Tetrabutylammonium bromide-mediated ring opening reactions of N-tosylaziridines with carboxylic acids in DMF

Article abstract of DOI:10.1039/c3ra46932h

Tetrabutylammonium bromide (TBAB) was found to be a highly effective catalyst at as low as 10 mol% for regioselective ring opening of a variety of N-tosylaziridines with various carboxylic acids to afford the corresponding ring-opening products (derived β-amino esters) in good to excellent yields and up to 100% regioselectivity in combination with DMF as the solvent.

Full text of DOI:10.1039/c3ra46932h

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Tetrabutylammonium bromide-mediated ring
opening reactions of N-tosylaziridines with
carboxylic acids in DMF†
Cite this: RSC Adv., 2014, 4, 6490
*
*
Xing Li, Gong Li, Honghong Chang, Yan Zhang and Wenlong Wei
Received 22nd November 2013
Accepted 19th December 2013
Tetrabutylammonium bromide (TBAB) was found to be a highly effective catalyst at as low as 10 mol% for
regioselective ring opening of a variety of N-tosylaziridines with various carboxylic acids to afford the
corresponding ring-opening products (derived b-amino esters) in good to excellent yields and up to
100% regioselectivity in combination with DMF as the solvent.
DOI: 10.1039/c3ra46932h
www.rsc.org/advances
various substituted b-amino esters with excellent yields and
good enantioselectivity through the efficient chemoselective
Introduction
and stereoselective ring openings of N-tosylaziridines with
carboxylic acids in DMF.
Aziridines are versatile intermediates for the synthesis of many
biologically active compounds. They are an extensively studied
class of molecules due to their structure and inherent ring
strain which leads to high and unique reactivity with various
nucleophiles, and the importance of the ring-opening products.
Selectively-protecting b-amino esters that may serve as precur-
sors for many organic syntheses and be used for other synthetic
purposes can be achieved through the ring opening of N-tosy-
laziridines with carboxylic acids which is a direct and appealing
route. Compared with many reports about ring-opening reac-
tions of epoxides with carboxylic acids,1,2 only a few limited
examples on the chemoselective and regioselective ring open-
ings of aziridines with carboxylic acids or their derivatives are
reported.3 So, the discovery of novel catalysts which are cheaper
and more efficient and the development of new catalytic
systems which are more effective remain a considerable chal-
lenge and are a long-standing problem and are still in demand.
In addition, tetrabutylammonium bromide (TBAB) has emerged
as an extremely useful homogeneous catalyst and shown good
catalytic ability in various organic transformations.4 It is an
inexpensive readily available ionic liquid with inherent prop-
erties like environmental compatibility, greater selectivity,
operational simplicity. It is therefore of interest to examine the
behavior of TBAB as a catalyst in the synthesis of various
substituted b-amino esters. To the best of our knowledge, the
generality and applicability of TBAB in the ring openings of
N-tosylaziridines with carboxylic acids are not observed. In this
paper, we wish to report the application of TBAB as a simple,
mild, remarkable and effective catalyst for the preparation of
Results and discussion
With tetrabutylammonium bromide (TBAB)5 as a catalyst, and
the ring opening of N-tosylcyclohexylaziridine (1a) with 4-
nitrobenzoic acid (2a) as the model reaction, we began with our
studies by examining solvents. Of those examined, DMF was the
most effective solvent providing the desired ring-opening
product in 24% yield (Table 1, entry 5). Worse results were
obtained with CH2Cl2, THF and DMSO (Table 1, entries 2–4 vs.
5). No product was detected when this reaction was performed
in CH3CN (Table 1, entry 1). Temperature screening revealed
that there was an evident tendency that higher temperature
resulted in higher yields (Table 1, entries 6–9). The yield of this
reaction arrived at the highest value (51%) at 65 ꢀC (Table 1,
entry 9). Subsequently, the amount of TBAB was examined
(Table 1, entries 10–13). Unfortunately, the absence of TBAB
resulted in the lower yield (Table 1, entry 10). With the increase
of catalyst loading, the reactivity was improved gradually
and the yield rose steadily (Table 1, entries 11 and 12 vs. 10).
