Urea-catalyzed N-H insertion-arylation reactions of nitrodiazoesters

Article abstract of DOI:10.1021/jo500698q

The power of hydrogen-bond donor catalysis has been harnessed to elicit and control carbene-like reactivity from nitrodiazoesters. Specifically, select ureas have been identified as effective catalysts for N-H insertion and multicomponent coupling reactions of nitrodiazoesters, anilines, and aromatic nucleophiles, thereby preparing a variety of α-aryl glycines in high yield. Experimental and computational studies designed to probe the plausible reaction pathways suggest that difluoroboronate ureas are particularly well-suited to catalyze reactions of nitrodiazoesters with a range of anilines through a polar reaction pathway. Urea-facilitated loss of nitrite followed by addition of a nucleophile conceivably generates the observed aryl glycine products.

Full text of DOI:10.1021/jo500698q

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pubs.acs.org/joc
Urea-Catalyzed N−H Insertion−Arylation Reactions of
Nitrodiazoesters
Sonia S. So,‡ Shameema Oottikkal,‡ Jovica D. Badjic, Christopher M. Hadad,* and Anita E. Mattson*
́
Department of Chemistry and Biochemistry, 100 West 18th Avenue, The Ohio State University, Columbus, Ohio 43210, United
States
S
* Supporting Information
ABSTRACT: The power of hydrogen-bond donor catalysis
has been harnessed to elicit and control carbene-like reactivity
from nitrodiazoesters. Specifically, select ureas have been
identified as effective catalysts for N−H insertion and
multicomponent coupling reactions of nitrodiazoesters, ani-
lines, and aromatic nucleophiles, thereby preparing a variety of
α-aryl glycines in high yield. Experimental and computational studies designed to probe the plausible reaction pathways suggest
that difluoroboronate ureas are particularly well-suited to catalyze reactions of nitrodiazoesters with a range of anilines through a
polar reaction pathway. Urea-facilitated loss of nitrite followed by addition of a nucleophile conceivably generates the observed
aryl glycine products.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Reaction Scope. Urea-catalyzed N−H insertion/multi-
The discovery of new reactions catalyzed by small organic
molecules is essential to advancing the field of organocatalysis.
As a means to alleviate concerns of sustainability and
environmental impact, the study of organocatalytic alternatives
to those reactions typically relying on transition metal catalysis
is a particularly attractive direction of research.1 Ureas and
thioureas have emerged as useful organocatalysts operating
through hydrogen-bonding interactions and offer promising
platforms for development as catalysts for reactions that
traditionally require metals.2
Etter’s groundbreaking co-crystallization data of ureas with
various guest molecules contributed to an inspirational starting
point for the development of urea catalysis.3 For example, the
urea−nitro group recognition was observed by Etter and co-
workers for a urea N,N-dimethyl-p-nitroaniline complex (1,
Figure 1). Urea−nitro group recognition may play a critical role
in a number of recently developed organocatalytic method-
ologies involving a variety of nitro compounds, including
nitroalkanes,4 nitroalkenes,5 and nitrocyclopropanes.6 We have
recently discovered that nitrodiazoesters also present compel-
ling opportunities for new organocatalytic method develop-
ment, plausibly taking advantage of urea−nitro group
recognition (2).7 At the onset of our studies, the control of
nitrodiazoester reactivity was reliant on catalysis with transition
metals, such as rhodium or copper, and limited to cyclo-
propanation8 and selected insertion reactions.9 This paper
provides a detailed account of our experimental and computa-
tional investigations into the reaction of nitrodiazoesters (3)
under the influence of various urea derivatives (6a−e, Table 1)
for N−H insertion/multicomponent coupling14 reactions for
the preparation of aryl glycines10 (7) in high yield (Scheme 1).
component coupling of nitrodiazoester 3 proved to be a
general strategy for the synthesis of aryl glycine derivatives 7
(Scheme 2).7a The nucleophilic aryl component 5 was easily
extended to a variety of anilines. Both N-methylaniline and
N,N-diethylaniline gave rise to high yields of aryl glycines 7a
and 7b (85% and 87%). Substituted anilines, such as 2,6-
dimethylaniline and 2,6-diisopropylaniline, were also readily
incorporated into the final products as exemplified by high
isolated yields of 7c and 7d (91% and 96%). A wide selection of
indoles was also accommodated in the multicomponent
coupling process. For example, indole and 5-methoxyindole
afforded 7e and 7f in 72% and 95% yields, respectively. Even
electron-poor indoles were tolerated in the reaction. 5-
Chloroindole enabled isolation of 7g in 58% yield, while 5-
bromoindole generated 7h in 68% yield after the urea-catalyzed
multicomponent coupling. Interestingly, the scope of the
reaction with respect to the aniline for N−H insertion was
the most limiting parameter identified thus far. The best N−H
insertion partners found in our hands for aryl glycine formation
have been aniline (7i, 85%), 4-methoxyaniline (7j, 78%), 4-
fluoroaniline (7k, 72%), and 4-methylaniline (7l, 70%). At this
time, we are able to form the desired product by controlling the
stoichiometry of the starting anilines. For example, in the case
of 7k, where both the 4-fluoroaniline and aniline components
are capable of undergoing N−H insertion, we selectively insert
into the N−H bond of 4-fluoroaniline by adding an excess of
this compound.
