Control of the Chemoselectivity of Metal N-Aryl Nitrene Reactivity: C-H Bond Amination versus Electrocyclization

Article abstract of DOI:10.1021/jacs.6b07026

A mechanism study to identify the elements that control the chemoselectivity of metal-catalyzed N-atom transfer reactions of styryl azides is presented. Our studies show that the proclivity of the metal N-aryl nitrene to participate in sp³-C-H bond amination or electrocyclization reactions can be controlled by either the substrate or the catalyst. Electrocyclization is favored for mono-β-substituted and sterically noncongested styryl azides, whereas sp³-C-H bond amination through an H-atom abstraction-radical recombination mechanism is preferred when a tertiary allylic reaction center is present. Even when a weakened allylic C-H bond is present, our data suggest that the indole is still formed through an electrocyclization instead of a common allyl radical intermediate. The site selectivity of metal N-aryl nitrenes was found to be controlled by the choice of catalyst: Ir(I)-alkene complexes trigger electrocyclization processes while Fe(III) porphyrin complexes catalyze sp³-C-H bond amination in substrates where Rh₂(II) carboxylate catalysts provide both products.

Full text of DOI:10.1021/jacs.6b07026

Article
pubs.acs.org/JACS
Control of the Chemoselectivity of Metal N‑Aryl Nitrene Reactivity:
C−H Bond Amination versus Electrocyclization
Chen Kong,†,§ Navendu Jana,†,§ Crystalann Jones,† and Tom G. Driver*,†,‡
†Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, United States
‡Institute of Next Generation Matter Transformation, College of Chemical Engineering, Huaqiao University, 668 Jimei Boulevard,
Xiamen, Fujian 361021, P. R. China
S
* Supporting Information
ABSTRACT: A mechanism study to identify the elements that control the
chemoselectivity of metal-catalyzed N-atom transfer reactions of styryl azides
is presented. Our studies show that the proclivity of the metal N-aryl nitrene
to participate in sp3-C−H bond amination or electrocyclization reactions can
be controlled by either the substrate or the catalyst. Electrocyclization is
favored for mono-β-substituted and sterically noncongested styryl azides,
whereas sp3-C−H bond amination through an H-atom abstraction−radical
recombination mechanism is preferred when a tertiary allylic reaction center is
present. Even when a weakened allylic C−H bond is present, our data suggest
that the indole is still formed through an electrocyclization instead of a
common allyl radical intermediate. The site selectivity of metal N-aryl nitrenes
was found to be controlled by the choice of catalyst: Ir(I)-alkene complexes
trigger electrocyclization processes while Fe(III) porphyrin complexes catalyze
sp3-C−H bond amination in substrates where Rh2(II) carboxylate catalysts
provide both products.
only emerge from studying systems that contain multiple
potential sites of reaction,16 and applying the conclusions into
the origin of reactivity preferences to control reaction
outcomes.
INTRODUCTION
■
Achieving absolute control over the product distribution of a
catalytic reaction continues to be vigorously pursued by
synthetic chemists. While significant progress has been made
across many reaction types to access different scaffolds from the
same starting materials and reagents by manipulating the
identity of the catalyst,1,2 this control remains elusive in C−H
bond amination reactions and remains an important and largely
unrealized goal.3 The reactivity patterns of metal nitrenes have
been exploited to create new C−N bonds from C−H bonds
and π-systems,1 and to date, the advances in these fields have
been largely driven using nitrenes substituted with a strong
electron-withdrawing group (Scheme 1).4−9 These investiga-
tions have established chemoselectivity trends,3 which permit
the use of these C−H bond aminations in target-oriented
syntheses.10 In contrast, these preferences remain unknown for
metal N-aryl nitrenes despite the prevalence of the resulting
aryl amines and N-heteroaromatics in pharmaceuticals and
materials.11−13 As an additional complication, metal N-aryl
nitrenes also react with adjacent π-systems through electro-
cyclization processes to produce N-heteroaromatics.14 Under-
standing and controlling the reactivity of metal N-aryl nitrenes
to participate in an electrocyclization or C−H bond amination
reaction is critical to the rational design of target-oriented
syntheses that use this reaction at a late stage to install the
valuable N-aryl moiety, which is ubiquitous in indole
alkaloids,15 as well as the design of new reactions that harness
the reactivity of metal N-aryl nitrenes. This understanding will
Our investigations into the reactivity of ortho-substituted aryl
azides toward Rh2(II) carboxylate complexes revealed that
certain substrates preferred to undergo sp3-C−H bond
amination instead of the expected electrocyclization domino
reaction (Scheme 2).17−19 Exposure of β-acyl trisubstituted
styryl azides to Rh2(esp)2 triggered an electrocyclization-acyl
migration domino reaction to produce 1,2,3-trisubstituted
indoles, such as 9, from azides 8.20 In the absence of catalyst,
no reaction occurred. We found that the identity of the α-
substituent impacted the identity of the product. When the
substrate contained an α-aryl or α-n-alkyl group, the expected
1,2,3-trisubstituted indole was obtained as the only product.
