Iridium porphyrin catalyzed N-H insertion reactions: Scope and mechanism

Article abstract of DOI:10.1021/om400098v

Ir(TTP)CH₃ catalyzed N-H insertion reactions between ethyl diazoacetate (EDA) or methyl phenyldiazoacetate (MPDA) and a variety of aryl, aliphatic, primary, and secondary amines to generate substituted glycine esters with modest to high yields. Aniline substrates generally gave yields above 80%, with up to 10⁵ catalyst turnovers, and without slow addition of the diazo reagent. Good yields were also achieved with aliphatic amines, though higher catalyst loadings and slow addition of the amine were necessary in some cases. Primary amines reacted with EDA to generate both single- and double-insertion products, either of which could be produced selectively in high yield with the proper choice of stoichiometric ratios and reaction temperature. Notably, mixed trisubstituted amines, RN(CH₂CO₂Et) (CHPhCO₂Me), were generated from the insertion of 1 equiv of EDA and 1 equiv of MPDA into primary amines. The N-H insertion mechanism was examined using substrate competition studies, trapping experiments, and multiple spectroscopic techniques. Substrate competition studies using pairs of amines with EDA or MPDA revealed Hammett correlations with respective slopes of ρ = 0.15 and ρ⁺ = -0.56 as well as kinetic isotope ratios of k _H/k_D = 1.0 ± 0.2 and 2.7 ± 0.2. Competitive amine binding to the iridium center was demonstrated by kinetics and equilibrium binding studies. Equilibrium binding constants ranged from 10² to 10⁵. Monitoring the reaction by absorption spectroscopy revealed a transient metalloporphyrin complex. The lifetime of this species was dependent on the nature of the amine substrate, which suggests that the catalytic cycle proceeds through a metal-ylide intermediate.

Full text of DOI:10.1021/om400098v

Article
pubs.acs.org/Organometallics
Iridium Porphyrin Catalyzed N−H Insertion Reactions: Scope and
Mechanism
Bernie J. Anding and L. Keith Woo*
Department of Chemistry, Iowa State University, Ames, Iowa 50011-3111, United States
S
* Supporting Information
ABSTRACT: Ir(TTP)CH3 catalyzed N−H insertion reac-
tions between ethyl diazoacetate (EDA) or methyl phenyl-
diazoacetate (MPDA) and a variety of aryl, aliphatic, primary,
and secondary amines to generate substituted glycine esters
with modest to high yields. Aniline substrates generally gave
yields above 80%, with up to 105 catalyst turnovers, and
without slow addition of the diazo reagent. Good yields were
also achieved with aliphatic amines, though higher catalyst
loadings and slow addition of the amine were necessary in
some cases. Primary amines reacted with EDA to generate
both single- and double-insertion products, either of which
could be produced selectively in high yield with the proper
choice of stoichiometric ratios and reaction temperature.
Notably, mixed trisubstituted amines, RN(CH2CO2Et)(CHPhCO2Me), were generated from the insertion of 1 equiv of EDA
and 1 equiv of MPDA into primary amines. The N−H insertion mechanism was examined using substrate competition
studies, trapping experiments, and multiple spectroscopic techniques. Substrate competition studies using pairs of
amines with EDA or MPDA revealed Hammett correlations with respective slopes of ρ = 0.15 and ρ+ = −0.56 as well as
kinetic isotope ratios of kH/kD = 1.0
0.2 and 2.7
0.2. Competitive amine binding to the iridium center was
demonstrated by kinetics and equilibrium binding studies. Equilibrium binding constants ranged from 102 to 105.
Monitoring the reaction by absorption spectroscopy revealed a transient metalloporphyrin complex. The lifetime of this
species was dependent on the nature of the amine substrate, which suggests that the catalytic cycle proceeds through a
metal−ylide intermediate.
addition of the diazo reagent.26 Nonetheless, more effective,
INTRODUCTION
■
efficient, and selective N−H insertion catalysts are still
N−H insertion reactions of diazocarbonyl compounds are
atom-efficient and rapid routes to an array of synthetically and
biologically important nitrogen-containing compounds.1−5
Studies over the last few decades demonstrate that N−H
insertions occur under thermal and transition-metal-catalyzed
conditions.6 Under catalyst-free conditions, donor/acceptor
carbenes inserted into aliphatic and aryl amines in 53−96%
yield, but the reactions required refluxing temperatures in
trifluorotoluene, an expensive and high-boiling solvent.7
A similar method with toluene solvent afforded significantly
reduced yields in the range of 15−60%.8 More efficient and
milder conditions were achieved using transition-metal
catalysts containing rhodium,9−14 copper,3,15−18 rhenium,19
ruthenium,20−23 and iron.22−27 Although sophisticated
rhodium and copper systems have been developed, these
catalysts are poisoned by amines, which typically limits their
use to amides, carbamates, and anilines.14 Furthermore, most
catalysts require long reaction times, high catalyst loadings,
and dropwise addition of the diazo reagent to avoid
dimerization byproducts. As a notable exception, iron
porphyrins were not poisoned by amine substrates, were
efficient at low catalyst loadings, and did not require slow
needed.25
Mangion and co-workers were the first to report the use of
an iridium catalyst, [Ir(COD)Cl]2, for N−H insertions.28 In
their work, reactions between anilines and sulfoxonium ylides
generated glycine esters in 76−93% yield at ambient temper-
atures. Insertions into aliphatic amines were also observed,
albeit only for intramolecular conversions at elevated temper-
atures. Although this serves as the first reported example of
iridium-catalyzed N−H insertions, there is precedent for
macrocyclic iridium complexes as catalysts for carbene transfer
reactions, including cyclopropanation,29−31 C−H inser-
tion,30,32−34 and Si−H insertion.30,35 These catalysts are often
reactive at temperatures lower than −40 °C and robust, with
turnover numbers (TONs) as high as 4.8 × 105. The present
work provides the first account of a macrocyclic iridium com-
plex, Ir(TTP)CH3 (TTP = tetratolylporphyrinato dianion), as a
catalyst for N−H insertion reactions with amines and diazo
reagents.
