j)
a
10
11
12
13b
14c
4-iPrC6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
Ph
iPr (1k)
Me (1b)
Me (1b)
Me (1b)
Me (1l)
Standard conditions: 1a (0.4 mmol), 2 (1.5 equiv.), 5 mol% catalyst,
and 200 mg of activated 4 A MS in 4 mL of toluene at room
b
temperature. 3 equiv. of aldehydes were used. All the reactions
d
afforded the cis-product as the single isomer. 1a (10 mmol), 1.5 equiv.
c
of 2a, and 1 mol% of catalyst were used.
a
Standard conditions: 1(0.4 mmol), 2(1.5 equiv.), 5 mol% catalyst, and 200
b
mg of activated 4 A MS in 4 mL of toluene at room temperature. 3 equiv.
c
of aldehyde was used. The N-Ts group was replaced by N-Ns group.
ð2Þ
and 90% isolated yields, respectively, indicating the ester group
does not affect the reaction (Table 2, entries 8–9). The results of
1b with aldehydes 2b, 2e and 2g further indicate that electron-rich
aryl aldehydes work better than those electron-deficient ones
(Table 2, entries 11–13). It is noteworthy that the replacement
of tosyl by the nosyl group in 1a (1l) did not alter the reactivity
of the corresponding aziridine to produce the desired N-Ns
oxazolidine 28 in 82% yield (Table 2, entry 14).
With the optimal reaction conditions in hand, the scope of
the Ni(II)-catalyzed formal [3+2] cycloaddition reaction was
explored by variation of aldehyde component 2, and the results
are summarized in Table 1. In general, the cycloadditions of
aziridine 1a with electron-rich aromatic aldehydes work
better than those with electron-deficient aromatic aldehydes.
The reactions of aziridine 1a with benzaldehyde 2b, 3-methyl-
benzaldehyde 2c and 4-isopropylbenzaldehyde 2d proceed
smoothly to afford the corresponding cycloadducts in
64–72% yields under standard conditions (Table 1, entries 1–3).
92% yield of the cycloadduct 8 can be achieved by using
4-methoxybenzaldehyde 2e as dipolarophile, while the reaction
of 2-methoxybenzaldehyde 2f with 1a only gives moderate
yield, which may be caused by the steric interactions (Table 1,
entries 4–5). The reactions of 4-chlorobenzaldehyde 2g and
4-bromobenzaldehyde 2h require longer time to give the
corresponding products 10–11 in moderate yields (Table 1,
entries 6–7) with further convertible functional groups (Br or Cl).
Gratifyingly, furan-2-carbaldehyde 2i, 1-naphthaldehyde 2j,
and even cinnamaldehyde 2k can be used as the dipolaro-
philes to give the corresponding products 12–14 in high yields
(Table 1, entries 8–10). It should be noteworthy that all the
reactions afford exclusively the cis-isomer.
Furthermore, this novel reaction can be easily scaled up to
10 mmol with only 1 mol% catalyst loading in a slightly higher
yield, demonstrating the synthetically utility of this protocol
(Table 1, entry 11). Gratifyingly, a preliminary experiment
showed that an enantioselective variant of this [3+2] cyclo-
addition can be achieved by the application of commercially
available Pybox 2913 as the chiral ligand. The reaction of 1a and
2a proceeds well at room temperature to give the cis-1,3-oxazo-
lidine in 60% ee with a good yield [eqn (3), Scheme 1]. Though
the ee value is only moderate at present stage, it still demonstrates
that an asymmetric reaction is feasible using this approach.
The plausible reaction pathways leading to oxazolidines and
oxazole 4 are proposed (see Supporting Informationw). By
coordination of Ni(ClO4)2 to the dicarboxylates, the aziridines
are liable to give AMYs, which would be trapped by the aldehydes
subsequently.6a,c However, when heated, the unavoidable
proximity of the generated azomethine ylide to the CQO
bond of either of the two ester groups may lead to a rapid
1,5-dipolar electrocyclization, thus gives a different product.2q
In summary, we have discovered a novel and efficientNi(ClO4)2-
catalyzed carbon-carbon bond cleavage of N-tosylaziridines,
We next turned to study the scope of this reaction by
variation of the aziridine component (Table 2). In general,
the desired products can be obtained in excellent yields with
excellent diastereoselectivity. Both electron-withdrawing and
electron-donating groups can be introduced to the aryl moiety
of the aziridine 1 (Table 2, entries 1–7) and it seems that
there is no substituent effect on the reactivity. The reactions of
N-tosyl-aziridines 1i and 1j also work very well under standard
conditions to give the corresponding products 22 and 23 in 82%
Scheme 1 Catalytic enantioselective variant.
Chem. Commun., 2011, 47, 7824–7826 7825
c
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which provides a mild, highly diastereo- and regioselective
method for synthesis of highly substituted oxazolidines
through [3+2] cycloaddition of the derived N-tosyl metal
coordinated ylides and aldehydes. The reaction undergoes
a different reaction pathway under the classical thermal
conditions. Moderate enantioselectivity can be achieved by
application of Pybox as the chiral ligand, which may be
improved by further modification. Furthermore, this protocol
is very useful in organic synthesis, considering the high
efficiency of the catalyst, as well as the convenient preparation
of the substrates.10 Further studies including the reaction
scope, synthetic application and examination of other asym-
metric catalysis are ongoing and will be reported in due course.
The authors are grateful to the National Basic Research
Program of China (973 Program, 2009CB825300), Ministry of
Education of PRC, and the National Natural Science Foun-
dation of China (20972054) for their financial support.
4 For Lewis acid-promoted C–C bond cleavage of N-arylaziridine
dicarboxylates leading to azomethine ylides, see: (a) M. Vaultier
and R. Carrie, Tetrahedron Lett., 1978, 1195–1198; (b) P. D. Pohlhaus,
R. K. Bowman and J. S. Johnson, J. Am. Chem. Soc., 2004, 126,
2294–2295.
5 A. Paasche, M. Arnone, R. F. Fink, T. Schirmeister and B. Engels,
J. Org. Chem., 2009, 74, 5244–5249.
6 (a) Z. Chen, L. Wei and J. Zhang, Org. Lett., 2011, 13, 1170–1173;
(b) T. Wang and J. Zhang, Chem.–Eur. J., 2011, 17, 86–90; (c) L. Li,
X. Wu and J. Zhang, Chem. Commun., 2011, 47, 5049–5051;
(d) T. Wang and J. Zhang, Chem. Commun., 2011, 47, 5578–5580.
7 For cycloaddition reactions of azomethine ylides to aldehydes, see:
(a) J. W. Lown, G. Dallas and J. P. Moser, J. Chem. Soc., 1970,
2236–2248; (b) J. W. Lown and M. H. Akhtar, Can. J. Chem.,
1972, 50, 2236–2248; (c) A. Padwa, Y. Y. Chen, U. Chiacchio and
W. Dent, Tetrahedron, 1985, 41, 3529–3535; (d) F. Orsini,
F. Pelizzoni, M. Forte, R. Destro and P. Gariboldi, Tetrahedron,
1988, 44, 519–541; (e) L. M. Harwood, J. Macro, D. J. Watkin,
C. E. Williams and L. F. Wong, Tetrahedron: Asymmetry, 1992, 3,
1127–1130; (f) D. Alker, D. Hamblett, L. M. Harwood,
S. M. Robertson, D. J. Watkin and C. E. Williams, Tetrahedron,
1998, 54, 6089–6098; (g) D. J. Aldous, G. B. Drew, W. N. Draffin,
E. M. N. Hamelin, L. M. Harwood and L. M. Thurairatnam,
Synthesis, 2005, 3271–3278; (h) V. A. Brome, L. M. Harwood and
H. M. I. Osborn, Can. J. Chem., 2006, 84, 1448–1455;
(i) B. Seashore-Ludlow and P. Somfai, Eur. J. Org. Chem., 2010,
3927–3933. and ref. 3o.
Notes and references
1 For recent reviews of 1,3-dipolar cycloaddition reactions of azo-
methine ylides, see: (a) C. Najera and J. M. Sansano, Top.
Heterocycl. Chem., 2008, 12, 117–145; (b) G. Pandey, P. Banerjee
and S. R. Gadre, Chem. Rev., 2006, 106, 4484–4517; (c) I. Coldham
and R. Hufton, Chem. Rev., 2005, 105, 2765–2809; (d) C. Najera
and J. M. Sansano, Angew. Chem., Int. Ed., 2005, 44, 6272–6276;
(e) C. Najera and J. M. Sansano, Curr. Org. Chem., 2003, 7,
1105–1150; (f) Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Towards Heterocycles and Natural Products,
ed. A. Padwa and W. H. Pearson, Wiley, New York, 2003;
(g) S. Kanemasa, Synlett, 2002, 1371–1387; (h) K. V. Gothelf,
in Cycloaddition Reactions in Organic Synthesis, ed. S. Kobayashi
and K. A. Jørgensen, Wiley-VCH, Weinheim, 2002, pp. 211-245.
2 (a) J. B. Sweeney, Chem. Soc. Rev., 2002, 31, 247–258;
(b) V. H. Dahanukar and L. A. Zavialov, Curr. Opin. Drug Discovery
Dev., 2002, 5, 918–927; (c) X. E. Hu, Tetrahedron, 2004, 60,
2701–2743; (d) L. G. Ma and J. X. Xu, Prog. Chem., 2004, 16, 220;
(e) I. D. G. Watson, L. Yu and A. K. Yudin, Acc. Chem. Res., 2006,
39, 194–206. For other selected examples, see: (f) J. O. Baeg,
C. Bensimon and H. Alper, J. Am. Chem. Soc., 1995, 117,
4700–4701; (g) I. Ungureanu, P. Klotz and A. Mann, Angew. Chem.,
Int. Ed., 2000, 39, 4615–4617; (h) V. K. Yadav and V. Sriramurthy,
J. Am. Chem. Soc., 2005, 127, 16366–16367; (i) T. Munegumi,
I. Azumaya, T. Kato, H. Masu and S. Saito, Org. Lett., 2006, 8,
379–382; (j) P. A. Wender and D. Strand, J. Am. Chem. Soc., 2009,
131, 7528–7529; (k) J. Bornholdt, J. Felding, R. P. Clausen and
J. L. Kristensen, Chem.–Eur. J., 2010, 16, 12474–12480;
(l) B. T. Kelley and M. M. Joullie, Org. Lett., 2010, 12, 4244–4247.
3 (a) H. W. Heine and R. Peavy, Tetrahedron Lett., 1965, 3123–3126;
(b) A. Padwa and L. Hamilton, Tetrahedron Lett., 1965, 4363–4367;
(c) R. Huisgen, W. Scheer, G. Szeimies and H. Huber, Tetrahedron
Lett., 1966, 397–404; (d) R. Huisgen, W. Scheer and H. Huber, J. Am.
Chem. Soc., 1967, 89, 1753–1755; (e) F. Texier and R. Carrie,
J. Chem. Soc., Chem. Commun., 1972, 199–200; (f) M. Vaultier and
R. Carrie, Tetrahedron, 1976, 32, 2525–2531; (g) J. Vebrel, D. Gree
and R. Carrie, Can. J. Chem., 1984, 62, 939–944; (h) P. Deshong,
D. A. Kell and D. R. Sidler, J. Org. Chem., 1985, 50, 2309–2315;
(i) B. R. Henke, A. J. Kouklis and C. H. Heathcock, J. Org. Chem.,
1992, 57, 7056–7066; (j) M. Maggini, G. Scorrano and M. Prato,
J. Am. Chem. Soc., 1993, 115, 9798–9799; (k) T. Schirmeister, Liebigs
Ann./Recl., 1997, 1895–1897; (l) P. Garner, O. Dogan, W. J. Youngs,
V. O. Kennedy, J. Protasiewicz and R. Zaniewski, Tetrahedron, 2001,
57, 71–85; (m) M. R. Heinrich, I. P. Martin and S. Z. Zard, Chem.
Commun., 2005, 5928–5930; (n) S. Grabowsky, T. Pfeuffer,
W. Morgenroth, C. Paulmann, T. Schirmeister and P. Luger, Org.
Biomol. Chem., 2008, 6, 2295–2307; (o) J. Danielsson, L. Toom and
P. Somfai, Eur. J. Org. Chem., 2011, 607–613; (p) O. A. Attanasi,
P. Davoli, G. Favi, P. Filippone, A. Forni, G. Moscatelli and F. Prati,
Org. Lett., 2007, 9, 3461–3464; (q) A. S. Pankova, V. V. Voronin and
M. A. Kuznetsov, Tetrahedron Lett., 2009, 50, 5990–5993.
8 For reviews of C–Cbond activations, see: (a) M. Shi, L. X. Shao,
J.-M. Lu, Y. Wei, K. Mizuno and H. Maeda, Chem. Rev., 2010, 110,
5883–5913; (b) J. Zhang and Y. Xiao, in Handbook of Cyclization
Reactions; ed. S. Ma, Wiley-VCH, Weinheim, 2010, vol. 2,
pp. 733–812; (c) M. J. Campbell, J. S. Johnson, A. T. Parsons,
P. D. Pohlhaus and S. D. Sanders, J. Org. Chem., 2010, 75,
6317–6325; (d) M. Rubin, M. Rubina and V. Gevorgyan, Chem.
Rev., 2007, 107, 3117–3179; (e) C. H. Jun, Chem. Soc. Rev., 2004, 33,
610–618; (f) M. E. van der Boom and D. Milstein, Chem. Rev., 2003,
103, 1759–1792; (g) W. D. Jones, Nature, 1993, 364, 676–677;
(h) R. H. Crabtree, Chem. Rev., 1985, 85, 245–269. For selected
recent papers, see: (i) T. Seiser and N. Gramer, J. Am. Chem. Soc.,
2010, 132, 5340–5341; (j) A. Sattler and G. Parkin, Nature, 2010, 463,
523–526; (k) L. Liu and J. Zhang, Angew. Chem., Int. Ed., 2009, 48,
6093–6096; (l) C. Li, Y. Zeng, H. Zhang, J. Feng, Y. Zhang and
J. Wang, Angew. Chem., Int. Ed., 2010, 49, 6413–6417.
9 (a) A. Monge, I. Aldana, H. Cerecetto and A. Rivero,
J. Heterocycl. Chem., 1995, 32, 1429–1439; (b) G. P. Moloney,
D. J. Craik, M. N. Iskander and T. L. Nero, J. Chem. Soc., Perkin
Trans. 2, 1998, 199–206; (c) N. A. Porter, J. D. Bruhnke, W. Wu,
I. J. Rosenstein and R. A. Breyer, J. Am. Chem. Soc., 1991, 113,
7788–7790; (d) M. Shen and C. Li, J. Org. Chem., 2004, 69,
7906–7909; (e) A. Tessier, N. Lahmar, J. Pytkowicz and
T. Brigaud, J. Org. Chem., 2008, 73, 3970–3973; (f) T. H. Fife
and L. Hagopian, J. Am. Chem. Soc., 1968, 90, 1007–1014;
(g) F. Gosselin, A. Roy, P. D. O’Shea, C. Chen and
R. P. Volante, Org. Lett., 2004, 6, 641–644.
10 For synthesis of N-tosylaziridine dicarboxylates, see: (a) R. Fan and
Y. Ye, Adv. Synth. Catal., 2008, 350, 1526–1530; (b) R. Fan, L. Wang,
Y. Ye and J. Zhang, Tetrahedron Lett., 2009, 50, 3857–3859.
11 CCDC 795474 (3) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data request/cif.
12 L. Lu, P. Lu and S. Ma, Eur. J. Org. Chem., 2007, 676–680.
13 For selected recent examples using indane-Pybox as chiral ligand
for enantioselective catalysis, see: (a) G. Liang and D. Trauner,
J. Am. Chem. Soc., 2004, 126, 9544–9545; (b) J.-X. Ji, J. Wu and
A. S. C. Chan, Proc. Natl. Acad. Sci. U. S. A., 2005, 102,
11196–11200; (c) D. A. Evans and J. Wu, J. Am. Chem. Soc.,
2005, 127, 8006–8007; (d) D. A. Evans, K. R. Fandrick and
H. J. Song, J. Am. Chem. Soc., 2005, 127, 8942–8943;
(e) S. W. Smith and G. C. Fu, J. Am. Chem. Soc., 2008, 130,
12645–12647; (f) J.-F. Zhao, H.-Y. Tsui, P.-J. Wu, J. Lu and
T.-P. Loh, J. Am. Chem. Soc., 2008, 130, 16492–16493;
(g) Y.-J. Zhao, B. Li, L.-J. S. Tan, Z.-L. Shen and T.-P. Loh,
J. Am. Chem. Soc., 2010, 132, 10242–10244; (h) J.-F. Zhao,
B.-H. Tan and T.-P. Loh, Chem. Sci., 2011, 2, 345–348.
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