Introduction of a tertiary C−H bond into the α-position,
however, changed the outcome of the reaction. Instead of an
electrocyclization−migration domino reaction, allylic C−H
bond amination was observed to produce indoline 13 from
styryl azide 12.
In our studies into 3H-indole formation,21,22 the presence of
a tertiary allylic C−H bond was also found to change the course
of Rh2(II)-catalyzed amination reactions (Scheme 3). While
electrocyclization−migration was observed with styryl azide 16
Received: July 7, 2016
© XXXX American Chemical Society
A
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produce 2H-indole 19 as a 3.5:1 mixture of diastereomers. The
preference for electrocyclization−migration could be restored
by conformationally locking the tertiary allylic C−H bond:
exposure of camphor-derived styryl azide 20 to Rh2(esp)2
smoothly converted it to indole 21 through an electro-
cyclization followed by migration of the methyl carboxylate
to the nitrogen atom.22
Scheme 1. Substrate versus Catalyst Control of the
Chemoselectivity of the Metal Nitrene Catalytic
Intermediate
Our curiosity was piqued by these unexpected sp3-C−H
bond amination products, and at the conclusion of these
studies, we wanted to systematically probe the effect that the
ortho-substituent had on the outcome of the amination reaction
in order to establish a predictive model. Toward that end, we
decided to examine substrates that would examine the
relationship between the steric and the electronic environment
of the two potential reaction centers to determine their impact
on whether allylic C−H bond amination or electrocyclization
took place. In addition to investigating substrate control over
the reaction outcome, we also wanted to determine if catalysts
could overcome the inherent substrate preference.
RESULTS AND DISCUSSION
■
Investigation into Substrate Control of Reaction
Outcome. To find examples where allylic C−H bond
amination occurred in the absence of a tertiary sp3-C−H
bond, the reactivity of a series of styryl azides toward Rh2(II)-
carboxylate catalysts was examined. These substrates were
assembled in two steps from the β-ketoester through a cross-
coupling sequence using 2-azidobenzene-boronic pinacolate
ester 23 to introduce the aryl azide portion using conditions
developed in our laboratory (eq 1).23 The resulting styryl azides
Scheme 2. Observation of an sp3-C−H Bond Amination in
Lieu of Electrocyclization−Migration Reaction
were exposed to 5 mol % of Rh2(esp)2 (Table 1). In the
absence of catalyst, no reaction occurred. Styryl azides bearing
cyclic enone ortho-groups were converted into indoles 26a and
26b irrespective of the identity of the β-substituent (entries 1
and 2). While piperidone-derived styryl azide 24c afforded the
3H-indole electrocyclization product (entry 3),21 3-oxoproline-
derived 24d, containing an in conjugation N-Boc carbamate,
produced the secondary allylic C−H bond amination hetero-
cycle 26d as the only product, albeit in reduced yield (entry 4).
Together with entries 1 and 2, these results show that
introduction of an additional carbonyl- or N-Boc carbamate
β-substituent makes the electrocyclization pathways energeti-
cally unfavorable by weakening the allylic C−H bond to
produce heterocycles from exclusive C−H bond amination.
