Tunable, chemoselective amination via silver catalysis

Article abstract of DOI:10.1021/ja406654y

Organic N-containing compounds, including amines, are essential components of many biologically and pharmaceutically important molecules. One strategy for introducing nitrogen into substrates with multiple reactive bonds is to insert a monovalent N fragment (nitrene or nitrenoid) into a C-H bond or add it directly to a C-C bond. However, it has been challenging to develop well-defined catalysts capable of promoting predictable and chemoselective aminations solely through reagent control. Herein, we report remarkable chemoselective aminations that employ a single metal (Ag) and a single ligand (phenanthroline) to promote either aziridination or C-H insertion by manipulating the coordination geometry of the active catalysts.

Full text of DOI:10.1021/ja406654y

Communication
pubs.acs.org/JACS
Tunable, Chemoselective Amination via Silver Catalysis
Jared W. Rigoli, Cale D. Weatherly, Juliet M. Alderson, Brian T. Vo, and Jennifer M. Schomaker*
Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, United States
S
* Supporting Information
Table 1. Chemoselective Aziridination and C−H Amination
ABSTRACT: Organic N-containing compounds, includ-
ing amines, are essential components of many biologically
and pharmaceutically important molecules. One strategy
for introducing nitrogen into substrates with multiple
reactive bonds is to insert a monovalent N fragment
(nitrene or nitrenoid) into a C−H bond or add it directly
to a CC bond. However, it has been challenging to
develop well-defined catalysts capable of promoting
predictable and chemoselective aminations solely through
reagent control. Herein, we report remarkable chemo-
selective aminations that employ a single metal (Ag) and a
single ligand (phenanthroline) to promote either aziridi-
nation or C−H insertion by manipulating the coordination
geometry of the active catalysts.
of Homoallenic Carbamates Catalyzed by Silver Catalysts
a
b
c
Substrate 3a. 5 mol % Rh2(esp)2, 2 equiv PhlO. Ag: 20 mol %
d
AgOTf, 25 mol % ligand, 2 equiv PhIO, 4 Å MS, CH2Cl2. A:
e
aziridination. I: insertion. Substrate 3b.
mines are present in a multitude of pharmaceuticals and
Anatural products with useful biological activities. As a result,
the development of synthetic methodologies for the chemo-,
regio-, and stereoselective introduction of C−N bonds has been
vigorously pursued.1a−e One attractive approach is the direct
insertion of a nitrene or nitrenoid species into a C−H or CC
bond of an unsaturated substrate, and many catalysts based on
Rh, Ru, Fe, Co, Cu, Mn, Au, and Ag have been exploited in this
context.2a−m However, chemoselective C−N bond formation in
substrates bearing both reactive C−H and CC bonds is a
particularly challenging task, as these compounds (Figure 1)
often give rise to multiple products or exhibit substrate-
controlled selectivity.3a−g
the transition metal. For example, Ru- and Fe-based catalysts
favor C−H amination over the aziridination pathway that is
preferred using Rh(II) carboxylates.4a,b A second tactic is to
utilize different supporting ligands with a single metal, but this
has been only marginally successful for chemoselective
amination.3a−d Finally, the nature of the nitrene precursor can
influence the reaction outcome.5a−c We refer to strategies
employing a single, well-defined complex to control a specific
amination event as ‘static’ approaches to catalysis (Figure 1, top).
Our previous studies on the chemoselective aziridination of
homoallenic carbamates to bicyclic methylene aziridines (Table
1) showed that Ag complexes supported by bidentate N ligands
provided superior chemoselectivity for aziridination compared to
Rh2(esp)2, irrespective of the substrate identity (compare entry 1
vs 2−7 and 9 vs 10−15).6,7a−f However, a tridentate ligand
reversed this selectivity (entries 8 and 16). This result stimulated
our curiosity, and a further perusal of the literature showed that
Ag has the unique ability to change coordination geometry in
response to changes in the Ag counteranion, the ligand identity,
or the metal/ligand ratio.8 If these changes in the coordination
geometries of the Ag catalysts were indeed responsible for
inducing divergent chemoselectivity, a ‘dynamic approach’ to
catalytic amination could be envisioned (Figure 1, bottom). In
this scenario, treatment of a single Ag salt with a single ligand
would yield a mixture of several potential catalytic species. Simple
perturbation of the equilibrium of this mixture could give
different catalytic species capable of promoting divergent
amination using reagent control.
One strategy employed to overcome the problem of substrate
control in metal-catalyzed amination is to change the identity of
Received: June 30, 2013
Published: November 4, 2013
Figure 1. “Static” vs “dynamic” chemoselective amination.
© 2013 American Chemical Society
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Communication
In order to test the potential for developing a dynamic catalyst
system, the metal:ligand stoichiometry of a AgOTf:phen catalyst
system was varied to determine the effect on chemoselectivi-
ty.8a−g Phenanthroline was chosen for its high yield in the
amination and its relatively low cost. To our delight, a clear
impact on the amination of 3b was observed (Table 2).