Received: February 3, 2013
© XXXX American Chemical Society
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RESULTS AND DISCUSSION
Table 2. Single Insertion into Primary Amines Using
Catalytic Ir(TTP)CH3
■
a
N−H insertion using catalytic Ir(TTP)CH3 was initially studied
for the reaction between aniline and ethyl diazoacetate (EDA)
(Table 1). Treating a CH2Cl2 solution of Ir(TTP)CH3 and
Table 1. N−H Insertion of EDA and Aniline Catalyzed by
a
Ir(TTP)CH3
yield (%)
double
amine
diazo reagent
single
dimers
aniline
EDA
92
88
87
87
89
77
85
85
38
76
11
88
31
87
30
79
72
7
8
1
p-toluidine
EDA
4
p-anisidine
EDA
8
5
p-chloroaniline
p-bromoaniline
p-cyanoaniline
p-nitroaniline
EDA
7
6
c
EDA
8
3
yield (%)
EDA
20
6
3
entry
amt of aniline (equiv)
1.1
1
2
dimers
EDA
9
1
2
3
4
5
6
70
76
87
93
25
19
10
5
5
5
b
benzylamine
EDA
15
27
18
12
0
0
b
1.1
b
tert-butylamine
EDA
35
6
2.0
3
cd
,
n-butylamine
EDA
3.0
2
e
acetamide
EDA
59
trace
32
4
d
d
0.5
32.
61.
18
48
bcf
,
,
aniline
MPDA
MPDA
MPDA
MPDA
MPDA
MPDA
d
d
0.25
3.
94.
bc f
, ,
tert-butylamine
tert-butylamine
0
a
be g
, −
Conditions: Ir(TTP)CH3 (0.06 mol %), aniline, and CH2Cl2 (2.0 mL)
0
c
,
d f
,
were treated with EDA (150 μmol). Yields were determined by NMR.
benzylamine
benzylamine
0
trace
trace
trace
b
b,
e g
−
The reaction started at −78 °C, and the mixture was warmed to
0
c
d
ambient temperature over 2 h. Yield based on EDA. Yield based on
aniline.
be f
,
,
acetamide
0
a
Conditions: Ir(TTP)CH3 (0.07 mol %) and amine (2.0 equiv) were
dissolved in CH2Cl2 (2.0 mL) and treated with EDA (1.0 equiv,
b
aniline with 1.1 equiv of EDA at ambient temperature gen-
erated a mixture of single (1) and double (2) N−H insertion
products in 70% and 25% yields, respectively, in less than 2 h.
The only observed byproducts were diethyl maleate and diethyl
fumarate, which resulted from dimerization of EDA. Similar to
the case for iron N−H insertion catalysts,26 dimerization yields
were unaffected by the rate of EDA addition; therefore,
dropwise addition of EDA was unnecessary. Changing the
stoichiometric ratios of the reactants, however, significantly
altered the product distribution. Increasing the amount of
aniline favored the formation of single-insertion product 1
while decreasing the amount of double-insertion and
dimerization products. In contrast, double-insertion product 2
and butenedioates were generated preferentially for reactions
where aniline was the limiting reagent. The proper choice of
stoichiometric ratios could produce either 1 in 93% yield or 2
in 94% yield. The reaction temperature also influenced
selectivity; starting the reaction at −78 °C and then warming
it the mixture to ambient temperature gave a modest increase in
single insertion (Table 1, entries 1 and 2). For all conditions,
low catalyst loadings (0.06 mol %) were sufficient to effect the
reaction with high yields. Turnover numbers as high as 105
were observed without any indication of catalyst deactivation.
On the basis of the above results, two separate Ir(TTP)CH3-
catalyzed procedures were developed to optimize the selective
formation of either the single- or double-insertion product. To
generate single-insertion products, reactions were run at
−78 °C using a 2-fold excess of amine relative to EDA. High
single-insertion yields were found for reactions between aryl
amines and EDA (Table 2). Double insertion occurred in less
than 10% yield with all aryl substrates except for p-cyanoaniline,
where the diglycyl ester was generated in 20% yield. Aliphatic
amines required increased catalyst loadings (0.25−0.50 mol %).
Additionally, higher temperatures were used for t-butylamine
150 μmol). Yields were determined by NMR. 0.25 mol % catalyst
c
d
loading. Run at ambient temperature for ca. 24 h. 0.5 mol % catalyst
e
f
g
loading. Refluxing. Using 1.1 equiv of amine. Ir(TTP)CH3, MPDA,
and CH2Cl2 were treated with amine dropwise.
and acetamide. Single-insertion products were formed in good
yields for benzylamine and n-butylamine, but reactions with
tert-butylamine generated the single-insertion product in
modest yield and with little selectivity. Attempts to insert
EDA into an amide N−H bond also resulted in low yields and
selectivity.
This method was also extended to methyl phenyldiazoacetate
(MPDA). With aryl amines and amides, single-insertion
products were generated in good yields (Table 2). However,
reactions with aliphatic amines were sluggish and low yielding
over a ca. 24 h time frame, suggesting that these amines were
poisoning the catalyst and preventing MPDA coordination.
Accordingly, the order of addition was altered so that MPDA
was allowed to interact with Ir(TTP)CH3 before slow addition
of the amine. This method works for MPDA because its rate of
dimerization is slow, whereas EDA under these conditions
would completely dimerize.36,37 The initial catalyst solution
darkened from orange to dark green, on addition of MPDA,
signifying the formation of a metal−carbene intermediate.32
Subsequent dropwise addition of the amine quickly quenched
this intermediate and turned the solution color back to orange.
