The high yield and regioselective conversion of an unactivated aziridine to an oxazolidinone using carbon dioxide with ammonium iodide as the catalyst

Article abstract of DOI:10.1016/j.tetlet.2010.06.110

The conversion of an unactivated 2-alkylaziridine to the corresponding oxazolidinone generally requires a very high pressure of carbon dioxide, a high temperature, an expensive catalyst, and/or a long reaction time. Here, a new, high yield (over 95%), and highly regioselective (over 95%) conversion of an unactivated aziridine to an oxazolidinone is reported. This reaction is easy to perform because it requires a low pressure of carbon dioxide, low temperature, no co-solvent, and the catalyst is the salt ammonium iodide.

Full text of DOI:10.1016/j.tetlet.2010.06.110

Tetrahedron Letters 51 (2010) 4552–4554
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The high yield and regioselective conversion of an unactivated aziridine to an
oxazolidinone using carbon dioxide with ammonium iodide as the catalyst
*
Chau Phung, Allan R. Pinhas
Department of Chemistry, University of Cincinnati, PO Box 210172, Cincinnati, OH 45221-0172, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The conversion of an unactivated 2-alkylaziridine to the corresponding oxazolidinone generally requires a
very high pressure of carbon dioxide, a high temperature, an expensive catalyst, and/or a long reaction
time. Here, a new, high yield (over 95%), and highly regioselective (over 95%) conversion of an unactivated
aziridine to an oxazolidinone is reported. This reaction is easy to perform because it requires a low pressure
of carbon dioxide, low temperature, no co-solvent, and the catalyst is the salt ammonium iodide.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 17 May 2010
Revised 20 June 2010
Accepted 21 June 2010
Available online 25 June 2010
1. Introduction
In this Letter, a high yield and highly regioselective conversion
of an unactivated 2-alkylaziridine to the corresponding oxazolidi-
According to recent reviews, in comparison to activated aziri-
dines, few papers have been published on the chemistry of readily
available unactivated N-alkyl aziridines. One reaction of an N-alkyl
aziridine is the insertion of carbon dioxide into a C–N bond to gen-
erate an oxazolidinone, an important compound used as a chiral
auxiliary, as a metal ligand, and as a pharmaceutical (specifically
as an antibiotic).1–3 Although carbon dioxide is abundant, renew-
able, nonflammable, and inexpensive, it is chemically stable.4,5
Therefore, the insertion reaction generally requires the presence
of a difficult to synthesize catalyst, high pressure (typically over
100 atm), and/or high temperature (typically over 100 °C).6–9
A number of years ago, to the best of our knowledge for the first
time, we showed that a salt, specifically LiI, can promote the inser-
tion of CO2 into the C–N bond of an unactivated N-alkylaziridine
(Scheme 1).10,11 When the 2-position of the ring is substituted by
an aryl group (1), almost a quantitative yield of one regioisomer
(2) is obtained. However, when the 2-position is substituted by
an alkyl group (3), the yield is still very high but two isomers are
formed in a 2:1 ratio (major isomer 4 and minor isomer 5). When
HMPA was added to the reaction of 3, the ratio of the isomers be-
came 97% to 3%. All alkyl groups studied so far behave very simi-
larly. Thus, the specific R or alkyl group does not have an effect
on the yield or the regioselectivity. A theoretical study has shown
that both the Li+ and the IÀ must bond to the aziridine for the inser-
tion reaction to occur.12
none is discussed. The reaction proceeds at room temperature or
below, at 1–4 atm CO2, with ammonium iodide as the catalyst,
and with THF as the solvent.
2. Results and discussion
2.1. Comparison of different salts
Initially, our goal was to test the theoretical prediction12 that
both the Li+ and IÀ of LiI were needed to catalyze the CO2 insertion
reaction. Following our typical procedure10 for the transformation
shown in Scheme 1 (3 R = PhCH2, alkyl = CH3, room temperature,
3 atm pressure, 4 h), but using a variety of salts, the data in Table 1
were obtained. Consistent with the theoretical analysis of this reac-
tion, the lithium salts give higher yields than the sodium salts, which
give higher yields than the potassium salts. In addition, the iodides
give higher yields than the bromides, which give higher yields than
the chlorides.
However, the best yield is obtained with ammonium iodide.
This result is probably because the ammonium ion (pKa = 9.5) coor-
dinates with the aziridine to generate an aziridinium (pKa = 8.3),13
a ring system known to readily ring open.14,15 Therefore, we
decided to study the reaction of NH4I in greater detail.
2.2. Effect of pressure
Since that time, a couple of other salts have been shown to cat-
alyze this type of insertion reaction; however, as mentioned above,
those methods typically require pressures greater than 100 atm,
temperatures greater than 100 °C, and/or 2-phenyl substitution
for the C–N insertion reaction to proceed.6–9
To determine the effect of pressure on this reaction, the conver-
sion of 3 in THF with NH4I was examined at three different pres-
sures (Table 2, entries 1–3). These pressures were chosen
because they are easily obtained from a tank of carbon dioxide
and because they can be used in normal laboratory glassware. It
was found that the higher the pressure, the higher the yield and
regioselectivity.
* Corresponding author. Tel.: +1 513 556 9255; fax: +1 513 556 9239.
E-mail address: allan.pinhas@uc.edu (A.R. Pinhas).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.110

C. Phung, A. R. Pinhas / Tetrahedron Letters 51 (2010) 4552–4554
4553
O
R
N
R
LiI
N
O
CO2
THF
aryl
aryl
1
2
O
O
R
N
R
R
LiI
N
O
N
O
+
CO2
THF
alkyl
alkyl
alkyl
3
4
5
Scheme 1.
Table 1
Comparing different salts to promote the conversion of 3 to 4 + 5
at shorter time. Specifically, at 40 min, the percentage of isomer 4
is 91% in comparison to the 88% at 4 h.
Yielda (%)
Regioselectivitya
(% isomer 4)
The yield and regioselectivity obtained with NH4I are very sim-
ilar to those observed with LiI when HMPA is added and are higher
than those reported in the literature with a variety of other salts.
Another important part of this reaction is that no co-solvent is
needed and the time required for the reaction is fairly short
(40 min vs, greater than 4 h).
Entry
Salts
1
2
3
4
5
6
7
8
LiI
LiBr
LiCl
NaI
NaBr
NaCl
KI
85
76
33
83
27
0
66
84
99
69
97
—
2.4. Effect of moisture
Trace
0
—
—
KBr
9
KCl
0
—
84
—
—
—
Because NH4I is hygroscopic, the effect of water on this reaction
needed to be determined. It was found that the addition of water to
the reaction has no effect on the yield; however, the regioselectiv-
ity decreases from 91% to about 82%. Therefore, care needs to be ta-
ken to avoid moisture in these reactions.
10
11
12
13
NH4I
NH4Br
NH4Cl
No salt
94
Trace
0
0
a
All reactions were repeated at least three times, and all yields
and regioselectivity values are reproducible to less than 3%.
2.5. Effect of temperature
2.3. Effect of reaction time
Based on theoretical calculations, it has been suggested that for
an aziridinium ion, the ring opening reaction of the less substituted
C–N bond has lower activation energy than the ring opening reac-
tion of the more substituted C–N bond.14 This idea implies that at a
lower temperature, a higher regioselectivity would be obtained.
Thus, the effect of temperature on the reaction of 3 + CO2 was
investigated (Table 2, entries 3, 11 and 12).
Based on previous experience, the reaction of 3 + CO2 using LiI
as the catalyst takes a minimum of 4 h in THF or in THF/HMPA.
However, monitoring the NH4I reaction as a function of time (10,
20, 40, 60, 120, 180, and 240 min, Table 2 entries 3–9) showed that
the yield of 96% was obtained in about 40 min and it did not
change with longer time, including after two days (Table 2, entry
10). In addition, the regioselectivity actually increased very slightly
Consistent with the calculations, when the reaction of 3 is run at
0 °C for 4 h, the yield increases to 99%, with 96% of that material
Table 2
Dependence of percentage yield and regioselectivity on different variables
Entry
Pressure (atm)
Temperature (°C)
Time (min)
NH4I amount (equiv)
Yielda (%)
Isomer 4 a(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1
3
4
4
4
4
4
4
4
1
4
4
4
4
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
240
240
240
10
20
40
1
1
1
1
1
1
1
1
1
1
1
1
0.05
0.05
91
94
97
43
87
96
97
98
96
96
99
91
53
98
77
84
88
95
92
91
90
90
90
80
96
78
94
91
60
120
180
2 days
240
40
45
rt
rt
40
120
a
All reactions were repeated at least three times, and all yields and regioselectivity values are reproducible to less than 3%.

4554
C. Phung, A. R. Pinhas / Tetrahedron Letters 51 (2010) 4552–4554
being the major isomer 4. In contrast, when the temperature of the
reaction is increased from room temperature to 45 °C, the regiose-
lectivity decreases to less than 80% of the major isomer.
before the CO2 was added. For the reaction with added water,
0.25 mL of water was added to the THF solution before the CO2
was added. For the catalytic reaction, only 9.0 mg (0.060 mmol)
NH4I was used.
2.6. Catalytic NH4I
After the reaction was completed, the THF solution was added
to 50 mL of diethyl ether. The ether solution was washed once with
20 mL of 10% sodium bisulfate and twice with 20 mL of water. The
ether then was dried with anhydrous K2CO3 and evaporated to dry-
ness, yielding the oxazolidinone mixture. As done previously, GC–
MS and 1H NMR spectroscopy were used to analyze the reaction
mixture.10
Rather than using a stoichiometric amount of NH4I, this reaction
also can be performed using a catalytic amount of NH4I (Table 2,
entries 13 and 14). However, when catalytic NH4I (5 mol %) is used
for the reaction of 3 + CO2, the product formation occurs much
more slowly (53% yield vs, 97% yield in 40 min). When this cata-
lytic reaction is allowed to proceed for 2 h, the yield increases to
98%, with 91% of the mass as isomer 4.
Acknowledgments
2.7. Maximization of isomer 4
The authors thank Professor David Smithrud and the reviewers
for many helpful suggestions. A.R.P. thanks the faculty and staff of
the Department of Pharmacology and Toxicology and the Depart-
ment of Chemistry of the University of Louisville for their hospi-
Thus as shown in Table 2, using NH4I as the catalyst and THF as
the solvent, unactivated 2-alkylaziridine 3 will undergo insertion
of CO2 into the less substituted C–N bond to give isomer 4 in high
yield (over 95%), in high regioselectivity (over 95%), at low pressure
(3 or 4 atm), at low temperature (room temperature or below), and
in a short time (40 min at rt or 4 h at 0 °C).
tality during
written.
a sabbatical leave when this manuscript was
References and notes
1. Zappia, G.; Gacs-Baitz, E.; Monache, G. D.; Misiti, D.; Nevola, L.; Botta, B. Curr.
Org. Synth. 2007, 81.
2.8. Maximization of isomer 5
2. Watson, I. D. G.; Yu, L.; Yudin, A. K. Acc. Chem. Res. 2006, 39, 194.
3. Hu, X. E. Tetrahedron 2004, 60, 2701.
For turning around the results in the previous section, larger
amounts of insertion into the more substituted C–N bond to give
isomer 5 should be obtained with LiI, at lower pressure, higher
temperature, and longer reaction time. When the reaction of com-
pound 3 with CO2 was run in THF with LiI, at 1 atm CO2, at 55 °C,
for 3 days, only 33% of the oxazolidinone was isomer 4 and 67%
was what was formerly minor isomer 5. Unfortunately, the yield
was only 70%, because at the higher temperature, a large amount
of piperazine (a six-membered ring dimer of an aziridine) was
formed.
