Ring opening of a trisubstituted aziridine with amines: Regio- and stereoselective formation of substituted 1,2-diamines

Article abstract of DOI:10.1021/ol101584z

Figure Presented. The formation of substituted 1,2-diamines via nucleophilic ring opening of a trisubstituted ethynyl aziridine was performed with complete regio- and stereoselective control. Various amines with different levels of nucleophilicity were employed and gave similar results. The ring opening reaction is not limited to ethynyl aziridines, as other alkyl trisubstituted aziridines gave the same results. This method allows for the formation of unique vicinal diamines while providing a fully substituted carbon center in a stereoselective manner under mild conditions.

Full text of DOI:10.1021/ol101584z

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4244-4247
Ring Opening of a Trisubstituted
Aziridine With Amines: Regio- and
Stereoselective Formation of Substituted
1,2-Diamines
Brandon T. Kelley and Madeleine M. Joullie´*
Department of Chemistry, UniVersity of PennsylVania, 231 South 34th Street,
Philadelphia, PennsylVania 19104
mjoullie@sas.upenn.edu
Received July 8, 2010
ABSTRACT
The formation of substituted 1,2-diamines via nucleophilic ring opening of a trisubstituted ethynyl aziridine was performed with complete regio- and
stereoselective control. Various amines with different levels of nucleophilicity were employed and gave similar results. The ring opening reaction is
not limited to ethynyl aziridines, as other alkyl trisubstituted aziridines gave the same results. This method allows for the formation of unique vicinal
diamines while providing a fully substituted carbon center in a stereoselective manner under mild conditions.
Aziridines are useful intermediates in organic chemistry due
to their highly strained ring systems that allow for a wide
range of reactivity. Chiral nonracemic aziridines, in particu-
lar, are especially valuable in target syntheses.1 Nucleophilic
ring opening reactions are generally used to exploit this
reactivity; however, di-, tri-, and tetrasubstituted aziridines
exhibit diminished reactivity due to increased steric hin-
drance, and they also may suffer from poor regioselectivity
since both carbons on an aziridine are electrophilic. However,
acceptable levels of regio- and stereoselectivity can often
be achieved by varying the substituents or through the use
of Lewis acids.2 Very few non-Lewis acid-catalyzed inter-
molecular nucleophilic ring opening reactions exist to induce
preferential attack at the more substituted carbon of the
aziridine.3 Through the use of a Lewis acid, these reactions
benefit from quaternization of the nitrogen, but under basic
conditions there can be regioselective preference for attack
at the more substituted carbon. The use of phenol nucleo-
philes under mildly basic conditions has been thoroughly
investigated to generate tertiary alkyl-aryl ethers.4 However,
few investigations report the generation of a fully substituted
carbon through an aziridine ring opening reaction.5
Nucleophilic ring opening of aziridines with nitrogen
nucleophiles has attracted significant attention in the organic
community due to increasing interest of 1,2-diamine com-
pounds in synthetic and medicinal chemistry. (+)-CP-99,9946
is a potent and selective human neurokinin-1-P receptor
(3) (a) Lin, P.-y.; Bellos, K.; Stamm, H.; Onistschenko, A. Tetrahedron
1992, 48, 2359. (b) Maligres, P. E.; See, M. M.; Askin, D.; Reider, P. J.
Tetrahedron Lett. 1997, 38, 5253. (c) Sureshkumar, D.; Gunasundari, T.;
Ganesh, V.; Chandrasekaran, S. J. Org. Chem. 2007, 72, 2106.
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Li, P.; Forbeck, E. M.; Evans, C. D.; Joullie´, M. M. Org. Lett. 2006, 8,
5105. (c) Forbeck, E. M.; Evans, C. D.; Gilleran, J. A.; Li, P.; Joullie´, M. M.
J. Am. Chem. Soc. 2007, 129, 11463. (d) Grimley, J. S.; Sawayama, A. M.;
Tanaka, H.; Stohlmeywe, M. M.; Woiwode, T. F.; Wandless, T. J. Angew.
Chem., Int. Ed. 2007, 46, 8157. (e) Li, P.; Evans, C. D.; Wu, Y.; Cao, B.;
Hamel, E.; Joullie´, M. M. J. Am. Chem. Soc. 2008, 130, 2351.
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32. (b) Voronkov, M. V.; Kanamarlapudi, R. C.; Richardson, P. Tetrahedron
Lett. 2005, 46, 6907. (c) He, Z.; Yudin, A. K. Angew. Chem., Int. Ed. 2010,
49, 1607.
(1) (a) Hale, K. J.; Domostoj, M. M.; Tookes, D. A.; Irving, E.;
Scheinmann, F. Org. Lett. 2003, 5, 2927. (b) Smith, A. B., III; Kim, D.-S.
Org. Lett. 2004, 6, 1493. (c) Crawley, S. L.; Funk, R. L. Org. Lett. 2006,
8, 3995. (d) Liu, H.; Pattabiraman, V. R. Org. Lett. 2007, 9, 4211. (e)
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10.1021/ol101584z  2010 American Chemical Society
Published on Web 09/02/2010

