Iron-mediated intermolecular N-group transfer chemistry with olefinic substrates

Article abstract of DOI:10.1039/c3sc52533c

The dipyrrinato iron catalyst reacts with organic azides to generate a reactive, high-spin imido radical intermediate, distinct from nitrenoid or imido species commonly observed with low-spin transition metal complexes. The unique electronic structure of

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EDGE ARTICLE
Iron-mediated Intermolecular N-Group Transfer Chemistry with
Olefinic Substrates
Elisabeth T. Hennessy, Richard Y. Liu, Diana Iovan, Ryan A. Duncan, and Theodore A. Betley*
Received (in XXX, XXX) XthXXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 2011
5
DOI: 10.1039/b000000x
The dipyrrinato iron catalyst reacts with organic azides to generate a reactive, high-spin imido radical
intermediate, distinct from nitrenoid or imido species commonly observed with low-spin transition metal
complexes. The unique electronic structure of the putative group-transfer intermediate dictates the
chemoselectivity for intermolecular nitrene transfer. The mechanism of nitrene group transfer was probed
10 via amination and aziridination of para-substituted toluene and styrene substrates, respectively. The
Hammett analysis of both catalytic amination and aziridination reactions indicate the rate of nitrene
transfer is enhanced with functional groups capable of delocalizing spin. Intermolecular amination
reactions with olefinic substrates bearing allylic C–H bonds give rise to exclusive allylic amination with
no apparent aziridination products. Amination of substrates containing terminal olefins give rise
15 exclusively to allylic C–H bond abstraction, C–N recombination occurring at the terminal C with
transposition of the double bond. A similar reaction is observed with cis-β-methylstyrene where exclusive
amination of the allylic position is observed with isomerization of the olefin to the trans-configuration.
The high levels of chemoselectivity are attributed to the high-spin electronic configuration of the reactive
imido radical intermediate, while the steric demands of the ligand enforce regioselective amination at the
20 terminal position of linear α-olefins.
nitrenoid intermediate (Figure 1b) in a concerted asynchronous
Introduction
mechanism.4
The prevalence of nitrogen functionalities in bioactive
molecules and materials has inspired the development of
numerous techniques for direct C–H bond amination. Transition-
25 metal catalyzed approaches1,2 offer a unique opportunity to
control the reactivity and selectivity of nitrene transfer. Careful
modulation of metal identity and ligand design can drastically
dictate the degree of bonding and electronic structure of the
metal-bound nitrene intermediates, ranging from simple oxidant-
30 metal adducts, to singlet and triplet stabilized nitrenoids, to
closed- and open-shell metal imidos (Figure 1). In particular,
metal stabilized nitrene transfer using noble metal catalysts,
specifically dirhodium,3 have been successfully applied in the
context of complex molecule synthesis. These well-behaved
35 catalysts have been extensively studied and are believed to
transfer functionality to both olefins and C–H bonds via a singlet
Despite the success of the dirhodium class of catalysts, a
40 renewed interest in late, first-row transition metal nitrenoid
catalysts, composed of copper,5–9cobalt,10,11 manganese,12–15
nickel,16,17 and iron12,18,19 has emerged. Their high d-electron
count and compressed ligand fields create a unique opportunity
for ancillary ligands to strongly influence the bonding
45 interactions between the nitrene moiety and the metal center. For
instance, the binding of strong field ligands destabilizes metal-
ligand antibonding orbitals and promotes low-spin electronic
configurations. Similar to their second- and third-row congeners,
closed-shell first-row transition metals will interact with nitrene
50 precursors to generate either a metal-bound singlet nitrenoid
(Figure 1b) or a covalently-bound metal imido (Figure 1c).
Alternatively, weak field ligand environments favor population of
Figure 1. Available reactive intermediates and product distributions for transition metal-based nitrogen group transfer chemistry with
55 olefinic substrates.