The reaction color was allowed to revert back to dark green
before the next aliquot of amine was added. Using this
technique, single-insertion products were generated in 87% and
79% yields for tert-butylamine and benzylamine, respectively.
Double-insertion products were not observed for any reactions
with MPDA.
For the above reactions with aryl amines, prolonged stirring
of the reaction mixture (>8 h) led to the formation of imine
B
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esters resulting from oxidation of the single-insertion products
(eq 1). Similar oxidations have been shown with other late-
metal catalysts.38,39 The oxidation of monoglycine 1 was briefly
Table 4. N−H Insertion into Secondary Amines Using
d
Catalytic Ir(TTP)CH3
investigated under various conditions. Heating 1 in the
presence of catalytic Ir(TTP)CH3 at 55 °C for 36 h in air
produced imine 3 in 19% yield. Under the same condi-
tions without Ir(TTP)CH3, no oxidation was observed.
The amount of oxidation was increased slightly by heating
under an O2 atmosphere, but the yield was never greater
than 25%.
Double-insertion products were generated selectively at
ambient temperature with a 4-fold excess of diazo reagent to
amine. Reactions between EDA and arylamines afforded
double-insertion products in high yields. Good yields were
also found for benzylamine and n-butylamine, albeit with
slightly more single-insertion product formation relative to that
for arylamines (Table 3). However, reactions with tert-
Table 3. Double Insertion into Primary Amines Using
a
Catalytic Ir(TTP)CH3
a
b
Catalyst loading of 1.0 mol %. Using 2.0 equiv of N-isopropylaniline.
c
d
Using 0.25 mol % catalyst loading at reflux. Conditions: Ir(TTP)-
CH3 (0.07 mol %) and amine (1.1 equiv) were dissolved in CH2Cl2
(2.0 mL). The diazo reagent (1.0 equiv, 150 μmol) was added
dropwise over 30 s. Reactions were run at ambient temperature for
1−4 h. Yields were determined by NMR.
yield (%)
amine
aniline
single
double
3
2
97
98
97
98
98
96
83
89
78
24
21
p-toluidine
p-anisidine
3
or piperidine and EDA gave insertion products in good
yield, albeit at higher catalyst loadings (1.0 mol %) for
piperidine. A correlation between steric bulk and N−H inser-
tion efficiency was found for the reactions with N-alkylanilines.
As the bulk of the N-alkyl substituent was increased, reactions
proceeded more quickly, as indicated by rapid gas evolution
after EDA addition, but insertion yields decreased and the
amount of EDA dimerization increased. For example, reactions
with 1.1 equiv of N-methylanilines afforded insertion products
in 84% yield, whereas the same conditions with N-isopropylani-
line gave the insertion product in 61% yield. The yield for N-
isopropylaniline was increased to 86% using a 2-fold excess of
substrate. Following the same trend, attempts to generate a
mixed glycine ester by treating 4, the single-insertion product
from the reaction of aniline with MPDA, with EDA failed.
Compound 4 was too sterically encumbered, leading to rapid
and quantitative dimerization of EDA. As an alternative
approach to synthesizing mixed glycine esters, insertions into
secondary amines were briefly examined with MPDA. MPDA
reacted with N-methylanilines and compound 1 to generate
the corresponding trisubstituted amines in ca. 80% yields
(Table 4). The latter serves as the first reported method to
generate a mixed glycine ester from EDA and MPDA.
p-chloroaniline
p-bromoaniline
p-cyanoaniline
p-nitroaniline
benzylamine
n-butylamine
tert-butylamine
acetamide
2
2
3
9
11
22
1
21
a
Conditions: Ir(TTP)CH3 (0.07 mol %) and amine (1.0 equiv,
38 μmol) were dissolved in CH2Cl2 (2.0 mL), and EDA was added
dropwise (4.0 equiv). Reaction mixtures were stirred for 1−4 h at
ambient temperature. Yields were determined by NMR.
butylamine and acetamide gave modest yields with significant
amounts of dimerization of the diazo reagent. For most of the
double-insertion reactions, consumption of the amine substrate
was quantitative and dimerization of EDA did not diminish
insertion yields, indicating that N−H insertion occurred
preferentially over dimerization. This is noteworthy, given the
propensity of EDA to dimerize during cyclopropanation and
C−H insertion reactions, which are typically carried out using
excess substrate.29,32 In addition, some of the reactions for
double insertion exhibited a fleeting color change, signifying the
presence of an observable intermediate.
Reactivity trends indicated that amine substrates poison the
catalyst. The extent of this poisoning was elucidated further by
kinetics studies. The dependence of reaction rate on amine
concentration was measured for the reaction of aniline, methyl
Ir(TTP)CH3 was also capable of catalyzing N−H insertion
with secondary amines (Table 4). Reactions with N-alkylanilines
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diazoacetate (MDA), and catalytic Ir(TTP)CH3 at 300.0 K
(Figure 1). As the amine concentration was increased, the rate
para-substituted and N-alkyl-substituted aniline compounds
(Table 5). Comparing N-alkylaniline compounds showed that
Table 5. Equilibrium Binding Constants for the
Coordination of Amines to Ir(TTP)CH3 at 23 °C
amine
aniline
log K
4.4 0.1
4.0 0.1
2.7 0.4
2.0 0.1
5.4 0.4
5.0 0.1
4.4 0.1
3.4 0.1
N-methylaniline
N-ethylaniline
N-isopropylaniline
p-anisidine
p-toluidine
Figure 1. Rate comparison of MDA consumption for reactions with
Ir(TTP)CH3 (8.92 × 10−6 M), MDA (0.117 M), and varying amounts
of aniline (0.0595−0.209 M) in CD2Cl2 at 300.0 K.
