Two-step syntheses of 2,4,6-triisopropylbenzenesulfonyl aziridines

Article abstract of DOI:10.1016/j.tetlet.2005.03.013

In a continuing study on the α-lithiation of N-tosyl aziridines, it is reported that ortho-lithiation of the N-tosyl group is occurring under typical α-lithiation conditions (s-BuLi/PMDETA). Thus, a simple, two-step synthesis of N-2,4,6-triisopropylbenzen

Full text of DOI:10.1016/j.tetlet.2005.03.013

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3253–3256
Two-step syntheses of 2,4,6-triisopropylbenzenesulfonyl aziridines
Jianhui Huang and Peter OÕBrien*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 13 January 2005; accepted 2 March 2005
Available online 28 March 2005
Abstract—In a continuing study on the a-lithiation of N-tosyl aziridines, it is reported that ortho-lithiation of the N-tosyl group is
occurring under typical a-lithiation conditions (s-BuLi/PMDETA). Thus,
a simple, two-step synthesis of N-2,4,6-tri-
isopropylbenzenesulfonyl aziridines was optimised. The route involves epoxide ring opening using a sulfonamide, mesylation and
base-mediated ring closure. The scope and limitations of this route were assessed and five new N-2,4,6-triisopropylbenzenesulfonyl
aziridines were prepared in good yields. Since this method was unsuitable for the preparation of cyclooctene aziridine, an alternative
two-step method was developed. This method involved aminobromination of cyclooctene using NBS/2,4,6-triisopropyl-
benzenesulfonamide.
Ó 2005 Elsevier Ltd. All rights reserved.
Recent work in our group has focused on the alkyl-
lithium-mediated a-lithiation of N-tosyl aziridines such
as 1 and 3.1–3 Suspecting that lithiation ortho to the sul-
fonamide of the N-tosyl group4–6 may be occurring
under the reaction conditions, we decided to trap any
intermediate organolithiums with Me3SiCl. Thus, lithia-
tion of N-tosyl aziridine 1 using s-BuLi in the pre-
sence of pentamethyldiethylenetriamine (PMDETA) at
ꢀ78 °C for 4 h and subsequent trapping with Me3SiCl
gave substituted aziridine 27 in 19% yield together with
recovered starting aziridine 1 (25% yield). Under compa-
rable conditions, aziridine 3 gave 48 in 39% yield (with
35% recovered starting material). In contrast to cyclooc-
tene oxide,9 no trapping at the a-position of the azir-
idine was observed. Clearly, the N-tosyl-aziridino
protecting group is not an innocent bystander in alkyl-
lithium reactions and this is probably why an excess of
alkyllithium is typically employed for lithiation of
N-tosyl aziridines.1–3
With a view to developing aziridine a-lithiation condi-
tions that avoid excess alkyllithium as the base, we
considered using N-2,4,6-triisopropylbenzenesulfonyl
aziridines 5. The 2,4,6-triisopropylbenzenesulfonyl
group is of course well known from its use in the Shap-
iro reaction.4a,10 To our surprise, N-sulfonyl aziridines 5
have never previously been prepared and so a conve-
nient route to these compounds needed to be devised.
Keywords: Aziridines; Epoxides; Sulfonamides.
*
Corresponding author. Tel.: +44 01904 432535; fax: +44 01904 432516; e-mail: paob1@york.ac.uk
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.013