antagonist. (+)-Zanamiriv, or Relenza, and (-)-Oseltamivir
phosphate, commonly known as Tamiflu, are both antiviral
drugs (Figure 1).7 (+)-Zanamiriv was the first neuraminidase
Scheme 1. Nucleophilic Addition of Alkynyl Aziridines
at the propargylic position (SN2P) due to activation from the
alkyne, but a mixture of regioisomeric products can be obtained
with SN2′P attack on the alkyne to give an allene or attack
occurring at the homopropargylic carbon (SN2H). However,
when a trisubstituted ethynyl aziridine is employed, ring opening
occurs at the more substituted carbon. Thus, fully substituted
carbons can be obtained in a stereoselective manner.
The ethynyl trisubstituted aziridine that we have used in
this study was the known aziridine 14c for its relative ease
of synthesis. In addition, this aziridine possesses two
functional group handles: the silyl ether and the alkyne,
which can be further manipulated.
Figure 1. Select biologically active 1,2-diamines.
inhibitor developed commercially and is used in the treatment and
prophylaxis of both Influenza A and B viruses. (-)-Oseltamiriv
phosphate, a prodrug, behaves in a similar manner.
The use of an aziridine is one of the most straightforward
methods to make vicinal diamines because upon nucleophilic
ring opening with a nitrogen nucleophile a 1,2-diamine is
generated. However, this reaction can sometimes require the
use of a Lewis acid. There are numerous reports in the
literature where metal triflates,8 silica gel,9 metal halides,10
ꢀ-CD,11 and organoboranes12 are used to catalyze nucleo-
philic ring opening with simple amine nucleophiles. Also,
when disubstituted aziridines were used, the regioselectivity
was diminished. There are very few examples in the literature
where a trisubstituted aziridine has been employed, and the
conditions required to effect opening were harsh with
nucleophilic attack occurring at the less substituted carbon.5a
To solve the issue of regioselectivity and the use of a Lewis
acid, a trisubstituted ethynyl aziridine was employed. Ring
opening of alkynyl aziridines can occur in three ways: SN2P,
SN2′P, SN2H (Scheme 1).13 The most common attack occurs
Cyclic and aliphatic amines (Table 1) are not reported to
participate in ring opening reactions with activated aziridines
Table 1. Nucleophile Ring Opening with Cyclic and Aliphatic
Aminesa
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Snider, R. M. J. Med. Chem. 1992, 35, 4913. (b) Rosen, T.; Seeger, T. F.;
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1927. (h) Oshitari, T.; Mandai, T. Synlett 2006, 3395. (i) Davis, F. A.; Zhang,
Y.; Li, D. Tetrahedron Lett. 2007, 48, 7838.
(7) (a) Smith, P. W.; Sollis, S. L.; Howes, P. D.; Cherry, P. C.; Starkey,
I. D.; Cobley, K. N.; Weston, H.; Scicinski, J.; Merritt, A.; Whittington,
A.; Wyatt, P.; Taylor, N.; Green, D.; Bethell, R.; Madar, S.; Fenton, R. J.;
Morley, P. J.; Pateman, T.; Beresford, A. J. Med. Chem. 1998, 41, 787. (b)
Smith, P. W.; Robinson, J. E.; Evans, D. N.; Sollis, S. L.; Howes, P. D.;
Trivedi, N.; Bethell, R. C. Bioorg. Med. Chem. Lett. 1999, 9, 601.
(8) (a) Meguro, M.; Asao, N.; Yamamoto, Y. Tetrahedron Lett. 1994,
35, 7395. (b) Meguro, M.; Yamamoto, Y. Heterocycles 1996, 43. (c) Sekar,
G.; Singh, V. K. J. Org. Chem. 1999, 64, 2537.
(9) Anand, R. V.; Pandey, G.; Singh, V. K. Tetrahedron Lett. 2002, 43,
3975.
(10) (a) Anaya de Parrodi, C.; Vazques, V.; Quintero, L.; Juarista, E.
Synth. Commun. 2001, 31, 3295. (b) Yadav, J. S.; Reddy, B. V. S.; Rao,
K. V.; Raj, K. S.; Prasad, A. R. Synthesis 2002, 2002, 1061. (c) Yadav,
J. S.; Reddy, B. S. V.; Jyothirmai, B. Synlett 2002, 2002, 53. (d) Swamy,
N. R.; Venkateswarlu, Y. Synth. Commun. 2003, 33, 547.
a Reaction condtions: aziridine (1 equiv), amine (2 equiv), PhCH3 (0.1 M).
b Isolated yield. c Same reaction conditions as footnote a with the following
exception: amine (6 equiv). d Same reaction conditions as footnote a with the
following exception: CH2Cl2/MeCN (1:1); (0.1 M). e Same reaction conditions
as footnote a with the following exception: amine (4 equiv).
(11) Reddy, M. A.; Reddy, L. R.; Bhanumathi, N.; Rao, K. R. Chem.
Lett. 2001, 246.
(12) (a) O’Neil, I. A.; Woolley, J. C.; Southern, J. M.; Hobbs, H.
Tetrahedron Lett. 2001, 42, 8243. (b) Watson, I. D. G.; Yudin, A. K. J.
Org. Chem. 2003, 68, 5160.
Org. Lett., Vol. 12, No. 19, 2010
4245