p-chloroaniline
p-cyanoaniline
constant for MDA consumption decreased considerably. The
rate constant is quite sensitive to changes at low aniline
concentrations, but this inhibition effect appeared to saturate at
high aniline concentrations, thus allowing the catalyst to
tolerate high amine concentrations without deactivating
completely. In a similar study, the influence of substrate bulk
on reaction rate was examined by comparing the rate of MDA
consumption for aniline, N-methylaniline, N-ethylaniline, and
N-isopropylaniline. Increasing the bulk of the N-alkyl
substituent presumably inhibited its binding to the Ir center
and led to a dramatic increase in the rate of MDA consumption
(Figure 2), which was consistent with the reactivity trends
log K dramatically decreased as the bulk of the alkyl group was
increased, demonstrating that the ligand bulk had a significant
impact on binding. There was a similar relationship between log
K and the electronic character of the amine. Anilines with
electron-donating substituents at the para position had larger
equilibrium constants. Overall, the observed trends in ligand
binding were consistent with the kinetics results. Amines with
lower binding constants resulted in faster MDA consumption
under N−H insertion conditions, providing additional evidence
that competitive amine binding to the Ir center inhibited the
catalysis. The values of these log K values are reasonable in
comparison to those previously reported for binding between
Ir(OEP)(C3H7) and amines.40
Substrate competition reactions were examined to gain
further insight into the reaction mechanism. In the presence of
EDA and catalytic Ir(TTP)CH3, competitive reactions between
aniline and a series of para-substituted anilines generated a
Hammett correlation with slope ρ = 0.15 (Figure 3), suggesting
Figure 2. Effect of substrate sterics on the rate of MDA consumption
for reactions with Ir(TTP)CH3 (8.92 × 10−6 M), MDA (0.117 M),
and amine (0.119 M) in CD2Cl2 at 300.0 K.
previously discussed for secondary amines (Table 4). The sub-
strate electronics also influenced the reaction rate (Figure S1
in the Supporting Information), as observed indirectly
during Hammett correlation experiments (vide infra). Using
para-substituted aniline substrates and MDA, it was found that
reactions with electron-withdrawing substrates consumed MDA
more quickly than those with electron-donating substrates. This
electronic effect seemed to be less drastic than the steric effect.
Coordination of amine substrates to Ir(TTP)CH3 was
explored further by absorption spectroscopy using a UV/vis
titration method similar to that reported previously.40 To
evaluate the influence of amine electronics and sterics on ligand
binding, equilibrium constants were obtained for several
Figure 3. Hammett plots for the reactions between para-substituted
anilines and EDA or MPDA in the presence of catalytic Ir(TTP)CH3.
Substrates include p-anisidine, p-toluidine, p-chloroaniline, p-bromoa-
niline, p-cyanoaniline, and p-nitroaniline. The EDA series was fit to
standard σ values, whereas the MPDA series gave the best fit with σ+ values.
a slight buildup of negative charge during the reaction. This
result was unexpected, because similar reactions involving EDA
and a metalloporphyrin catalyst, including Fe(TPP)Cl-
catalyzed N−H insertion, produced Hammett correlations
with a negative ρ value.23,27 As a comparison, a similar
D
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correlation study was conducted using insertions of MPDA into
amines with Ir(TTP)CH3 as the catalyst. This study revealed a
Hammett correlation with a negative slope ρ+ = −0.56,
consistent with the previous study using Fe(TPP)Cl (ρ+ =
−0.66).27 A better Hammett fit for the MPDA reactions was
obtained using σ+ values (R2 = 0.93) rather than the standard
σ values (R2 = 0.86).
1,4-cyclohexadiene (C−H insertion).29,32 Since O−H insertion
had not been previously reported for Ir(TTP)CH3, phenol was
chosen on the basis of its reactions with Fe(TPP)Cl.24 For
reactions involving aniline, N−H insertion was heavily favored,
producing compound 1 in quantitative yields regardless of the
other substrate. This result is in contrast with that for
dirhodium catalysts, for which O−H insertion is favored over
N−H insertion.14 The other competition reactions generated a
mixture of products along with significant amounts of
dimerization materials (Table 6). Overall, these results indicate
the following reactivity trend: N−H insertion ≫ cyclo-
propanation > O−H insertion > C−H insertion.
Kinetic isotope effects (KIEs) were examined using aniline
and C6H5ND2 in the presence of Ir(TTP)CH3 (Table 6). For
Table 6. Substrate Competition Studies Using Catalytic
c
Ir(TTP)CH3
As mentioned above, double-insertion reactions exhibited a
transient color change, implying the involvement of an
intermediate species. This intermediate was investigated by
absorption spectroscopy for the reaction between aniline and a
4-fold excess of EDA in the presence of 0.28 mol % of
Ir(TTP)CH3. The Soret band of Ir(TTP)CH3 in CH2Cl2,
which initially displayed λmax at 407 nm, red-shifted to 415 nm
after addition of aniline to signify the formation of
hexacoordinate Ir(TTP)CH3(aniline). EDA was added sub-
sequently, and the reaction progress was monitored every
10 s. Over the course of 105 s, the band at 415 nm was
partially consumed to give rise to two bands at 377 and 441 nm
(Figure 4). These intermediate bands returned to a single band
Figure 4. Absorption spectra for the reaction between aniline (27 μmol)
and EDA (105 μmol) in the presence of Ir(TTP)CH3 (0.075 μmol,
7.5 × 10−5 M in CH2Cl2) over 105 s. The spectra shown depict the
solution absorbance before EDA was added (light gray) and the
reaction progress from initial EDA addition toward the maximum
absorbance of the intermediate bands (gray to black).