AgOTf:phen yielded mainly C−H insertion. Trisubstituted
allenes (entries 1, 6−7) exhibited good selectivity under both
conditions, while less substituted allenes (entries 2−5, 8) usually
gave better selectivity in C−H insertion. Interestingly, the
addition of 10 mol % of 2,6-bis(1,1-dimethylethyl)-4-methyl-
phenol (BHT) appeared to improve the conversion of the C−H
insertion (entries 4, 8−10).7f
Simple changes in the AgOTf:phen stoichiometry also
provided good chemoselectivity in the amination of homoallylic
carbamates (Table 4). The cis-disubstituted 6a showed increased
Table 2. Effect of AgOTf:phen Stoichiometry on the
Aziridination/Insertion Ratio
Table 4. Selective Amination of Homoallylic Carbamates
AgOTf:phen ratios close to 1:1 (entries 1−4) promoted
aziridination to 4b as the major reaction pathway, while
increasing the amount of phen gave C−H insertion to 5b as
the dominant mode of reactivity (entries 5, 6). The dramatic
reversal in the reaction outcome suggests that an equilibrium
between Ag(phen)OTf and Ag(phen)2OTf exists and that each
complex favors a different mode of reactivity.
The scope of the ‘dynamic’ amination was explored using
homoallenic carbamates (Table 3). In all cases, a 1:1.25 ratio of
AgOTf:phen favored aziridination,6 while a 1:3 ratio of
a
b
Rh cat.: 3 mol %, 2 equiv PhIO, 4 Å MS, CH2Cl2. Aziridination: 20
c
mol % AgOTf, 25 mol % phen, 2 equiv PhlO, 4 Å MS, CH2Cl2. C−H
insertion: 10 mol % AgOTf, 30 mol % phen, 3.5 equiv PhlO, 4 Å MS,
CH2Cl2. NMR yields with mesitylene as the internal standard.
d
Table 3. Tunable Amination of Homoallenic Carbamates
selectivity for aziridination in switching from Rh2(OAc)4 to
1:1.25 AgOTf:phen (entry 1), while changing the AgOTf:phen
ratio to 1:3 promoted exclusive insertion. This trend held for
both the cis-disubstituted 6b (entry 2) containing substitution in
the tether and the trans-disubstituted 6c (entry 3). The
stereochemistry of the olefin was transferred to the resulting
aziridines and allylic amines with no detectable isomerization.
The 1,1′-disubstituted 6d gave better selectivity and yield for
aziridination compared to Rh2(OAc)4, although the C−H
insertion was moderate. Substrate 6e gave poor results using
Ag(phen)OTf, but good selectivity for insertion.
Attempts to isolate the proposed 1:1 and 1:2 AgOTf:phen
complexes in the solid state (Table 2) resulted in the recovery of
only Ag(phen)2OTf.9 Nonetheless, Ag(phen)2OTf was capable
of dissociating and reassembling into two distinct catalytic
species capable of divergent amination (Scheme 1). Reaction of
3a with the preformed Ag(phen)2OTf gave a 90:8 mixture of
products in favor of the C−H insertion, consistent with the
Scheme 1. Solution-State Behavior of a Preformed
Ag(phen)2OTf Catalyst for Chemoselective Amination
a
Aziridination: 20 mol % AgOTf, 25 mol % phen, 2 equiv PhlO, 4 Å
b
MS, CH2Cl2. C−H insertion: 10 mol % AgOTf, 30 mol % phen, 3.5
c
d
equiv PhIO, 4 Å MS, CH2Cl2. 2,2′-bipyridine ligand. I = insertion. A
e
= aziridination, 10 mol % BHT added
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results described in Table 2. Addition of 10 mol % AgOTf to the
initial Ag(phen)2OTf complex completely reversed the chemo-
selectivity to provide 4a in 92% yield, while an extra 10 mol % of
phen shut down the competing aziridination pathway, giving 5a
in 90% yield.
This suggests that C−H insertion favors a singlet nitrene
pathway over hydrogen atom abstraction.
To shed light on the differences between Ag-catalyzed
pathways promoting aziridination vs insertion, initial rates were
measured for four homoallenic carbamates 3a, 3d, 19, and 21
(Table 5). As expected, the initial rate of aziridination was faster
Attempts to corroborate the proposed solution state geo-
metries for the two Ag catalysts illustrated in Table 2 were carried
out using NMR titration experiments with 4,4′-di-tert-butyl-2,2′-
bipyridine (tBu-bipy, substituted for phen to improve solubility)
and AgOTf. Unfortunately, rapid dynamic exchange, even at
temperatures as low as −85 °C, prevented direct observation of
the individual species present in solution (see Supporting
Table 5. Relative Rates of Aziridination and C−H Insertion
1
Information (SI) for details). However, the averaged H, 13C
chemical shifts indicated that the major species in the mixture
changed as the ratio of ligand:AgOTf was increased. A
combination of pulse gradient spin echo (PGSE) and MALDI
MS experiments showed that a monomeric Ag(L)OTf complex
was the major species in solution when a 1:1 AgOTf:ligand ratio
was used, while a monomeric Ag(L)2OTf complex predominated
when a 1:2 AgOTf:ligand ratio was used (details in SI). The
additional equivalent of ligand serves to perturb the equilibrium
of the Ag(L)OTf:Ag(L)2OTf mixture to favor the latter.