When the amount of TBAB was increased from 10 mol% to
15 mol%, the yield began to decline (Table 1, entries 12 and 13).
This examination suggested that TBAB played a great part in
this process and 10 mol% TBAB was suitable.
The efficiency of TBAF, TBAC, TBAB and TBAI was also
examined under the same conditions which were 0.2 mmol
N-tosylaziridine 1a, 10 mol% TBAX (X ¼ F, Cl, Br, I) and 1.5
equiv. of 4-nitrobenzoic acid 2a under air atmosphere in 2.0 mL
of DMF at 65 ꢀC for 24 h. As shown in Fig. 1, TBAF afforded the
product 3a with 81% yield which was somewhat higher than
that TBAB offered (79%). TBAC and TBAB except TBAI which
provided the lower yield (63%) gave the equally good yields.
Considering comprehensive factors, TBAB was adopted as the
Department of Chemistry and Chemical Engineering, Taiyuan University of
Technology, 79 West Yingze Street, Taiyuan 030024, People's Republic of China.
E-mail: lixing@tyut.edu.cn; Fax: +86-351-6111165; Tel: +86-351-6111165
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra46932h
6490 | RSC Adv., 2014, 4, 6490–6495
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Table 1 Effects of various factors on the ring-opening reaction of N- Table 2 Effects of the amount of 2a and solvent dosage on the ring-
tosylcyclohexylaziridine 1a with 4-nitrobenzoic acid 2aa
opening reaction of N-tosylcyclohexylaziridine 1a with 4-nitrobenzoic
acid 2aa
Entry
Solvent
T (ꢀC)
TBAB (mol%)
t (h)
Yieldb (%)
Entry
2a (equiv.)
Solvent dosage (mL)
t (h)
Yieldb (%)
1
2
3
4
5
6
7
8
CH3CN
CH2Cl2
THF
25
25
25
25
25
25
45
50
65
65
65
65
65
10
10
10
10
10
10
10
10
10
—
5
24
24
24
24
24
18
18
18
18
24
24
24
24
N.D.c
4
18
8
24
5
31
43
51
53
64
79
72
1
2
3
4
5
6
7
1.0
1.2
1.5
1.2
1.2
1.2
1.2
2.0
2.0
2.0
0.5
1.0
2.0
2.0
30
30
30
33
33
33
33
81
89
86
88
90
96
83
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
9
a
All reactions were performed with N-tosylaziridine 1a (50 mg,
10
11
12
13
b
0.2 mmol) in DMF at 65 ꢀC under the specied conditions. Isolated
yield.
10
15
a
All reactions were performed with N-tosylaziridine 1a (50 mg,
0.2 mmol) and 4-nitrobenzoic acid 2a (50.1 mg, 0.3 mmol, 1.5 equiv.)
conditions which demonstrated the presence of TBAB is crucial
for obtaining high yields (Table 2, entry 7 vs. 6).
b
in 2.0 mL of solvent under the specied conditions. Isolated yield.
c
N.D. ¼ Not detected.
The results of an examination of the scope of the ring-
opening reactions of various N-tosylaziridines with a wide range
of carboxylic acids are presented in Tables 3 and 4, respectively.
In terms of the ring openings of N-tosylaziridines with p-nitro-
benzoic acid, except for 1b, 1d, 1h, 1j, 1m and 1p (Table 3,
entries 1, 3, 7, 9, 12 and 16), others indicated good to high
regioselectivity, which reected that the position of substituting
group took effect on the structure of products. Uniformly
excellent yields were observed for most substrates, too.7
Aromatic N-tosylaziridines bearing both electron-withdrawing
(Table 3, entries 5–7 and 12) and electron-donating groups
(Table 3, entries 2–4 and 8–9) supplied good to excellent yields.
