Aziridines in one step from hydantoins via Red-Al mediated ring-contraction

Article abstract of DOI:10.1016/j.tetlet.2011.06.092

We have developed a new method to synthesize aziridines from their corresponding hydantoins in one step using an excess of Red-Al overnight in refluxing toluene. This allows direct access to N-H aziridines without the need for protecting group strategies.

Full text of DOI:10.1016/j.tetlet.2011.06.092

Tetrahedron Letters 52 (2011) 4558–4561
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Tetrahedron Letters
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Aziridines in one step from hydantoins via Red-Al mediated ring-contraction
⇑
,
Fredrik von Kieseritzky a, , Johan Lindström a
a Medicinal Chemistry, CSNP iMed, AstraZeneca R&D Södertälje, 151 85 Södertälje, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a new method to synthesize aziridines from their corresponding hydantoins in one
step using an excess of Red-Al overnight in refluxing toluene. This allows direct access to N–H aziridines
without the need for protecting group strategies.
Received 15 May 2011
Revised 14 June 2011
Accepted 24 June 2011
Available online 2 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aziridines
Hydantoins
Ring-contraction
Reduction
Red-Al
Aziridines are of importance in organic chemistry as intermedi-
ates1 within heterocyclic chemistry, medicinal chemistry and total
synthesis. Indeed, there are registered drugs bearing the azirdine
motif.1c,2 Synthetic routes leading directly to unprotected aziri-
dines (3, R3 = H) are considered especially attractive,3 but occur
significantly less often in the literature than routes containing pro-
tection group strategies. As a recent example of development in
this area, Xu and co-workers described an improved Wenker reac-
tion, starting from vicinal amino alcohols to give N–H aziridines.4
During recent work, we were investigating the reduction of
hydantoins 1, which are easily obtained according to well-estab-
lished methods from either ketones5 or 1,2-diketones,6 in order
to obtain 2-imidazolidinones 2 to be used in further functionaliza-
tions. The transformation of 1 into 2 is well-known, and is typically
carried out using a strong reducing agent, such as lithium alumi-
num hydride (LAH), sometimes in combination with aluminum
chloride.7 Owing to its preferable safety margins and ease of han-
dling, we turned our attention to the commercial 3.5 M solution of
sodium bis(2-methoxyethoxy)aluminum hydride in toluene (Red-
Al), which has comparable, but not identical reducing properties
to LAH,8 and which has been used to furnish a 2-imidazolidinone
2 from a hydantoin 1 under conditions strikingly similar to ours.9
However in our hands, attempted reductions with Red-Al often
resulted in the appearance of a curious by-product in varying pro-
portions. Typically, longer reaction times, elevated temperatures
and the use of an excess of Red-Al seemed to favor the formation
of this by-product, which we came to identify as aziridine 3.
Intrigued by these findings, we proceeded to investigate the
possibilities of steering the reaction so that it would consistently
give aziridine as the major product. It should be noted that until
now transformation of hydantoin 1 into the corresponding aziri-
dine 3 is a three- or four-step endeavor, thereby making our new
protocol an attractive shortcut. We herein present our preliminary
results on a one-step Red-Al mediated reduction/ring-contraction
of hydantoins 1 to directly give aziridines 3, a reaction which to
the best of our knowledge has not been reported before. Unde-
manding access to compounds of this type (2,2-bis-functional N–
H aziridines), which occur sparsely in the literature,10 would
potentially be of benefit to chemists in the field.
We chose 5,5-diphenylhydantoin (phenytoin) as the first sub-
strate due to its ready availability and the fact that treatment with
Red-Al would directly provide N-H aziridine. Encouragingly, we
quickly discovered expedient conditions under which the desired
aziridine 3 could be isolated and subsequently characterized as
the major product (Table 1, entries 1–3).11
When one phenyl group was exchanged for a methyl group
(entries 4–7), however, the reaction was considerably slower. We
tentatively propose that this is due to a less stabilized carbo-cation
intermediate (vide infra). When the second phenyl group was
exchanged for a methyl group (R1 = CH3, R2 = CH3, R3 = H; not
depicted), the reaction did not produce any aziridine at all, even
after several days at reflux. When the imide-nitrogen of 1 was
substituted with a methyl or benzyl group (R3 = CH3 or R3 = Bn),
the reaction was much more rapid and could be performed in a
shorter time and at a lower temperature (entries 8–10). Under
the conditions described, aryl bromides and aryl chlorides were,
somewhat disappointingly, fully dehalogenated (not depicted),
despite literature claims of the inertness of Red-Al toward these.8
⇑
Corresponding author. Tel.: +46 70 7515353.
E-mail address: fredrik.vonkieseritzky@oncotargeting.com (F. von Kieseritzky).
Present address: OncoTargeting AB, Virdings Allé 32B, 754 50 Uppsala, Sweden.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.092