Carbon−hydrogen bond dissociation energies are significantly
lower when an α-amine or carbonyl is present.24,25 In these
styryl azides this weakening would be transmitted through the
π-system to weaken the allylic C−H bond and enable
amination to occur. While no reaction was observed when a
primary β-amide-substituted styryl azide was submitted to
reaction conditions (entry 5), exposure of the secondary amide
24f produced indole 26f; no products of electrocyclization−
migration were observed (entry 6). Because this amide should
not have a larger effect on the bond strength than the β-
carboxylate, we interpret this result to mean that the
electrocyclization is also disfavored due to increased steric
Scheme 3. Observation of an sp3-C−H Bond Amination in
Lieu of Electrocyclization−Migration Reaction
to afford 3H-indole 17,21 exclusive sp3-C−H bond amination
was observed from submission of menthol-derived azide 18
(3:1 mixture of diastereomers) to reaction conditions to
B
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while the tertiary allylic C−H bond was retained; whereas in
styryl azide 29, the alkyl- or phenyl β-substituents were
replaced with hydrogen. Exposure of 27 and 29 to reaction
conditions produced only electrocyclization product, indoles 28
and 30. The results of these two azides reveal the sensitivity of
the electrocyclization on the steric environment of the ortho-
alkenyl substituent. We rationalize these outcomes on the
presence of a β-substituent, which will introduce destabilizing
steric interactions with the rhodium N-aryl nitrene since a 5-
atom-4-π-electron electrocyclization requires a planar transition
state for bond formation.26 We believe that these steric
interactions will raise the energy of the electrocyclization
transition state (TS-31) to make the allylic C−H bond
amination reaction (accessible through the H-atom transfer
transition state TS-32). The destabilizing steric interactions in
TS-31 are minimized when the Rβ-substituent is hydrogen to
favor electrocyclization to produce the N-heterocyclic product.
We anticipated that further insight into the competitive
nature of these two mechanisms could be gained from studying
substrates that afforded a mixture of the electrocyclization and
C−H bond amination products. To make C−H bond
amination competitive with electrocyclization on a sterically
accessible alkenyl unit, we replaced one of the tertiary allylic
alkyl groups with an aryl group. The presence of the aryl group
in aryl azide 33 would enable us to examine the effect of
changing the electronic environment of the sp3-C−H allylic site
on the ratio of electrocyclization to sp2-C−H bond amination.
The resulting substituent effect should be limited to only
affecting the ΔG‡ of C−H bond amination because the benzyl
methine insulates the alkene π-system.
Table 1. Allylic C−H Bond Amination versus
Electrocyclization
In line with these expectations, exposure of styryl azide 33 to
reaction conditions produced a mixture of the C−H bond
amination product, 2H-indole 34, and the electrocyclization-
migration product, indole 35 (Table 2). We found that as the
Table 2. Effect of Changing the Electronic Nature of the
Allylic C−H Bond on the Reaction Outcome
a
b
c
Isolated after silica gel chromatography. From ref 21. Decompo-
sition occurred when the reaction mixture was heated to 140 °C.
interactions that arise when the carboxylate is replaced with an
amide.
Next, the effect of changing the steric environment at the
electrocyclization reaction site was examined (Scheme 4). For
this study, we chose to examine styryl azidess (e.g., 18 and 24a)
where allylic C−H bond amination was observed and replace
the β-substituent with a hydrogen to determine whether the
preference for electrocyclization could be restored. In styryl
azide 27, the β-methyl carboxylate substituent was removed
a
b
b
c
•
entry
#
R
σpara
σmb
σJJ
34:35
yield, %
1
2
3
4
5
6
a
b
c
d
e
f
OMe
Me
H
−0.27
−0.17
0
−0.77
−0.29
0
0.23
0.15
0
1:4
83
94
82
66
56
84
1:5.1
1:5.8
1:10.7
1:13.0
1:83
F
0.06
0.23
0.35
−0.24
0.11
−0.02
0.22
−
Scheme 4. Effect of Changing the Steric Environment on the
Reaction Outcome
Cl
OCF3
b
−
a
c
From ref 27. From ref 34b. As determined using 1H NMR
spectroscopy with CH2Br2 as an internal standard.
