Synthesis of aziridines from alkenes and aryl azides with a reusable macrocyclic tetracarbene iron catalyst

Article abstract of DOI:10.1021/ja2090965

A new iron aziridination catalyst supported by a macrocyclic tetracarbene ligand has been synthesized. The catalyst, [(^Me,EtTC ^Ph)Fe(NCCH₃)₂](PF₆)₂, was synthesized from the tetraimidazoliu

Full text of DOI:10.1021/ja2090965

COMMUNICATION
pubs.acs.org/JACS
Synthesis of Aziridines from Alkenes and Aryl Azides with a Reusable
Macrocyclic Tetracarbene Iron Catalyst
S. Alan Cramer and David M. Jenkins*
Department of Chemistry, The University of Tennessee, Knoxville, Tennessee 37996-1600, United States
S Supporting Information
b
presents a new tetracarbene iron(II) complex that acts as a
ABSTRACT: A new iron aziridination catalyst supported
by a macrocyclic tetracarbene ligand has been synthesized.
The catalyst, [(Me,EtTCPh)Fe(NCCH3)2](PF6)2, was
synthesized from the tetraimidazolium precursor (Me,
EtTCPh)(I)4 and characterized by NMR spectroscopy, elec-
trospray ionization mass spectrometry, and single-crystal
X-ray diffraction. This iron complex catalyzes the aziridina-
tion of electron-donating aryl azides and a wide variety of
substituted aliphatic alkenes, including tetrasubstituted
ones, in a “C2 + N1” addition reaction. Finally, the catalyst
can be recovered and reused up to three additional times
without significant reduction in yield.
catalyst for aziridination with electron-donating and -withdrawing
aryl azides and a variety of substituted aliphatic alkenes. In addi-
tion, the catalyst is robust and can be recovered and reused for
multiple aziridination runs.
We previously reported the synthesis of the macrocyclic
tetraimidazolium (Me,EtTCPh)(I)4 (1), which can be deproto-
nated in the presence of divalent transition metals such as Pt to
prepare tetracarbene complexes.13 Unlike our previously re-
ported platinum complex [(Me,EtTCPh)Pt](PF6)2,13 an iron
complex could not be prepared via deprotonation with a weak
base. However, an in situ carbene strategy proved successful in
ligating the macrocyclic carbene to the iron center (Scheme 1).14
Lithium diisopropylamide deprotonates 1 at room temperature
in tetrahydrofuran (THF) in 5 min. Addition of a THF solution
of iron(II) iodide to this mixture followed by the addition of
thallium hexafluorophosphate in acetonitrile gives the octahedral
complex [(Me,EtTCPh)Fe(NCCH3)2](PF6)2 (2). Complex 2
constitutes a tetracarbene iron complex with easily accessible
coordination sites for catalytic reactions.15
espite the successful development of catalytic epoxidation
D
from alkenes over the last 30 years, the nitrogen analogue,
catalytic aziridination, has languished behind.1 Part of the reason
is the lack of nitrogenous variants of peroxides or dioxygen,
which are used to form epoxides in conjunction with alkenes.2
Since the aziridine functional group is found in natural products3
and also used in pharmaceuticals, broadening the scope of the
aziridination reaction is significant.4 Today, “C2 + N1” aziridina-
tion reactions that combine an alkene and a nitrene fragment
typically use iodoimine reagents such as PhIdNTs (Ts =
tosylate),1,2,5 chloramine-T,6 or tosyl azide7 as the nitrene
reagent. The disadvantage of these reactions is that the tosyl
group must be removed before the desired final substituent can
be placed on the ring, which reduces the atom economy and can
lead to ring degradation.1
Spectroscopic characterization of 2 was consistent with a
tetracarbene complex. Electrospray ionization mass spectrome-
try (ESI-MS) analysis of 2 showed a peak at m/z 506.2 associated
with [(Me,EtTCPh)Fe]2+ and another at m/z 1157.3 associated
with {[(Me,EtTCPh)Fe](PF6)}+, both with the correct isotopic
1
ratios. H NMR analysis demonstrated that the acetonitrile
ligands on 2 exchange in CD3CN solution, since 2 crystallized
from CH3CN solution (see below) showed peaks only for
unbound acetonitrile. 13C NMR analysis showed a resonance for
the carbene carbon at 196.65 ppm, consistent with other FeII
N-heterocyclic carbene (NHC) complexes.16 In addition, com-
plex 2 was found to be air-stable in the solid state.
Organic azides are an alternative to these current nitrene
reagents. Aryl azides can be easily synthesized in one step from
amines8 and are tolerant of a wide variety of functional groups.9
Finally, since the correct functionality can be installed on the
organic azide prior to catalysis, the use of organic azides instead
of PhIdNTs should improve the atom economy of these
reactions, thereby eliminating the step of removing the tosylate
group before installing the desired moiety on the nitrogen
atom.10 A catalytic “C2 + N1” aziridination that is successful with
a wide variety of substrates, both for alkenes and organic azides,
would be a significant advance in chemical synthesis.
A very limited number of catalytic ruthenium and iron por-
phyrin systems have been developed that perform “C2 + N1”
aziridination with organic azides, but they are limited to strongly
electron-withdrawing aryl azides (such as p-nitrophenyl azide)11
and/or styrene derivatives for the alkene.12 This communication
The X-ray crystal structure of 2 shows that the acetonitrile
ligands are bound in the solid state (Figure 1), giving an octa-
hedral complex. The average FeÀC bond distance is 2.01 Å,
which is slightly longer than that in the only other previously
reported FeII tetracarbene complex (1.96 Å).15 The trans
CÀFeÀC angles are 169.7 and 172.2°, demonstrating that there
is only a minimal distortion about the equatorial plane formed by
the macrocycle. Unlike four-coordinate Co and Ni complexes
bearing a 24-atom ringed macrocyclic tetracarbene ligand,17
has space for apical ligands to bind to the metal center.
2
To determine the best catalytic reaction conditions for
aziridination with an electron-donating aryl azide, a series of test
reactions were run with p-tolyl azide, 1-decene, and 2. The best
Received: September 27, 2011
Published: November 14, 2011
r
2011 American Chemical Society
19342
dx.doi.org/10.1021/ja2090965 J. Am. Chem. Soc. 2011, 133, 19342–19345
|

