A micellar iodide-catalyzed synthesis of unprotected aziridines from styrenes and ammonia

Article abstract of DOI:10.1002/anie.200704772

(Chemical Equation Presented) Aziridines from ammonia: Unprotected aziridines are formed from styrenes in one catalytic step. Ammonia is incorporated directly using an aqueous micellar solution containing bleach as oxidant and substoichiometric amounts of

Full text of DOI:10.1002/anie.200704772

Angewandte
Chemie
DOI: 10.1002/anie.200704772
Aziridination
A Micellar Iodide-Catalyzed Synthesis of Unprotected Aziridines from
Styrenes and Ammonia**
Csaba Varszegi, Martin Ernst, Frederik van Laar, Bert F. Sels, Ekkehard Schwab, and
Dirk E. De Vos*
Aziridines are useful intermediates and pharmaceuticals.
Therefore there is a growing need for their environmentally
benign production.[1] Many olefin aziridinations rely on the
addition of nitrenes, which are generated by either thermal or
photochemical azide decomposition or are formed in situ
from tosylimino phenyliodinane, sulfonyl azides, or chlor-
amine-T using metal catalysts.[2] Halogens have also been
proposed as catalysts in combination with chloramine-T,
which is both a strong nucleophile and an oxidant.[3] In this
route, pioneered by Sharpless[3a] and Komatsu,[3b] reaction of
the oxidized halogen (“Br+”, “I+”) with the double bond is
followed by nucleophilic attack of chloramine-T and cycliza-
tion. The main drawback of all previous reactions is the use of
complex nitrogen-containing sources, which lead to N-sub-
stituted aziridines that require a subsequent deprotection
step.[4] Direct routes from olefins to unprotected aziridines
have only been described for a,b-unsaturated carbonyl
compounds and often require complex NH donors.[5]
Ammonia, which is the most obvious nucleophilic nitro-
gen source, has barely been considered in aziridinations. Only
the Gabriel–Cromwell aziridination uses NH3, but the scope
of this reaction is restricted to a,b-unsaturated a-halocar-
bonyl compounds.[5a,b] The direct incorporation of ammonia
into olefins is therefore justly recognized as a top priority for
catalysis.[6]
Herein we describe the first successful catalytic synthesis
of unprotected aziridines from NH3 and simple olefins. Our
method resembles a halide-assisted epoxidation, in which the
olefin is attacked by “Br+” cation, which is formed in situ by
oxidation of bromide, and then by water as the oxygen
source.[7] The resulting bromohydrin is then cyclized to the
epoxide. As will be shown, a similar concept can be applied
for the N-functionalization of styrenes by replacing water
with ammonia as the nucleophile: unprotected aziridines are
formed in a one-pot, micellar system using iodide as a catalyst,
aqueous bleach as an oxidant, and ammonia as the nitrogen
source [Eq. (1)].
Styrene was used as a model olefin in our reactions. The
expected product, 2-phenylaziridine, was synthesized sepa-
rately as a reference by cyclization of 2-bromo-2-phenylethyl-
amine.[8] Initial noncatalytic experiments were carried out
with pre-oxidized halonium sources (“X+”), such as N-
halosuccinimide (NXS) or X2 (X = Br, I). The reactions
were performed under water-free conditions with NH3 in
dioxane and one equivalent of halonium ion in the presence
of an additional base. Remarkably, ammonia was incorpo-
rated to give 2-phenylaziridine in a yield of around 10%
(Table 1, entries 1–3). While the use of NBS led mostly to
bromohydrin and dibrominated by-products, the selectivities
were encouragingly high with NIS or I2 (about 99%).
Subsequent reactions were therefore performed with iodo-
nium ion.
Table 1: Aziridination of styrene with ammonia using NXSor I in the
2
absence of surfactants.[a]
Entry
Solvent
“X+” source
Yield [%][b]
1
dioxane
NBS2 (7)
2
dioxane
NIS10 (99)
3
dioxane
I2
6 (99)
4[c]
5[c]
6[d]
dioxane/H2O (9:1)
dioxane/H2O (9:1)
dioxane/H2O (9:1)
NIS11 (99)
I2
I2
15 (99)
8 (98)
[a] Reaction conditions: styrene (0.5 mmol), NBS/NIS (0.5 mmol) or I2
(0.5 mmol), NaOH (0.02 wt%), dioxane (4 mL), NH3 in dioxane (1 mL,
0.5m), room temperature, 2 h. [b] Selectivity given in brackets. [c] 10%
(0.5 mL) H2O added. [d] Reaction with 0.5 mL of 25% aqueous NH3
(approx. 13 equiv) in the absence of NaOH.