R-substituent became more electron-withdrawing, the amount
of allylic C−H bond amination was diminished. A correlation
was observed when the product ratios were plotted against
Hammett σpara constants (Figure 1).27 While increasing the
electron-deficiency of the aryl substituent favored the electro-
cyclization, a slight increase in the slope of the line was
observed when the electron-releasing substituent was replaced
with an electron-withdrawing substituent. This correlation
C
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Figure 2. Effect of changing the electronic environment of the
rhodium N-aryl nitrene: correlation of heterocycle product ratios with
Hammett σpara values.
Figure 1. Effect of changing the electronic environment at the allylic
C−H bond reaction center: correlation of heterocycle product ratios
with Hammett σpara values.
appears to consist of two intersecting lines: the effect of
electron-releasing substituents exhibits a smaller ρ-value (0.33)
than that of electron-withdrawing groups, which display a larger
ρ-value of 3.18 to imply a larger buildup of charge at the benzyl
carbon for these substrates. The intersecting lines also indicate
that a change of mechanism or a change in the rate-determining
step is also occurring.
Next, using this scaffold, the identity of the 4-substituent on
the aryl azide moiety was modified to gain insight into the effect
of changing the electronic nature of the rhodium N-aryl nitrene
on the outcome of the reaction (Table 3). For styryl azides 36,
observed for styryl azide 33.33 In contrast, styryl azide 36,
which varied the electronic environment at the aryl azide piece,
exhibited a linear relationship when its product ratio was
•
•
plotted against Arnold’s σα - or Creary’s σC -constants (Figure
3). We interpret this result to suggest the presence of a
nitrogen-based radical in the product-determining step.
Next, we examined the relationship between our relative rate
data and Jiang and Ji’s radical σmb and σ•JJ substituent constants,
which separate the polar (σmb) and spin (σ• ) delocalization
JJ
effects (Figure 4).34 To accomplish this, we applied the σmb and
Table 3. Effect of Changing the Electronic Nature of the
Rhodium N-Aryl Nitrene on the Reaction Outcome
a
b
b
•
c
entry
#
R
σpara
σmb
σJJ
37:38 yield, %
1
2
3
4
5
6
a
b
c
d
e
f
OMe
Me
H
−0.27
−0.17
0
−0.77
−0.29
0
0.23
0.15
0
1:12
1:7.2
1:5.8
1:5
78
79
82
92
76
80
F
0.06
0.23
0.35
−0.24
0.11
−0.02
0.22
−
Cl
1:6.6
OCF3
b
−
c
1:9.5
a
From ref 27. From ref 34b. As determined using 1H NMR
spectroscopy with CH2Br2 as an internal standard.
the presence of either an electron-donating- or -withdrawing
substituent increased the amount of electrocyclization product.
Plotting these product ratios versus Hammett σpara constants
produced a V-shaped curve (Figure 2). The shape of this curve
indicates that either the mechanism or the identity of the
turnover-limiting step is changing.28 Alternatively, the shape of
this curve could suggest the presence of radical intermediates in
one of the product-determining steps.29
To investigate the latter possibility, these data were
correlated to radical σ• substituent constants. Toward this
end, we examined the relationship between our relative rate
30
31
•
•
data and Arnold’s σα -, Creary’s σC -, and Jackson’s σJ•-
Figure 3. Correlation of heterocycle product ratios from styryl azide
constants.32 Using these constants, no linear correlation was
36 with (a) Arnold’s σα -constants and (b) Creary’s σC•-constants.
•
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Scheme 5. H-Atom Abstraction-Radical Recombination As a
Potential Common Mechanism for 2H-Indole and Indole
Formation
Rh2(II)-catalyzed decomposition of styryl azide 33 forms
rhodium nitrene 39. While a singlet species will be first formed
from loss of N2,35 our collaboration with Tantillo and co-
workers revealed that a very small barrier separates it from the
energetically preferred triplet rhodium nitrene 40.35 While this
species was shown by the calculations to be inert toward
cyclization with a β-substituted alkenyl group, we anticipated
that, in systems that bear a weakened allylic C−H bond,
hydrogen-atom abstraction could occur to form allyl radical
41.36 Radical recombination of 41 could form the minor
product, 2H-indole 34. Alternatively, bond rotation of 41 to 42
could occur to alleviate destabilizing steric interactions between
the rhodium N-aryl nitrene and the phenyl- and methyl
substituents of the allyl radical. Radical recombination forms
2H-indole 44, which isomerizes to form the more stable indole
35. While this mechanism might not be general, it could be
considered a possibility in systems that contain weakened allylic
C−H bonds.
