Aziridine synthesis in the presence of catalytic amounts of pyridiniums or viologens

Article abstract of DOI:10.1016/j.tetlet.2008.05.085

Pyridinium and viologen species were found to induce an aziridine-forming reaction from various imines and phenyldiazomethane. The reactions were generally high yielding and demonstrated cis-aziridine selectivity.

Full text of DOI:10.1016/j.tetlet.2008.05.085

Tetrahedron Letters 49 (2008) 4601–4603
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Aziridine synthesis in the presence of catalytic amounts
of pyridiniums or viologens
*
Zheng Xue, Arindam Mazumdar, Louisa J. Hope-Weeks , Michael F. Mayer
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyridinium and viologen species were found to induce an aziridine-forming reaction from various imines
and phenyldiazomethane. The reactions were generally high yielding and demonstrated cis-aziridine
selectivity.
Received 22 April 2008
Revised 17 May 2008
Accepted 19 May 2008
Available online 29 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
PMP
N
Aziridines are versatile precursors to an array of nitrogen-con-
taining functionalities by way of ring-opening reactions.1 The
majority of these reactions generally feature quantitative conver-
sion and high regioselectivity. As such, they have been additionally
recognized as members of one of the three main classes of reac-
tions that meet the criteria of click chemistry.2
5 mol % 3a
N PMP
PhCHN2
(1.3 equiv.)
N2
+
+
PMP
MeCN, rt
2a
PMP
Ph
1b
4a
PMP = para-methoxyphenyl
43%
Of modern catalytic methods for aziridine synthesis,3 the cata-
lytic synthesis of aziridines from diazo compounds (1) and imines
(2) has been investigated extensively.4,5 The vast majority of these
reactions are reported to occur via one of two common mecha-
nisms, that is, via addition of a carbenoid to an imine or via direct
attack of a diazo compound onto a Lewis acid-activated imine.
A recent Letter, however, disclosed the unique finding that aziri-
dine-formation occurs from various imines and ethyl diazoacetate
(EDA, 1a) in room temperature ionic liquids without any catalysts
or additives.6 A patent from the same group further described high
yieldingsynthesesof aziridinesfromEDA 1aandvariousiminesboth
in 1-butyl-3-methylimidazolium hexafluorophosphate (bmimPF6)
and in N-butylpyridinium hexafluorophosphate again without any
additives or catalysts.7 Given our interest in these reactions along
with our motivation to develop new catalyst platforms, we were in-
trigued by the mode of action of these ionic liquidsas well as the pos-
sibility of finding more potent analogs that could be used in catalytic
quantities.
We initially examined the possible reaction of EDA 1a with sev-
eral imines (2) in the presence of catalytic quantities of N-meth-
ylpyridinium hexafluorophosphate 3a but we observed only trace
amounts of aziridine products (4).8 When the more reactive phen-
yldiazomethane 1b was used in place of EDA 1a, we found a nota-
ble increase in the amount of aziridine formed. However, the
percent conversion of 2a and the isolated yield of 4a was quite
modest, Eq. 1.
ð1Þ
In a search for more efficient pyridinium additives, a series of com-
pounds (3b–f) that are structurally related to 3a were synthesized
and applied to the aziridine-forming reaction (Fig. 1).
R'
3a: R = Me, R' = H
3b: R = Bn, R' = H
3c: R = Me, R' = Me
3d: R = Me
3e: R = Bn
N R
R N
R N
R'
R = Ph
3f:
-
-
2 PF6
PF6
100
80
60
40
20
0
3f
3e
3d
3b
3a
3c
0
5
10
15
20
25
reaction time (h)
* Corresponding author. Tel.: +1 806 742 0019; fax: +1 806 742 1289.
E-mail addresses: Louisa.Hope-Weeks@ttu.edu (L. J. Hope-Weeks), mf.mayer@
ttu.edu (M. F. Mayer).
Figure 1. Consumption of imine 2a, measured by 1H NMR spectroscopy, in react-
ions performed as in Eq. 1 with additives 3a–f at a fixed ionic strength (2.5 mM PF6ꢀ
4 mol % 3a–c; and 2 mol % 3d–f).