Addition of water to reactions with I2 in dioxane increased
the aziridine yield to 15%, without loss of selectivity (Table 1,
entry 5). Moreover, no additional base was required when
excess aqueous ammonia was used (Table 1, entry 6). As long
as sufficiently alkaline conditions are maintained, ammonia
seems to be a more competitive nucleophile than water or
hydroxide ions. The high selectivity of the reaction reflects the
stability of aziridines towards the alkaline conditions.
[*] C. Varszegi, Prof. Dr. B. F. Sels, Prof. Dr. D. E. De Vos
Centre for Surface Chemistry and Catalysis
Katholieke Universiteit Leuven
Kasteelpark Arenberg 23, 3001 Leuven (Belgium)
Fax: (+32)16-321-998
Instead of using a solvent, we decided to try to improve
the mixing of aqueous ammonia and the apolar olefin in a
micellar system. Table 2illustrates the promoting effect of
surfactants on the aziridination of styrene. With non-ionic
surfactants, such as ethoxylated fatty alcohols or sorbitan
esters, the yield of 2-phenylaziridine increased remarkably. In
E-mail: dirk.devos@biw.kuleuven.be
Dr. M. Ernst, Dr. F. van Laar, Dr. E. Schwab
BASF AG, Chemicals Research and Engineering
67056 Ludwigshafen (Germany)
[**] D. E. De Vos is grateful to BASF AG (Ludwigshafen) for supporting
this research.
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Table 2: Aziridination of styrene with ammonia using I2 or iodide/
NaOCl.[a]
Entry
“I+” source (equiv)
NaOCl solution [mL]
Yield [%][b]
1
2
3
I2 (1.0)
I2 (2.0)
–
I2 (1.0)
NH4I (1.0)
–
–
–
–
–
0.4
0.4
67 (99)
88 (98)
0
<0.1
66 (99)
0
4[c]
5
6
[a] Reaction conditions: styrene (0.5 mmol), I2 (0.5 mmol) or NH4I
(0.5 mmol)/10–13% aqueous NaOCl (0.4 mL, 40 mL every 5 min), 25%
aqueous NH3 (5 mL), Brij 35 (2 wt%), room temperature, 2 h. [b] Selec-
tivity given in brackets. [c] Reaction without Brij 35.
Figure 1. 2-Phenylaziridine yield with 1.3m NH3 as a function of NH4I
concentration. Reactions were carried out according to the general
conditions described in Table 2 (entry 5).
a typical reaction, aqueous ammonia (25%) was added to I2
(0.1m) and Brij 35 (2wt%). [9] After styrene addition (0.1m),
the reaction yielded 67% of 2-phenylaziridine with 99%
selectivity after 2 h at 298 K (Table 2, entry 1). The yield even
increased to 88% with an excess of I2 (Table 2, entry 2). No
aziridine was detected in an experiment performed without I2
(Table 2, entry 3), and only a trace of product was formed in
the absence of a surfactant (Table 2, entry 4). A gradual
increase of the Brij 35 concentration led to a boost in aziridine
yield above 0.2wt% of surfactant. This concentration corre-
sponds to the critical micelle concentration in the mixture (as
confirmed by dynamic light scattering (DLS) measurements)
and hence leads to a dramatic increase of the interfacial area.
No epoxide was formed, and traces of benzaldehyde (< 2%
selectivity) are the only side-product.
While previous experiments employed pre-oxidized iodo-
nium sources, it is more desirable to use cheaper iodide salts
and an oxidant. However, O2 is not suitable as an oxidant as
the use of NH3 creates alkaline conditions and O2 only
oxidizes iodide under acidic conditions. H2O2 oxidizes iodide
under neutral or slightly alkaline conditions but it is unstable
at high pH values, especially in the presence of halides.[10]
However, 2-phenylaziridine was formed in 66% yield
(approximately 99% selectivity) when 0.4 mL of a 10–13%
NaOCl solution was added gradually to a solution of
ammonium iodide (0.1m) and styrene (0.1m) in 25% aqueous
NH3 containing 2wt% Brij 35 (Table 2, entry 5). This yield is
the same as that achieved under similar conditions with one
equivalent of I2. The degree of alkalinity in the micellar
solution is also crucial as, while NH3 needs alkaline conditions
to act as a nucleophile, iodide oxidation is generally faster at
low pH values.[11] When NaI was used instead of NH4I, less
aziridine was formed. The aziridine yield varied only slightly
(63–77%) when using NH3 concentrations of between 25%
(ca. 13m) and 1.3m at 0.1m NH4I. At a fixed NH3 concen-
tration (1.3m), a maximum 2-phenylaziridine yield of 90%
was obtained using 40 mol% of NH4I with respect to the
olefin (Figure 1). Importantly, iodide is applied in sub-
stoichiometric amounts, thereby implying that it is re-oxidized
repeatedly by hypochlorite.
Table 3: Scope of the catalytic aziridination with aqueous NH3 in the
presence of iodide.[a]
Entry
1
Olefin
Aziridine
Yield [%][b]
84 (99)
2
3
4
5
75 (99)
56 (99)
74 (99)
71 (99)
6
30 (98)
7
8
74 (99)
70 (99)
9
92 (99)
56 (98)
10
[a] Reaction conditions: olefin (0.5 mmol), NH4I (50 mol%), 10–13%
aqueous NaOCl (0.4 mL, 40 mL every 5 min), Brij 35 (2 wt%), H2O
(4.5 mL), 25% aqueous NH3 (0.5 mL), room temperature, 2 h. [b] Selec-
tivity given in brackets.
(92%) than styrene itself, while b-methylstyrene provided a
lower yield (56%; Table 3, entries 1, 9, and 10). This situation
suggests that the electrophilic iodonium species attacks the
olefin and that the positive charge on the a-carbon atom in
the reaction of a-methylstyrene is stabilized to a greater
extent than in the other two reactions.
Various olefins were tested to evaluate the reaction scope
(Table 3). Moderate to excellent yields were obtained with
ring-substituted styrenes, including substrates containing
electron-donating or -withdrawing groups (Table 3,
entries 2–8). a-Methylstyrene gave a higher aziridine yield
Aziridine yields were much lower for aliphatic olefins
with various substitution patterns, despite varying the time,
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Aziridination using iodide/NaOCl: Brij 35 (90 mg, 2wt%) and
temperature, and reactant and surfactant concentrations. A
likely explanation for this is that the iodonium ion dispropor-
tionates into iodide and iodate in alkaline solutions if its
reaction with the olefins is slow.[12] Indeed, it is known that
aliphatic olefins react less readily than styrenes with iodonium
ions,[3e,f] although iodonium ions can be activated by Lewis
acids in an approach that is currently being elaborated.[13]
Nevertheless, the selective formation of small amounts of
unprotected aziridines from aliphatic olefins proves that the
reaction is, in principle, possible.
NH4I (37 mg, 0.05m, 0.5 equiv) were dissolved in water (4.5 mL).
After addition of styrene (57 mL, 0.1m) and 25% aqueous NH3
(0.5 mL; approx. 1.3m), NaOCl (0.4 mL of a 10–13% aqueous
solution) was added gradually (40 mL every 5 min). After stirring for
2h at 298 K, the reaction mixture was carefully extracted with diethyl
ether. The organic layer was dried with anhydrous MgSO4 and
analyzed by GC. The identity of 2-phenylaziridine was also confirmed
by the formation of 2-chloro-2-phenylethylamine after ring-opening
with aqueous HCl. EI-MS data for 2-phenylaziridine: m/z (%): 119
(10), 118 (100), 117 (14), 91 (22), 89 (12), 77 (5), 63 (9), 51 (7), 36 (6).
A proposal for a full reaction cycle is depicted in
Scheme 1. Support for catalysis by the iodonium ion comes
from the observation that no aziridine is formed in the
Received: October 15, 2007
Published online: January 18, 2008
Keywords: alkenes · ammonia · aziridines · iodide · micelles
.
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Experimental Section
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À
À
ethylene
lauryl
ether,
CH3(CH2)11 O(CH2CH2O)23 H,
1198 gmolÀ1) is a registered trademark of ICI Americas, Inc.
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