Figure 4. Correlation of heterocycle product ratios with Jiang and Ji’s
σmb and σJJ values. (a) Substituent effect observed at the allylic C−H
reaction site; (b) substituent effect observed on the aryl azide.
•
To investigate if both 2H-indole 34 and indole 35 are formed
through a common allyl radical intermediate, the reactivity of
styryl azide 33b-d3 was tested (Scheme 6). This labeled
σ•JJ substituent constants to our relative rate data (log kelectrocycl
k
/
•
CHamin = ρmbσmb + ρJJ σ•JJ + C) for heterocycle formation from
styryl azides 33 and 36. For the reaction of styryl azides 33, no
linear correlation was observed using σmb and σ• constants
Scheme 6. Relationship between Isotopolog Identity and
Ratio of 2H-Indole 34 and Indole 35 Using Rh2(esp)2 As the
Catalyst
JJ
(Figure 4a). We interpret this result to indicate that the
electronic effects observed during the product-determining step
are entirely polar in nature and that no radical character is built
up on the benzyl position during this step. In contrast,
correlation was observed when the substituents were changed
on styryl azide 36 to result in the straight line when log krel
=
−0.248σmb + 0.711σ• + 0.702 (Figure 4b). The negative ρmb
JJ
value is consistent with an electrophilic metal N-aryl nitrene
•
catalytic intermediate, and the positive ρJJ suggests that the
spin density is localized on the nitrogen atom. In both cases,
•
the magnitude of |ρJJ /ρmb| > 1 suggests that the spin
delocalization effect is more important than the polar
substituent effect.34 Together with the lack of correlation
observed with the benzyl series, these results suggest that H-
atom abstraction by the rhodium N-aryl nitrene occurs though
an early transition state in which little C−H bond homolysis
has occurred. For these analyses, however, caution must be
used in over-interpreting these ρ-values because these σmb and
substrate was chosen because we anticipated that that the ratio
of the N-heterocyclic products from 33b-d3 would be similar to
the case of 33b-d0 since H-atom abstraction of the allylic C−H
bond occurs for both and changing the bond strength should
not affect the ratio if the product-determining step occurs
afterward. In contrast, if the mechanism for indole 35 occurs
instead through an electrocyclization of the rhodium N-aryl
nitrene, then the formation of the 2H-indole product should be
significantly diminished because electrocyclization avoids
breaking the stronger C−D bond. Exposure of styryl azide
σ• substituents were developed from benzyl carboradicals.34
JJ
The correlation of our relative rate data to Jiang and Ji’s polar
and spin delocalization substituent constants suggests that
indole 37 might also be formed through an H-atom
abstraction−radical recombination mechanism instead of an
electrocyclization (Scheme 5). In this potential mechanism,
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33-d3 to reaction conditions formed >99% of indole 35b with
only a trace of 2H-indole 34b observed. We interpret the
increased amount of indole 35b-d3 to indicate that it is formed
through an electrocyclization and not through a common allyl
radical intermediate.
Investigation into Catalyst Control of Reaction Out-
come. Because the more significant effect was observed when
the electronic nature of the aryl azide moiety was modified, we
anticipated that changing the identity of the catalyst might also
control the ratio of electrocyclization to C−H bond amination
(Table 4 and Figure 5). To investigate this assertion, styryl
affected neither the yield of heterocycle formation or the ratio
of 46:47 (entry 2). The effect of the rhodium carboxylate
catalyst in overturning the natural inclination of the free N-aryl
nitrene is seen in entry 3: although the conversion at 120 °C is
only 15%, the electrocyclization product, indole 47, was
observed as nearly the only product. Altering the identity of
the carboxylate ligands had a measurable effect on the product
ratio. Rhodium octanoate behaved similarly to Rh2(esp)2 albeit
affording the heterocycle products in a slightly lower yield
(entry 4). Changing the carboxylate ligand to a caprolacta-
mate37 resulted in selective formation (1:10) of the indole
electrocyclization product (entry 5). The allylic C−H bond
amination product 46 was favored slightly with chiral,
nonracemic ligands S-DOSP and S-PTAD with a higher ratio
of 46 obtained with the larger S-PTAD ligand (entries 6−
9).38,39 A slightly higher preference for 46 (3.9:1) was observed
with Rh2(S-PTAD)4, which could be increased to 4.8:1 if the
reaction temperature was lowered to 90 °C. No further increase
in the preference for sp3-C−H bond was observed using Rh2(S-
PTAD)4 either if the dielectric of the solvent was changed
through the addition of a tetraalkylammonium salt or if the
solvent was changed to a chlorinated solvent. These results
reveal that the reaction outcome of styryl azide 45 is affected by
both the presence of the rhodium(II) catalyst and the identity
of its ligands.