Plausible Mechanistic Pathways. In light of the discovery
of an unexpected, yet general, urea-catalyzed multicomponent
Received: March 25, 2014
Published: May 5, 2014
© 2014 American Chemical Society
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Figure 1. Urea−nitro group recognition as a platform for catalysis.
Table 1. Energetics of Complexation between α-Nitrodiazoester 3 and Various Urea Derivatives 6a−e, As Calculated at the
a
B3LYP/6-311++G**//B3LYP/6-31G* Level of Theory (in kcal/mol) at 298 K
entry
1
urea
CX
C−N
N−H
H--O
N−O
ΔE
ΔH
ΔG
6a
1.27
1.37
1.35
1.39
1.38
1.38
1.02
1.02
1.01
1.01
1.02
1.02
1.01
1.01
1.01
1.01
2.00
2.12
2.01
2.21
2.37
2.15
2.06
2.98
2.18
2.18
1.23
1.24
1.23
1.24
1.22
1.25
1.26
1.22
1.23
1.24
−9.8
−13.8
−1.5
2
3
4
5
6b
6c
6d
6e
1.23
1.66
1.22
1.23
−7.0
−3.4
−3.9
−6.4
−10.7
−8.8
−8.2
−8.0
−0.2
+3.3
+2.3
+1.9
1.39
1.39
a
The various bond distances of the hydrogen bonded complex are given in Å.
Scheme 1. Urea-Catalyzed N−H Insertion/Multicomponent Coupling
coupling of diazo compounds, the plausible reaction pathway
was considered more closely. Several experimental observations
collected during the substrate scope study afforded clues that
offered initial direction to our mechanistic studies (Scheme 3).
First, direct C−H insertion was ruled out as the first step of the
reaction pathway because no reaction was observed between 3
and heterocycles lacking nucleophilic N−H bonds available for
insertion, such as diethylaniline or indole, and all starting
materials were easily recovered (Observation 1). Not only was
4, the aniline component, required for the reaction, the success
of the reaction hinged on the concentration of the aniline
derivative. The best yields were obtained in the presence of at
least 10 equiv of 4-fluoroaniline; anything less afforded reduced
yields (Observation 2). These experimental observations led us
to reason that N−H insertion was the first bond-forming event
in the reaction pathway.
With evidence suggesting that N−H insertion is the first step
in the reaction pathway, the specifics of this step were more
closely considered. Observation 1 of Scheme 4 outlines a
control experiment in which two molecules of aniline (one
molecule acting as the N−H insertion partner 4 and one
molecule acting as nucleophilic component 5) reacted with 3
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a
Scheme 2. Urea-Catalyzed N−H Insertion/Multicomponent Substrate Scope
a
See the Supporting Information for experimental details.
Scheme 3. Initial Clues into the Reaction Pathway
without a urea catalyst and afforded just 8% of the desired
product 7a: this demonstrated the importance of the urea
(entry 1). Additionally, our results outlined in Observation 2
led us to determine that the boronate ureas were likely acting
through hydrogen bonding and not Lewis acid interactions.
The diminished, yet still moderate, activities of 3-
(trifluoromethyl)phenyl difluoroboronate urea 6f and phenyl
difluoroboronate urea 6g imply that the boron moiety was most
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Scheme 4. Evidence Supporting the Role of the Urea Catalyst
likely participating in internal coordination to the urea
carbonyl, and not activation of the reaction substrate. We
suspect that the electron-withdrawing effects of the trifluor-
omethyl groups affect the hydrogen bond donating ability of
the ureas (72% and 61% yields, entries 3 and 4, respectively),
leading to slightly diminished results when compared to 3,5-
bis(trifluoromethyl)phenyl difluoroboronate urea 6a (83%,
entry 2). Not surprisingly, acetamide 6h, a single-hydrogen
bond donor catalyst afforded just 33% of the desired product,
suggesting that dual hydrogen bonding was a necessary
component of the boronate urea catalyst for obtaining high
yields of the desired product 7a. 1H and 11B NMR
spectroscopic studies probing the structure of boronate urea
6a in solution, under the reaction conditions, remain
inconclusive.
urea−nitrodiazoester binding, and the lack of reactivity in the
absence of a urea catalyst, we reasoned that coordination of the
urea catalyst 6a to ethyl nitrodiazoacetate 3 forms complex 2 to
initiate the catalytic cycle and set out to collect additional
computational and experimental data supporting this theory.