a
Reaction generated a significant amount of an undetermined side-
b
at 415 nm over the course of minutes. Isosbestic behavior was
followed for a majority of the reaction, except immediately after
EDA addition and near the end, when aniline consumption was
nearly complete. This deviation from isosbestic behavior
indicates that the transition from Ir(TTP)CH3(aniline) to the
intermediate is not a smooth process, suggesting that aniline
must first dissociate from the hexacoordinate resting state in
order for EDA to react with Ir(TTP)CH3 and form the
intermediate. Interestingly, repeating this procedure using a
1:2 ratio of aniline to EDA did not produce a change in the
415 nm band (Figure S11 in the Supporting Information). A
second addition of EDA, making an effective overall 4-fold
excess of EDA to aniline, was required to reproduce the
intermediate spectrum. Attempts to detect the intermediate
product. Diethyl maleate and diethyl fumarate were the only other
reaction products. Conditions: Ir(TTP)CH3 (0.07 mol %), substrate
c
A (5.0 equiv), substrate B (5.0 equiv), and CH2Cl2 (2.0 mL) were
treated with diazo reagent (120 μmol) at ambient temperature. Yields
were determined by NMR.
reactions with EDA, no KIE was observed. However, MPDA
produced a KIE (2.7
0.2) consistent with similar systems
where proton transfer was rate-limiting.16,41 This study, along
with the Hammett correlation results, demonstrated that
reactions with EDA are less sensitive to the nature of the
amine substrate than those with MPDA. Other competition
reactions were investigated to explore the relative rate of N−H
insertion reactions in comparison to cyclopropanation, C−H
insertion, and O−H insertion. The substrates chosen to
represent each reaction were among the most efficient
for their respective reactions: styrene (cyclopropanation) and
1
complex by H NMR spectroscopy failed. Furthermore, an
intermediate was not observed under similar conditions with
MPDA.
E
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The bands shown in Figure 4 are very similar to the 375 and
443 nm bands observed previously for the metal−carbene
complex formed from Ir(TTP)CH3 and MPDA.32 The
intermediate spectrum observed here may represent a metal−
carbene complex, but the alternative of an aniline-stabilized
metal−carbene complex or a metal−ylide complex, similar to
those shown for osmium porphyrins,42 is also possible. Further
insight was gained by monitoring the formation and
lifetimes of intermediate complexes for reactions with different
para-substituted aniline compounds. The reaction progress
for each substrate was compared by plotting the intensity
of the intermediate band at 441 nm versus time (Figure 5).
The same result was found using a variety of different stoichio-
metric ratios, indicating that a free ylide compound either is
short-lived or is not formed under any of the present reaction
conditions. An alternative trapping experiment was attempted
with diallylamine as the substrate. The allyl moieties can trap
metal−ylide intermediates via a rapid intramolecular 2,3-
sigmatropic rearrangement.26 Treating diallylamine with an equi-
molar amount of EDA in the presence of catalytic Ir(TTP)CH3,
at ambient temperature, generated primarily N−H insertion
product 7 (52%) along with small amounts of compound 8
(10%), presumably formed as a result of a tandem N−H
insertion and 2,3-sigmatropic rearrangement (eq 3). Monitoring
Figure 5. Formation of the intermediate after EDA addition, as
monitored by the plot of the intermediate band at 441 nm versus time.
Reaction conditions: Ir(TTP)CH3 (7.24 × 10−5 M), EDA (0.105 M),
and various aniline substrates (0.026 M). Data points were collected at
30 s intervals.
1
the reaction by H NMR revealed that compound 7 formed
Bands corresponding to an intermediate were not observed
with p-cyanoaniline; only a slight broadening of the Ir(TTP)-
CH3(L) Soret band occurred. With all other aniline substrates,
the rate of formation of the intermediate slowed and the
lifetime of the intermediate was prolonged as the para
substituents became more electron rich. The formation trend
is consistent with electron-rich amines binding more strongly to
Ir and delaying the appearance of the intermediate, due to
slower amine dissociation. However, the metal binding trend
does not explain the short intermediate lifetime for the
electron-deficient substrates p-chloroaniline and p-cyanoaniline.
If a metal−carbene complex was the intermediate, electron-
deficient substrates would nucleophilically attack and consume
the intermediate more slowly than electron-rich substrates.
Moreover, if amine substrates were participating only in metal
binding, one would expect similar intermediate profiles for
aniline and p-chloroaniline, given their similar binding con-
stants (Table 5). A more likely explanation is that the aniline
substrates are stabilizing the intermediate species. This implies
that the substrate must be bound in the intermediate and
strongly implicates a metal−ylide intermediate, similar to those
suggested for related N−H insertion catalysts.16,26
Trapping experiments were conducted to probe the involve-
ment of metal−ylide intermediates. In a previous study,
Aviv and Gross found that treating aniline with EDA in the
presence of catalytic Fe(TPP)Cl and stoichiometric diethyl
azodicarboxylate (DEAD) generated compound 6 as the sole
product (eq 2).26 Compound 6 formed as a result of DEAD
trapping the free ylide intermediate (5). Using catalytic
Ir(TTP)CH3 under the same conditions, the N−H inser-
tion product 1 was generated without any trace of compound 6.
initially and compound 8 grew in slowly as diallylamine became
scarce. Addition of excess EDA at the end of the reaction
resulted in continued production of 8 at the expense of
compound 7. Throughout the reaction, the secondary amine
corresponding to 2,3-sigmatropic rearrangement of diallylamine
was never observed. It can be concluded that compound 8
formed by metal-ylide formation with 7 followed by 2,3-
sigmatropic rearrangement, demonstrating that proton transfer
occurred preferentially to intramolecular sigmatropic rearrange-
ment. Regardless, the fact that tertiary allylic amines undergo a
2,3-sigmatropic rearrangement further supports the potential
for metal−ylide intermediates.
Under ambient light, Ir(TTP)CH3 is sensitive to photolytic
cleavage of the Ir−CH3 bond, which generates Ir(TTP)Cl(CO)
in the presence of halogenated solvents.43 To ensure that this is
not significant during N−H insertion, photolysis of Ir(TTP)-
CH3 and Ir(TTP)CH3(aniline) was examined by absorption
spectroscopy using both ambient and sun lamp light sources.