Table 4. Effect on the Reaction Outcome by Changing the
Identity of the Rh2(II)-Catalyst’s Ligands
a
entry
Rh2(O2CR)4
T, °C
46:47
yield, %
1
2
3
4
5
6
7
8
9
Rh2(esp)2
120
110
120
110
100
100
110
100
90
1:1.6
1:1.7
1:16
91
90
15
78
73
Rh2(esp)2
none
Rh2(oct)4
1:2.1
1:10
Next, we examined changing the metal of the N-atom
transfer catalyst (Table 5). We anticipated that a larger effect
Rh2(cap)4
b
Rh2(S-DOSP)4
Rh2(S-PTAD)4
Rh2(S-PTAD)4
Rh2(S-PTAD)4
1.28:1
3.9:1
4.4:1
4.8:1
64
84
85
Table 5. Relationship between the Identity of the Metal of
the N-Atom Transfer Catalyst and the Reaction Outcome
c
61
a
As determined by 1H NMR spectroscopy using CH2Br2 as the
b
c
internal standard. Only 84% conversion observed. Only 72%
conversion observed.
a
entry
MLnXm
Rh2(esp)2
mol %
T, °C
46:47
yield, %
1
2
3
4
5
110
110
110
110
100
100
100
125
110
100
100
1:1.7
0:100
0:100
0:100
3.6:1
8:1
90
88
84
41
68
[Ir(cod)(OMe)]2
FeBr2
5
20
20
2
FeBr3
b
5
CoTPP
b
c
6
CoOEP
2
18
b
7
b
Fe(TPP)Cl
Fe(TPP)Cl
Fe(TPFPP)Cl
Fe(TOMePP)Cl
Fe(OEP)Cl
2
13:1
7.3:1
3.3:1
17:1
60:1
52
52
72
52
77
8
2
b
9
2
b
10
2
b
11
2
a
As determined by 1H NMR spectroscopy using CH2Br2 as the
b
internal standard. Reaction performed in DCE with 100 wt % of 4 Å
molecular sieves added. Only 28% conversion observed.
c
would be observed on the reaction outcome if the metal was
involved in C−N bond formation or C−H bond cleavage.
Consistent with this hypothesis, changing the identity of the
metal had a significant effect on the preference for electro-
cyclization or C−H bond amination. While Rh2(esp)2 gave a
mixture of 2H-indole 46 and indole 47 (entry 1), exposure of
styryl azide 45 to 5 mol % of [Ir(cod) (OMe)]2 produced only
indole 47 (entry 2) in 88%. Indole 47 was also only observed
using 20 mol % of ferrous or ferric chloride,40 with a
significantly higher yield observed with ferrous chloride (entries
Figure 5. Structures of the Rh2(II)-carboxylate catalysts investigated.
azide 45 was chosen because we anticipated that adding a
methyl substituent to the allylic position of the ortho-enone
substituent might make the C−H bond amination competitive
with electrocyclization. In line with our hypothesis, exposure to
Rh2(esp)2 afforded a 1:1.6 ratio of 2H-indole 46 and indole 47
(Table 4, entry 1). Reducing the temperature of the reaction
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3 and 4). In contrast, 2H-indole 46 was observed as the major
product when cobalt or iron porphyrin complexes were
employed as the catalyst (entries 5−11).6,41 A higher
preference for C−H bond amination was obtained with more
electron-rich metal porphyrin catalysts. Because these com-
plexes are well established to catalyze C- and N-atom transfer
reactions through one-electron mechanisms,42 we anticipated
that higher activities might be observed with these catalysts if
an H-atom abstraction−radical recombination was an accessible
mechanism. In line with this assertion, we found that only 2
mol % of Co(TPP) at a lower temperature (100 °C) was
required to produce 46 as the major product (entry 5).