With information about the nature of the two catalytic species
in hand, we wanted to understand the factors responsible for our
unexpected and tunable chemoselectivity. The exact mechanisms
of metal-catalyzed aminations have been notoriously difficult to
unravel and often involve multiple reaction pathways.2,7f Yet, we
felt even preliminary insights into the mechanism could help
extend our dynamic catalysis beyond the scope here.
Experiments to determine whether Ag-catalyzed amination
proceeds through a stepwise or concerted mechanism were
carried out using the stereochemical probes ( )-9 and ( )-12
(Scheme 2). Only ( )-10 and ( )-14 were observed and no
a
1
The rate of product formation was monitored by H NMR using
mesitylene as the internal standards. The indicated initial rates are the
average of the three runs, and the standard deviations are included in
the SI. Yield after 21 h, 73% conversion. The ratio of 4d:5d was 1:1.
b
c
than C−H insertion for both tri- and disubstituted allenes
(compare entries 4 and 6, as well as 11 and 13). When sites for
potential C−H insertion were blocked in substrates 19 and 21,
the Ag(phen)OTf catalyst still gave aziridination (entries 1 and
8), but the Ag(phen)2OTf complex gave either no reaction
(entry 2) or significantly decreased reactivity (entry 9). This
suggests that the steric congestion around the Ag center plays an
important role in dictating the chemoselectivity, with a more
hindered Ag center promoting insertion over the aziridination
which is favored by a less sterically congested Ag center. This is
likely due to the difficulty of overcoming steric clashing with the
ligands when the substrate attempts to adopt the appropriate
orientation of the olefin for reaction with the nitrene (see 26 in
Figure 2, vide infra). When two ligands are coordinated to the Ag
Scheme 2. Stereochemical Probes for Radical Intermediates
isomerization was detected, suggesting a concerted event. A
substrate 15 containing a radical trap yielded only 16 and no ring-
opened product, arguing against long-lived radical intermediates.
A kinetic isotope effect (KIE) experiment yielded a 3.4 0.1
mixture of isotopomers ( )-18-D and ( )-18-H (eq 1). KIEs in
Figure 2. Possible mechanisms for Ag-catalyzed divergent, chemo-
selective amination.
center, insertion into the C−H bond of 26 presents a more
favorable pathway, in contrast to the aziridination that occurs
through the proposed 1:1 Ag:L complex 24.
BHT was initially employed to ascertain the impact of a radical
inhibitor on the amination (Table 3), where the presence of this
additive appeared to improve the conversion of disubstituted
homoallenic carbamates to allenic amines. Closer examination of
the role of BHT (Table 5) showed that the initial rates in the
the range of 1−3 are believed to correspond to a concerted
pathway, while KIEs in the range of 6−12 usually signal a
stepwise process involving potential radical intermediates.3c,11a−c
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aziridination of 19 and 21 were decreased in the presence of the
radical inhibitor (compare entries 1 and 3, and entries 8 and 10).
However, the effect of BHT on the rate of C−H insertion was
variable (compare entries 6−7 and 13−14) and did result in an
increase in the rate of insertion when a disubstituted allene was
employed (entries 13 vs 14). Interestingly, the addition of BHT
to 3d in the presence of 1:1.25 AgOTf:phen (entry 12) gave a 1:1
ratio of aziridine 4d to allenic amine 5d. This suggests BHT may
also play a role in altering the Ag(L)OTf:Ag(L)2OTf equilibrium
by shifting it toward Ag(L)2OTf, but further study will be needed
to completely understand its impact on the reaction.
The retention of stereochemistry at a chiral center, the low KIE
value, the lack of isomerization in the reactions of homoallylic
carbamates (Table 4), and the absence of ring opening in the
cyclopropane 15 all support a concerted pathway involving a
singlet nitrene for the C−H insertion (Figure 2, Path B).3b,c,7e,f
However, the aziridination Path A could involve either singlet or
triplet nitrene intermediates, or perhaps both. The differences in
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization for new com-
pounds are provided. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
schomakerj@chem.wisc.edu
■
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by start-up funds provided by the
UWMadison. Dr. Charles Fry of the UWMadison is
thanked for help with NMR spectroscopy, and Professors John
Berry, Hans Reich, and Chuck Casey of UWMadison are also
thanked for helpful comments and discussion.
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