The dinosyl group: A powerful activator for the regioselective alcoholysis of aziridines

Article abstract of DOI:10.1002/ejoc.201100358

The N-2,4-dinitrophenylsulfonyl group (dinosyl, DNs) was found to be an excellent choice for the N-activation of aziridines towards ring cleavage with primary, secondary, andsterically demanding tertiary alcohols. Alcoholysis does not need any additional

Full text of DOI:10.1002/ejoc.201100358

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100358
The Dinosyl Group: A Powerful Activator for the Regioselective Alcoholysis of
Aziridines
Christian Stanetty,*[a] Markus K. Blaukopf,[a] Bodo Lachmann,[b] and Christian R. Noe[b]
Keywords: Nitrogen heterocycles / Sulfonamides / Regioselectivity / Protecting groups / Solvolysis
The N-2,4-dinitrophenylsulfonyl group (dinosyl, DNs) was
found to be an excellent choice for the N-activation of azirid-
ines towards ring cleavage with primary, secondary, and
sterically demanding tertiary alcohols. Alcoholysis does not
need any additional catalyst and is regioselective for the less-
hindered position. No racemization in the aziridine formation
or cleavage step was observed, and the resulting DNs-sulfon-
amides can be deprotected quantitatively under mild condi-
tions.
Introduction
N-Activated aziridines are versatile synthetic intermedi-
ates[1–3] (e.g., several syntheses of Oseltamivir[4]) and easily
accessible from amino alcohols,[5–9] from carbene attack on
imines (aza-Darzens reaction),[10] or by direct aziridination
of alkenes.[11–14] Although aziridines are close analogs to
epoxides, substitution at the nitrogen atom offers an ad-
ditional handle for tuning their reactivity. Among a large
variety of possible activating groups, sulfonyl and in par-
ticular tosyl activation is widely used, for good reasons. N-
Ts-Aziridines exhibit relatively high reactivity towards ring
cleavage and they do not undergo side reactions at the acti-
vating group, which is observed with N-acyl- or carbamate-
type aziridines.[15,16] In our research towards new synthetic
ligands for the polyamine binding site of the NMDA recep-
tor[17–19] we encountered difficulties in the synthesis of com-
pound B, intended as a prototype for a combinatorial li-
brary of compounds with general structure A (Figure 1).
We considered nucleophilic ring opening of an activated
2-benzylaziridine with a corresponding alcohol intermedi-
ate as a short and elegant solution for this synthetic prob-
lem. While sufficiently activated aziridines undergo ring
cleavage with a variety of strong nucleophiles[16,20] easily,
weak nucleophiles like alcohols generally require either the
application of the corresponding alkoxide[15,21–25] or, more
frequently, the use of Lewis acids as catalysts.[26–32] Only
few sporadically mentioned examples of uncatalyzed
alcoholysis (MeOH, EtOH) of aziridines are re-
Figure 1. Envisioned synthetic strategy towards structure A.
ported.[15,21,25,33] Addressing this, we were striving for easily
accessible N-activated aziridines that are reactive enough to
undergo regioselective alcoholysis without any additional
activation. N-Ts-Aziridines were considered as an obvious
starting point, although ring cleavage with weak nucleo-
philes like alcohols in general still requires additional acti-
vation. However, several publications have underlined the
increased reactivity of 2- or 4-nitrophenylsulfonylaziridines
(Nosyl, Ns) with strong nucleophiles compared to Ts-azir-
idines,[21,34,35] and very recently the cleavage of Ns-azirid-
ines with phenolates was described.[36]
We were optimistic that the formal addition of a second
nitro group leading to 2,4-dinitrophenylsulfonylaziridines
(Dinosyl, DNs) should sufficiently activate the ring system
to allow catalyst-free alcoholysis under neutral conditions,
even with sterically demanding alcohols (Figure 2).
Furthermore, mild and high-yielding deprotection methods
based on S nucleophiles are already established for the
DNs-sulfonamide moiety.[37–39] This represents another ad-
vantage over Ts activation leading to sulfonamides, which
[a] Department of Chemistry,
University of Natural Resources and Life Sciences,
Muthgasse 18, 1190 Vienna, Austria
Fax: +43-47654-6059
are very stable compounds that require harsh deprotection
E-mail: Christian.stanetty@boku.ac.at
[b] Department of Medicinal Chemistry,
Faculty of Life Sciences, University of Vienna,
Althanstrasse 14, 1090 Vienna, Austria
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100358.
[40]
conditions like mischmetal/TiCl4
or SmI2/amine/
water[41] – to mention only the milder and more modern
methodologies – thus significantly limiting functional group
tolerance.
