A catalytic synthesis of aziridines without the usual byproducts

Article abstract of DOI:10.1055/s-2007-984872

Complementary to existing routes, the Lewis acid catalyzed reactions of phenyldiazomethane with α-imino esters selectively produce cis-aziridine-2-carboxylates without competitive formation of enamino ester or carbene dimer byproducts. Georg Thieme Verlag

Full text of DOI:10.1055/s-2007-984872

LETTER
2025
A Catalytic Synthesis of Aziridines without the Usual Byproducts
C
A
atalytic
S
ynthesis
r
of
A
zir
i
idines
w
n
ithout the
U
d
sua
l
Byprod
a
ucts m Mazumdar, Zheng Xue, Michael F. Mayer*
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA
Fax +1(806)7421289; E-mail: mf.mayer@ttu.edu
Received 9 March 2007
R
H
H
Abstract: Complementary to existing routes, the Lewis acid cata-
lyzed reactions of phenyldiazomethane with a-imino esters selec-
tively produce cis-aziridine-2-carboxylates without competitive
formation of enamino ester or carbene dimer byproducts.
R
LA
N2
N
O
N
CO2Et
OEt
Ar
H
Ar
1
major enamino ester byproduct
Key words: catalysis, diazo compounds, heterocycles, imines,
Lewis acids
R
LA
N2
R
N
N
Aziridines are versatile precursors for the synthesis of an
assortment of nitrogen-containing compounds by way of
ring-opening reactions. The majority of these reactions
Ar
EtO2C
1
Ar
CO2Et
H
2
generally feature quantitative conversion and high regio-
selectivity and, as such, have been recognized as members
of one of the three most useful classes of reactions that
R
N
+
ArCHN2
aryldiazomethane
2
meet the criteria of click chemistry. Of modern catalytic
imino ester
CO2Et
3
methods for aziridine synthesis, the catalytic synthesis of
aziridines from diazo compounds and imines has been in- Scheme 1 Key intermediates (1 and 2) of Lewis acid catalyzed azi-
4
,5
ridine syntheses from imines and diazo compounds (LA = Lewis acid)
vestigated extensively. In particular, the catalytic reac-
tion of ethyl diazoacetate (EDA) with a variety of imines
has been the focus due to the commercial availability of
EDA and because the resulting aziridine-2-carboxylate
ester is a convenient source of a variety of compounds
arrangement of this type in this system. Thus the synthesis
of equivalent aziridine-2-carboxylates would require use
9
10
6
of an a-imino ester and an aryldiazomethane.
including unnatural a- and b-amino acids.
Herein we report an unexplored variation of the highly
studied aziridine-forming reaction that involves a diazo
compound and an imine. This route leads to the same de-
sired products as formed from EDA and N-benzylidene-
anilines, however, this variation provides minimal
carbene dimers and no enamino ester byproducts.
One of the problems so far in the development of the
catalytic synthesis of aziridine-2-carboxylate esters from
imines and diazoacetates is the competitive formation of
byproducts; the type being dependent upon the kind of
catalyst employed. For example, reactions thought to
proceed via a metallocarbene generally produce dimers of
4
,5
the carbene. Alternatively, transformations that proceed This complementary method was initially tested as shown
via reaction of the diazoacetate with a Lewis acid activat- in Equation 1. The reaction was carried out by treating a
ed imine produce enamino ester byproducts via migration hexane solution of the N-PMP-protected a-imino ester 3
of the Ar group (major byproduct shown in Scheme 1) or with BF ·Et O (5 mol%) at –78 °C. After ten minutes,
3
2
H (minor byproduct, not shown) within intermediate 1.
phenyldiazomethane (4; 1.1 equiv, 3 M in CH Cl ) was
2 2
added all at once. The solution was stirred for 1.5 hours,
after which time the low-temperature bath was removed
and the solution was allowed to warm over 45 minutes.
