Metal-free one-pot synthesis of 2-substituted and 2,3-disubstituted morpholines from aziridines

Article abstract of DOI:10.3762/bjoc.11.59

The metal-free synthesis of 2-substituted and 2,3-disubstituted morpholines through a one-pot strategy is described. A simple and inexpensive ammonium persulfate salt enables the reaction of aziridines with halogenated alcohols to proceed via an S_N2-type ring opening followed by cyclization of the resulting haloalkoxy amine.

Full text of DOI:10.3762/bjoc.11.59

Metal-free one-pot synthesis of 2-substituted and
2,3-disubstituted morpholines from aziridines
Hongnan Sun, Binbin Huang, Run Lin, Chao Yang and Wujiong Xia*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 524–529.
State Key Laboratory of Urban Water Resource and Environment, the
Academy of Fundamental and Interdisciplinary Sciences, Harbin
Institute of Technology, Harbin 150080, P. R. China
doi:10.3762/bjoc.11.59
Received: 21 February 2015
Accepted: 08 April 2015
Published: 22 April 2015
Email:
Wujiong Xia* - xiawj@hit.edu.cn
Associate Editor: C. Stephenson
* Corresponding author
© 2015 Sun et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
ammonium persulfate; aziridine; metal free; morpholine
Abstract
The metal-free synthesis of 2-substituted and 2,3-disubstituted morpholines through a one-pot strategy is described. A simple and
inexpensive ammonium persulfate salt enables the reaction of aziridines with halogenated alcohols to proceed via an SN2-type ring
opening followed by cyclization of the resulting haloalkoxy amine.
Introduction
Morpholines are common structural cores of a broad range of 23]. Despite these advances, the synthetic approach to 2-substi-
biological and pharmacological natural or synthetically impor- tuted and 2,3-disubstituted morpholines is still scarce. Recently,
tant organic molecules [1]. In particular, a number of 2-substi- Ghorai and co-workers disclosed an intriguing strategy for the
tuted and 2,3-disubstituted morpholines are clinically available synthesis of substituted morpholines through Cu(OTf)2-
drugs (Figure 1). For example, the trans-2,3-disubstituted catalyzed ring-opening/closing reactions of aziridines and
morpholine, phendimetrazine (bontril), is a clinically available halogenated alcohols in high yield and enantioselectivity
appetite suppressant [2], the 2-substituted morpholine, reboxe- (Scheme 1a) [21]. However, this method suffered from the need
tine, is a clinically active, efficacious, and well-tolerated antide- for transition metal catalysts and low temperatures in the initial
pressant drug [3-5], and the cis-2,3-disubstituted morpholine, stage. Thus, the discovery of an operationally simple and eco-
aprepitant, is approved for the use in the prevention of friendly synthetic approach is a desirable complement to current
chemotherapy-induced nausea and vomiting [6].
methodologies.
In addition to pharmacological properties, morpholines are also Recently we have reported the visible light-mediated ring
used in organic synthesis as bases, catalysts, and chiral auxil- opening of aziridines by a number of nucleophiles, such as
iaries [7-13]. Thus, up to now, numerous strategies toward the LiBr, NaN3 and alcohols [24]. As a part of an ongoing program
synthesis of substituted morpholines have been reported [14- on the ring opening of aziridines [25-31], we have developed an
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Beilstein J. Org. Chem. 2015, 11, 524–529.
observed as the only ring-opening product. After screening
different persulfates, in concordance with Zeng [32], we found
that ammonium persulfate ((NH4)2S2O8) is superior to Na2S2O8
and K2S2O8 in the transformation, leading to chloroethoxy-
amine 2a in an excellent yield (93%) in short time.
Table 1: Metal-free ring opening of 2-phenyl-N-tosylaziridine (1a) with
2-chloroethanol using different persulfates as oxidant.a
Entry
S2O82−
Time (h)
Yield (%)b
Figure 1: Pharmaceutically active 2- and 2,3-disubstituted morpho-
lines.
1
2
3
Na2S2O8
K2S2O8
13
16
0.5
94
96
93
(NH4)2S2O8
efficient method for the synthesis of 2-substituted and 2,3-
disubstituted morpholines from aziridines utilizing a simple and
inexpensive ammonium persulfate salt as the oxidant at room
temperature (Scheme 1b) [32,33].
aAziridine 1a (0.3 mmol), (NH4)2S2O8 (0.6 mmol, 2 equiv) in
2-chloroethanol (10 equiv) as the solvent; bisolated yield.
Encouraged by the result that treatment of 2a with KOH at
room temperature in THF led to morpholine 3a in 90% yield,
Results and Discussion
Our investigation started with the treatment of 2-phenyl-N- we performed the reaction by addition of KOH to the mixture of
tosylaziridine (1a) with 2-chloroethanol in the presence of 1a and (NH4)2S2O8 in 2-chloroethanol after the reaction and
sodium persulfate at room temperature for 13 h (Table 1). To hoped to prepare 3a in one pot. Gratifyingly the reaction
our delight, NMR studies showed that chloroethoxyamine 2a is proceeded smoothly to furnish 3a in 93% yield (Scheme 2).
Scheme 1: One-pot synthesis of morpholines through ring opening of aziridines with haloalcohols.
Scheme 2: Metal-free one-pot synthesis of morpholine 3a from aziridine 1a.
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Beilstein J. Org. Chem. 2015, 11, 524–529.
To investigate the scope of this methodology, various substi- tuted aziridines 1a–j were well tolerated and the desired
tuted aziridines were prepared from the corresponding alkenes morpholines 3a–j were obtained in good yields (Table 2, entries
and submitted them to the reaction conditions. As shown in 1–10). N-Tosylaziridine 1k was also a viable substrate for the
Table 2, both electron-deficient and electron-rich 2-aryl-substi- reaction leading to the corresponding bicyclic morpholine 3k in
Table 2: Metal-free one-pot synthesis of morpholines from aziridines.a
Entry
Substrate
Morpholine
Yield (%)b
1
2
1a, R = H
1b, R = 3-OMe
1c, R = 4-Me
1d, R = 4-t-Bu
1e, R = 4-F
3a, 93
3b, 90
3c, 88
3d, 84
3e, 84
3f, 80
3g, 87
3h, 78
3i, 83
3
4
5
6
1f, R = 4-Cl
7
1g, R = 2-Cl
1h, R = 4-CF3
1i, R = 4-NO2
8
9
10
3j, 82
1j
11
12
1k
3k, 95
3l, 75
4l, 16
4m, 47
4n, 30
1l
13
14
1m
3m, 40
3n, 45
1n
aIn all cases 2-chloroethanol served as the solvent; bisolated yield.
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Beilstein J. Org. Chem. 2015, 11, 524–529.
95% yield (Table 2, entry 11). In addition, the reaction of 2,3- membered compound (S)-3ob in 65% and 60% yield with 52%
disubstituted aziridines (acyclic and/or cyclic ones), separable and 67% ee, respectively.
mixtures of regioisomers 3l,m and 4l,m were obtained arising
from isomeric ring opening (Table 2, entries 12 and 13). We Based on the above results, a viable mechanism was proposed
speculated that the observed regioselectivity might depend on as shown in Scheme 4. Initially, aziridine 1a might participate
the combined action of electronic effects and the position of in single-electron transfer (SET) with the persulfate anion to
substitution [31]. Under identical reaction conditions, the sepa- render the radical cation A [32,34]. Concerted ring opening and
rable 2-butylmorpholine 3n and 3-butylmorpholine 4n could be nucleophilic addition leads to amino radical intermediate B,
easily prepared from aziridine 1n (Table 2, entry 14).
which is converted to the haloalkoxy amine intermediate 2a
after abstraction of one hydrogen atom from alcohol. Finally, an
To further investigate the applicability of this strategy in intramolecular ring closure affords the morpholine product 3a
organic synthesis, we next performed a series of experiments to in the presence of KOH [21].
determine the potential of the straightforward synthesis of opti-
cally pure morpholines from chiral aziridines. The initial Conclusion
investigation was carried out by the replacement of racemic In conclusion, we have developed a simple and practicable
2-phenyl-N-tosylaziridine (1a) with optically pure (S)-2-phenyl- metal-free protocol for the synthesis of 2-substituted and 2,3-
1-tosylaziridine under the standard reaction conditions. To our disubstituted morpholines. Compared with the previous proce-
delight, (R)-3a was obtained in 93% yield and 70% ee dure, this reaction is conducted with a simple and inexpensive
(Scheme 3). For optically pure (S)-2-alkyl-substituted aziridines ammonium persulfate salt as the oxidant to realize the ring
1p,q, separable (R)-2-alkylmorpholines 3p,q and (S)-3-alkyl- opening of aziridines for the reaction with haloalcohols through
morpholines 4p,q were prepared in pure forms (95–99% ee) and a radical cation intermediate pathway. Furthermore, a range of
low to moderate overall yields. Furthermore, the enantiospe- optically pure morpholines could be achieved by the use of
cific synthesis of seven and eight-membered homologues of chiral aziridines.