Changing the porphyrin ligand from tetraphenyl- to octae-
thylporphyrin improved the ratio of 46:47 from 3.6 to 8:1, but
the conversion to the N-heterocycle plummeted to 28% (entry
6). A similar preference for 2H-indole formation was observed
when the metal was changed from Co(II) to Fe(III). Iron
tetraphenylporphyrin chloride catalyzed the formation of 2H-
indole 46 with greater selectivity (13:1) in comparison to
Co(TPP) albeit in slightly reduced yield (entry 7). In an
attempt to improve the yield, the reaction temperature was
increased from 100 to 125 °C. Unfortunately, the yield
remained static and the selectivity for 2H-indole 46 was
attenuated from 13:1 to 7.3:1 (entry 8). Next, we investigated
changing the electronic nature of the iron porphyrin ligand
(entries 9−11). We found that it played a critical role in
promoting 2H-indole 46: reduced selectivity (3.3:1) was
observed using electron-poor iron perfluoroarylporphyrin,
whereas the more electron-rich iron tetramethoxyarylporphyrin
improved the selectivity for 46 to 17:1 (entries 9 and 10). The
best selectivity for 2H-indole 46 formation was obtained using
the electron-rich iron octaethylporphyrin chloride to afford 46
in a 60:1 ratio (entry 11). This survey revealed that the identity
of the metal N-atom catalyst does control the reaction
outcome. Indole 47 can be formed as the only product using
5 mol % of [Ir(cod)(OMe)]2 or 20 mol % of simple FeBr2,
whereas 2 mol % of iron(III) octaethylporphyrin chloride leads
to selective 2H-indole 46 formation with only a trace of indole
47 observed.
interpret this result to indicate that indole is formed through an
electrocyclization process while 2H-indole is formed through an
H-atom abstraction radical−recombination mechanism. The
value of the primary kinetic isotope effect (approximately 30)43
is significantly larger than the classical value for H-atom transfer
(6.5)44 and suggests that tunneling is occurring.
The reactivity of the styryl azide 45-d2 was also investigated
using Rh2(esp)2 as catalyst to examine if a similar change in the
ratio of product 2H-indole 46 and indole 47 was observed
(Scheme 8). A 1:1.63 ratio of 2H-indole 46 to indole 47 was
Scheme 8. Comparison of Ratio of 2H-Indole 46 and Indole
47 Using Rh2(esp)2 as the Catalyst
obtained from stryryl azide 45-d0 using Rh2(esp)2. Similar to
the use of Fe(OEP)Cl as catalyst, significantly less allylic C−H
bond amination was observed when 45-d2 was submitted to
Rh2(esp)2 producing a 1:10 ratio of 46-d2 and 47-d2. The
exhibited primary kinetic isotope effect, however, is much
smaller (approximately 6)43 to suggest that tunneling is not
occurring. We interpret these data in support of two separate
mechanisms: allylic C−H bond amination produces 2H-indole
46 while an electrocyclization−migration sequence affords
indole 47.