To preclude formation of these byproducts during the syn-
thesis of aziridine-2-carboxylate esters while retaining the
same functionality in the starting materials, we conceived
two principles. First, to minimize formation of carbene
dimers, we avoided use of transition metal catalysts that
PMP
7
are known to form carbenoid species. Second, to prevent
5 mol% BF ·OEt
3
2
N
N
CO2Et
+
PhCHN2
formation of the major enamino ester byproduct, we envi-
sioned intermediate 2 (Scheme 1) as a stand-in for inter-
mediate 1. While there is some precedence for migration
PMP
hexane, –78 °C, 1.5 h
–78 °C → r.t., 45 min
Ph
CO2Et
3
4
(rac)-
5
89% (78:22, cis:trans)
8
of the ethyl carboxylate group, we expected minimal re-
Equation 1 Lewis acid catalyzed synthesis of aziridines without
enamino ester byproduct formation (PMP = p-methoxyphenyl)
SYNLETT 2007, No. 13, pp 2025–2028
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Advanced online publication: 27.06.2007
DOI: 10.1055/s-2007-984872; Art ID: S01307ST
©
Georg Thieme Verlag Stuttgart · New York

2
026
A. Mazumdar et al.
LETTER
The H NMR spectrum of the crude product showed com- Table 2 Catalyst Screena
1
plete conversion of the imine. After column chromatogra-
phy, both cis- and trans-aziridines 5 were isolated; the
c
c
Entry Catalyst
Conversion cis:transb cis (%) trans (%)
(
%)
combined yield was 89%. While a trace of stilbenes was
1
detected in the H NMR spectrum of the crude product, no
1
2
3
4
5
6
7
8
Yb(OTf)3
100
100
100
97
all cis
49:1
90
89
87
45
49
55
66
67
70
–
enamino ester byproducts were observed, including the
1
1
Zn(OTf)
2
–
byproduct derived from H migration. Without the Lewis
acid, no aziridines were observed under these reaction
conditions.
BF ·OEt
all cis
4.8:1
3.1:1
7.3:1
6.6:1
49:1
–
3
2
AlCl3
19
15
13
9
A unique aspect of this complementary approach to aziri-
dine synthesis is the high yield of product that possesses
substitution on the N-aromatic ring, especially N-PMP
protection. Analogously substituted N-benzylidene-
anilines are relatively low yielding substrates in catalytic
TiCl
98
4
SnCl4
90
AgOTf
98
1
2
aziridine syntheses involving EDA.
Cu(OTf)2
CF SO H
98
–
Several solvents were tested in the BF -catalyzed reaction
3
9
100
all cis
–
(
Table 1). When CH Cl or Et O was used (entries 1 and
3
3
2
2
2
a
2
), the yield of aziridine was comparable to that found
Reaction conditions were the same as in Equation 1 except for use
of the noted catalyst (5 mol%) and CH Cl as solvent.
Determined from the H NMR spectrum of the crude product.
Isolated yield of aziridine based on imine.
when hexane was used. However, with these solvents, the
aziridine cis/trans ratio was significantly improved.
2
2
b
c
1
Table 1 Solvent Screena
c
c
Entry
Solvent
cis:transb
all cis
13.2:1
7.3:1
cis (%)
trans (%)
stituted imine, likely due to lower diastereoselectivity fol-
lowed up by significant and selective decomposition of
the trans-aziridine isomer under the Lewis acidic reaction
1
2
3
4
5
CH Cl2
87
85
83
67
70
58
–
2
Et O
1
4m
2
conditions. The N-benzyl-type imines (entries 4 and 5)
underwent a similar reaction but with minor decomposi-
tion of the trans-aziridine. In comparison, the N-sulfonyl-
type imines were generally less reactive (not shown).
THF
2
MeOH
hexane
toluene
4.5:1
13
19
22
4:1
For entries 1–3 in Table 2, the reactions produced fairly
1
clean crude products as determined by H NMR spectro-
6
2.8:1
scopy. Thus, reduction of the catalyst loading seemed pos-
sible. For these cases the amount of Lewis acid catalyst
could be reduced by an order of magnitude (Table 4). Un-
der otherwise identical reaction conditions, a catalyst
loading as low as 0.5 mol% afforded a good yield of
aziridine without increasing the time of the reaction or
a
Reaction conditions were the same as in Equation 1 except for use of
the noted solvent.
Determined from the H NMR spectrum of the crude product.
b
c
1
Isolated yield of aziridine based on imine.