under Lewis acid catalysis,10 but the mild non-Lewis
acidic conditions described here gave excellent yields
(70%-quant) of the ring opened product. Cyclic amines
differed in their reaction times (0.5-3 h) with 1, but all
gave the desired product in excellent yields. Both primary
and secondary aliphatic amines were slower in their
respective reaction times, compared to cyclic amines, so
an excess of the amine was used to accelerate the reaction.
It is important to note that this had no adverse effects on
the outcome of the reaction, and the reaction was also
compatible with an alcohol functional group on the
nucleophile (entries 2 and 3).
at the nitrogen atom to give product 12a in 89% yield.
Protection of the phenol was not necessary.
Amino pyrazolone 13 and amino acid derivatives, either
as the free base or the hydrochloride salt, were also able
to act as nucleophiles toward the aziridine (Table 3). An
Table 3. Nucleophilic Ring Opening with Amino Pyrazolone
and Amino Acidsa
Aromatic amines (Table 2) also gave good yields of the
ring opened products. Both electron-deficient (entries 2
Table 2. Nucleophilic Ring Opening with Aromatic Aminesa
a Reaction conditions: aziridine (1 equiv), amine (2 equiv), CH2Cl2 (0.1
M). b Isolated yield. c Reaction conditions: amine (6 equiv), PhCH3 (0.1
M). d Salt was neutralized with equal molar amount of TEA and amine
salt. e Reaction conditions: amine (4 equiv), CH2Cl2/MeCN (1:1), at 55 °C.
f Same reaction conditions as footnote e with the following exception: amine
(6 equiv).
equimolar amount of triethylamine was used to neutralize
the hydrochloride salt, and the amino acids that had two
other groups that displayed no reactivity (entries 4 and
5), gave the 1,2-amine as the only product.
The regio- and stereochemistry of the products were
confirmed by X-ray analysis. From the ORTEP drawings
of 2a and 7a (Figure 2) it is clear that the nitrogen of the
amine is bonded to the more substituted carbon of the
former aziridine and that the reaction proceeded with
inversion.
a Reaction conditions: aziridine (1 equiv), aromatic amine (2 equiv),
PhCH3 (0.1 M). b Isolated yield. c Same reaction conditions as footnote a
with the following exception: reaction heated to 55 °C. d Same reaction
conditions as footnote a with the following exception: DMF (0.1 M).
The ring opening reaction with amines can be applied
to various types of trisubstituted aziridines (Table 4).
Aziridine 18, which is diastereomeric at the C2 position,
proceeded well, yielding only one regioisomer. This result
shows that the reaction is stereospecific with the ring
opening occurring with inversion. The reaction is ame-
and 3) and electron-rich (entry 5) aryl amines were
sufficiently nucleophilic to participate. Electron-deficient
aromatic amines did require mild heating, as a result of
their poor nucleophilicity, but even upon heating, the
regioselectivity was maintained. This is of interest because
non-nucleophilic N-containing compounds are known to
need a catalyst for conjugate addition to electron-poor
olefins,14 but, in our hands, a catalyst was not necessary.
4-Hydroxyaniline, under neutral conditions, reacted solely
(13) Chemla, F.; Ferreira, F. Curr. Org. Chem. 2002, 6, 539.
(14) Gimbert, C.; Moreno-Man˜as, M.; Pe´rez, E.; Vallribera, A. Tetra-
hedron 2007, 63, 8305.
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Org. Lett., Vol. 12, No. 19, 2010