Finally, the generality for iron octaethylporphyrin chloride to
change the reaction outcome in β-substituted styryl azides was
investigated (Scheme 9). Upon exposure to a Rh2(II)-
To gain further insight into factors that affect the reaction
outcome using iron octaethylporphyrin chloride as the catalyst,
styryl azide 45-d2 was examined (Scheme 7). We anticipated
that the product ratio from 45-d2 would be the same as in the
case of 45-d0 if both 2H-indole 46 and indole 47 were formed
through a common allyl radical intermediate. Similar to our
investigation of aryl azide 33b-d3 using Rh2(esp)2, exposure of
45-d2 to reaction conditions resulted in a significant reduction
of the ratio of 2H-indole 46 to indole 47. As before, we
Scheme 9. Reversing the Inherent Chemoselectivity of a
Styryl Azide by Catalyst
Scheme 7. Relationship between Isotopolog Identity and
Ratio of 2H-Indole 46 and Indole 47 Using Fe(OEP)Cl as
the Catalyst
G
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Article
carboxylate catalyst, these substrates can be transformed into
3H-indole 50 or spirocycle 51 through a [1,2] migration of one
of the β-substituents in the electrocyclization product 49. We
anticipated if the reaction was changed from a two-electron- to
a one-electron process, however, that a different N-heterocycle
would be accessed by changing the identity of the reactive
intermediate. Instead of triggering a migration or ring
contraction via the electrocyclization product cation 49, H-
atom abstraction of the iron N-aryl nitrene would produce allyl
radical 52.45 This radical intermediate could be captured by the
nitrogen-centered radical to produce 2H-N-heterocycle 53 or
54. To test this, styryl azides 16a and 55 were exposed to 2 mol
% of Fe(OEP)Cl and 2H-indoles 53a and 56 were produced as
the only products. The regioselectivity of C−N bond formation
suggests that allyl radical 57 is sufficiently long-lived for bond
rotation to occur before radical recombination between the
more substituted side and the nitrogen-centered radical.
Consistent with our hypothesis that radical intermediates are
generated, the addition of the radical inhibitor TEMPO or 1,4-
cyclohexadiene blocked heterocycle formation.
To further explore the reactivity of the catalytic intermediates
generated from styryl azide 16a and Fe(OEP)Cl, a series of
competition experiments were performed using para-substi-
tuted styryl azides 16 (eq 2). We found that the presence of
either an electron-donating or -withdrawing R-substituent
increased the rate of the reaction. The relative rates of the
starting styryl azides 16 were analyzed using the Hammett
equation using σpara values to produce a V-shaped curve
suggesting the formation of radical intermediates (Figure 6a).
Next, our relative rate data were plotted using Jiang and Ji’s
Figure 6. Correlation of relative rates between substituted styryl azides
16 and 16a with (a) σpara-constants and (b) Jiang and Ji’s σmb and σJJ
values.
•
radical σmb and σ• substituent constants (Figure 6b).34 The
JJ
best linear correlation was obtained using log krel = −0.483σmb
+ 1.13σ•JJ + 0.05. Similar to data observed from Rh2(esp)2 and
styryl azide 36, a negative ρmb value and a positive ρJJ were
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b07026.
•
■
S
obtained to suggest that the spin density is localized on an
electrophilic nitrogen atom. In comparison to our earlier
•
Rh2(II)-study of styryl azide 36, a similar absolute value of |ρJJ /
Experimental procedures, spectroscopic and analytical
data for the products (PDF)
ρmb| (2.33 versus 2.87) was obtained to suggest that the spin
delocalization effect is also important with this substrate series
using Fe(OEP)Cl as the catalyst. These correlations suggest
that radical intermediates are formed in this Fe-catalyzed
reaction.
AUTHOR INFORMATION
Corresponding Author
*tgd@uic.edu
■
CONCLUSIONS
■
Author Contributions
Our studies provide mechanistic insight into the controlling
elements of the reactivity of metal N-aryl nitrene. Electro-
cyclization is favored for mono-β-substituted and sterically
noncongested styryl azides, whereas sp3-C−H bond amination
is preferred when weakened allylic reaction centers are present.
In the presence of a sufficiently activating amino- or carbonyl β-
substituent, tertiary allylic C−H bond amination will occur
even if the π-system is sterically noncongested. Our results
show that the site selectivity of metal N-aryl nitrenes can be
controlled by the choice of catalyst: Ir(I)-alkene complexes
trigger electrocyclization processes while Fe(III) porphyrin
complexes catalyze sp3-C−H bond amination in substrates
where Rh2(II) carboxylate catalysts provide both products.
§C.K. and N.J. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Science Foundation CHE-
1564959, University of Illinois at Chicago, Office of the Vice-
Chancellor for Research, Huaqiao University Xiamen, and the
Fujian Hundred Talents Plan for their generous financial
support. We thank Mr. Furong Sun (UIUC) for high resolution
mass spectrometry data, and Dr. Rakesh Sahu for help in setting
up the multiple variable linear regression analyses.
H
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J
DOI: 10.1021/jacs.6b07026
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX