Investigation of transition metal-catalyzed nitrene transfer reactions in water

Article abstract of DOI:10.1016/j.bmc.2018.04.002

Transition metal-catalyzed nitrene transfer is a powerful method for incorporating new C–N bonds into relatively unfunctionalized scaffolds. In this communication, we report the first examples of site- and chemoselective C–H bond amination reactions in aq

Full text of DOI:10.1016/j.bmc.2018.04.002

Bioorganic & Medicinal Chemistry xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Investigation of transition metal-catalyzed nitrene transfer reactions
in water
1
1
⇑
Juliet M. Alderson , Joshua R. Corbin , Jennifer M. Schomaker
Department of Chemistry, University of Wisconsin–Madison, 1101 University Avenue, Madison, WI 53706 USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Transition metal-catalyzed nitrene transfer is a powerful method for incorporating new CAN bonds into
relatively unfunctionalized scaffolds. In this communication, we report the first examples of site- and
chemoselective CAH bond amination reactions in aqueous media. The unexpected ability to employ
water as the solvent in these reactions is advantageous in that it eliminates toxic solvent use and enables
reactions to be run at increased concentrations with lower oxidant loadings. Using water as the reaction
medium has potential to expand the scope of nitrene transfer to encompass a variety of biomolecules and
highly polar substrates, as well as enable pH control over the site-selectivity of CAH bond amination.
Ó 2018 Elsevier Ltd. All rights reserved.
Received 17 February 2018
Revised 27 March 2018
Accepted 1 April 2018
Available online xxxx
Keywords:
Amines
Nitrene transfer in water
Silver catalysis
CAH amination
1. Introduction
In the context of transition metal-catalyzed nitrene transfer,
general experimental protocols typically involve the use of anhy-
The development of selective carbon–nitrogen (CAN) bond-
forming reactions is of great interest, as amines are present in a
multitude of bioactive natural products and pharmaceuticals.
While there are several synthetic methods available to introduce
CAN bonds into organic substrates, transition metal-catalyzed
nitrene transfer reactions are appealing for the direct amination
of CAH bonds. An important challenge in nitrene transfer catalysis
is to identify strategies that enable selective reaction at a desired
site in the presence of multiple reactive CAH bonds. A variety of
transition metal catalysts, including ones based on Rh, Ru, Fe,
Mn, Cu, Ir, Co and Ag, have been studied with the goal of achieving
predictable catalyst control over the CAN bond forming event.1 In
our own research program, we have successfully utilized the
unique ability of Ag to adopt diverse coordination geometries in
solution to control nitrene transfer selectivity, based on simple
changes to the reaction conditions. For example, we have devel-
oped tunable, chemoselective nitrene transfer protocols where
the Ag:ligand ratio determines the selectivity between aziridina-
tion and CAH insertion in homoallylic and homoallenic carbamates
(Scheme 1, top).2 Additionally, site-selective CAH insertion of Ag-
supported nitrenes derived from sulfamates have been developed
where the selectivity is dictated and tuned by the identity of the
ligand (Scheme 1, middle).3
drous organic solvents, including isopropyl acetate, dichloro-
methane, chloroform or acetonitrile. Water has long been
thought to be detrimental to nitrene transfer reactions, as there
is potential to limit the formation of a critical imidoiodinane inter-
mediate A (Scheme 1, bottom), change the catalyst geometry by
serving as a ligand for the metal, promote catalyst death, or destroy
the electrophilic metal nitrene B. For these reasons, molecular
sieves or other desiccants are typically used; however, the impact
of water on nitrene transfer has never been explicitly studied.
Since Breslow’s example of a successful Diels-Alder reaction in
water, there have been efforts directed towards identifying other
useful organic reactions that take place in water or ‘on water’.4 In
some cases, these reactions employ more environmentally benign
conditions and display increased reactivity and/or selectivity.5,6 In
light of these developments, we were curious whether our Ag-cat-
alyzed nitrene transfer reactions might tolerate the presence of
water and enable the utilization of highly polar substrates, elimi-
nate the use of chlorinated solvents, decrease the current high
loadings of PhIO oxidant and perhaps lead to improved chemo-
and site-selectivities. In this manuscript, we divulge our investiga-
tions into how various metal-catalyzed CAH aminations are
affected by the inclusion of water.
2. Results and discussion
⇑
Corresponding author.
E-mail address: schomakerj@chem.wisc.edu (J.M. Schomaker).
These authors contributed equally.
Initial experiments focused on tunable chemoselectivity using
carbamates as the nitrene precursors (Table 1). In our previous
1
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J.M. Alderson et al. / Bioorganic & Medicinal Chemistry xxx (2018) xxx–xxx
Table 2
Water tolerance of sulfamate nitrene transfer reagents.
indicating the geometry of the silver catalyst is likely not
changing in the presence of water. When the nitrene transfer
reaction of 4 was run in water as the solvent, full conversion to
products 4a and 4b was noted, albeit in slightly lower yield
compared to dichloromethane (entry 4), presumably due to the
lower solubility of 4 in water. Heating the reaction to 40 °C
increased the yield of 4a-b to 73%, with the remainder of the