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ligand, and nitrene unit bears on reactivity and selectivity through
30 the isolation of the reactive metal-nitrenoid intermediate. We
previously reported20 intermolecular amination and aziridination
with aryl and alkyl azides using ferrous dipyrrinato complexes
t
(RL)FeCl(Et2O) [R = 2,4,6-Ph3C6H2 (Ar), 1-adamantyl (1), Bu
(2)] (Figure 2). Isolation and characterization of the radical
35 imido complex (ArL)FeCl(N(p-tBuC6H4)), wherein a high-spin
Fe(III) (S = 5/2) is antiferromagnetically coupled to the imido
radical (S = –1/2) to give an overall high-spin ground state (S = 2),
suggests a similar electronic structure for the proposed iron-
bound imido radical 3. Such an electronic structure places
40 significant radical character on both the FeN  and  bond
vectors, facilitating both H-atom abstraction and radical
recombination pathways. In this report, we have explored the
implications of the reactive intermediate’s unique electronic
structure on both the reaction mechanism and chemoselectivity of
45 intermolecular N-group transfer. We have established the
catalyst’s strong preference for allylic amination over
aziridination with aliphatic olefin substrates. Additionally, we
report on the functionalization of α-olefins to linear allylic
amines with outstanding regioselectivity.
Figure 2. Ferrous dipyrrinato complexes 1 and 2 are competent
catalysts for benzylic and allylic amination and styrene
aziridination, operating through the proposed reactive imido
radical intermediate 3.
5
metal-ligand antibonding orbitals and high-spin electronic
configurations. Communication between highly paramagnetic
metal centers and N-group transfer reagents has the potential to
translate radical character directly to the N-atom or along the
10 metal-nitrogen bond vector (Figure 1d or 1e).
Given the range of accessible metal-nitrene electronic
configurations, it is not surprising that the established catalysts
exhibit dramatically different reactivity, particularly when
considering the functionalization of olefinic substrates (Figure 1).
15 For instance, exposure of a macrocyclic tetracarbene-ligated Fe-
complex exclusively catalyzes the aziridination of aliphatic
50 Results and Discussion
A. Benzylic Amination and Aziridination
olefins,19 while
a phthalocyaninato Fe-complex facilitates
We previously reported20 that 1 catalyzes nitrogen group
transfer to styrene and toluene with 1-azidoadamantane, resulting
in the formation of 1-adamantyl-2-phenylazidridine (85% yield
55 and benzyladamantylamine (60% yield) respectively. In attempts
to expand the substrate scope, a series of para-substituted
toluenes and styrenes were subjected to 1 (5-10 mol%) and 1-
azidoadamantane (Table 1). All substrates successfully
underwent the desired intermolecular nitrogen group transfer,
60 demonstrating that catalysis is amenable to substrates with both
electron withdrawing and donating groups and ethereal C–H
bonds (Table 1, entries 4 and 8). The yield for aziridination at
preferential intramolecular allylic C–H amination,18 and an Fe-
porphyrin complex generates mixtures of both aziridine and
20 allylic amine products.12 While each of these complexes is
confined to a tetragonal field by tetra-chelating macrocyclic
ligands, the ligand field strength, metal oxidation state, and
nitrene source vary and are likely responsible for the changes in
chemoselectivity. However, in each of these examples, the
25 structure and electronic configuration of the reactive intermediate
are only posited, as is the case for nearly all C–H amination
catalysts.
Ideally, one would like to probe the influence a given metal,
Table 1. Scope of N-group transfer.
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Figure 3. (a) Linear-free-energy correlation of log kR vs σ+ for the reactions of 1 with AdN3 (1 equiv) and a series of para-substituted
toluenes (red) and styrenes (blue). (b) Linear-free-energy correlation of log kR vs (σmb, σJJ) for the reactions of 1 with AdN3 (1 equiv)
and a series of para-substituted toluenes (red) and styrenes (blue). For the amination reaction, ρmb, ρJJ = 0.086, 0.24. For the aziridination
reaction, ρmb, ρJJ = -0.0073, 0.18.
5
room temperature are overall higher than that for amination (75-
85% vs. 46–60%); this trend correlates with the lower propensity
for the aziridine product to bind to the catalyst and retard the rate
of catalysis. Amination yields can be improved upon heating to
10 60 ºC (entry 1) to encourage product dissociation from the
electrophilic Fe center.
lack of isomerization is less definitive. Either the reaction is
occurring via a concerted mechanism or a two-step mechanism
50 with radical recombination out-competing C–C bond rotation.
The adamantyl units on both the dipyrrin and imido generate a
very narrow cleft in which the substrate can orient itself. The
crowded environment likely impedes C–C bond rotation and
renders radical recombination more facile. However, we cannot
Styrene aziridination is amenable to a variety of organoazides.
Exposure of 1 and styrene to 5 equivalents of tert-butyl azide
(Table 1, entry 10) resulted in the corresponding aziridine in
15 good yield (86%). The yield for 1-azidobutane drops significantly
(entry 11, 53%), likely due to imide decomposition pathways. In
general, primary and secondary alkyl azides rapidly react with 1
to generate the imide intermediate, but are then prone to undergo
either intramolecular C–H amination to yield N-heterocycles or
20 α-hydrogen abstraction to yield linear imines21 rather than
intermolecular group transfer chemistry. Copper9 and iridium22
complexes also generate imines upon exposure to primary and
secondary azides through nitrenoid intermediates. Aryl azides are
also compatible with the aziridination reaction. Para-substitution
25 of the aryl ring eliminates a bimolecular imido decomposition
pathway, and noticeably improves the yield of aziridination
(entry 12 vs. entry 13). Unfortunately application of either
sulfonyl (entry 14) or silyl (entry 15) azides does not result in
productive N-group transfer but rather catalyst decomposition
30 through unproductive H-atom abstraction or ligand amination
pathways, respectively.
55
Scheme 1. Aziridination of cis-deutero-styrene occurs without
rotation about the C1–C2 bond, generating only cis-1-adamantyl-
2-deutero-3-phenylaziridine. The coupling constant (6.3 Hz)
between the vicinal hydrogens is indicative of a cis orientation.
60 rule out
a concerted aziridination mechanism with this
experiment alone.
The electronic nature of the transition state was further studied
by conducting a Hammett analysis of both the aziridination and
amination reactions. The relative rates of catalytic aziridination
65 and amination of a series of para-substituted styrenes and
toluenes using 1 with one equivalent of 1-azidoadamantane were
determined through pairwise competition experiments. Equimolar
mixtures of styrene or toluene and a para-substituted styrene or
toluene derivative, respectively, were treated with 1-
70 azidoadamantane in the presence of a stoichiometric amount of
the Fe complex 1. The ratios of the resulting aziridines and
B. Mechanism of Benzylic Amination and Aziridination
Reactions
1
benzylamines were determined by GC/MS analysis and by H
NMR integration of the spectra taken on unpurified material. The
results are summarized in Table 1.
We previously reported that the mechanism of catalytic
35 toluene amination and styrene aziridination proceeds via one-
electron pathways, largely based on the non-classical KIE value
(12.8) for toluene amination and the high-spin electronic
structure of the putative intermediate 3. Following this initial
report, we have conducted a series of labelling and Hammett
40 studies to further corroborate a mechanistic proposal in which
short-lived carboradical intermediates are formed en route to the
functionalized products.
Exposure of 1 and 1-azidoadamantane to excess cis-β-
deuterostyrene resulted in the isolation of cis-1-adamantyl-2-
45 deutero-3-phenylaziridine, with no evidence of the trans isomer
(Scheme 1). While isomerization of the cis-olefin to a mixture of
cis- and trans-aziridines is suggestive of a stepwise mechanism,
75
In all cases, kR (kX/kH) slightly exceeds one, suggesting that the
rate of amination and aziridination is marginally enhanced with
substitution by both electron donating and electron withdrawing
groups. Plotting log kR versus σ+ parameters (Figure 3a) results in
a non-linear correlation between reaction rate and electron-
80 donating ability of the para-substituent. Linear correlations are
consistent with cationic charge stabilization in the transition state
and typically observed in concerted amination chemistry with
Rh2-carboxylate catalysts.4 The lack of correlation with our
catalyst led us to consider the incorporation of
a spin
85 delocalization parameter, σJJ, developed by Jiang and co-
workers.23 The log kR vs (σmb, σJJ) plot (Figure 4) gave rise to an

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Figure 4. (a) Possible mechanisms of allylic amination. (b) Product analysis of reaction with cis-β-methylstyrene elucidates reaction
mechanism proceeding through H–atom abstraction (HAA)/radical rebound (RR).
appreciably more linear relationship (R2 = 0.99, 0.93 for
amination and aziridination respectively). Multiple coefficient
linear regression for the dual-parameter equation
reaction time to 24 hours resulted in only a slight increase in
product formation (29%) and a significant portion of unreacted
45 azide remains (64%). As the reaction temperature is increased,
product dissociation from the Fe center is encouraged, allowing
for catalyst turnover and increased yields (29% at 25 ºC versus
43% at 60 ºC) but without reaching full conversion. At elevated
temperatures (100 ºC), the azide is completely consumed, yet the
50 yield of the desired N-adamantyl-N-hex-2-enylamine is
diminished. We suspect that free nitrene forms via thermal
decomposition of 1-azidoadamantane under these conditions,
generating significant amounts of diazene and 1-
aminoadamantane. Additionally, several new products
55 corresponding to N-group transfer to 1-hexene appear in the
GC/MS trace at this temperature. Importantly, the linear allylic
amine is not formed to any extent in the absence of catalyst 2,
regardless of the reaction temperature.
5


(1)
log kR = ρmbσmb + ρJJ σJJ

provided ρmb = 0.086 and ρJJ = 0.24 for amination and ρmb = –
0.0073 and ρJJ = 0.18 for aziridination. The positive ρJJ values


reveal that the para-substituents delocalize spin in the transition
10 state. In addition, the large |ρJJ/ρmb| values (2.8 amination, 24.7
aziridination) indicate that the spin delocalization effect is
dominant in the N-group transfer reactions. Octahedral
(porphyrinato)Ru- (|ρJJ/ρmb aziridination
(trispyrazolylborate)Cu-based
|
= 0.5)24 and tetrahedral
(|ρJJ/ρmb aziridination 1.2)25
|
=
15 aziridination and amination catalysts behave similarly; the
relative reaction rates were relatively insensitive to substituent
effects. Such behaviour is indicative of a two-step reaction
mechanism involving radical intermediates.
Recently developed C–H amination protocols have highlighted
60 the ability to run intermolecular reactions with limiting amounts
of the C–H bond substrate.26–28 As such, we were interested in
determining the effect of diluting the olefin substrate with a
chemically inert solvent. As expected, the highest yields (46%)
occurred when the reaction was conducted in 1-hexene without
65 dilution (300 equivalents substrate). Addition of benzene to the
reaction mixture (aryl C–H bonds are unreactive) significantly
C. Allylic Amination
20
Next, the reactivity of a series of olefins with 2 and 1-
azidoadamantane was investigated (Table 1, entries 16-19) in
order to determine the preference for aziridination over allylic C–
H bond amination. Reaction of 2 with cis-β-methylstyrene (Table
1, entry 16) resulted in the exclusive formation of N-
25 cinnamyladamantan-1-amine with complete isomerization to the
trans olefin. Cyclic alkenes cyclohexene and cyclooctene
similarly resulted in allylic amination products in comparatively
poorer yields (17% and 18%, respectively). In fact, the
hampered catalysis [yield
% (equiv. substrate, % v/v 1-
hexene/benzene)]: 26% (150, 50%); 18% (75, 25%), 12% (30,
10%); 6% (15, 5%). This trend can be attributed to increasingly
70 competitive diazene and 1-aminoadamantane formation as the
substrate is diluted with benzene.
stoichiometric reaction of
2
with
1
equivalent of 1-
Under optimized conditions, we explored the reactivity of a
terminal, linear diene (entry 19). Again, primary amination
products were obtained in moderate yield favoring the trans
75 olefin isomer. Diamine formation was not observed due to the
large excess of diene substrate. No reaction is observed with
substrates lacking allylic C–H bonds (e.g. tert-butylethylene).
While the method has synthetic limitations, the interesting
chemo- and regioselectivity of linear allylic amination inspired us
80 to investigate the mechanism of this transformation. Typically,
intermolecular transition metal-catalyzed allylic amination does
not proceed with exclusive olefin transposition.29,30 However,
precedence for this transformation has been demonstrated
previously using simple FeII and FeIII halide salts30 and Fe
30 azidoadamantane in cyclohexene resulted in only 12% of the
allylic amine. While some azide remained unconsumed, a
significant amount of radically coupled bi-cyclohexenyl product
was formed (as determined by GC/MS).
Exposure of 2 and 1-azidoadamantane to linear, non-styrenyl
35 terminal olefins resulted in exclusive formation of the linear
allylic amine products (Table 2, entry 18 and 19) as a mixture of
cis and trans isomers. Stoichiometric application of catalyst 2 to
1-azidoadamantane at room temperature in excess 1-hexene
resulted in the formation of the allylic amine N-adamantyl-N-hex-
40 2-enylamine in 77% yield, with the remaining mass balance
belonging to 1-aminoadamantane and 1,2-diadamantyldiazene.
Lowering the catalyst loading (20 mol%) and extending the
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60 2 T. G. Driver, Org. Biomol. Chem., 2010, 8, 3831.
pthalocyanine
complexes
in
the
presence
of
phenylhydroxylamine.31 Recently, a hetero-bimetallic Pd and Cr
catalytic protocol has also been developed to affect a similar
amination reaction.27
3
J. Du Bois, Org. Process. Res. Dev., 2011, 15, 758; J. L. Roizen, M.
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4
5
We have proposed two possible mechanistic pathways (Figure
4). Both mechanisms begin with formation of the reactive imido
radical intermediate 3, consisting of three bulky adamantyl units
(two on the dipyrinnato ligand, one on the imido N). The olefin
then approaches the sterically crowded reaction centre trans to
10 the Cl ligand. As such, heightened reactivity is observed with the
least bulky, mono-substituted olefin substrates (Table 1, entries
18 and 19). In pathway A (Figure 4a), approach of the olefin
induces C–N bond formation at the primary carbon with
homolytic cleavage of the π-bond. Next, the carboradical rapidly
15 recombines with the Fe-bound amide to generate an aziridine
product. Finally, under the reaction conditions, the aziridine is
ring opened to the primary allylamine through either a heterolytic
(as drawn) or homolytic pathway. In pathway B, the Fe-imido
intermediate abstracts an H-atom from the olefin substrate to
20 generate an allylic radical, followed by radical recombination at
the terminal carbon.
Analysis of the reaction with cis-β-methylstyrene was used to
distinguish between pathways A and B (Figure 4b). If pathway A
were operative, initial aziridination would generate 1-adamantyl-
25 2-methyl-3-phenylaziridine. In situ aziridine ring opening would
then install the amino group at the benzylic carbon. If pathway B
were operative, radical recombination would occur
regioselectively at the less-hindered terminal position of the
unsymmetrical allylic radical to generate N-cinnamyladamantan-
30 1-amine. As discussed earlier, the linear allylic amine is the only
product of the reaction, suggesting that pathway B is operative.32
This is an appealing mechanistic possibility, as it correlates well
with our proposed mechanism for the benzylic amination of
toluenes.
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35 Conclusions
100
2036.
19 S. A. Cramer and D. M. Jenkins, J. Am. Chem. Soc., 2011, 133,
In line with previous studies of this system, we have determined
that one-electron reaction pathways dominate intermolecular N-
group transfer chemistry when mediated by the dipyrrinato
19342.
20 E. R. King, E. T. Hennessy, T. A. Betley, J. Am. Chem. Soc., 2011,
133, 4917.
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40 over aziridination has been established for a range of allylic C–H
bond containing substrates. We attribute the extremely high
levels of chemoselectivity to the high-spin electronic
configuration of the reactive imido radical intermediate 3.
Further, the steric demands of our ligand coupled with the bulky
45 adamantyl imido fragment enforce regioselective amination at the
terminal position of linear α-olefins. The preservation of
unsaturation following imido transfer furnishes products that are
amenable to subsequent functionalization.
110
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Acknowledgement
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50 This work was supported by a grant from the NSF (CHE-
0955885) and Harvard University. E.T.H. is grateful for a
Predoctoral Fellowship from the DOE SCGF (DE-AC05-
060R23100) administered by ORISE-ORAU. T.A.B. is grateful
for a George W. Merck Fellowship.
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32 The amination of cyclooctene provides further support of pathway B
over pathway A. The conformation of a potential cyclooctene
aziridine may prohibit ring opening via deprotonation. As such, if
pathway A were operative, we would anticipate isolation of the
aziridine product as reported by S. Cenini, S. Tollari, A. Penoni, and
C. Cereda, J. Mol. Cat. A: Chemical, 1999, 137, 135.
55 Notes and References
Department of Chemistry and Chemical Biology, Harvard University,
Cambridge, MA 02139, USA. E-mail: betley@chemistry.harvard.edu
1
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