With either light source, photolysis of Ir(TTP)CH3 in CH2Cl2
generated Ir(TTP)Cl(CO), as indicated by a shift of the Soret
band from 407 to 421 nm. Conversion was quantitative and
complete in less than 15 min using the sun lamp. In contrast,
radiating Ir(TTP)CH3(aniline) under the same conditions did
not lead to a shift in the Soret band (Figure S21 in the
Supporting Information), demonstrating that the photolytic
cleavage of the Ir−CH3 bond is drastically inhibited in the
presence of amines. In addition, attempts were made to trap
transient radical intermediates under N−H insertion conditions
using 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO). N−H
insertion reactions carried out in the presence of TEMPO
showed no qualitative change in the reaction rate or product
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distribution, indicating further that species with radical
character were not substantial during the reaction.
The above evidence supports the catalytic cycle shown in
Scheme 1, which is analogous to the stepwise mechanism
yields, with up to 105 catalyst turnovers and without the need
for slow addition of the diazo reagent. Although competitive
amine binding to the catalyst was demonstrated, insertions with
aliphatic amines still proceeded in good yields in many cases.
Slow addition of the amine was required only for reactions
between aliphatic amines and MPDA. Mixed glycine ester
products, RN(CH2CO2Et)(CHPhCO2Me), were generated for
the first time using an N−H insertion protocol.44,45 In general,
mechanistic studies support a stepwise mechanism with a
metal−ylide intermediate, where proton transfer is simulta-
neous with ylide dissociation from the iridium center.
Scheme 1. Proposed Catalytic Cycle for N−H Insertion
Reactions Catalyzed by Ir(TTP)CH3
EXPERIMENTAL SECTION
■
General Considerations. Unless noted otherwise, all manipu-
lations were performed under a dry nitrogen atmosphere. Substrates
were reagent grade and used without purification for catalytic
reactions. For quantitative analyses, aniline substrates containing
colored impurities, specifically p-toluidine, were recrystallized from
ethyl acetate. Ir(TTP)CH3 and MPDA were prepared according to
previously reported methods.46−48 C6H5ND2 was prepared by treating
aniline with D2O. CH2Cl2 was dried and deoxygenated by passage
through columns of alumina and reduced copper. For kinetics
reactions, CDCl3 was dried over molecular sieves, deoxygenated by
three freeze−pump−thaw cycles, and passed through a plug of
activated alumina under a glovebox atmosphere. Absorption spectra
were collected using a Hewlett-Packard/Agilent Technologies 8453
UV−vis spectrophotometer. General NMR spectra were collected
using Varian VXR 300 MHz and Varian VXR 400 MHz spectrometers,
and kinetic measurements were done using a Bruker DRX 400 MHz
spectrometer. 1H NMR peak positions were referenced against
residual proton resonances of deuterated solvents (δ, ppm: CDCl3,
7.26 (1H) and 77.16 (13C)). Gas chromatography was performed on
an HP-6890 instrument fitted with an HP-5 capillary column (30 m
length, 0.25 mm internal diameter, 0.25 μm film thickness). Column
chromatography was performed using silica gel (40−63 μm)
purchased from Sorbent Technologies. Characterization data for
most N−H insertion products were previously reported.26,27,49−56
Procedure for Single Insertion into Primary Amines. Method A.
A CH2Cl2 stock solution of Ir(TTP)CH3 (4.25 × 10−3 M stock
solution, between 0.07 and 0.50 mol %) was transferred to a side-arm,
round-bottom flask and taken to dryness under a nitrogen stream.
The catalyst was dissolved in CH2Cl2 (2.0 mL) and amine substrate
(373 μmol). The solution was cooled to −78 °C in a dry ice/acetone
bath and then treated with the diazo reagent (154 μmol). Reaction
mixtures were warmed to ambient temperature over the course of
1−2 h, and volatiles were removed in vacuo after the diazo reagent was
fully consumed, which required 2−24 h depending on the substrate.
The reaction progress could be monitored by TLC or GC. Yields were
proposed for a copper catalyst involving a simultaneous proton
transfer and catalyst dissociation step.16 Initially, the diazo
reagent and the amine substrate compete for binding to the
vacant site of Ir(TTP)CH3. Amine binding forms an inactive
hexavalent complex, whereas binding of the diazo reagent to
Ir(TTP)CH3 produces a diazonium complex. Once formed, the
diazonium complex loses dinitrogen to form a metal−carbene
complex, as was shown for the analogous Ir-catalyzed C−H
insertion reactions.32 Amine substrates react with the electro-
philic metal−carbene complex to form a metal−ylide
intermediate, which is supported by absorption spectroscopy
studies. Although the above data cannot determine if metal−
ylide formation is stepwise or concerted (i.e., whether or not a
metal−carbene complex truly forms), this process must be
rapid, as indicated by the drastic chemoselectivity between
different substrates such that N−H insertion is strongly favored
over carbene dimerization, cyclopropanation, C−H insertion,
and O−H insertion (Tables 4 and 6, vide supra). Once the
metal−ylide complex is formed, proton transfer produces the
glycine ester product and regenerates Ir(TTP)CH3. Since
attempts to trap a free ylide compound with DEAD were
unsuccessful, proton transfer apparently occurs simultaneously
with ylide dissociation from the metal center. Kinetic isotope
effect studies, where amine substrate is present in excess,
support a rate-limiting proton transfer for reactions with
MPDA but not for those with EDA. However, the observation
of a metal−ylide intermediate under conditions of excess EDA
implies that the rate-limiting step changes depending on the
reaction conditions.
1
determined by H NMR using mesitylene as the internal standard
(57.5 μmol). Samples could be purified by column chromatography on
silica gel using an eluent system of ethyl acetate and hexanes.