Computational Urea−Nitrodiazoester Binding Stud-
ies. Foundational discoveries from our laboratory have led us
to conclude that select boronate ureas are especially well-suited
to activate and catalyze reactions of nitro compounds.11 In line
with our previous observations, difluoroboronate urea 6a was
identified as the highest yielding and most active catalyst for the
reaction of nitrodiazoester 3 with aniline 4 and nucleophile 5
(Scheme 1). Two deliberately incorporated design elements
contribute to the enhanced activity of catalyst 6a: (i) the
strategically placed difluoroboryl group causing increased
polarization of the urea functionality through internal
coordination and (ii) the 3,5-bis(trifluoromethyl)phenyl
functionality. Since its introduction in 2002 from Schreiner
and co-workers,12 the 3,5-bis(trifluoromethyl)phenyl group has
emerged as a privileged structure in hydrogen bond donor
catalyst design; it may aid in enhancing the urea acidity and
offer added stability to transition states.12b To further explore
the role of urea catalysis in the activation of nitrodiazoesters, a
d e t a i l e d co mp u t a t i o na l i n v e s ti g a t i o n a t t h e
B3LYP/6-311++G**//B3LYP/6-31G* level of theory was
carried out on the proposed complexes of nitrodiazoester 3
with various urea derivatives 6a−e to understand the mode and
strength of complexation. Out of several possible isomers of the
Having established its necessity, two roles that the urea
catalyst may play were hypothesized: (1) urea activation of the
aniline or (2) urea activation of the nitrodiazoester
(Observation 3, Scheme 4). Little experimental evidence
suggesting direct activation of the aniline with the urea catalyst
1
by H NMR spectroscopic analysis was found. Computation-
ally, we have calculated that protonation of the aniline followed
by reaction with the nitrodiazoester is endothermic by 28.22
kcal/mol, rendering this process unfavorable (see the
Supporting Information for details). On the other hand,
urea−nitrodiazoester binding was readily observed by 1H
NMR spectroscopy (Figure 2). Given the literature precedent
for urea−nitro group recognition, our own data suggesting
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1
Figure 2. Urea-nitrodiazoester binding titration studied by H NMR spectroscopy in acetone-d6 at 298.0 K. (A) Selected titration spectra with
corresponding concentrations and NMR chemical shifts. Titration data (0−262 equiv of guest 3) were fit to a 1:1 binding model. See the Supporting
Information for experimental details. (B) Job plot analysis suggesting 1:1 binding stoichiometry.
complex considered, the most stable complex (2, Table 1) has
two hydrogen bonds between the nitro group of α-nitro-
diazoester 3 and the urea. The calculated energetics of the
complexation show that the most stable complex 2 is formed
between the α-nitrodiazoester and difluoroboronate urea 6a,
followed by pinacol ester boronate urea 6b (Table 1). The
enhanced acidity of 6a (pKa(DMSO) = 7.5) and 6b
(pKa(DMSO) = 9.5),11 due to the intramolecular coordination
between boron and oxygen, results in stronger hydrogen-
bonded complexes with α-nitrodiazoester 3.13 The structural
parameters of the complex 2 with various urea derivatives are
given in Table 1. The shortest hydrogen bond (2.00 and 2.12
Å) is formed between α-nitrodiazoester 3 and urea 6a, followed
by 6b (2.01 and 2.21 Å). The enhanced hydrogen-bond
donating ability of the urea derivative 6a is also reflected in
shorter C−N and longer CO bonds of the urea complex
(C−N = 1.37, 1.35 Å and CO = 1.27 Å) when compared to
urea 6d (C−N = 1.38 Å and CO = 1.22 Å) and urea 6e (C−
N = 1.39 Å and CO = 1.22 Å), respectively, which are
incapable of benefiting from internal coordination. X-ray
crystallography confirmed that the carbonyl bond length of
urea 6a (1.274 Å) is indeed significantly longer than that of
urea 6d (1.221 Å) when hydrogen bonded to nitrobenzene.
Thus, the analysis confirms that urea 6a is in fact a more
enhanced hydrogen bond donor in the formation of complex 2.
Experimental Urea−Nitrodiazoester Binding Studies.
The interaction of nitrodiazoester 3 with difluoroboronate urea
1
6a was readily observed with H NMR spectroscopy (Figure
2A). An observed shift in the N−H proton signals by 1H NMR
allowed for a direct correlation to the binding affinity of urea 6a
to the nitro group of nitrodiazoester 3. At this time, we are
unable to assign protons HA and HB. Extensive 2D NMR
experimentation has yielded inconclusive results and analyses
are ongoing in our laboratory to definitively designate the urea
N−H protons. Following the diagnostic shifts of HA and HB,
upon titration of 0 to 262 equiv of nitrodiazoester 3, enabled
the calculation of an apparent experimental binding constant of
245 22 M−1 for HA and 295 30 M−1 for HB in acetone-
d6.13b A Job plot analysis supported a 1:1 binding stoichiometry
of urea 6a and nitrodiazoester 3 (Figure 2B).13
With evidence suggesting that urea activation of diazoesters
through hydrogen-bonding interactions initiates the reaction,
two plausible reaction steps were considered: (1) an N−H
insertion reaction pathway proceeding through a hydrogen-
bond stabilized carbene (pathway A) and (2) a polar reaction
pathway proceeding through a nucleophilic addition of aniline
to activated diazoester complex 2 (pathway B, Scheme 5).