F. von Kieseritzky, J. Lindström / Tetrahedron Letters 52 (2011) 4558–4561
4559
Table 1
Conditions and product distribution via Scheme 1
Entry
Starting material 1
Red-Al (equiv)
Time (h)
Tempa (°C)
Yield of 2b
Yield of 3b
O
O
O
O
O
H
N
HN
NH
NH
NH
NH
HN
HN
HN
NH
O
1
3.5
1
100
(30%)
(70%)
O
H
N
HN
NH
O
2
4.0
20
Reflux
(70%)
(30%)
O
H
N
HN
NH
O
3
5.0
24
Reflux
68% isolated
(<20%)
O
O
H
N
HN
HN
NH
O
HN
4
5.0
5
Reflux
(0%)
57% isolated
O
H
N
NH
O
HN
NH
5
5.0
24
Reflux
(100%)
(0%)
O
O
H
N
HN
NH
HN
NH
O
6
5.0
1
reflux
O
O
O
(0%)
71% isolated
O
O
H
N
HN
NH
O
HN
NH
7
5.0
24
Reflux
O
(40%)
O
O
(60%)
15% isolated
32% isolated
(continued on next page)

4560
F. von Kieseritzky, J. Lindström / Tetrahedron Letters 52 (2011) 4558–4561
Table 1 (continued)
Entry
Starting material 1
Red-Al (equiv)
Time (h)
Tempa (°C)
Yield of 2b
Yield of 3b
O
O
O
O
N
HN
HN
HN
N
HN
N
N
N
O
8
5.0
6
55
O
O
O
O
O
(>50%)
33% isolated
O
N
N
HN
O
9
5.0
0.5
Reflux
O
O
(100%)
(0%)
O
Bn
N
Bn
Bn
N
HN
O
10
5.0
6
55
O
O
(40%)
48% isolated
a
External oil bath temperature. ‘Reflux’ was oil bath set to 120 °C.
Yields within parentheses were determined by LCMS or GCMS (at full conversion of the starting material).
b
1
O
O
R3
N
R3
red.
Red-Al (excess)
Conditions
R3
HN
R1
N
HN
R1
N
R1
R2
O
+
R2
O
R2
O
O
O
O
1
2 (expected)
3 (unexpected)
R3
R3
N
HN
R1
N
NH
O
R1
Scheme 1. Synthesis of aziridines 3 directly from hydantoins 1.
R2
R2
2
In conclusion, several hydantoins 1 on treatment with an excess
of Red-Al (typically 5 equiv) under reflux for 0.5–24 h, gave aziri-
dines 3 as the major products. Isolated yields were considerably
higher when an ion-exchange column was employed in the
work-up, as opposed to traditional silica column chromatography.
The exact mechanism for this reaction is at this stage not fully
understood. In all cases, 2-imidazolidinones 2 were detected as
intermediates, but at no point were imidazolidines observed,
which would be the case if the second carbonyl had been reduced.
When phenytoin (1, R1 = Ph, R2 = Ph, R3 = H) in a separate experi-
ment was treated with 10 equiv of DIBAL-H in toluene, under
otherwise identical conditions (reflux overnight), 2-imidazolidi-
none 2 was obtained as a single product, according to LCMS.
R3
N
R3
N
R2
R1
R2
R3
3
Scheme 2. A proposed mechanism.

F. von Kieseritzky, J. Lindström / Tetrahedron Letters 52 (2011) 4558–4561
4561
5873–5883; (c) Czopek, A.; Byrtus, H.; Kolaczkowski, M.; Pawlowski, M.;
Dybala, M.; Nowak, G.; Tatarczynska, E.; Wesolowska, A.; Chojnacka-Wojcik, E.
Eur. J. Med. Chem. 2010, 45, 1295–1303.
Subsequent addition of sodium ethoxide (excess) to the crude reac-
tion mixture together with additional heating did lead to some azi-
ridine formation (approx. 20%). This leads us to believe that Red-Al
serves firstly as a reducing agent and secondly as an alkoxide base.
Aluminum complexation at some stage of the reaction is also con-
ceivable. Thus we tentatively propose the following mechanism
(Scheme 2). The driving force for aziridine formation might be con-
sumption of the leaving group by Red-Al, pushing the equilibrium
toward product formation.
The scope, limitations, applicability, possible stereochemical
control and functional group tolerance of the herein reported reac-
tion are currently under investigation and the outcomes will be
communicated separately.
6. For recent examples, see: (a) Muccioli, G. G.; Poupaert, J. H.; Wouters, J.;
Norberg, B.; Poppitz, W.; Scriba, G. K. E.; Lambert, D. M. Tetrahedron 2003, 59,
1301–1307; (b) Riedner, J.; Vogel, P. Tetrahedron: Asymmetry 2004, 15, 2657–
2660; (c) Safari, J.; Naeimi, H.; Ghanbari, M. M.; Sabzi Fini, O. Russ. J. Org. Chem.
2009, 45, 477–479; (d) Hashmi, I. M.; Aslam, A.; Ali, S. K.; Ahmed, V.-U.; Ali, F. I.
Synth. Commun. 2010, 40, 2869–2874.
7. (a) Marshall, F. J. J. Am. Chem. Soc. 1956, 78, 3696–3697; (b) De la Cuesta, E.;
Ballesteros, P.; Trigo, G. G. Heterocycles 1981, 16, 1647–1650; (c) Reinhard, S.;
Schnur, R. C.; Belletire, J. L.; Peterson, M. J. J. Med. Chem. 1998, 31, 230–243; (d)
Reichard, G. A.; Stegone, C.; Paliwal, S.; Mergelsberg, I.; Majmundar, S.; Cheng,
T.; Tiberi, R.; McPhail, A. T.; Piwinski, J. J.; Shih, N.-Y. Org. Lett. 2003, 5, 4249–
4251.
8. Gugelchuk, M.; Silva, L. F., III; Vasconcelos, R. S.; Quintiliano, S. A. P. Sodium
bis(2-methoxyethoxy)aluminum hydride. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; John Wiley & Sons: New York, 2007.
doi:10.1002/047084289X.rs049.pub2. and references cited therein.
9. Marquez, V. E.; Twanmoh, L.-M.; Wood, H. B., Jr.; Driscoll, J. S. J. Org. Chem.
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Acknowledgments
10. A SciFinder search conducted on April 11, 2011 on 2,2-diphenylaziridines with
1- and 3-positions blocked from further substitution resulted in a hit list of
only six compounds.
Fernando Huerta, Jens Åhman, Alexander Munro and Colin Ray
are thanked for their most valuable theoretical input, and the latter
two are also gratefully acknowledged for proof-reading the manu-
script. Fanny Bjarnemark assisted with the HRMS analysis.
11. A representative experiment: 2,2-diphenylaziridine (3; R1 = Ph, R2 = Ph, R3 = H):
To a stirred slurry of 5,5-diphenylhydantoin (1 mmol, 254 mg) in dry toluene
(1 mL) under argon at rt was added Red-Al in toluene (3.5 M, 5 mmol, 1.43 mL)
over 20 min. CAUTION: excessive foaming, gas and heat evolution! When the
initial reaction had subsided, the temperature was slowly increased to reflux
(oil bath at 120 °C) and the mixture maintained at this temperature for 24 h.
The mixture was cooled to 0 °C and the reaction quenched by careful addition
of aqueous NaOH (2 M, 5 mL), followed by CH2Cl2 (5 mL). The resulting
biphasic mixture was stirred at rt for 1 h before the organic phase was
separated (Sorbent Phase Separator) and evaporated. The residue was slurried
in MeOH (5 mL) and added to a 6 cc PoraPak Rxn CX Retained Base column. The
column was flushed with methanol (10 mL), after which the product was
eluted with methanolic NH3 (7 M, 10 mL). The collected fraction was
evaporated to give oil, which under high vacuum gave a white solid. Yield:
132 mg (68%).1H NMR (500 MHz, DMSO-d6) d 1.96 (s, 2H), 3.26 (s, 1H), 7.10–
7.41 (m, 10H)13C NMR (125 MHz, CDCl3) d 29.1, 46.5, 126.4, 127.6, 128.0,
145.3MS (ES): m/z [M+H]+ 196.1 (100) HRMS: m/z calcd for C14H14N [M+H]+:
196.1126; found: 196.1129.
References and notes
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