Several readily available Lewis acid catalysts were sacrificing the percent conversion of imine. Even 0.1
screened (Table 2). Of the Lewis acids tested, Yb(OTf)3 mol% Yb(OTf) converted 94% of the imine and resulted
3
was superior (entry 1). With 5 mol% Yb(OTf) , the reac-
3
tion proceeded with 100% conversion of the imine and
only the cis-aziridine isomer was observed. In contrast, no Table 3 Aziridine Synthesis from Other Imino Estersa
enamino ester byproducts or carbene dimers were ob-
Rb
Ph
cis:transc
all cis
cis (%) trans (%)
d
d
Entry
served. However, when a metallocarbene-forming Cu(II)
catalyst was employed (entry 8), aziridine formation was
notably limited by the competing formation of cis- and
trans-stilbenes. For further comparison, a protic acid
1
2
3
4
61
70
59
55
59
–
–
4-MeC H
all cis
6
4
1
3
(
TfOH) was tested (entry 9) but provided less aziridine
2-MeOC H
9:1
5
6
4
than the top-performing Lewis acids.
CHPh2
2.2:1
24
20
Other ethyl imino esters were screened as well (Table 3).
Reports of additions to imino esters are usually limited to
N-PMP, N-benzhydryl, or N-sulfonyl imino esters due to
imine stability problems. We found that similarly sub-
stituted imino esters were sufficiently stable and
amenable to the aziridine-forming reaction. The imines of
entries 1–3 underwent transformation to the aziridines
with lower isolated yields, compared to the N-PMP-sub-
5
(±)CH(Me)Ph
(10:9):(3:2)
a
Reaction conditions were similar to Equation 1 except for use of the
noted imine, Yb(OTf) (5 mol%) and CH Cl as solvent.
3
2
2
b
c
d
R is the N-substituent on the imine.
Determined from the H NMR spectrum of the crude product.
Isolated yield of aziridine based on imine.
1
Synlett 2007, No. 13, 2025–2028 © Thieme Stuttgart · New York

LETTER
Catalytic Synthesis of Aziridines without the Usual Byproducts
2027
in an 87% yield of aziridine (74% cis, 13% trans). In con- References and Notes
trast, previous reports on Yb(OTf) -catalyzed aziridine
3
(
1) (a) Hu, X. E. Tetrahedron 2004, 60, 2701. (b) Sweeney, J.
syntheses from N-benzylideneanilines and EDA invari-
B. Chem. Soc. Rev. 2002, 31, 247. (c) Zwanenburg, B.; ten
Holte, P. Top. Curr. Chem. 2001, 216, 93. (d)McCoull, W.;
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Chem., Int. Ed. Engl. 1994, 33, 599. (f) Pearson, W. H.;
Lian, B. W.; Bergmeier, S. C. In Comprehensive
1
4
ably employed 10 mol% catalyst. In fact, the level of
efficiency observed here is the highest reported to date in
the catalytic synthesis of aziridines from any combination
1
5
of a variety of imine and diazo compounds. Interesting-
ly, in all cases where minimal Lewis acid was used, the
Heterocyclic Chemistry II, Vol. 1A; Padwa, A., Ed.;
Pergamon: Oxford, 1996, 1.
1
6
trans-aziridine could be isolated.
(
(
2) (a) Fokin, V. V.; Wu, P. In Aziridines and Epoxides in
Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH:
Weinheim, 2006, Chap. 12. (b) Kolb, H. C.; Finn, M. G.;
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Table 4 Optimization of Catalyst Loadinga
c
c
Entry Catalyst
Conversion cis:transb cis (%) trans (%)
(
%)
1
2
Yb(OTf)3
Zn(OTf)2
100
100
100
7.3:1
3.9:1
7.1:1
87
78
79
9
2003, 103, 2905. (c) Jacobsen, E. N. In Comprehensive
14
7
Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: New York, 1999, Chap. 17.
3
BF ·OEt2
3
(4) (a) Lu, Z.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007,
129, 7185. (b) Deng, Y.; Lee, Y. R.; Newman, C. A.; Wulff,
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Zhu, S. Synlett 2005, 1429. (d) Lee, S.-H.; Song, I.-W. Bull.
Korean Chem. Soc. 2005, 26, 223. (e) Vanderhoydonck, B.;
Stevens, C. V. Synthesis 2004, 722. (f) Li, Y.; Chan, P. W.
H.; Zhu, N.-Y.; Che, C.-M.; Kwong, H.-L. Organometallics
a
Reaction conditions were the same as in Equation 1 except for use
of the noted catalyst (0.5 mol%) and CH Cl as solvent.
2
2
b
c
1
Determined from the H NMR spectrum of the crude product.
Isolated yield of aziridine based on imine.
2004, 23, 54. (g) Redlich, M.; Hossain, M. M. Tetrahedron
In an effort to maximize the usefulness of this method, we
Lett. 2004, 45, 8987. (h) Williams, A. L.; Johnston, J. N.
J. Am. Chem. Soc. 2004, 126, 1612. (i) Krumper, J. R.;
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Suárez, R.; García-Granda, S.; Miguel, D. Organometallics
examined deprotection of the N-PMP aziridine. Using
1
7
ceric ammonium nitrate (CAN), we found that the PMP
group could be removed under mild conditions to afford
the corresponding N-H aziridine in good yield
(
Equation 2).
2
002, 21, 1540. (l) Spanedda, M. V.; Crousse, B.; Narizuka,
PMP
N
H
N
2
.5 equiv CAN, MeCN–H2O (1.4:1)
S.; Bonnet-Delpon, D.; Bégué, J.-P. Collect. Czech. Chem.
Commun. 2002, 67, 1359. (m) Mayer, M. F.; Wang, Q.;
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(n) Loncaric, C.; Wulff, W. D. Org. Lett. 2001, 3, 3675.
0
°C, 2 h
Ph
(
CO2Et
rac)-cis- 5
Ph
(
CO2Et
rac)-cis- 6
2%
8
(
o) Aggarwal, V. K.; Ferrara, M.; O’Brien, C. J.; Thompson,
Equation 2 Deprotection of the racemic N-PMP aziridine
A.; Jones, R. V. H.; Fieldhouse, R. J. Chem. Soc., Perkin
Trans. 1 2001, 1635. (p) Doyle, M. P.; Hu, W.; Timmons,
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W.; Fang, J.; Li, J.; Wang, P. G. Tetrahedron 1999, 55,
In summary, we have developed a Lewis acid catalyzed
1
8
route to aziridines that lacks competitive pathways to
enamino ester or carbene dimer byproducts. The synthesis
of N-PMP-protected aziridine-2-carboxylate esters pro-
ceeds with excellent conversion of starting materials and
high cis/trans product ratios can be observed. In contrast,
existing catalytic routes to N-PMP-protected aziridines
are relatively low yielding. The reactions here proceeded
well even with very low levels of catalyst and rapid addi-
tion of the diazo compound, in minimal excess. These
results are additionally interesting because a-imino esters,
bearing two coordination sites, are good substrates for a
12929. (x) Juhl, K.; Hazell, R. G.; Jørgensen, K. A. J. Chem.
Soc., Perkin Trans. 1 1999, 2293. (y) Mayer, M. F.;
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(z) Nagayama, S.; Kobayashi, S. Chem. Lett. 1998, 685.
(
5) (a) Rasmussen, K. G.; Juhl, K.; Hazell, R. G.; Jørgensen, K.
A. J. Chem. Soc., Perkin Trans. 2 1998, 1347. (b)Mohan, J.
M.; Uphade, B. S.; Choudhary, V. R.; Ravindranathan, T.;
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G.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 1 1997,
1
9
variety of catalytic asymmetric transformations.
Acknowledgment
1287. (d) Gunnoe, T. B.; White, P. S.; Templeton, J. L.;
We thank Texas Tech University and the Robert A. Welch Founda-
tion (Grant No. D-1635) for financial support of this research
project.
Casarrubios, L. J. Am. Chem. Soc. 1997, 119, 3171.
(e) Aggarwal, V. K.; Thompson, A.; Jones, R. V. H.;
Standen, M. C. H. J. Org. Chem. 1996, 61, 8368.
(
f) Casarrubios, L.; Pérez, J. A.; Brookhart, M.; Templeton,
J. L. J. Org. Chem. 1996, 61, 8358. (g) Rasmussen, K. G.;
Jørgensen, K. A. Chem. Commun. 1995, 1401. (h) Zhu, Z.;
Synlett 2007, No. 13, 2025–2028 © Thieme Stuttgart · New York

2
028
A. Mazumdar et al.
LETTER
Espenson, J. H. J. Org. Chem. 1995, 60, 7090. (i) Hansen,
K. B.; Finney, N. S.; Jacobsen, E. N. Angew. Chem., Int. Ed.
Engl. 1995, 34, 676. (j) Moran, M.; Bernardinelli, G.;
Müller, P. Helv. Chim. Acta 1995, 78, 2048. (k)Bartnik, R.;
Mlostoń, G. Tetrahedron 1984, 40, 2569. (l) Bartnik, R.;
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Pierre, J.-L. Bull. Soc. Chim. Fr. 1972, 2493.