;
For crystallographic analysis. Tel.: +1 806 742 4487; fax: +1 806 742 1289.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.085

4602
Z. Xue et al. / Tetrahedron Letters 49 (2008) 4601–4603
Table 1
Substrate Scopea
Entry
Imineb
R1
R2
Loading (mol %) 3f
Time (h)c
Cis:transd
Yielde (%) cis, trans
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
p-MeO–C6H4
Ph
p-MeO–C6H4
Ph
p-MeO–C6H4
p-MeO–C6H4
Ph
2
2
2
2
5
5
5
10
10
10
10
10
8
12
10
12
24 (94%)
12
8
12
24 (95%)
12
>50:1
20:1
10:1
8:1
6.5:1
9:1
10:1
6.6:1
>50:1
3.5:1
2.3:1
1:50
88, —
86, 4
79, 7
91f
Ph
Ph
p-NO2–C6H4
Ph
p-Br–C6H4
o-Br–C6H4
n-Bu
p-MeO–C6H4
Ph2CH
Ph
81f
p-NO2–C6H4
Ph
Ph
84, 8
91f
91f
Ph
54, —
73, 16
50, 20
—, 93
10
11
12
2j
2k
2l
CO2Et
CO2Et
t-Bu
24 (97%)
12 (95%)
a
Reactions performed at room temperature in MeCN with 1.3 equiv 1b.
Imine 2 substitution is R1–CH@NR2.
Time required for complete consumption of the imine, unless otherwise noted by % conversion in parentheses.
Determined from the 1H NMR spectrum of the crude product.
Isolated yields of aziridines 4.
b
c
d
e
f
Aziridines isolated as a mixture of cis and trans isomers.
When N-benzylpyridinium hexafluorophosphate 3b was
imines tested. The most obvious trend observed was that elec-
tron-rich imines generally underwent the quickest reaction with
the least amount of 3f.
The unsubstituted N-benzylideneaniline 2d underwent reaction
to give a 91% isolated yield of aziridine 4d as an 8:1 mixture of dia-
stereomers, entry 4. The configuration of the major isomer of 4d
was confirmed to be the cis-isomer by single crystal X-ray analysis,
Figure 2.10 This result is consistent with the 3J coupling constants
found for the major, non-symmetrically-substituted aziridine
isomers (4) in entries 1–11 of Table 1.
Importantly, satisfactory reactions were not restricted to elec-
tron-rich aromatic imines. Electron-deficient imines, however,
did require longer reaction periods and higher loadings of 3f to
achieve nearly complete consumption of the imine. For example,
the p-nitrophenyl-substituted imines 2e and 2f required 5 mol %
3f and at least 50% more time (vs 2a) to consume the imine. Addi-
tionally, the N-butyl imine 2i underwent reaction with excellent
stereoselectivity, comparable to imine 2a.
employed, a further enhancement in the conversion of 2a was
observed along with an increase in the yield of 4a. However, when
additive 3c was tested, the conversion of 2a was considerably
reduced. We figured this rate trend paralleled the relative electro-
philicity of these pyridinium species. With that in mind, we pre-
pared the more electron-deficient viologens (3d–f) and tested
their capacity to induce the aziridine-forming reaction from 1b
and 2a. Indeed, both 2 mol % methyl viologen 3d (ꢀ450 mV vs
SCE)9 and 2 mol % benzyl viologen 3e (ꢀ370 mV vs SCE)9 were
more effective than 4 mol % of the top-performing pyridinium 3b.
Lastly, 2 mol % phenylviologen 3f (ꢀ247 mV vs SCE)9 induced a
fairly clean cis-aziridine-forming reaction with consumption of
the imine within 8 h.
Since phenylviologen 3f was reasonably efficient at inducing
the aziridine-forming reaction, we used 3f in a study of the steric
and electronic limitations of the imine in this reaction, Table 1.
We found that the reaction was general and satisfactory for all
The ethyl carboxylate-substituted imines 2j and 2k underwent
reactions with the lowest observed diastereoselectivities. As
expected though, the aziridines 4j and 4k were not accompanied
by formation of isomeric b-amino-a,b-unsaturated esters as is
the case when the same aziridines are synthesized via Lewis
acid-catalyzed reactions of N-benzylidene imines and ethyl diazo-
acetate.5m This is presumably due to the reversed positioning of
the phenyl and ethylcarboxylate moieties, which would otherwise
R2
N
+
N2
LA
N
R2
R1
Ph
R1
LA
N R2
Ph
LA
R1
N R2
R1
N2
LA = Lewis acid
PhCHN2
Figure 2. X-ray crystal structure of 4d.
Scheme 1.

Z. Xue et al. / Tetrahedron Letters 49 (2008) 4601–4603
4603
facilitate migration of the phenyl group.4a Lastly, in contrast to all
other imines tested, as shown in Table 1, imine 2l reacted stereose-
lectively to provide the trans-aziridine isomer 4l.
Mechanistically, while adventitious proton catalysis has not
been ruled out,11 the predominant cis-aziridine selectivity
observed here is consistent with that found in most Lewis acid-
catalyzed aziridine-forming reactions from imines and diazo com-
pounds. This result may be indicative of a similar mechanism of
imine activation and aziridine synthesis, Scheme 1, as noted by
Xia and co-workers.6
In summary, through observation of the correlation of rate of
consumption of the imine with standard reduction potentials of
the pyridinium and viologen additives, we have optimized the viol-
ogen additive such that a reasonably efficient cis-aziridine-forming
reaction can be induced by catalytic amounts of viologens from
phenyldiazomethane and various imines.
Organometallics 2004, 23, 54; (k) Redlich, M.; Hossain, M. M. Tetrahedron Lett.
2004, 45, 8987; (l) Williams, A. L.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126,
1612; (m) Krumper, J. R.; Gerisch, M.; Suh, J. M.; Bergman, R. G.; Tilley, T. D. J.
Org. Chem. 2003, 68, 9705; (n) Yadav, J. S.; Reddy, B. V. S.; Rao, M. S.; Reddy, P. N.
Tetrahedron Lett. 2003, 44, 5275; (o) Morales, D.; Pérez, J.; Riera, L.; Riera, V.;
Corzo-Suárez, R.; Garc´ıa-Granda, S.; Miguel, D. Organometallics 2002, 21, 1540;
(p) Spanedda, M. V.; Crousse, B.; Narizuka, S.; Bonnet-Delpon, D.; Bégué, J.-P.
Collect. Czech. Chem. Commun. 2002, 67, 1359; (q) Mayer, M. F.; Wang, Q.;
Hossain, M. M. J. Organomet. Chem. 2001, 630, 78; (r) Loncaric, C.; Wulff, W. D.
Org. Lett. 2001, 3, 3675; (s) Aggarwal, V. K.; Ferrara, M.; O’Brien, C. J.;
Thompson, A.; Jones, R. V. H.; Fieldhouse, R. J. Chem. Soc., Perkin Trans. 1 2001,
1635; (t) Doyle, M. P.; Hu, W.; Timmons, D. J. Org. Lett. 2001, 3, 933; (u) Lee,
S.-H.; Han, T.-D.; Yu, K.; Ahn, K.-H. Bull. Korean Chem. Soc. 2001, 22, 449; (v)
Crousse, B.; Narizuka, S.; Bonnet-Delpon, D.; Bégué, J.-P. Synlett 2001, 679; (w)
Antilla, J. C.; Wulff, W. D. Angew. Chem., Int. Ed. 2000, 39, 4518; (x) Sengupta, S.;
Mondal, S. Tetrahedron Lett. 2000, 41, 6245; (y) Redlich, M.; Mahmood, S. J.;
Mayer, M. F.; Hossain, M. M. Synth. Commun. 2000, 30, 1401; (z) Kubo, T.;
Sakaguchi, S.; Ishii, Y. Chem. Commun. 2000, 625.
5. (a) Xie, W.; Fang, J.; Li, J.; Wang, P. G. Tetrahedron 1999, 55, 12929; (b) Antilla, J.
C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 5099; (c) Juhl, K.; Hazell, R. G.;
Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 1 1999, 2293; (d) Wright, D. L.;
McMills, M. C. Org. Lett. 1999, 1, 667; (e) Mayer, M. F.; Hossain, M. M. J. Org.
Chem. 1998, 63, 6839; (f) Nagayama, S.; Kobayashi, S. Chem. Lett. 1998, 685; (g)
Rasmussen, K. G.; Juhl, K.; Hazell, R. G.; Jørgensen, K. A. J. Chem. Soc., Perkin
Acknowledgment
Trans.
2 1998, 1347; (h) Mohan, J. M.; Uphade, B. S.; Choudhary, V. R.;
We thank the Robert A. Welch Foundation for financial support
of this research project (Grant No. D-1635).
Ravindranathan, T.; Sudalai, A. Chem. Commun. 1997, 1429; (i) Rasmussen, K.
G.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 1 1997, 1287; (j) Gunnoe, T. B.;
White, P. S.; Templeton, J. L.; Casarrubios, L. J. Am. Chem. Soc. 1997, 119, 3171;
(k) Aggarwal, V. K.; Thompson, A.; Jones, R. V. H.; Standen, M. C. H. J. Org. Chem.
1996, 61, 8368; (l) McMills, M. C.; Wright, D. L.; Zubkowski, J. D.; Valente, E. J.
Tetrahedron Lett. 1996, 37, 7205; (m) Casarrubios, L.; Pérez, J. A.; Brookhart, M.;
Templeton, J. L. J. Org. Chem. 1996, 61, 8358; (n) Rasmussen, K. G.; Jørgensen, K.
A. Chem. Commun. 1995, 1401; (o) Zhu, Z.; Espenson, J. H. J. Org. Chem. 1995, 60,
7090; (p) Hansen, K. B.; Finney, N. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. Engl.
1995, 34, 676; (q) Moran, M.; Bernardinelli, G.; Müller, P. Helv. Chim. Acta 1995,
78, 2048; (r) Jephcote, V. J.; John, D. I.; Williams, D. J. J. Chem. Soc., Perkin Trans. 1
1986, 2195; (s) Bartnik, R.; Mloston´ , G. Tetrahedron 1984, 40, 2569; (t) Bartnik,
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.05.085.
References and notes
´
R.; Mloston, G. Synthesis 1983, 924; (u) Baret, P.; Buffet, H.; Pierre, J.-L. Bull. Soc.
Chim. Fr. 1972, 2493.
1. (a) Hu, X. E. Tetrahedron 2004, 60, 2701; (b) Sweeney, J. B. Chem. Soc. Rev. 2002,
31, 247; (c) Zwanenburg, B.; ten Holte, P. Top. Curr. Chem. 2001, 216, 93; (d)
McCoull, W.; Davis, F. A. Synthesis 2000, 1347; (e) Pearson, W. H.; Lian, B. W.;
Bergmeier, S. C.. In Comprehensive Heterocyclic Chemistry II; Padwa, A., Ed.;
Oxford: Pergamon, 1996; Vol. 1A, p 1; (f) Tanner, D. Angew. Chem., Int. Ed. Engl.
1994, 33, 599.
2. (a) Fokin, V. V.; Wu, P. In Aziridines and Epoxides in Organic Synthesis; Yudin, A.
K., Ed.; Wiley-VCH: Weinheim, 2006; Chapter 12; (b) Kolb, H. C.; Finn, M. G.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004.
3. (a) Mößner, C.; Bolm, C. In Transition Metals for Organic Synthesis; Beller, M.,
Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2, p 389; (b) Müller, P.; Fruit,
C. Chem. Rev. 2003, 103, 2905; (c) Jacobsen, E. N. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York,
1999; Chapter 17.
4. (a) Mazumdar, A.; Xue, Z.; Mayer, M. F. Synlett 2007, 2025; (b) Wipf, P.; Lyon,
M. A. ARKIVOC 2007, 12, 91; (c) Pellicciari, R.; Amori, L.; Kuznetsova, N.; Zlotsky,
S.; Gioiello, A. Tetrahedron Lett. 2007, 48, 4911; (d) Lu, Z.; Zhang, Y.; Wulff, W. D.
J. Am. Chem. Soc. 2007, 129, 7185; (e) Deng, Y.; Lee, Y. R.; Newman, C. A.; Wulff,
W. D. Eur. J. Org. Chem. 2007, 2068; (f) Alonso, C. M. A.; Neves, M. G. P. M. S.;
Tomé, A. C.; Silva, A. M. S.; Cavaleiro, J. A. S. Jordan J. Chem. 2006, 1, 95; (g) Zhu,
S.; Liao, Y.; Zhu, S. Synlett 2005, 1429; (h) Lee, S.-H.; Song, I.-W. Bull. Korean
Chem. Soc. 2005, 26, 223; (i) Vanderhoydonck, B.; Stevens, C. V. Synthesis 2004,
722; (j) Li, Y.; Chan, P. W. H.; Zhu, N.-Y.; Che, C.-M.; Kwong, H.-L.
6. Sun, W.; Xia, C.-G.; Wang, H.-W. Tetrahedron Lett. 2003, 44, 2409; However,
another group reported a similar aziridine-forming reaction from EDA 1a and
in situ-generated imines in bmimPF6 with the Lewis acid Bi(OTf)3: Yadav, J. S.;
Reddy, B. V. S.; Reddy, P. N.; Rao, M. S. Synthesis 2003, 1387. In this case, the
Lewis acid presumably both aided formation of the imine and decreased the
time required for the aziridine-forming reaction.
7. Xia, C.; Sun, W.; Wang, H. Process for Preparation of Aziridine Derivatives. CN
1412179, 2003.
8. These results are in accordance with observations by Xia and co-workers who
observed no aziridines when catalytic amounts of bmimPF6 were used, see
Ref. 6.
9. Monk, P. M. S. The Viologens; Wiley: New York, 1998.
10. Single crystals of the major isomer of 4d that were suitable for X-ray
crystallographic analysis were grown from a CH2Cl2/MeOH (1:1) solution.
Crystallographic data (excluding structure factors) for the structure of cis-
1,2,3-triphenylaziridine 4d in this Letter have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 685188. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk.).
11. Selective cis-aziridine-forming reactions from imines and diazo compounds are
also known to be catalyzed by Brønsted acids, see Ref. 4l.