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A Powerful Activator for the Regioselective Alcoholysis of Aziridines
DNs-aziridine 7 and analogous Ns- and Ts-aziridines 11
and 10 were treated under identical conditions with a
variety of alcohols (primary to tertiary) with HPLC moni-
toring.
Representative results are compiled in Table 1, which
underline the superiority of the DNs activation with respect
to reactivity and site specificity. While DNs-aziridine 7 was
quickly cleaved by tBuOH in quantitative yield and without
formation of any byproducts, Ns-aziridine 11 needed a sub-
stantially longer reaction time. Conversion of Ts-aziridine
10 reached completion only with MeOH (18a,[44] within
8 d), whereas only incomplete formation of 19a/19b was
achieved with iPrOH. In all experiments the regioselectivity
was in clear favor of the normal product (1H NMR spectro-
scopic analysis of crude materials).
Figure 2. Comparison of the dinosyl, nosyl,-and tosyl groups.
Results and Discussion
An initial proof of concept experiment was designed uti-
lizing 2-benzylaziridine as an example, which was synthe-
sized with Ts, Ns, and DNs activation to allow comparison
of reactivity. Known N-Ts- and N-Ns-aziridines 10[41] and
11[42] were prepared starting from phenylalaninol (1)
through a simple one-pot procedure involving sulfonylation
with an excess amount of TsCl/NsCl followed by treatment
with aqueous KOH during workup.[42] For the preparation
of DNs-aziridine 7, a two-step protocol was established.
Initial equimolar N-dinosylation through an adapted tosyl-
ation protocol[43] to give sulfonamide 4 was followed by ring
closure with an excess amount of TsCl (Scheme 1). This
two-step process allows to save on the more-expensive
DNsCl.
Table 1. DNs activation vs. Ns and Ts activation.
Entry Substrate
Y
Alcohol
Target
Time [h]
a/b[a]
1
2
3
4
5
6
7
8
7
7
7
DNs
DNs
DNs
DNs
Ns
Ns
Ts
Ts
MeOH
BnOH
iPrOH
tBuOH
iPrOH
tBuOH
MeOH
iPrOH
12a
13a
14a
15a
16a
17a
18a
19a
7
7
7
7
72
95:5
92:8
96:4
7
Ͼ99:1[b]
94:6
11
11
10
10
96
Ͼ99:1[b]
85:15
93:7
192
incompl.[c]
1
[a] According to H NMR spectroscopic analysis of the crude ma-
terial. [b] No minor compound was observed by HPLC or 1H
NMR spectroscopy. [c] Stopped at 80% conversion after 22 d at
65 °C.
It is noteworthy that DNs-aziridine 7 has a lower solubil-
ity in the used alcohols than 10 and 11. In diluted solutions,
the superiority of DNs activation is even more pronounced,
which was demonstrated for alcoholysis of 7, 10, and 11 in
iPrOH at 0.1% concentration (Figure 3).
Scheme 1. Synthesis of DNs-, Ns-, and Ts-aziridines 7–11.
The first alcoholysis experiments were conducted with 2-
Bn-DNs-aziridine 7 in MeOH as potentially the most reac-
tive alcohol. Already at room temperature, conversion of
the starting material was observed at a low reaction rate.
By raising the temperature to 65 °C, fast and complete con-
version of 7 was achieved within several hours. The ob-
served ratio between the two possible regioisomers was in
clear favor of the product related to attack at the unsubsti-
tuted carbon center (i.e., 12a, normal product) and against
attack at the substituted carbon (i.e., 12b, abnormal prod-
uct). No other byproducts were observed. Consequently, Figure 3. Alcoholysis of 7, 10, and 11 in 0.1% dry iPrOH (HPLC).
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C. Stanetty, M. K. Blaukopf, B. Lachmann, C. R. Noe
SHORT COMMUNICATION
For a systematic evaluation of DNs activation, two ad-
ditional DNs-aziridines (2-isopropylaziridine 8 and parent
compound 9) were prepared analogously to 7 (Scheme 1).
To evaluate the influence of steric demand of the C2 sub-
stituent on the reaction rate and regioselectivity, 8 and 9
were treated with selected alcohols under the same condi-
tions (5%; 65 °C) as those used for 7 (Table 2), including
two examples from Table 1). In all experiments clean and
complete conversion was observed within a reasonable
amount of time and the regioselectivity for the normal
product was high (Table 2). However, two conclusions can
be drawn from the obtained data. First, the regioselectivity
towards the normal product increases with increasing steric
demand of the alcohol (both series). Second, aziridine 8 (R
= iPr) requires prolonged reaction times and shows slightly
lower regioselectivity than 2-benzylaziridine 7 independent
of the applied alcohol. Following this trend, aziridine 9
showed the fastest conversion, although this effect was only
observable under more dilute conditions due to the ex-
tremely low solubility of 9. For all reported experiments the
major regioisomers (normal products) were isolated in pure
form either by recrystallization or by silica gel chromatog-
raphy.