Method B. This method was used for reactions between MPDA and
the aliphatic amines benzylamine and tert-butylamine. Two separate
solutions were prepared under a nitrogen atmosphere. The first
contained Ir(TTP)CH3 (0.391 μmol) and CH2Cl2 (2.0 mL), and the
second contained CH2Cl2 (1.0 mL) and amine substrate (165 μmol).
The former was heated to reflux and then treated with MPDA
(154 μmol). After the solution rapidly turned dark green, it was treated
with the amine solution dropwise. Each drop caused the color to
change briefly to a light orange before returning to dark green. Once
all the amine solution was added and the reaction solution maintained
a light orange color, volatiles were removed and the residue was
1
analyzed by H NMR.
Procedure for Double Insertion into Primary Amines.
CH2Cl2 stock solutions of Ir(TTP)CH3 (26 μL from a 4.25 ×
10−3 M stock solution, 0.111 μmol) and amine substrate (ca. 1 M,
38.5 μmol) were transferred to a side-arm, round-bottom flask and
taken to dryness under a nitrogen stream. The solids were dissolved in
CONCLUSIONS
■
Ir(TTP)CH3 catalyzed the N−H insertion reactions of various
aryl, aliphatic, primary, and secondary amines with diazoacetate
reagents. Reactions with arylamines produced the highest
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CH2Cl2 (2.0 mL), and then the diazo reagent (154 μmol) was added
dropwise over 30 s. After the diazo reagent was fully consumed, which
generally required 1−4 h of stirring at ambient temperature, volatiles
Ethyl 2-(Isopropyl(phenyl)amino)acetate. Purification by col-
umn chromatography on silica gel (1/40 ethyl acetate/hexanes) gave
the product as a light yellow oil (59.9 mg, 77% yield). 1H NMR
(CDCl3, 400 MHz): δ 7.22 (t, J = 7.2 Hz, 2H), 6.72 (t, J = 7.2 Hz,
1H), 6.69 (d, J = 7.2 Hz, 2H), 4.24−4.14 (m, 3H), 3.92 (s, 2H), 1.27
(t, J = 6.8 Hz, 3H), 1.21 (d, J = 6.4 Hz, 6H). 13C{1H} NMR (CDCl3,
300 MHz): δ 172.39, 148.61, 129.39, 117.18, 112.76, 61.11, 48.12,
46.94, 20.11, 14.38. HRMS (ESI): calcd for C13H19NO2 (M + H)+
m/z 222.1489, found m/z 222.1488.
1
were removed in vacuo. Yields were determined by H NMR using
mesitylene as the internal standard (57.5 μmol).
Procedure for Insertion into Secondary Amines. A portion of
Ir(TTP)CH3 (4.25 × 10−3 M stock solution, between 0.07 and
0.50 mol %) was taken to dryness under a nitrogen stream and then
dissolved in CH2Cl2 (2.0 mL) and amine (162 μmol). The solution
was treated with diazo reagent (154 μmol) and stirred at ambient
temperature unless otherwise noted until the diazo reagent was
completely consumed (1−4 h). Volatiles were removed in vacuo.
Methyl 2-((2-Ethoxy-2-oxoethyl)(phenyl)amino)-2-phenyla-
cetate. Purification by column chromatography on silica gel (1/20
ethyl acetate/hexanes) gave the product as a light yellow oil (36.7 mg,
73% yield). 1H NMR (CDCl3, 400 MHz): δ 7.36 (s, 5H), 7.27 (t, J =
8.0 Hz, 2H), 6.86 (t, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 2H), 5.71 (s,
1H), 4.06 (ABq, JAB = 18.4 Hz, ΔνAB = 22.7 Hz, 2H), 4.00 (q, J =
7.0 Hz, 2H), 3.79 (s, 3H), 1.12 (t, J = 7.0 Hz, 3H). 13C{1H} NMR
(CDCl3, 300 MHz): δ 172.42, 171.13, 148.80, 135.06, 129.42, 129.09,
128.84, 128.65, 119.30, 114.16, 65.37, 60.77, 52.35, 50.59, 14.20.
HRMS (ESI): calcd for C19H21NO4 (M + H)+ m/z 328.1544 and
(M + Na)+ m/z 350.1363, found m/z 328.1549 and 350.1368.
1
Yields were determined by H NMR using mesitylene (57.5 μmol) as
the standard.
Amine N−H Insertion Competition Reactions. A vessel was
prepared containing Ir(TTP)CH3 (0.118 μmol), both amine
substrates (778 μmol each), and CH2Cl2 (4.0 mL). The diazo reagent
(154 μmol) was added, and the solution was stirred at ambient
temperature until the diazo reagent was completely consumed, which
generally took 12−48 h. For samples that were analyzed by 1H NMR,
which include those for the Hammett correlation study with EDA, the
solution was then stirred with D2O (ca. 2 mL) for 12 h. The organic
portion was separated, taken to dryness in vacuo, and analyzed by
1H NMR using mesitylene (57.5 μmol) as the standard. Reactions
investigating the Hammett relationship with MPDA were analyzed by
GC using hexadecane (68.3 μmol) as the standard. Products from
reactions investigating KIE were purified by column chromatography
on silica gel using an ethyl acetate/hexanes eluent (1/10 for products
formed from EDA and 1/30 for products formed from MPDA). The
purified materials were stirred with D2O (2.0 mL) for ca. 12 h, taken
Ethyl 2-(Diallylamino)acetate (7). Ir(TTP)CH3 (4.26 × 10−3
M
stock solution, 0.02 mol %) was taken to dryness under a nitrogen
stream and then dissolved in CH2Cl2 (2.0 mL) and diallylamine
(983 μmol). The solution was treated with EDA (490 μmol) and
stirred overnight at ambient temperature. Removal of volatiles in vacuo
and purification by column chromatography on silica gel (1/20 ethyl
acetate/hexanes) gave the product as a light yellow oil (49.2 mg, 60%
1
yield). H NMR (CDCl3, 400 MHz): δ 5.85 (ddt, Jab = 16.8 Hz,
Jac = 10.0 Hz, Jad = 6.4 Hz, 2H), 5.21−5.13 (m, 4H), 4.15 (q, J = 7.2 Hz,
2H), 3.30 (s, 2H), 3.23 (d, J = 6.4 Hz, 4H), 1.25 (t, J = 7.2 Hz, 3H).