Figure 2. ORTEP drawings of compounds 2a and 7a.
nable to other functional groups at C3, as aziridine 19
has a tert-butyl ester4c and 20 has the silyl ether
homologated by one carbon from the aziridine ring. The
regioselective ring opening of the homologated aziridine
(20) indicates that the functional group at C3 does not
play a role in directing the regioselectivity as the electronic
properties of the aziridine should change, but the same
regioselectivity is observed. The trisubstituted ethyl (21)
and allyl (22) aziridines also underwent ring opening,
albeit with a longer reaction time (3 days), thus showing
that the alkyne is not needed to direct the ring opening.
In conclusion, we have developed a method to make
substituted 1,2-diamines via nucleophilic ring opening of an
aziridine. The ring opening occurs exclusively at the more
hindered and electronically activated C2-carbon with inver-
sion of configuration.
Table 4. Nucleophilic Ring Opening of Various Trisubstituted
Aziridines with Pyrrolidinea
Acknowledgment. Financial support for this research
was provided by NSF (CHE-0951394). Financial support
for the departmental instrumentation was provided the
National Institutes of Health (1S10RR23444-1). We thank
Dr. George T. Furst, Dr. Rakesh Kohli, and Dr. Pat Carroll
of the University of Pennsylvania Spectroscopic Service
Center, for assistance in securing and interpreting high-
field NMR spectra, mass spectra, and X-ray data, respec-
tively.
Supporting Information Available: Spectroscopic data
and procedures for aziridines 20 and 22 and ring opened
products 2a-22a. The crystallographic data for aziridine
20 and ring opened products 2a and 7a. This material is
availablefreeofchargeviatheInternetathttp://pubs.acs.org.
a Reaction conditions: aziridine (1 equiv), pyrrolidine (2 equiv), PhCH3
(0.1 M). b Isolated yield.
OL101584Z
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