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a
Scheme 5. Plausible Pathways of Urea-Catalyzed N−H Insertion/Multicomponent Coupling of Nitrodiazoesters
a
The energies listed are total energy differences (ΔE) in kcal/mol calculated at the B3LYP/6-311++G**//B3LYP/6-31G* level of theory.
Scheme 6. Experimental Observations Suggesting Carbene Formation Does Not Occur
Experimentally, several observations suggested that a
nucleophilic addition reaction pathway was preferred over a
pathway proceeding through a carbene (Scheme 6). Again, it
was very interesting to observe the reliance of the reaction on
the presence of aniline derivatives. In the absence of anilines,
electron-rich aromatic rings, such as indole and N,N-diethylani-
line, were unable to react with 3, and all starting materials could
be recovered (C, Scheme 6). Efforts to cyclopropanate 3 under
the influence of urea catalysis were also met with no success,
and at 30 °C after 24 h, 3, styrene ,and the urea catalyst were
completely recovered (D). Similarly, all of our attempts at O−
H insertion reactions were met with complete recovery of 3
(E). Even any attempt at inserting into the N−H bond of a
variety of aliphatic amines produced no reaction and only
decomposition of the starting diazoester was observed (F).
Further evidence of the preferred reaction pathway surfaced
from the lack of reactivity of 3 combined with boronate urea 6a.
At 23 °C, a temperature in which the title N−H insertion/
arylation reaction is observed, there are no new products
observed and all of 3 is recovered (A). Heating of the same
control reaction to 30 °C resulted in only slight decomposition
of 1 after 48 h (B). If the reaction was indeed proceeding
through a carbene intermediate, then the carbene would form
in the absence of the nucleophile; however, we only observed
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Figure 3. Comparative reaction profile for the insertion reaction of α-nitrodiazoester into the N−H bond of anilines with and without urea catalysts.
a
Scheme 7. Possible Routes for Aryl Glycine Formation
a
The energies listed are total energy differences (ΔE) in kcal/mol calculated at the B3LYP/6-311++G**//B3LYP/6-31G* level of theory.
the starting diazo compound. Although probing the mechanism
via the direct observation of a nitrocarbene intermediate would
be ideal, the well-documented rearrangement of nitrocarbenes
to the N-acyl nitroso species prevent study of the reaction
mechanism via this method.15,16 Additionally, it is possible for
nitrodiazoester 3 to rearrange to the N-acyl nitroso species
without formation of a carbene intermediate. Thus, our
observation of byproducts resulting from rearrangement to
the N-acyl nitroso species does not clearly suggest a carbene
pathway.7a The broad lack of reactivity in the absence of
anilines, combined with the recovery of 3 in the presence of 6a
but no aniline, led us to reason the reaction pathway was likely
proceeding through a nucleophilic addition reaction pathway
and not through the formation of a carbene intermediate.
Density functional theory (DFT) calculations provided
further substantiation of a preferred polar reaction pathway as
opposed to a pathway proceeding through a carbene. This
evidence was achieved through calculating the reaction energies
associated with difluoroboronate urea 6a, pinacol ester
boronate urea 6b, 3,5-bis(trifluoromethyl)phenyl thiourea 6c,
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3,5-bis(trifluoromethyl)phenyl urea 6d, and unsubstituted
diphenyl urea 6e for the N−H insertion/multicomponent
coupling of nitrodiazoester 3 with two anilines. As shown in
Scheme 5, pathway A is proposed to proceed with loss of N2
through TS-I to form urea-stabilized nitrocarbene intermediate
9. The N−H insertion of carbene 9 into aniline 4 through TS-
II gives rise to zwitterionic species 8, which forms α-nitroester
10 after proton transfer. With our most active urea catalyst,
boronate urea 6a, TS-I has a calculated ΔE of 23.9 kcal/mol.
Insertion of 9 into the N−H bond of aniline occurs with an
activation barrier of 5.0 kcal/mol to generate urea complex 8
(−49.9 kcal/mol). The carbene-free mechanism to access α-
amino-α-nitroester 10 is outlined in pathway B. From complex
2, nucleophilic attack by aniline, followed by loss of N2, forms
zwitterionic species 8, providing access to nitroester 10 after a
proton transfer. When compared to pathway A, TS-III has a
lower activation barrier than TS-I (21.6 vs 23.9, Scheme 5).
Although the activation barriers are close, the preference of TS-
III over TS-I is retained, independent of methods of calculation
or solvation. Taken collectively, the experimental and computa-
tional data support the preference for polar reaction pathway B.
Role of Urea on the N−H Insertion Reaction. We have
calculated the energies of transition states, intermediates, and
products involved in the insertion reaction in the presence of
different ureas and compared these values with the insertion
reaction in the absence of a urea catalyst. A comparative
reaction profile for the insertion reaction in the presence and
absence of urea catalysts is shown in Figure 3. The analysis of
the insertion of α-nitrodiazoester 3 into the N−H bond of
aniline 4a in the absence of a urea catalyst shows that the
transition states and intermediates are less stable when
compared to urea-catalyzed reactions. For example, zwitterion
8 without a urea catalyst is less stable by 16.6 kcal/mol
(Scheme 5: entry 1, −33.2 kcal/mol vs entry 2, −49.8 kcal/
mol). Similarly, formation of nitroester 10 is less favorable by
8.4 kcal/mol than compared with urea 6a (−54.8 kcal/mol vs
−63.2 kcal/mol). However, the energetics of the reaction
without a urea catalyst are such that it is feasible for the reaction
to proceed, albeit with less efficiency. This is corroborated by
the 8% yield of aryl glycine 7i (Scheme 4) observed when
diazoester 3 is reacted with aniline, but without catalyst.
nitroester 10 makes pathway E unlikely. When comparing the
energetics of pathways C and D, it is difficult to assign a clearly
preferred pathway. We have not located a transition state for
the one-step transformation from nitroester 10 to the structure
11 through pathway C. Both pathways seem plausible, and at
this time, all of our efforts to experimentally probe the
conversion of nitroesters 10 to aryl glycines 7 have been
prevented by the apparent unstable nature of the α-amino
nitroester 10; we have been unable to isolate or independently
prepare this species. As a model study, we probed the reactivity
of α-alkoxy-α-nitroester 16 as a suitable alternative to α-amino-
α-nitroester 10 (Scheme 8). Subjecting 16 with N,N-
Scheme 8. Reaction of α-Benzyloxy-α-nitroester with Aryl
Nucleophiles
diethylaniline and 20 mol % of difluoroboronate urea 6a at
23 °C yielded no reaction, and only the α-alkoxy-α-nitroester
was recovered. Heating the reaction mixture to 40 °C still
afforded no desired product, although slight decomposition
(<10%) of the starting material was observed. Aniline was also
unsuccessful in substituting the NO2 group. We observed no
formation of products of N-attack or C-attack and only the
starting material 16 was recovered. Even the more nucleophilic
5-methoxyindole did not add to the α-alkoxy-α-nitroester 16 at
23 °C nor at 40 °C. These experimental data suggest that SN2-
type substitution of the nitro group by aryl nucleophiles in the
reaction system is unlikely. Instead, loss of NO2− and formation
of an iminium type intermediate is a feasible reaction pathway.
We are continuing efforts to directly probe the mechanism of
aryl glycine formation.
Effects of Urea Derivatives on the Insertion−Arylation
Mechanism. We were able to study the effect of the urea
catalyst structure on the N−H insertion reaction of nitro-
diazoester 3, aniline 4a, and another equivalent of aniline 4a for
the formation of aryl glycine 7i (Table 2). Initial rate studies7a
demonstrate that urea 6a is capable of providing rate
enhancements up to 8.4 times (kobs = 9.19 × 10−5 s−1, Table
2) when compared to the traditional thiourea 6c (kobs = 1.10 ×
10−5 s−1) and urea 6d (kobs = 1.38 × 10−5 s−1) in the formation
of aryl glycine 7i. Boronate urea 6b was found to provide the
slowest rate of reaction (kobs = 0.77 × 10−5 s−1). These data are
supported by our DFT calculations (Scheme 5). The reaction
barrier to form the transition state TS-III is reduced by 4.2, 3.7,
3.3, and 2.8 kcal/mol in the presence of urea 6a, 6b, 6d, and 6c,
respectively, compared to the reaction with unsubstituted
diphenyl urea derivative, 6e. Among the urea derivatives,
nucleophilic addition intermediate 8 is generated most
favorably in the presence of urea derivative 6a, which forms
the strongest hydrogen-bonded complex 2 with α-nitro-
diazoester 3. In the multicomponent coupling of two molecules
Aryl Glycine Formation. With evidence suggesting a polar
N−H insertion reaction pathway, our attention turned toward
elucidating the reaction mechanism for the formation of
observed aryl glycine products 7. Three different routes for the
conversion of α-amino-α-nitroester 10 to the isolated aryl
glycine products 7 were considered (Scheme 7). Through
pathway C, direct N-addition of nucleophile 5 to nitroester 10
−
would afford protonated aminal 11 with loss of NO2 .