Figure 4. Chiral HPLC from racemic and enantiopure 23a.
Table 2. Comparative alcoholysis of DNs-aziridines 7, 8, and 9.
Scheme 2. Deprotection and proof of structure.
Entry Substrate
R
Alcohol Target Time [h]
a/b[a]
Deprotection was fast and high yielding using thiophenol
(2 equiv.) in DCM/DMF (99:1). The products were purified
by column chromatography, and the amino ethers were con-
verted into the hydrochloride salts and recrystallized to give
pure 28 and 29, which are known compounds. Their physi-
cal data were consistent with the literature,[45] thus support-
ing that also racemization did not occur during cleavage of
the DNs group.
1
2
3
4
5
6
7
8
9
7
7
8
8
8
8
9
9
9
9
Bn
Bn
iPr
iPr
iPr
iPr
H
H
H
H
MeOH
tBuOH
MeOH
BnOH
iPrOH
tBuOH
MeOH
BnOH
iPrOH
tBuOH
12a
15a
20a
21a
22a
23a
24
25
26
27
7
7
17
65
40
95:5
Ͼ99:1[b]
87:13
88:12
92:8
60
Ͼ99:1[b]
single isomers
Ͻ2[c]
Ͻ3[c]
Ͻ3[c]
Ͻ3[c]
10
1
[a] According to H NMR spectroscopic analysis of the crude ma-
terial. [b] No minor compound was observed by HPLC or 1H
NMR spectroscopy. [c] Due to very low solubility of 9, data is from
2 mg/mL experiment.
Conclusions
In conclusion, the N-2,4-dinitrophenylsulfonyl (Dinosyl,
DNs) group was found to be the most potent activator for
the uncatalyzed alcoholysis of aziridines up to date. The
DNs-Aziridines 7 and 8 used so far were prepared from newly prepared DNs-aziridines are shelf stable and readily
optically pure (S)-amino alcohols. In order to investigate available from the corresponding amino alcohols in
possible racemization during the formation and ring-cleav- enantiopure form. They undergo uncatalyzed alcoholysis
age process, smaller amounts of racemic (R/S)-7 and 8 were with primary, secondary, and tertiary alcohols, exhibiting
prepared and submitted to selected alcoholysis experiments. complete and byproduct-free conversion and high selectiv-
These racemic materials were then analyzed by chiral ity for the cleavage at the sterically less-hindered carbon
HPLC analysis. For compound 23a, baseline separation of center. It was shown that no racemization occurred during
the two enantiomers was achieved (Figure 4). To further aziridine formation and alcoholysis (chiral HPLC) under
support ring cleavage without racemization, DNs-sulfon- the conditions applied. The resulting DNs-sulfonamides are
amides 12a and 16a were selected for deprotection based on shelf stable compounds as well and allow further N-decora-
a literature protocol[39] (Scheme 2).
tion (alkylation,[37,38] Mitsunobu-type[37,38,46–49] or Pd-cata-
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A Powerful Activator for the Regioselective Alcoholysis of Aziridines
lyzed transformations[50,51]) with subsequent deprotec-
tion[37,46] or immediate deprotection[39] to the primary
amine, which was demonstrated for two selected examples.
Currently, the methodology of the DNs-mediated
alcoholysis is expanded towards more valuable alcohols
that cannot be applied as solvents in excess amounts. There-
fore, appropriate co-solvents are being evaluated and trans-
fer to microwave- and flow-conditions is under investiga-
tion. The successful implementation of this new methodol-
ogy to the initial research problem will be reported together
with the corresponding pharmacological data.
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Representative Procedure for the Alcoholysis of DNs-Aziridines 7–9
(S)-N-[1-Benzyl-2-(1-methylethoxy)ethyl]-2,4-dinitrophenylsulfon-
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1551, 1426, 1367, 1348, 1168, 1080, 912, 839, 816, 747 cm–1. 1H
NMR (200 MHz, CDCl3): δ = 1.07 (d, J = 6.1 Hz, 3 H, CH3), 1.09
(d, J = 6.1 Hz, 3 H, CH3), 2.77 (dd, J = 14.0, 8.4 Hz, 1 H, PhCHH),
2.95 (dd, J = 13.9, 6.2 Hz, 1 H, PhCHH), 3.30–3.62 (m, 3 H,
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CH3), 21.9 (q, CH3), 38.8 (t, PhCH2), 57.5 (d, NCH), 69.6 (t,
OCH2), 72.3 (d, OCH), 120.6 (d, DNs-C3), 126.6, 127.1 (2 d, PhC4,
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SHORT COMMUNICATION
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Received: March 14, 2011
Published Online: May 4, 2011
Minor changes have been made after publication in Early View.
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