morpholine was also conducted to extend the potential applica-
tion of the strategy. For example, when 2-chloroethanol was Experimental
replaced by 3-bromopropanol, the seven-membered product General procedure for the one-pot synthesis of morpholines:
(R)-3ab was obtained in 72% yield and 84% ee. Similarly, reac- A 10 mL round bottom flask equipped with a magnetic stirring
tion of (R)-2-phenyl-N-tosylazetidine (1o) with 2-bromoethanol bar was charged with aziridine/azetidine 1 (0.3 mmol, 1 equiv),
and/or 3-bromopropanol under the one-pot reaction conditions, (NH4)2S2O8 (137 mg, 0.6 mmol, 2 equiv) and haloalcohol
afforded the seven-membered product (S)-3o and the eight- (10 equiv). The mixture was stirred at rt for the appropriate time
Scheme 3: Metal-free one-pot synthesis of optically pure morpholine derivatives from chiral aziridines.
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Beilstein J. Org. Chem. 2015, 11, 524–529.
Scheme 4: Proposed mechanism.
3. Hajós, M.; Fleishaker, J. C.; Filipiak-Reisner, J. K.; Brown, M. T.;
Wong, E. H. F. CNS Drug Rev. 2004, 10, 23–44.
doi:10.1111/j.1527-3458.2004.tb00002.x
until the starting material disappeared completely (monitored by
TLC). Then, 5.0 mL THF and excess KOH (12 equiv) were
added to the reaction mixture and the mixture was stirred at rt.
After the reaction was completed, the resulting suspension was
quenched with saturated aqueous sodium bicarbonate solution
and extracted with ethyl acetate. The organic layers were
combined, washed with brine and dried over anhydrous sodium
sulfate. Solvents were removed under reduced pressure and the
residue was purified by column chromatography on silica gel
using ethyl acetate/hexane mixtures to afford the pure products.
4. Wong, E. H. F.; Sonders, M. S.; Amara, S. G.; Tinholt, P. M.;
Piercey, M. F. P.; Hoffmann, W. P.; Hyslop, D. K.; Franklin, S.;
Porsolt, R. D.; Bonsignori, A.; Carfagna, N.; McArthur, R. A.
Biol. Psychiatry 2000, 47, 818–829.
doi:10.1016/S0006-3223(99)00291-7
5. Scates, A. C.; Doraiswamy, P. M. Ann. Pharmacother. 2000, 34,
1302–1312. doi:10.1345/aph.19335
6. Pendergrass, K.; Hargreaves, R.; Petty, K. J.; Carides, A. D.;
Evans, J. K.; Horgan, K. J. Drugs Today 2004, 40, 853–863.
doi:10.1358/dot.2004.40.10.863745
7. Takahata, H.; Takahashi, S.; Kouno, S.-i.; Momose, T. J. Org. Chem.
1998, 63, 2224–2231. doi:10.1021/jo971995f
Supporting Information
8. Betancort, J. M.; Barbas, C. F., III. Org. Lett. 2001, 3, 3737–3740.
doi:10.1021/ol0167006
Supporting Information File 1
Experimental procedures, characterization data and copies
of 1H and 13C NMR spectra for products.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-59-S1.pdf]
9. Dave, R.; Sasaki, N. A. Org. Lett. 2004, 6, 15–18.
doi:10.1021/ol035998s
10.Mayer, S.; List, B. Angew. Chem., Int. Ed. 2006, 45, 4193–4195.
doi:10.1002/anie.200600512
11.Quin, Y.-C.; Pu, L. Angew. Chem., Int. Ed. 2006, 45, 273–277.
doi:10.1002/anie.200503206
12.Nelson, S. G.; Wang, K. J. Am. Chem. Soc. 2006, 128, 4232–4233.
doi:10.1021/ja058172p
Acknowledgements
13.Mossé, S.; Laars, M.; Kriis, K.; Kanger, T.; Alexakis, A. Org. Lett. 2006,
8, 2559–2562. doi:10.1021/ol0607490
We are grateful for the financial supports from China NSFC
(Nos. 21002018, 21072038 and 21472030), SKLUWRE (No.
2015DX01), the Fundamental Research Funds for the Central
Universities (Grant No. HIT.BRETIV.201310) and HLJNSF
(B201406).
14.Leonard, N. J.; Jann, K. J. Am. Chem. Soc. 1960, 82, 6418–6419.
doi:10.1021/ja01509a061
15.Lenoard, N. J.; Jann, K. J. Am. Chem. Soc. 1962, 84, 4806–4813.
doi:10.1021/ja00883a035
16.Kogami, Y.; Okawa, K. Bull. Chem. Soc. Jpn. 1987, 60, 2963–2965.
doi:10.1246/bcsj.60.2963
References
17.Pedrosa, R.; Andrés, C.; Mendiguchia, P.; Nieto, J. J. Org. Chem.
2006, 71, 8854–8863. doi:10.1021/jo061547k
1. Wijtmans, R.; Vink, M. K. S.; Schoemaker, H. E.; van Delft, F. L.;
Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis 2004, 641–662.
doi:10.1055/s-2004-816003
18.Sladojevich, F.; Trabocchi, A.; Guarna, A. J. Org. Chem. 2007, 72,
4254–4257. doi:10.1021/jo070036a
2. Rothman, R. B.; Baumann, M. H. Curr. Top. Med. Chem. 2006, 6,
1845–1859. doi:10.2174/156802606778249766
19.Metro, T.-X.; Pardo, D. G.; Cossy, J. J. Org. Chem. 2008, 73, 707–710.
doi:10.1021/jo701554h
528

Beilstein J. Org. Chem. 2015, 11, 524–529.
20.Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Angew. Chem., Int. Ed.
2008, 47, 3784–3786. doi:10.1002/anie.200800373
21.Ghorai, M. K.; Shukla, D.; Das, K. J. Org. Chem. 2009, 74, 7013–7022.
doi:10.1021/jo901297d
22.Wang, L.; Liu, Q.-B.; Wang, D.-S.; Li, X.; Han, X.-W.; Xiao, W.-J.;
Zhou, Y.-G. Org. Lett. 2009, 11, 1119–1122. doi:10.1021/ol802862p
23.Sawant, R. T.; Stevenson, J.; Odell, L. R.; Arvidsson, P. I.
Tetrahedron: Asymmetry 2013, 24, 134–141.
doi:10.1016/j.tetasy.2012.12.004
24.Sun, H.; Yang, C.; Lin, R.; Xia, W. Adv. Synth. Catal. 2014, 356,
2775–2780. doi:10.1002/adsc.201400476
25.Hu, X. E. Tetrahedron 2004, 60, 2701–2743.
doi:10.1016/j.tet.2004.01.042
26.Fokin, V. V.; Wu, P. Epoxides and Aziridines in Click Chemisty. In
Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.;
Wiley-VCH: Weinheim, 2006; pp 443–475.
doi:10.1002/3527607862.ch12
27.Watson, I. D. G.; Yu, L.; Yudin, A. K. Acc. Chem. Res. 2006, 39,
194–206. doi:10.1021/ar050038m
28.Singh, G. S.; D’hooghe, M.; De Kimpe, N. Chem. Rev. 2007, 107,
2080–2135. doi:10.1021/cr0680033
29.Schneider, C. Angew. Chem., Int. Ed. 2009, 48, 2082–2084.
doi:10.1002/anie.200805542
30.Lu, P. Tetrahedron 2010, 66, 2549–2560. doi:10.1016/j.tet.2010.01.077
31.Stanković, S.; D’hooghe, M.; Catak, S.; Eum, H.; Waroquier, M.;
Van Speybroeck, V.; De Kimpe, N.; Ha, H.-J. Chem. Soc. Rev. 2012,
41, 643–665. doi:10.1039/C1CS15140A
32.Wei, Y.; Tang, J.; Cong, X.; Zeng, X. Green Chem. 2013, 15,
3165–3169. doi:10.1039/C3GC41403E
33.Xia, W. J.; Sun, H. N.; Yang, C. A method of synthesizing compounds
Morpholinium. Chin. Pat. Appl. CN104193695 A, Dec 10, 2014.
34.Gaebert, C.; Mattay, J.; Toubartz, M.; Steenken, S.; Müller, B.; Bally, T.
Chem. – Eur. J. 2005, 11, 1294–1304. doi:10.1002/chem.200400557
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