It is surprising that para-phenyl substituted N-tosylaziridines
gave somewhat lower yields (Table 3, entries 7 and 12). It was
noteworthy that the steric hindrance had evident effect on the
yield (Table 3, entry 13). Ring-opening reactions of aliphatic
N-tosylaziridines were all performed smoothly to afford the
corresponding products in good to excellent yields with high
regioselectivity (Table 3, entries 17 and 18).
Fig. 1 The examination of the activity of catalysts on the ring-opening
reaction (reaction conditions: N-tosylcyclohexylaziridine 1a (50 mg,
0.2 mmol), TBAX (X ¼ F, Cl, Br, I) (0.02 mmol, 10 mol%) and 1.5 equiv. of
4-nitrobenzoic acid 2a under air atmosphere in 2.0 mL of DMF at 65 ꢀC
for 24 h.).
Furthermore, we explored various carboxylic acids with 1a
(Table 4) to realize the electronic and steric effect of substituent
most suitable catalyst. These can be interpreted in terms of groups of aromatic carboxylic acids on the yield of this reaction.
acidic strengths of HF, HCl, HBr and HI, respectively. Excitedly, most acids gave the excellent yields (Table 4, entries
The exploration of the ratio of substrates indicated that 1.2 1–8). At the same time, aliphatic carboxylic acids are also found
equiv. of 4-nitrobenzoic acid 2a was the most suitable (Table 2, to be good substrates and could afford the desired products
entry 2). Then, we also screened solvent dosage. Although a with good yields that were lower than aromatic carboxylic acids
continuous increase in the yield was observed upon increasing (Table 4, entries 9–11 vs. 1–8).
the solvent dosages, the increase was minimal (Table 2, entries 4–
For the purpose of examining the synthetic potential of the
6). Considering the operational reproducibility, stability and present approach, a gram-scaled synthesis of ring-opening
rising space of the yield, 2.0 mL of DMF was chosen. In summary, products was performed for this catalytic system. As shown in
extensive screening showed that the optimized reaction condi- Scheme 1, in the presence of 10 mol% of TBAB, 10 mmol of
tions were 10 mol% TBAB and 1.2 equiv. of 4-nitrobenzoic acid N-tosylaziridine 1c reacted with 1.2 equiv. of 2a to provide 3c as
under air atmosphere in 2.0 mL DMF at 65 ꢀC (Table 2, entry 6).6 the single product in a total yield of 98% (4.454 g). Similarly,
83% yield was obtained in the absence of TBAB under the same subgram quantities of products 3k and 4k with the isomer 3k as
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 6490–6495 | 6491

View Article Online
RSC Advances
Paper
Table 3 Ring-opening reactions of various N-tosylaziridines with 4-nitrobenzoic acid 2aa
Entry
1c
N-Tosylaziridine
Product 3 or 4
Yieldb (%)
Ratio 3 : 4
93
54 : 46
2
>99
>99
—
3d
55 : 45
4
86
—
5c
>99
>99
88 : 12
6
—
7d
87
67 : 33
8c
>99
>99
87 : 13
61 : 39
9d
10c
81
83 : 17
6492 | RSC Adv., 2014, 4, 6490–6495
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Table 3 (Contd.)
Entry
11c
N-Tosylaziridine
Product 3 or 4
Yieldb (%)
Ratio 3 : 4
75
78 : 22
12d
81
62
67 : 33
13
—
14
15
96
—
—
>99
16c
17
73
95
34 : 66
—
18
91
—
a
All reactions were performed with N-tosylaziridines 1 (0.2 mmol) and 2a (0.24 mmol, 1.2 equiv.) in DMF (2.0 mL) at 65 ꢀC for 33 h. b Isolated yield.
c
1
Combined yield of isolated 3 and 4. d The ratios of the two isomers were determined by H NMR.
the major product (3.269 g, 80% total yield, 3k : 4k ¼ 5 : 1) were
obtained.