(12) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds:
From Cyclopropanes to Ylides; Wiley: Toronto, 1998, also
see references 4i, 5f, and 5i.
(13) The protic acid, TfOH, was recently found to be an effective
catalyst for aziridine formation of imines with diazo
acetates, see reference 4h.
(
(
6) Cardillo, G.; Gentilucci, L.; Tolomelli, A. Aldrichim. Acta
003, 36, 39.
7) For recent progress in the development of potential carbene-
forming catalysts that suppress diazo coupling, see:
(14) Other reported catalytic aziridine syntheses that employ
2
Yb(OTf) use 10 mol%, presumably due to no optimization,
3
see references: 4e, 4l, 4r, 4w, 4x, 4z, and 5c.
(15) The only other report of a highly active Lewis acid catalyst
in the synthesis of aziridines from imines with any diazo
(
a) Fructos, M. R.; Belderrain, T. R.; de Frémont, P.; Scott,
N. M.; Nolan, S. P.; Díaz-Requejo, M. M.; Pérez, P. J.
Angew. Chem. Int. Ed. 2005, 44, 5284. (b) Fructos, M. R.;
Belderrain, T. R.; Nicasio, M. C.; Nolan, S. P.; Kaur, H.;
Díaz-Requejo, M. M.; Pérez, P. J. J. Am. Chem. Soc. 2004,
compound involves use of SnCl (0.05 mol% for 50%
4
conversion in 50 min), see reference 5a.
(16) In these cases, an insufficient level of Lewis acid is present
to selectively decompose the trans-aziridine isomer, as has
been reported in reference 4m.
126, 10846. (c) Huang, L.; Chen, Y.; Gao, G.-Y.; Zhang, X.
P. J. Org. Chem. 2003, 68, 8179.
8) Marx, J. N.; Argyle, J. C.; Norman, L. R. J. Am. Chem. Soc.
(17) Bravo, P.; Capelli, S.; Crucianelli, M.; Guidetti, M.;
Markovsky, A. L.; Meille, S. V.; Soloshonok, V. A.;
Sorochinsky, A. E.; Viani, F.; Zanda, M. Tetrahedron 1999,
55, 3025.
(
(
1974, 96, 2121.
9) A couple catalytic aziridine-forming reactions of a-imino
esters have been reported but none employ aryldiazo-
methanes, see references 4h and 4x.
(18) Typical Synthetic Procedure: To a CH Cl solution (5 mL)
2
2
of imine 3 (216 mg, 1.04 mmol) at –78 °C was added
BF ·Et O (5 mol%, 6.5 mL, 52 mmol) and the solution was
(
10) (a) Phenyldiazomethane was synthesized according to
3
2
literature procedure: Creary, X. Org. Synth. 1986, 64, 207.
stirred at –78 °C for 15 min. To this pale yellow solution was
(b) Aryldiazomethanes are not commercially available and
added, all at once, 4 (1.1 equiv, 327 mL of 3.5 M 4 in CH Cl )
2
2
there have been several reports of explosions related to use
of these substances. Encouraging developments have been
recently reported for the in situ generation of aryldiazo-
methane compounds, see: Fulton, J. R.; Aggarwal, V. K.; de
Vicente, J. Eur. J. Org. Chem. 2005, 1479.
and stirring was continued for 1.5 h at –78 °C. The reaction
flask was then removed from the –78 ºC bath and stirring
was continued for another 45 min during which time the
reaction mixture came to r.t. The reaction mixture was
diluted with CH Cl (5 mL), washed with a sat. aq solution
2
2
(
11) We observed no polymerization of 4 in the presence of the
imine. However, a solution of 4 has undergone slow
polymerization (2–3 d) under similar conditions (2.3 mol%
BF ·Et O, 0.33 M 4 in toluene at –80 °C). For polymeri-
of NaHCO (3 × 10 mL), dried over Na SO and filtered. The
3
2
4
solvent was removed under reduced pressure to provide a
yellow oil that was purified on silica gel by flash column
chromatography using PE–EtOAc (from 95:5 to 85:15) to
3
2
5
f
zations of 4, see: Bawn, C. E. H.; Ledwith, A.; Matthies, P.
J. Polym. Sci. 1958, 33, 21.
provide pure cis-5 (269.7 mg, 87%) as an off-white solid.
(19) Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc. Chem. Res. 2003,
36, 10.
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