−
Alternatively, through pathway D, loss of NO2 facilitated by
the formation of iminium 12 allows for addition of the
nucleophile to yield 11, which we propose is in equilibrium
with iminium 12.18 Lastly, carbene 13 could be formed from
loss of HNO2 from zwitterion 8 (pathway E) followed by
insertion into the N−H bond of aniline would lead to 11. In all
cases, it was computed that N-attack was preferred over
Friedel−Crafts-type addition of the aromatic nucleophile
(pathway D′ and pathway C′); however, after proton transfer,
aminal 14 is energetically less stable than aryl glycine 7 by 8.3
kcal/mol. Thus, reversible formation of iminium 12 could lead
to thermodynamically stable aryl glycine 7 through inter-
mediate 15. Of the three routes considered, the higher
energetic state of 13 (∼40 kcal/mol higher) compared to
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ab
Gaussian 09 suite of programs, along with the standard basis sets
available in the suite.23
Table 2. Initial Rate Studies of Urea Catalysts
EXPERIMENTAL SECTION
■
General Methods. Methylene chloride was purified by passage
through a bed of activated alumina.24 Purification of reaction products
was carried out by flash chromatography using 60 Å (40−63 μm)
activated basic aluminum oxide powder that was deactivated to
Brockmann Activity II. Analytical thin-layer chromatography was
performed on 0.25 μm silica gel 60-F254 plates. Visualization was
accomplished with UV light and ceric ammonium molybdate stains
followed by heating. Melting points (mp) are reported uncorrected.
Infrared spectra for liquid products were obtained as a thin film on a
NaCl disk and spectra for solid products were collected by preparing a
NaBr pellet containing the title compound. Nuclear magnetic
resonance spectra were recorded in deuterated solvents on 400 or
500 MHz spectrometers. Proton nuclear magnetic resonances (1H
NMR; CHCl3, δ 7.26 and DMSO, δ 2.50) and proton-decoupled
carbon (13C NMR; CDCl3, δ 77.16; DMSO, δ 39.5) are reported in
parts per million (ppm, δ) using the solvent as internal standard.
Proton decoupled fluorine (19F NMR) spectra are reported in ppm
using CF3C6H5 as an external standard (−63.72). Boron spectra (11B
NMR) are reported in ppm using BF3·OEt2 as an external standard
(0.00). Electrospray mass spectra (ESI-MS) were obtained using a
MicrOTOF. Aniline, N,N-diethylaniline, 4-fluoroaniline, 2,6-diisopro-
pylaniline, 2,6-dimethylaniline, and N-methylindole were freshly
distilled before use. Unless otherwise noted, all other commercially
available reagents and solvents were used without further purification.
Caution: While we have not experienced any problems handling ethyl
nitrodiazoacetate, appropriate care should be exercised when handling
any diazo compound or nitrodiazo compound.
c
d
entry
6
time (h)
yield (%)
kobs (× 10−5, s−1
)
1
2
3
4
5
20 mol % 6a
20 mol % 6b
20 mol % 6c
20 mol % 6d
--
24
24
24
24
24
83
61
27
58
8
9.19
0.77
1.10
1.38
--
a
The concentrations of nitrodiazoester 3 and aniline 4a were kept high
for pseudo-first-order conditions. Reactions performed using 10 equiv
of aniline at a concentration of 1 M. See the Supporting Information
for detailed experimental procedures. Isolated yield. An average of
kobs determined at multiple catalyst loadings; see the Supporting
Information.
b
c
d
of aniline 4a with nitrodiazoester 3, the formation of aryl
glycine 7i is most stabilized (−63.4 kcal/mol, Scheme 7, entry
2) in the presence of urea 6a.19 Boronate urea 6a provided the
highest yield of the N−H insertion product 7i (83%), followed
by boronate urea 6b (61%), thiourea 6c (27%), and urea 6d
(58%). Contradictory to the experimentally isolated low yield
of aryl glycine product 7i observed with thiourea 6c, calculated
energetics for the reaction with thiourea 6c does not show
markedly less stable intermediates or transition states compared
to other urea derivatives. The decomposition of the catalyst
under the reaction conditions could be a possible explanation
for the low yield of N−H inserted product in the case of
thiourea 6c.
In summary, boronate ureas have been identified as effective
catalysts for the preparation of aryl glycines via the N−H
insertion/multicomponent coupling reaction of nitrodiazoest-
ers, anilines, and nucleophiles. The proposed mechanisms of
insertion/arylation were deduced from both experimental and
computational evidence. Investigations into the reaction
pathway suggest urea-facilitated stepwise N−H insertion is
more favored than a concerted N−H insertion mechanism
proceeding through a urea-stabilized nitrocarbene. Formation
of an iminium-type intermediate results in loss of HNO2,
allowing for addition of an aryl nucleophile. In the case of
aniline, it is likely that N-attack occurs first to reversibly form an
aminal moiety. Thermodynamic equilibration leads to isolation
of the C-bound aryl glycine products. We are working toward
reporting results of ongoing investigations currently underway
in our laboratory further probing urea-activation of nitro-
diazoesters.