Journal of the American Chemical Society
COMMUNICATION
Scheme 1. Synthesis of [(Me,EtTCPh)Fe(NCCH3)2](PF6)2 (2)
Table 1. Aziridination Reactions with 2 as the Catalyst
Figure 1. X-ray crystal structure of [(Me,EtTCPh)Fe(NCCH3)2](PF6)2
(2). Red, blue, and gray ellipsoids (50% probability) represent Fe, N,
and C, respectively. Counteranions, solvent molecules, and H atoms
have been omitted for clarity.
Scheme 2. Sample Aziridination Reaction Catalyzed by 2
a Isolated yields. b Required chromatography.
respectively). The yield for 9-(p-tolyl)-9-azabicyclo[6.1.0]nonane
(entry 4) was almost quantitative (97% yield) with just 0.1%
catalyst loading. The reaction with trans-4-octene (entry 5) was
much slower and lower-yielding, probably because of the steric
bulk of the propyl groups. Furthermore, tri- and tetrasubstituted
alkenes such as 1-methylcyclohexane and 2,3-dimethyl-2-butene
(entries 6 and 7, respectively) were successful. The reaction with
2,3-dimethyl-2-butene was run at 70° because of its lower boiling
point, which may have contributed to the lower yield. In contrast,
Gallo’s group reported that trisubstituted alkenes did not react
with aryl azides and a RuÀporphyrin catalyst.12 Likewise, pre-
vious examples of similar tetrasubstituted aziridines have been
prepared only by photolysis of electron-withdrawing organic
azides to make the free nitrene prior to reaction with the alkene.18
In these two cases (entries 6 and 7), we have catalyzed the first
examples of “C2 + N1” aziridinations involving those classes of
alkenes and an aryl azide.
Since the catalyst 2 is insoluble in the reaction mixture at room
temperature, we believed that it could be recovered and reused
once the catalysis was complete. Since the reaction with cis-
cyclooctene (Table 1, entry 4) gave the best yield with low
catalyst loading, we repeated the reaction three times with the
same batch of catalyst. The results demonstrated that the catalyst
is reusable for this reaction with only a negligible decrease in yield
by the fourth run (see Table 2 in the SI). In addition to improv-
ing the atom economy of the reaction by using aryl azides, the
ability to reuse the catalyst without significant loss of yield is quite
beneficial.
results were obtained by using a 0.1 mol % catalyst loading of 2
with a 29-fold excess of alkene and no additional solvent
(Scheme 2). After 18 h at 90 °C, the reaction was complete
(all of the organic azide had reacted), and the reaction mixture
was cooled to room temperature and the catalyst removed by
filtration over Celite. Removal of the remaining organics under
reduced pressure followed by column chromatography yielded
pure 2-octyl-(p-tolyl)aziridine in 70% isolated yield (Table 1,
entry 1). The identity of the product was determined by 1H and
13C NMR spectroscopy, GCÀMS, and high-resolution MS [see
the Supporting Information (SI)]. Increasing the catalyst loading
to 1% (entry 2) improved the isolated yield to 82%. One
advantage of this methodology is the ease of catalyst separation
from the product, since 2 is insoluble in the reaction mixture at
room temperature.
To test the effectiveness of the catalytic system, additional
azides and alkenes were evaluated (Table 1). The catalyst success-
fully performed aziridination with 1-decene and electron-
withdrawing azides such as 1-azido-4-(trifluoromethyl)benzene
(entry 3) with a slightly higher yield than for previously reported RuÀ
porphyrin systems.11a Disubstituted alkenes, including cis- and
trans-substituted examples, were both successful (entries 4 and 5,
19343
dx.doi.org/10.1021/ja2090965 |J. Am. Chem. Soc. 2011, 133, 19342–19345

Journal of the American Chemical Society
COMMUNICATION
Scheme 3. Proposed Reaction Mechanism for the Aziridination
and are consistent with an Fe(IV) imide. These results showcase
a more direct approach to the formation of aziridines from readily
available substrates with improved atom economy.
’ ASSOCIATED CONTENT
S
Supporting Information. Complete experimental details
b
and X-ray crystallographic data (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
Jenkins@ion.chem.utk.edu
’ ACKNOWLEDGMENT
This research was funded in part by a Joint Research and
Development Grant from the State of Tennessee.
’ REFERENCES
(1) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.;
Wiley-VCH: Weinheim, Germany, 2006.
(2) Abu-Omar, M. M. Dalton Trans. 2011, 40, 3435.
(3) (a) Kasai, M.; Kono, M. Synlett 1992, 778. (b) Colandrea, V. J.;
Rajaraman, S.; Jimenez, L. S. Org. Lett. 2003, 5, 785. (c) Liu, R.; Herron,
S. R.; Fleming, S. A. J. Org. Chem. 2007, 72, 5587.
(4) (a) Loncaric, C.; Wulff, W. D. Org. Lett. 2001, 3, 3675.
(b) Sharma, P.; Kumar, A.; Upadhyay, S.; Sahu, V.; Singh, J. Eur. J.
Med. Chem. 2009, 44, 251. (c) Nemeikaite-Ceniene, A.; Sarlauskas, J.;
Anusevicius, Z.; Nivinskas, H.; Cenas, N. Arch. Biochem. Biophys. 2003,
416, 110.
Figure 2. Example ESI-MS spectrum measured for an acetonitrile solu-
tion of [(Me,EtTCPh)FedN(p-CF3ÀPh)](PF6)2 (a variant of 3). The
inset shows the highlight for the [(Me,EtTCPh)FedN(p-CF3ÀPh)]2+ ion.
(5) Fantauzzi, S.; Caselli, A.; Gallo, E. Dalton Trans. 2009, 5434.
(6) Aviv, I.; Gross, Z. Chem. Commun. 2007, 1987.
(7) (a) Omura, K.; Murakami, M.; Uchida, T.; Irie, R.; Katsuki, T.
Chem. Lett. 2003, 32, 354. (b) Leung, S. K.-Y.; Tsui, W.-M.; Huang, J.-S.;
Che, C.-M.; Liang, J.-L.; Zhu, N. J. Am. Chem. Soc. 2005, 127, 16629.
(c) Liu, Y.; Che, C.-M. Chem.—Eur. J. 2010, 16, 10494.
(8) Smith, P. A. S.; Brown, B. B. J. Am. Chem. Soc. 1951, 73, 2438.
(9) Li, Y.; Gao, L.-X.; Han, F.-S. Chem.—Eur. J. 2010, 16, 7969.
(10) Br€ase, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem.,
Int. Ed. 2005, 44, 5188.
(11) (a) Cenini, S.; Tollari, S.; Penoni, A.; Cereda, C. J. Mol. Catal. A:
Chem. 1999, 137, 135. (b) Fantauzzi, S.; Gallo, E.; Caselli, A.; Ragaini, F.;
Macchi, P.; Casati, N.; Cenini, S. Organometallics 2005, 24, 4710.
(c) Piangiolino, C.; Gallo, E.; Caselli, A.; Fantauzzi, S.; Ragaini, F.;
Cenini, S. Eur. J. Org. Chem. 2007, 743.
(12) Fantauzzi, S.; Gallo, E.; Caselli, A.; Piangiolino, C.; Ragaini, F.;
Cenini, S. Eur. J. Org. Chem. 2007, 6053.
(13) Bass, H. M.; Cramer, S. A.; Price, J. L.; Jenkins, D. M.
Organometallics 2010, 29, 3235.
(14) (a) Poyatos, M.; Mata, J. A.; Peris, E. Chem. Rev. 2009, 109
3677. (b) Peris, E. Top. Organomet. Chem. 2007, 21, 83.
(15) McGuinness, D. S.; Gibson, V. C.; Steed, J. W. Organometallics
2004, 23, 6288.
On the basis of previously studied aziridination reactions with
aryl azides, a potential intermediate in this reaction mechanism is
an iron(IV) imide, 3 (Scheme 3).5 Threefold-symmetric strong
σ-donor ligands have been demonstrated to stabilize iron imides
in the 2+,19 3+,20 and 4+21 oxidation states, but these complexes
do not react with alkenes to give aziridines. While we have not
been able to isolate [(Me,EtTCPh)FedNAr](PF6)2 (3), the ESI-
MS data are consistent with its formation. Addition of 1-azido-
4-(trifluoromethyl)benzene to a solution of 2 at room tempera-
ture in acetonitrile gave an ESI-MS spectrum with a peak at
m/z 585.7 associated with [(Me,EtTCPh)FedN(p-CF3Ph)]2+
(Figure 2).
In conclusion, we have synthesized a new iron aziridination
catalyst supported by a macrocyclic tetracarbene ligand.
This tetracarbene iron complex, [(Me,EtTCPh)Fe(NCCH3)2]
(PF6)2, was synthesized from the tetraimidazolium precursor
(
Me,EtTCPh)(I)4 and characterized by NMR spectroscopy, mass
spectrometry, and single-crystal X-ray diffraction. This catalyst
reacts with aryl azides and a wide variety of substituted aliphatic
alkenes to give aziridines in a “C2 + N1” addition reaction. We
were able to form 9-(p-tolyl)-9-azabicyclo[6.1.0]nonane in
nearly quantitative yield from cis-cyclooctene and p-tolyl azide.
In addition, we were able synthesize aziridines with 2,3-dimethyl-
2-butene, a tetrasubstituted alkene. These aliphatic alkenes are
generally considered to be more challenging reagents than the
styrene variants studied previously. Furthermore, the catalyst can
be recovered and reused up to three additional times with only a
nominal reduction in yield. To investigate the potential inter-
mediate in the reaction, mass spectrometry data were collected
(16) Kaufhold, O.; Hahn, F. E.; Pape, T.; Hepp, A. J. Organomet.
Chem. 2008, 693, 3435.
(17) (a) McKie, R.; Murphy, J. A.; Park, S. R.; Spicer, M. D.; Zhou,
S.-z. Angew. Chem., Int. Ed. 2007, 46, 6525. (b) Park, S. R.; Findlay, N. J.;
Garnier, J.; Zhou, S.; Spicer, M. D.; Murphy, J. A. Tetrahedron 2009,
65, 10756. (c) Findlay, N. J.; Park, S. R.; Schoenebeck, F.; Cahard, E.;
Zhou, S.-z.; Berlouis, L. E. A.; Spicer, M. D.; Tuttle, T.; Murphy, J. A.
J. Am. Chem. Soc. 2010, 132, 15462.
(18) (a) Soundararajan, N.; Platz, M. S. J. Org. Chem. 1990, 55, 2034.
(b) Poe, R.; Schnapp, K.; Young, M. J. T.; Grayzar, J.; Platz, M. S. J. Am.
Chem. Soc. 1992, 114, 5054.
19344
dx.doi.org/10.1021/ja2090965 |J. Am. Chem. Soc. 2011, 133, 19342–19345