4. Sakakura, T.; Choi, J.-C.; Yasuda, H. Chem. Rev. 2007, 107, 2365.
5. Arakawa, H.; Aresta, M.; Armor, J. N.; Barteau, M. A.; Beckman, E. J.; Bell, A. T.;
Bercaw, J. E.; Creutz, C.; Dinjus, E.; Dixon, D. A.; Domen, K.; DuBois, D. L.; Eckert,
J.; Fujita, E.; Gibson, D. H.; Goddard, W. A.; Goodman, D. W.; Keller, J.; Kubas, G.
J.; Kung, H. H.; Lyons, J. E.; Manzer, L. E.; Marks, T. J.; Morokuma, K.; Nicholas, K.
M.; Periana, R.; Que, L.; Rostrup-Nielson, J.; Sachtler, W. M. H.; Schmidt, L. D.;
Sen, A.; Somorjai, G. A.; Stair, P. C.; Stults, B. R.; Tumas, W. Chem. Rev. 2001, 101,
953.
6. Wu, Y.; He, L.-N.; Du, Y.; Wang, J.-Q.; Miao, C.-X.; Li, W. Tetrahedron 2009, 65,
6204.
7. He, L.; Du, Y.; Miao, C.; Wang, J.; Dou, X.; Wu, Y. Front. Chem. Eng. China 2009, 3,
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8. Du, Y.; Wu, Y.; Liu, A.-H.; He, L.-N. J. Org. Chem. 2008, 73, 4709.
9. Jiang, H.-F.; Ye, J.-W.; Qi, C.-R.; Huang, L.-B. Tetrahedron Lett. 2010, 51, 928.
10. Hancock, M. T.; Pinhas, A. R. Tetrahedron Lett. 2003, 44, 5457.
11. After Ref.10 was accepted for publication but before it was printed, a very
similar manuscript was accepted: Sudo, A.; Morioka, Y.; Koizumi, E.; Sanda, F.;
Endo, T. Tetrahedron Lett. 2003, 44, 7889.
12. Mu, W.-H.; Chasse, G. A.; Fang, D.-C. J. Phys. Chem. A 2008, 112, 6708.
13. O’Rourke, C. E.; Clapp, L. B.; Edwards, J. O. J. Am. Chem. Soc. 1956, 78, 2159.
14. See: Catak, S.; D’hooghe, M.; De Kimpe, N.; Waroquier, M.; Van Speybroeck, V. J.
Org. Chem. 2010, 75, 885. and references cited therein.
3. Experimental section
Into a 48 mL thick walled flask, with a stir bar, was added aziri-
dine 3 (0.180 g, 1.22 mmol), 1.22 mmol of salt (LiI, 0.162 g; LiBr,
0.106 g; LiCl, 0.052 g; NaI, 0.184 g; NaBr, 0.126 g; NaCl, 0.071 g;
KI, 0.203 g; KBr, 0.146 g; KCl, 0.091 g; NH4I, 0.177 g; NH4Br,
0.120 g; or NH4Cl, 0.066 g), and 2 mL of THF. The reaction mixture
was then subjected to carbon dioxide gas at room temperature for
the appropriate length of time. The pressure was monitored by a
gauge and adjusted to 1, 3, or 4 atm by bleeding off excess pressure
at the beginning of the reaction. For the 45 °C reaction and for the
0 °C reaction, the flask was put into an oil bath or an ice/water bath
15. One reviewer suggested a control experiment using KI and a catalytic amount
of CF3COOH. When this was tried, the results were the same as the reaction
+
using only KI, and thus, the NH4 IÀ is not simply a proton source. The second
+
reviewer suggested an alternative mechanism in which instead of the NH4
reacting with the aziridine, it is coordinating with the CO2. The coordinated
CO2 and the IÀ then react with the aziridine ring.