Typical Procedure for N−H Insertion Reactions.7a A dry,
screw-capped reaction vial containing a magnetic stir bar was charged
with ethyl nitrodiazoacetate 3 (30 mg, 0.189 mmol) and catalyst 6a
(15 mg, 0.038 mmol). Toluene (189 μL) was added if necessary.
Aniline 4 and nucleophile 5 were added immediately, and the reaction
was fitted with cap and septum and put under a positive pressure of Ar.
The reaction was allowed to stir at the indicated temperature and
duration. The reactions were immediately purified by flash column
chromatography with a minimal amount of neutral alumina, basic
alumina, or silica gel. All spectra for compounds 7b,7a 7c,7a 7e,7c 7f,7b
7h,7c 7i,7a and 7k7a matched previously reported values.
Ethyl 2-((4-Fluorophenyl)amino)-2-(4-(methylamino)phenyl)-
acetate (7a). The reaction was allowed to stir neat at 23 °C for 48
h with 4-fluoroaniline (179 μL, 1.89 mmol) and N-methylaniline (205
μL, 1.89 mmol). The reaction was immediately purified by flash
column chromatography with a minimal amount of silica gel (5:95
ethyl acetate/hexanes to 50:50 ethyl acetate/hexanes), yielding 49 mg
(85%) of 7a: Rf = 0.21 (20:80 ethyl acetate/hexanes); FTIR (film)
1
3053, 2986, 1732, 1614, 1510, 1421, 1265, 909 cm−1; H NMR (400
MHz, CDCl3) δ 7.28−7.25 (m, 2H), 6.85−6.80 (m, 2H), 658−6.56
(m, 2H), 6.52−6.48 (m, 2H), 4.88 (d, J = 5.6 Hz, 1H), 4.69 (d, J = 5.2
Hz, 1H), 4.26−4.24 (m, 1H), 4.24−4.08 (m, 1H), 3.75 (br s, 1H),
2.82 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
172.5, 156.0 (d, J = 233.9 Hz), 149.5, 142.8 (d, J = 1.5 Hz), 128.3,
125.7, 115.6 (d, J = 22.4 Hz), 114.2 (d, J = 24.9 Hz), 112.7, 61.7, 61.0,
30.7, 14.2; HRMS (ESI) mass calcd for C17H19F1N2O2Na [M + Na]+
325.1323, found [M + Na]+ 325.1329.
Ethyl 2-(4-Amino-3,5-diisopropylphenyl)-2-((4-fluorophenyl)-
amino)acetate (7d). The reaction was allowed to stir neat at 40 °C
for 48 h with 2,6-diisopropylaniline (1.89 mmol) and 4-fluoroaniline
(179 μL, 1.89 mmol). The reaction was immediately purified by flash
column chromatography with a minimal amount of basic alumina
(20:80 diethyl ether/hexanes to 100% diethyl ether), yielding 68 mg
(96%) of 7d: Rf = 0.78 (100% diethyl ether); FTIR (film) 3401, 2962,
2927, 2870, 1731, 1624, 1510, 1466, 1308, 1280 cm−1; 1H NMR (400
MHz, CDCl3) δ 7.09 (s, 2H), 6.87−6.82 (m, 2H), 6.55−6.52 (m, 2H),
4.90 (d, J = 6.8 Hz, 1H), 4.55 (d, J = 8.8 Hz, 1H), 4.27−4.20 (m, 1H),
4.18−4.10 (m, 1H), 3.76 (br s, 2H), 2.93−2.86 (m, 2H), 1.27−1.21
(m, 15 H); 13C NMR (100 MHz, CDCl3) δ 172.6, 156.1 (d, J = 234
COMPUTATIONAL METHODS
■
The geometries of all of the structures involved in the urea-catalyzed
insertion reaction of aniline with α-nitrodiazoester, including local
minima and transition states, were optimized using the hybrid DFT
method, B3LYP/6-31G*.20,21 Vibrational frequency calculations were
performed for each of the optimized geometries to verify whether the
stationary point was a minimum or a transition state on the potential
energy surface. Using the B3LYP/6-31G* geometries, single-point
energy calculations were performed at the B3LYP/6-311++G** to
further evaluate the energetics of the various reactions. Solvent effects
were modeled using the polarizable continuum model (PCM), with
toluene as the solvent.22 All calculations are carried out using the
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Featured Article
Hz), 143.0, 140.4, 132.7, 126.6, 121.9, 115.6 (d, J = 22.4 Hz), 114.3 (d,
J = 7.3 Hz), 61.7, 61.3, 28.1, 22.4, 14.1; HRMS (ESI) mass calcd for
C22H29F1N2O2Na1 [M + Na]+ 395.2105, found [M + Na]+ 395.2091.