13C{1H} NMR (CDCl3, 300 MHz): δ 171.45, 135.33, 118.35, 60.47,
57.35, 54.00, 14.39. HRMS (ESI): calcd for C10H17NO2
(M + H)+ m/z 184.1332, found m/z 184.1331.
1
to dryness, and analyzed by H NMR.
UV−vis Observation of Ylide Intermediate. In a 1 mm path
length cell in air, Ir(TTP)CH3 (17 μL from a 4.26 × 10−3 M stock
solution in CH2Cl2, 0.0724 μmol) and amine (61 μL from a 0.426 M
stock solution in CH2Cl2, 26.0 μmol) were diluted to 1.0 mL in
CH2Cl2. A spectrum at time t = 0 was acquired. Then, EDA
(105 μmol) was added quickly. An absorption spectrum was acquired
as quickly as possible (t = ca. 20 s) and then at 30 s intervals starting at
t = 30 s.
TEMPO and DEAD Trapping Experiments. Ir(TTP)CH3 from a
CH2Cl2 stock solution (4.25 × 10−3 M stock solution, 0.07 mol %)
was taken to dryness under a nitrogen stream and then dissolved in
CH2Cl2 (2.0 mL), amine (120 μmol), and DEAD (or TEMPO where
applicable, 120 μmol). Reaction mixtures were treated with EDA
(119 μmol) at ambient temperature. Products were analyzed by
1H NMR.
Kinetics Reactions. A portion of Ir(TTP)CH3 from a CH2Cl2
stock solution (6.57 × 10−5 M, 2.34−6.97 × 10−3 μmol) was collected
in a medium-walled NMR tube and taken to dryness. Under a
glovebox atmosphere, the tube was charged with aniline (from a
CDCl3 stock solution, 25.0−87.8 μmol) and mesitylene standard
(40.0 μL from a 5.06 × 10−2 M CDCl3 stock solution, 2.02 μmol) and
diluted to 4.20 × 102 μL with CDCl3. The tube was fitted with a
septum and taken to the NMR instrument. After the instrument was
tuned and the temperature equilibrated at 300.0 K, MDA (29.0 μL
from a 1.70 M CDCl3 stock solution, 49.3 μmol) was added and the
reaction was monitored by spectra acquired at 60 s intervals.
Determination of Amine Binding Constants. For all spectra,
samples were prepared in a 1 mm path length cell and in benzene,
rather than CH2Cl2, to avoid photolysis of the Ir−CH3 bond. Molar
extinction coefficients were determined by generating Beer’s law plots
for Ir(TTP)CH3 and the coordination complexes formed with
Ir(TTP)CH3 and N-alkylanilines, para-substituted anilines, or
pyridine. For these samples, concentrations of Ir(TTP)CH3 ranged
from 8.80 × 10−6 to 1.09 × 10−4 M in benzene, and coordination
complexes were examined in 0.1 M solutions of the respective amine.
After determination of all the molar extinction coefficients, equilibrium
constants were measured for solutions with known initial concen-
trations of Ir(TTP)CH3 ((4.00−5.27) × 10−5 M) and amine (4.68 ×
10−5 to 1.83 × 10−2 M).
Ethyl 2-(Allyl(2-ethoxy-2-oxoethyl)amino)pent-4-enoate (8).
Ir(TTP)CH3 (4.26 × 10−3 M stock solution, 0.02 mol %) was taken
to dryness under a nitrogen stream and then dissolved in CH2Cl2
(2.0 mL) and diallylamine (487 μmol). The solution was cooled to
−78 °C in a dry ice/acetone bath, treated with EDA (490 μmol), and
warmed to ambient temperature over 1 h. This process was repeated
for a second addition of EDA (980 μmol total). Removal of volatiles in
vacuo and purification by column chromatography on silica gel (1/30
ethyl acetate/hexanes) gave the product as a clear oil (23.8 mg, 29%
yield). 1H NMR (CDCl3, 400 MHz): δ 5.81 (m, 2H), 5.22−5.02
(m, 4H), 4.14 (m, 4H), 3.54 (m, 2H), 3.42−3.38 (m, 2H), 3.29−3.23
(m, 1H), 2.46 (m, 2H), 1.25 (m, 6H). 13C{1H} NMR (CDCl3, 300
MHz): δ 172.50, 171.85, 135.75, 134.48, 117.99, 117.18, 63.64, 60.50,
60.37, 55.53, 51.67, 34.87, 14.49, 14.30. HRMS (ESI): calcd for
C14H23NO4 (M + Na)+ m/z 292.1519, found m/z 292.1530.
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures givign data from kinetics studies, equilibrium binding
studies, absorption spectroscopic observation of the inter-
mediate, photolysis experiments, and spectra of previously
unreported compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail for L.K.W.: kwoo@iastate.edu.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
H
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ACKNOWLEDGMENTS
■
NSF grant CHE-0809901 and a GAANN fellowship (B.J.A.)
provided partial financial support for this work.
ABBREVIATIONS
■
EDA, ethyl diazoacetate; MPDA, methyl phenyldiazoacetate;
TTP, tetratolylporphyrinato dianion; OEP, octaethylporphyr-
inato dianion; DEAD, diethyl azodicarboxylate; TEMPO,
2,2,6,6-tetramethylpiperidine 1-oxyl; TON, turnover number;
KIE, kinetic isotope effect; NMR, nuclear magnetic resonance;
GC, gas chromatography; TLC, thin-layer chromatography;
HRMS, high-resolution mass spectrometry; ESI, electrospray
ionization
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