In order to dene the role of TBAB, one test using tetrabu-
tylammonium acetate as nucleophile was performed (see
Based on the observations above, an investigation on a mono- Scheme 3). It was observed that 65% yield (Table 4, entry 10,
substituted chiral N-tosylaziridine8 as a starting material was per- 68% yield for acetate) was obtained when 1.2 equiv. of
formed under the same optimized conditions to test the generality TBAOOCCH3 was used instead of CH3COOH as the reagent
and the detailed mechanism (Scheme 2). TBAB catalyzed smoothly which demonstrated that the acidity of the used acid did not
the ring opening of (R)-N-tosylaziridines 1b0 with p-nitrobenzonic play a crucial role during the ring opening.
acid 2a under the mild conditions, giving the corresponding
product 3b0 and 4b0 in 82% total yield (3b0 : 4b0 ¼ 6 : 1).
According to the results of our research, we proposed a
possible catalytic cycle mechanism for the ring-opening reaction
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 6490–6495 | 6493

View Article Online
RSC Advances
Paper
Table 4 Ring-opening reactions of various carboxylic acids with N-
tosylcyclohexylaziridine 1aa
Entry
1
Carboxylic acid
Product
Yieldb (%)
86 (3s)
Scheme 1 Scaled-up version of the ring-opening reactions.
2
94 (3t)
3
4
5
72 (3u)
97 (3v)
90 (3w)
Scheme 2 The ring opening of chiral (R)-N-tosylaziridines 1b0.
6
7
99 (3x)
99 (3y)
Scheme 3 The ring opening about tetrabutylammonium acetate.
8
92 (3z)
9
73 (3za)
68 (3zb)
10
11
57 (3zc)
a
All reactions were performed with N-tosylcyclohexylaziridine 1a
(50 mg, 0.2 mmol) and carboxylic acids 2 (0.24 mmol, 1.2 equiv.)
under air atmosphere in DMF (2.0 mL) at 65 ꢀC for 33 h. b Isolated yield.
Scheme
4 The plausible catalytic cycle for the ring-opening
reactions.
which is shown in Scheme 4. Firstly, the interaction of the tet-
rabutylammonium bromide (TBAB)9 and carboxylic acid leads to
the tetrabutylammonium acid salt (M1) and in situ generated
HBr, whereupon HBr is trapped by weakly basic solvent DMF to
afford M2. Subsequently, the latter M2 reacts again with the
N-tosylaziridine 1a to form the protonated but loosely bound
pair M4. Finally, the collapse of M4 gives the desired product and
regenerates TBAB, and thus establishes the catalytic cycle.
Conclusions
N-tosylaziridine-bromo ion pair M3. The exchange of tetrabuty- In conclusion, the TBAB-oriented catalytic method described
lammonium acid salt M1 and protonated N-tosylaziridine-bromo here appears to be an efficient, simple and mild strategy for
gives protonated and loosely bound N-tosylaziridine-acid salt ion acidolysis of N-tosylaziridines. More importantly, good to
6494 | RSC Adv., 2014, 4, 6490–6495
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
excellent yields have been obtained for a wide variety of
substrates and 23 new compounds were obtained. It was also
found that the absence of TBAB in this reaction would give the
desired ring-opening product with lower yield in longer time,
which conrms the promoting effect of TBAB for this reaction.
In addition, the advantages such as non-toxicity and stability of
the reagents, easy work-up, high yields and almost no side
reaction make this method a useful addition to the present
methodologies in organic synthesis.
and M. M. Lomas, J. Org. Chem., 1994, 59, 3135; (m)
C. Moberg, L. Rakos and L. Tottie, Tetrahedron Lett., 1992,
33, 2191; (n) J. Otera, Y. Niibo, N. Tatsumi and H. Nozaki,
J. Org. Chem., 1988, 53, 275; (o) Y. Niibo, T. Nakata, J. Otera
and H. Nozaki, Synlett, 1991, 97; (p) M. Chini, P. Crotti,
C. Gardelli and F. Macchia, Synlett, 1992, 673; (q)
N. Iranpoor, I. Mohammadpoor-Baltork and F. S. Zardaloo,
Tetrahedron, 1991, 47, 9861.