Ethyl 2-(5-Chloro-1H-indol-3-yl)-2-((4-fluorophenyl)amino)-
acetate (7g). The reaction was allowed to stir at 40 °C for 48 h in
toluene (189 μL) with 4-fluoroaniline (179 μL, 1.89 mmol) and 5-
chloroindole (48 mg, 0.189 mmol). The reaction was immediately
purified by flash column chromatography on silica gel (20:80 ethyl
acetate/hexanes to 100% ethyl acetate), yielding 38 mg (58%) of 7g:
Rf = 0.2 (35:65 ethyl acetate:hexanes); FTIR (film) 3409, 3052, 2984,
ACKNOWLEDGMENTS
■
The Ohio Supercomputer Center is gratefully acknowledged
for generous allocations of computational resources to C.M.H.
The National Science Foundation (C.M.H., DMR-1212842),
American Chemical Society Petroleum Research Fund
(A.E.M.), The Ohio State University Comprehensive Cancer
Center (A.E.M.), and The Ohio State University Department
of Chemistry and Biochemistry (A.E.M.) are gratefully
acknowledged.
1
1734, 1618, 1489 cm−1; H NMR (400 MHz, CDCl3) δ 8.19 (br s,
1H), 7.81 (d, J = 2.0 Hz, 1H), 7.30−7.28 (m, 1H), 7.20−7.17 (m,
2H), 6.87−6.83 (m, 2H), 6.57−6.55 (m, 2H), 5.26 (d, J = 4.0 Hz,
1H), 4.68 (d, J = 6.0 Hz, 1H), 4.30−4.22 (m, 1H), 4.17−4.12 (m,
1H), 1.23 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.1,
156.2 (d, J = 234 Hz), 142.7, 135.0, 126.8, 125.9, 124.4, 123.0, 119.2,
115.7 (d, J = 22.4 Hz), 114.4 (d, J = 7.3 Hz), 112.5, 112.4, 61.8, 54.9,
14.1; HRMS (ESI) mass calcd for C18H16Cl1F1N2O2 [M + Na]+
369.0777, found [M + Na]+ 369.0763.
Ethyl 2-(4-Aminophenyl)-2-((4-methoxyphenyl)amino)acetate
(7j). The reaction was allowed to stir at 23 °C for 72 h in toluene
(189 μL) with p-anisidine (163 mg, 1.32 mmol) and aniline (17.2 μL,
0.189 mmol). The reaction was immediately purified by flash column
chromatography with a minimal amount of neutral alumina (5:95 ethyl
acetate/hexanes to 50% ethyl acetate), yielding 44.3 mg (78%) of 7j as
an orange solid: Rf = 0.81 (100% diethyl ether); FTIR (film) 3059,
2991, 1739, 1659, 1622, 1519, 1379, cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.26−7.24 (m, 2H), 6.72 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 8.4
Hz, 2H), 6.54 (d, J = 9.2 Hz, 2H), 4.88 (d, J = 5.2 Hz, 1H), 4.53 (d, J
= 4.8 Hz, 1H), 4.23−4.17 (m, 1H), 4.16−4.10 (m, 1H), 3.71 (s, 3H),
3.67 (br s, 2H), 1.21 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 172.7, 152.5, 146.5, 140.6, 128.4, 127.7, 115.4, 115.0, 114.9,
61.6, 61.3, 55.9, 14.2; HRMS (ESI) mass calcd for C17H20Na1N2O3 [M
+ Na]+ 323.1366, found [M + Na]+ 323.1365.
Ethyl 2-(4-Aminophenyl)-2-(p-tolylamino)acetate (7l). The re-
action was allowed to stir at 40 °C for 48 h in toluene (189 μL) with p-
toludine (101 mg, 0.945 mmol) and aniline (17.2 μL, 0.189 mmol).
The reaction was immediately purified by flash column chromatog-
raphy with a neutral alumina (5:95 ethyl acetate/hexanes to 50% ethyl
acetate), yielding 38 mg (70%) of 7l: Rf = 0.3 (35:65 ethyl acetate/
hexanes); FTIR (film) 3390, 3055, 2986, 1734, 1654, 1515, 1374,
1264, 1046, cm−1; 1H NMR (400 MHz, CDCl3) δ 7.26−7.24 (m, 2H),
6.93 (d, J = 8.0 Hz, 2H), 6.65−6.63 (m, 2H), 6.50−6.48 (m, 2H), 4.92
(d, J = 6.0 Hz, 1H), 4.67 (d, J = 6.0 Hz, 1H), 4.26−4.18 (m, 1H),
4.17−4.08 (m, 1H), 3.68 (br s, 2H), 3.20 (s, 3H), 1.21 (t, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 172.6, 146.5, 144.1, 129.8,
128.4, 127.6, 127.2, 115.4, 113.7, 61.6, 60.7, 20.5, 14.2; HRMS (ESI)
mass calcd for C17H20Na1N2O2 [M + Na]+ 307.1417, found [M +
Na]+ 307.1416.
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ASSOCIATED CONTENT
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■
S
* Supporting Information
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: hadad.1@osu.edu.
*E-mail: mattson@chemistry.ohio-state.edu.
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Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
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