Journal of the American Chemical Society
COMMUNICATION
(19) Brown, S. D.; Peters, J. C. J. Am. Chem. Soc. 2005, 127, 1913.
(20) (a) Brown, S. D.; Betley, T. A.; Peters, J. C. J. Am. Chem. Soc.
2003, 125, 322. (b) Betley, T. A.; Peters, J. C. J. Am. Chem. Soc. 2003,
125, 10782. (c) Mehn, M. P.; Brown, S. D.; Jenkins, D. M.; Peters, J. C.;
Que, L., Jr. Inorg. Chem. 2006, 45, 7417. (d) Lu, C. C.; Saouma, C. T.;
Day, M. W.; Peters, J. C. J. Am. Chem. Soc. 2007, 129, 4. (e) Scepaniak,
J. J.; Young, J. A.; Bontchev, R. P.; Smith, J. M. Angew. Chem., Int. Ed.
2009, 48, 3158.
(21) (a) Thomas, C. M.; Mankad, N. P.; Peters, J. C. J. Am. Chem.
Soc. 2006, 128, 4956. (b) Nieto, I.; Ding, F.; Bontchev, R. P.; Wang, H.;
Smith, J. M. J. Am. Chem. Soc. 2008, 130, 2716.
19345
dx.doi.org/10.1021/ja2090965 |J. Am. Chem. Soc. 2011, 133, 19342–19345