3 (a) Y. K. Liu, R. Li, L. Yue, B. J. Li, Y. C. Chen, Y. Wu and
L. S. Ding, Org. Lett., 2006, 8, 1521; (b) J. Wu, X. Y. Sun and
Y. Z. Li, Eur. J. Org. Chem., 2005, 4271; (c) J. S. Yadav,
B. V. S. Reddy, K. Sadashiv and K. Harikishan, Tetrahedron
Lett., 2002, 43, 2099; (d) M. D'hooghe, K. Vervisch, A. Van
Nieuwenhove and N. De Kimpe, Tetrahedron Lett., 2007, 48,
1771; (e) M. Kumar, S. Gandhi, S. S. Kalra and V. K. Singh,
Synth. Commun., 2008, 38, 1527; (f) J. S. Yadav,
B. V. S. Reddy, K. Sadashiv, K. Harikishan and
A. V. Narsaiah, J. Mol. Catal. A: Chem., 2004, 220, 153; (g)
R. H. Fan and X. L. Hou, Tetrahedron Lett., 2003, 44, 4411;
(h) X. Y. Sun, S. Q. Ye and J. Wu, Eur. J. Org. Chem., 2006, 4787.
Acknowledgements
We appreciate gratefully the Natural Science Foundation of
Shanxi Province (no. 2012021007-2 and no. 2011011010-2) for
nancial support. The project is also supported by Scientic
and Technological Innovation Programs of Higher Education
Institutions in Shanxi (no. 20120006).
Notes and references
´ ˆ
¨
1 (a) S. Balieu, A. E. Zein, R. D. Sousa, F. Jerome, A. Tatibouet, 4 (a) M. Smietana and C. Mioskowski, Org. Lett., 2001, 3, 1037;
S. Gatard, Y. Pouilloux, J. Barrault, P. Rollin and
S. Bouquillon, Adv. Synth. Catal., 2010, 352, 1826; (b)
M. W. C. Robinson, A. M. Davies, I. Mabbett,
D. C. Apperley, S. H. Taylor and A. E. Graham, J. Mol. Catal.
A: Chem., 2009, 314, 10; (c) M. Moghadam,
S. Tangestaninejad, V. Mirkhani, I. Mohammadpoor-Baltork
and S. A. Taghavi, Catal. Commun., 2007, 8, 2087; (d)
S. Tangestaninejad, M. Moghadam, V. Mirkhani,
¨
(b) D. Amantini, F. Fringuelli, F. Pizzo and L. Vaccaro, J. Org.
Chem., 2001, 66, 6734; (c) K. Selvakumar, A. Zapf and
M. Beller, Org. Lett., 2002, 4, 3031; (d) B. C. Ranu, S. S. Dey
and A. Hajra, Tetrahedron, 2003, 59, 2417; (e) B. C. Ranu,
A. Das and S. Samanta, J. Chem. Soc., Perkin Trans. 1, 2002,
1520; (f) S. Kantevari, M. V. Chary, A. P. R. Das,
S. V. N. Vuppalapati and N. Lingaiah, Catal. Commun., 2008,
9, 1575.