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J. Huang, P. OÕBrien / Tetrahedron Letters 46 (2005) 3253–3256
commonly employed methods each have their own
limitations.
Due to the lack of widespread syntheses of different N-
sulfonyl aziridines, we were attracted to a report by Alb-
anese et al. on the three-step synthesis of N-tosyl azir-
idines starting from epoxides.22,23 The epoxides were
ring opened with p-toluenesulfonamide and the resulting
amino alcohols were tosylated and cyclised using
K2CO3. In one example, another sulfonamide (p-
NO2C6H4SO2NH2) was used. By slightly modifying
AlbaneseÕs original methods,22a we have now success-
Despite extensive studies on aziridination methodol-
ogy,11 there are in fact few synthetic methods for the
synthesis of Ônon-tosylÕ N-sulfonyl aziridines. The most
obvious approach is sulfonylation of the parent NH azir-
idine (normally prepared by Staudinger reduction of
the corresponding azido alcohol,12 itself synthesised
from the epoxide and sodium azide). We have utilised
such an approach for proof of stereochemistry in some
of our previous studies (e.g. 6 ! 7 and 8 ! 9)13,14 but
these reactions have always proved low yielding in our
hands (24% yield of 7 and 41% yield of 9 are
representative).
fully synthesised
a range of N-2,4,6-triisopropyl-
benzenesulfonyl aziridines 5 using a simple two-step
protocol. In addition, we also developed a two-step syn-
thesis of N-2,4,6-triisopropylbenzenesulfonyl cyclooc-
tene aziridine using an aminobromination approach.24
Herein, we describe our results.
To start with, we optimised conditions for the synthesis
of N-tosyl aziridine 1, culminating in a two-step
approach that delivered 1 in 75% overall yield. Thus,
cyclohexene oxide was ring-opened using p-toluenesul-
fonamide in refluxingꢀ dioxane in the presence of
K2CO3 and BnNEtþ3 Cl to give amino alcohol 10 in
91% yield after chromatography. An extended reaction
time (72 h) was necessary for a high conversion to 10.
In an improvement to AlbaneseÕs route, we mesylated
10 and the crude mesylate was then directly cyclised to
N-tosyl aziridine 1. In this way, 1 was produced in
82% yield after chromatography. Our approach to 1
benefits from use of less equivalents of sulfonamide, a
shorter mesylation reaction time and the need for only
two chromatographic purifications; in addition, our
overall yield of 1 is higher.
Alternative and popular approaches for the direct syn-
thesis of aziridines from alkenes involve use of iodinanes
PhI = NSO2R15,16 (which can also be prepared in situ17)
and N-chloramine sulfonamide salts RSO2NClꢀ-
Na+,18,19 both of which we have used in other stud-
ies.1,13,20 With iodinanes, Andersson et al. have
reported the preparation of a few N-sulfonyl aziridines16
and the synthesis of N-SES-protected aziridines, pio-
neered by Dauban and Dodd, is well docu-
mented.11a,17,21 For N-chloramine sulfonamide salts,
commercially available Chloramine-T is almost always
used18 although Sharpless and co-workers have also
When p-toluenesulfonamide was replaced with N-2,4,6-
triisopropylbenzenesulfonamide, some of the reaction
times for step (i) were increased to 96 h to optimise the
yields. Using this two-step approach, aziridines 11–15
were prepared in satisfactory yields over the two steps
(29–69%).25 Despite N-2,4,6-triisopropylbenzenesulfon-
amide being more sterically hindered, the results ob-
tained compared well with p-toluenesulfonamide for
each of 11–15. Notably, the synthesis of the N-tosyl ana-
logue of dihydrofuran aziridine 13 using our protocol
(56% yield over two steps) is more efficient (in terms
of yield and overall reaction time) than a recently
t
had success with BuSO2NClꢀNa+.19 Thus, these
O
S
O
S
O
S
O
O
O
O
O
N
N
N
N S
O
BocN
O
S
O
N
Ph
11
12
13
14
15
(i) 85% (68 h)
(ii) 78% (a: 5 h, b: 4 h)
(i) 47% (72 h)
(ii) 62% (a: 16 h, b: 16 h)
(i) 86% (96 h)
(ii) 80% (a: 16 h, b: 16 h)
(i) 63% (72 h)
(ii) 76% (a: 16 h, b: 16 h)
(i) 73% (96 h)
(ii) 86% (a: 16 h, b: 16 h)
Ts: (i) 91% (72 h)
(ii) 82% (a: 5 h, b: 3 h)
Ts: (i) 79% (72 h)
(ii) 77% (a: 16 h, b: 16 h)
Ts: (i) 75% (72 h)
(ii) 74% (a: 16 h, b: 16 h)
Ts: (i) 59% (72 h)
(ii) 54% (a: 16 h, b: 16 h)
Ts: (i) 73% (72 h)
(ii) 73% (a: 16 h, b: 16 h)
Conditions:
Step (i) 1.2 eq 2,4,6-triisopropylbenzenesulfonamide or TsNH2, 0.1 eq K2CO3, 0.1 eq BnNEt3+Cl–, dioxane, 90 ˚C, 68-96 h
Step (ii) (a) 5 eq pyridine/MsCl, CH2Cl2, reflux, 5-16 h; (b) 4 eq K2CO3, MeCN, 45 ˚C, 4-16 h

J. Huang, P. OÕBrien / Tetrahedron Letters 46 (2005) 3253–3256
3255
Acknowledgements
We thank Dr. M. J. McGrath for his help with this
project.
References and notes
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For our planned lithiation studies, the preparation of N-
2,4,6-triisopropylbenzenesulfonyl cyclooctene aziridine
was of particular importance. Therefore, since ring
opening of cyclooctene oxide was unsuccessful we inves-
tigated another route to this aziridine based on amino-
bromination, as reported by Sudalai and co-workers.24
Thus, reaction of cyclooctene with N-2,4,6-triisopropyl-
benzenesulfonamide in the presence of NBS and manga-
nese sulfate gave amino bromide 16 in 78% yield after
chromatography. In contrast to SudalaiÕs observation,
we found that the yield of 16 was only moderately
reduced (to 69%) if the manganese sulfate catalyst was
omitted. Cyclisation of amino bromide 16 to aziridine
17 was readily accomplished in near-quantitative yield
using K2CO3. Hence, this approach also represents a
simple two-step synthesis of N-sulfonyl aziridines.
7. Data for 2: colourless oil; Rf (1:1 petrol–Et2O) 0.7; IR
(CH2Cl2): 2957, 2856, 1320, 1158 cmꢀ1
;
1H NMR
(400 MHz, CDCl3): 7.85 (d, J = 1.0, 1H), 7.56 (d,
J = 8.0, 1H), 7.29 (dd, J = 8.0, 1.0, 1H), 2.99–2.45 (m,
2H), 2.42 (s, 3H), 1.78–1.74 (m, 4H), 1.43–1.33 (m, 2H),
1.25–1.17 (m, 2H), 0.45 (s, 9H); 13C NMR (100.6 MHz,
CDCl3): 142.3, 141.1, 140.5, 137.3, 129.6, 129.1, 39.6, 22.7,
21.6, 19.5, 1.1; MS (CI, NH3) m/z 324 [100%, (M+H)+],
308 (70); HRMS (CI, NH3) m/z calcd for C16H25NO2SiS
(M+H)+ 324.1452, found 324.1454.
8. Data for 4: colourless oil; Rf (1:1 petrol–Et2O) 0.7; IR
(CH2Cl2): 2928, 2856, 1320, 1246, 1161 cmꢀ1 1H NMR
;
(400 MHz, CDCl3): 7.87 (d, J = 8.0, 1H), 7.55 (br s, 1H),
7.28 (dd, J = 8.0, 1.0, 1H), 2.82–2.73 (m, 2H), 2.42 (s, 3H),
2.03–1.98 (m, 2H), 1.58–1.25 (m, 10H), 0.42 (s, 9H); 13C
NMR (100.6 MHz, CDCl3): 142.5, 141.2, 140.4, 137.2,
129.6, 129.0, 43.7, 26.4, 26.1, 25.2, 21.6, 1.1; MS (CI,
NH3) m/z 352 [100%, (M+H)+], 336 (40); HRMS (CI,
NH3) m/z calcd for C18H29NO2SiS (M+H)+ 352.1770,
found 352.1767.
9. Hodgson, D. M.; Buxton, T. J.; Cameron, I. D.; Gras, E.;
Kirton, E. H. M. Org. Biomol. Chem. 2003, 1, 4293.
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Lett. 1976, 2947; (c) Stemke, J. E.; Bond, F. T. Tetrahe-
dron Lett. 1975, 1815.
11. For reviews, see: (a) Dauban, P.; Dodd, R. H. Synlett
2003, 1571; (b) McCoull, W.; Davis, F. A. Synthesis 2000,
1347; (c) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994,
33, 599.
In summary, two straightforward routes to previously
unknown N-2,4,6-triisopropylbenzenesulfonyl aziridines
11–15 and 17 have been developed. These approaches
have utility for the preparation of Ônon-tosylÕ N-sulfonyl
aziridines. The usefulness of such aziridines in alkylli-
thium-mediated reactions will be reported in due course.
12. (a) Ittah, Y.; Sasson, Y.; Shabak, I.; Tsaroom, S.; Blum, J.
J. Org. Chem. 1978, 43, 4271; (b) Gololobov, Y. G.;

3256
J. Huang, P. OÕBrien / Tetrahedron Letters 46 (2005) 3253–3256
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Soc. 1994, 116, 2742.
cooling, CH2Cl2 (5 mL) was added and the solids were
removed by filtration through Celite. The filtrate was dried
(MgSO4) and evaporated under reduced pressure to give
the crude product. Purification by flash chromatography
on silica with petrol–EtOAc (4:1) as eluent gave hydroxy
sulfonamide (737 mg, 86%) as a white solid, mp 141–
143 °C; Rf (1:1 petrol–Et2O) 0.2; IR (CH2Cl2): 3496, 3250,
1314, 1150 cmꢀ1 1H NMR (400 MHz, CDCl3): 7.17 (s,
;
16. So¨dergren, M. J.; Alonso, D. A.; Bedekar, A. V.;
Andersson, P. G. Tetrahedron Lett. 1997, 38, 6897; See
also: Meprathu, B. V.; Diltz, S.; Walsh, P. J.; Protasiewicz,
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2H), 4.83 (d, J = 8.0, 1H), 4.41 (td, J = 5.0, 3.0, 1H), 4.11
(sept, J = 7.0, 2H), 4.04 (dd, J = 10.0, 5.0, 1H), 3.96 (dd,
J = 10.0, 5.0, 1H), 3.75–3.66 (m, 1H), 3.65 (dd, J = 10.0,
3.0, 1H), 3.52 (dd, J = 10.0, 3.0, 1H), 2.91 (sept, J = 7.0,
1H), 2.35 (br s, 1H), 1.29–1.25 (m, 18H); 13C NMR
(67.9 MHz, CDCl3): 153.3, 150.3, 132.3, 124.0, 73.6, 71.3,
61.1, 34.1, 29.7, 24.84, 24.76, 23.5; MS (CI, NH3) m/z 387
[25% (M+NH4)+], 370 [100 (M+H)+]; HRMS (CI, NH3)
m/z calcd for C19H31NO4S (M+H)+ 370.2058, found
370.2052. A solution of hydroxy sulfonamide (500 mg,
1.36 mmol) in CH2Cl2 (7.5 mL) was added dropwise to a
stirred solution of pyridine (0.47 mL, 6.78 mmol) and
mesyl chloride (0.45 mL, 6.78 mmol) in CH2Cl2 (7.5 mL)
at 0 °C under N2. After 20 min, the solution was heated at
reflux for 16 h. After cooling, the solution was washed
with brine (15 mL), dried (MgSO4) and evaporated under
reduced pressure to give the crude mesylate. Then, a
stirred mixture of the crude mesylate and K2CO3 (750 mg,
5.44 mmol) in MeCN (15 mL) was heated at 45 °C under
N2 for 16 h. After cooling, CH2Cl2 (15 mL) was added and
the organic solution was washed with water (20 mL) and
brine (20 mL), dried (MgSO4) and evaporated under
reduced pressure. Purification by flash chromatography
on silica with petrol–EtOAc (9:1) as eluent gave aziridine
13 (380 mg, 80%) as a white solid, mp 177–180 °C; Rf (1:1
petrol–Et2O) 0.6; IR(CH2Cl2): 3089, 2955, 1313,
`
17. Dauban, P.; Saniere, L.; Tarrade, A.; Dodd, R. H. J. Am.
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1152 cmꢀ1 1H NMR (400 MHz, CDCl3): 7.18 (s, 2H),
;
4.33 (sept, J = 7.0, 2H), 3.99 (d, J = 10.0, 1H), 3.71 (d,
J = 10.0, 1H), 3.68 (s, 2H), 2.91 (sept, J = 7.0, 1H), 1.26 (d,
J = 7.0, 18H); 13C NMR (100.6 MHz, CDCl3): 153.5,
150.9, 130.8, 123.8, 68.0, 44.6, 34.2, 29.6, 24.8, 23.5; MS
(CI, NH3) m/z 352 [100, (M+H)+]; HRMS (CI, NH3) m/z
calcd for C19H29NO3S (M+H)+ 352.1952, found 352.1946.
26. Hodgson, D. M.; Bogdan, S.; Miles, T. J.; Witherington,
J. Chem. Commun. 2004, 2234.
25. Representative procedure for two-step synthesis of aziridines
from epoxides. 6-(2,4,6-Triisopropyl)-3-oxo-6-azabicyclo-
[3.1.0]hexane 13: a stirred mixture of 2,5-dihydrofuran
epoxide (200 mg, 2.33 mmol), K2CO3 (32 mg, 0.23 mmol),
BnEt3N+Clꢀ (52 mg, 0.23 mmol) and 2,4,6-triisopropyl-
benzenesulfonamide (784 mg, 2.80 mmol) in dioxane
(1 mL) was heated at 90 °C under N2 for 96 h. After