B. Yadollahi and S. M. R. Mirmohammadi, Monatshee fur 5 Several tetrabutylammonium salts (Bu4NX, X ¼ F, Cl, Br, and
Chemie, 2006, 137, 235; (e) H. Firouzabadi, N. Iranpoor,
A. A. Jafari and S. Makarem, J. Mol. Catal. A: Chem., 2006,
I) were reported to be effective in ring opening of aziridine
with other nucleophiles. For instance, see: (a) R. H. Fan,
Y. G. Zhou, W. X. Zhang, X. L. Hou and L. X. Dai, J. Org.
Chem., 2004, 69, 335; (b) J. Wu, X. L. Hou and L. X. Dai,
J. Org. Chem., 2000, 65, 1344.
´
´
250, 237; (f) J. M. Concellon, J. R. Suarez, V. del Solar and
R. Llavona, J. Org. Chem., 2005, 70, 10348; (g)
M. Moghadam, S. Tangestaninejad, V. Mirkhani and
R. Shaibani, Tetrahedron, 2004, 60, 6105; (h) V. Mirkhani, 6 With regard to the model substrate, 95% yield could be
S. Tangestaninejad, B. Yadollahi and L. Alipanah, obtained within 42 h in the absence of TBAB.
Tetrahedron, 2003, 59, 8213; (i) M. L. Kantam, K. Aziz, 7 In terms of most substrates, the prolonged reaction time (42
K. Jeyalakshmi and P. R. Likhar, Catal. Lett., 2003, 89, 95; (j)
A. Khala-Nezhad, M. N. S. Rad and A. Khoshnood,
Synthesis, 2003, 2552; (k) B. Tamami, N. Iranpoor and
H. Mahdavi, Synth. Commun., 2002, 32, 1251.
2 (a) N. Iranpoor and H. Adibi, Bull. Chem. Soc. Jpn., 2000, 73,
675; (b) N. Iranpoor, H. Firouzabadi, A. Safavi and
M. Shekarriz, Synth. Commun., 2002, 32, 2287; (c)
Y. Taniguchi, S. Tanaka, T. Kitamura and Y. Fujiwara,
Tetrahedron Lett., 1998, 39, 4559; (d) N. Iranpoor and
B. Zeynizadeh, Synth. Commun., 1999, 29, 1017; (e)
E. N. Jacobsen, F. Kakiuchi, R. G. Konsler, J. F. Larrow and
h) could not lead to uniformly good yields and lower yields
were provided for most N-tosylaziridine in the absence of
ꢀ
TBAB at 65 C.
8 About the preparation of chiral N-tosylaziridine 1b0, see:
(a) M. Nakanishi, A. F. Salit and C. Bolm, Adv. Synth.
´
Catal., 2008, 350, 1835; (b) P. Dauban, L. Saniere,
A. Tarrade and R. H. Dodd, J. Am. Chem. Soc., 2001, 123,
7707; (c) D. B. Llewellyn, D. Adamson and B. A. Arndtsen,
¨
Org. Lett., 2000, 2, 4165; (d) M. J. Sodergren, D. A. Alonso
and P. G. Andersson, Tetrahedron: Asymmetry, 1997, 8,
3563.
M. Tokunaga, Tetrahedron Lett., 1997, 38, 773; (f) Y. Masaki, 9 On studying the mechanism of the ring opening reaction, the
T. Miura and M. Ochiai, Synlett, 1993, 847; (g) Y. Masaki,
T. Miura and M. Ochiai, Bull. Chem. Soc. Jpn., 1996, 69, 195;
(h) C. Liu, Y. Hashimoto, K. Kudo and K. Saigo, Bull. Chem.
Soc. Jpn., 1996, 69, 2095; (i) B. M. Choudary and Y. Sudha,
Synth. Commun., 1996, 26, 2989; (j) N. Iranpoor, T. Tarrian
and Z. Movahedi, Synthesis, 1996, 1473; (k) N. Iranpoor and
P. Salehi, Synthesis, 1994, 1152; (l) C. Jaramillo, J. L. Chiara
control experiments with tetrabutylammonium acetate
(TBAOCOCH3) and tetrabutylammoniumhydrogen sulfate
(TBAHSO4) were conducted. When tetrabutylammonium
acetate was used as a catalyst, only 65% yield which was
lower than that TBAB provided was obtained with a certain
amount of byproduct aer 30 h. TBAHSO4 gave 88% yield
within 24 h.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 6490–6495 | 6495