mass balance made up of starting material (entry 5). Heating the
reaction also has the advantage of dissolving the polymeric PhIO
oxidant, which is insoluble in dichloromethane; this enables a
simpler workup procedure that does not require a filtration step.
Instead, extraction with either diethyl ether or ethyl acetate can
Scheme 1. Ag-catalyzed nitrene transfer.
Table 1
Effect of water on carbamate nitrene transfer reagents.
be utilized,
a
greener alternative to the standard
dichloromethane solvent. A control reaction in Et2O resulted only
in recovered 4, indicating that the chemistry is happening in the
aqueous medium and not during the extraction process. Heating
these reactions resulted in an essentially biphasic mixture,
suggesting the possibility that the chemistry may be happening
‘on-water’.8 Organic reactions occurring at the organic-liquid water
interface have the same economic and environmental benefits as
those happening in solution, but on-water reactions allow for the
use of substrates that are not soluble in aqueous systems. Overall,
these results indicate that water does not hinder reactivity in Ag-
catalyzed CAH bond amination reactions using sulfamates as the
nitrogen source. This surprising result stimulated our curiosity as
to whether other reported transition metal catalysts exhibit similar
activity in water.
work, a 1:1.25 ratio of AgOTf to 1,10-phenanthroline (phen) as the
ligand furnished selective aziridination to 2 (entry 1), whereas
employing a 1:3 ratio of AgOTf:phen resulted in the selective for-
mation of the CAH insertion product 3 (entry 2).2 As expected,
the exclusion of molecular sieves resulted in little product forma-
tion and recovery of the majority of the starting material 1 (entries
3–4). Although only minimal conversion was seen, it was interest-
ing to note that the selectivity was similar to reactions run with
molecular sieves. This observation suggests that water does not
occupy a coordination site on the silver catalyst and has little effect
on the coordination geometry of the purported silver nitrene.
Rather, the difficulty of oxidizing carbamates to the key iminoiod-
inane intermediate A (Scheme 1, bottom) likely gives rise to an
equilibrium that favours the starting materials over A when water
is not sequestered. The sensitivity of carbamate-derived iminoiod-
inanes to water prompted us to examine other nitrene precursors.
Next, we investigated the effect of water on 4, a sulfamate-
derived nitrene precursor, where CAH insertion can occur at either
a benzylic or tertiary alkyl CAH site (Table 2); Pérez has reported a
single example of Cu-catalyzed styrene aziridination using
PhI@NTs in water.7 Our previous work showed that a tris(2-pyri-
dyl-methyl)amine (tpa) ligand favors benzylic insertion to furnish
5 (entry 1).1j,3 Interestingly, when the desiccant was excluded,
there was essentially no impact on yield or selectivity (entry 2).
This observation was encouraging, as it suggested that water is
not as detrimental to CAH amination as had previously been
thought. Even with the addition of water (entry 3), the reaction
still proceeded smoothly with no change in the 4a:4b ratio,
Table 3 describes results using 4 in the presence of a variety of
other reported transition metal catalyst systems.1,9–12 Dinuclear Rh
catalysts, including the popular Rh2esp2 (esp = a,a, ,
a0 a0-tetram-
ethyl-1,3-benzenedipropanoate), all favored tertiary C(sp3)-H
insertion to furnish 4b (entries 1–3), mimicking the selectivity
and activity observed in organic solvents.9 The preference for 4b
increased as the size of the carboxylate bridging ligand increased
from OAc to esp to TPA (triphenylacetate). Catalysts based on Ru,
Fe, and Mn (entries 4–6) gave no product formation (entries 4–
6).10–12 Additional Ag(I) catalysts developed in our group, including
(tBuBipy)2AgOTf, [(Py5Me2)AgOTf]2, and
[a-Me-(anti)-Py3PipAg]
OTf were subjected to the same reaction conditions as (tpa)AgOTf
(entries 7–9).13–16 (tBuBipy)2AgOTf in water resulted in lower mass
balance than reactions run in dichloromethane, perhaps due to the
increased fluxionality of this complex, as compared to other Ag cat-
alysts; the site-selectivity slightly favored 4b (entry 7). Both [(Py5-
Me2)AgOTf]2 and
[a-Me-(anti)-Py3PipAg]OTf delivered results
similar to those observed for (tpa)AgOTf. These results show that
by utilizing complementary Rh and Ag catalysts, tunable site-selec-
tive CAH amination can be achieved using water as the reaction
medium.
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J.M. Alderson et al. / Bioorganic & Medicinal Chemistry xxx (2018) xxx–xxx
3
Table 3
tions (0.4 M vs. 0.05 M). For ease of reaction setup, a 0.2 M concen-
tration was preferred for studies of catalyst loading (entries 9–11).
When the amount of (tpa)AgOTf was decreased to 5 mol% (entry 9),
incomplete conversion was observed in the standard 30 min reac-
tion time. This was easily corrected by running the reaction over-
night (entry 8), enabling the catalyst loading to be further
decreased to 2 mol% (entry 11), provided isolated (tpa)AgOTf is uti-
lized to ensure the proper Ag:ligand stoichiometry. Furthermore,
Ag-nitrene catalysis tolerated a variety of electrolytes in buffered
solutions at a range of acidic and basic pH values (entries 12–14).
With optimized conditions in hand, other sulfamates were
briefly investigated and the site-selectivities of the CAH amination
compared to previous results in dichloromethane (Table 5).
Another substrate 5, displaying both benzylic CAH and tertiary
CAH insertion sites, behaved similarly using (tpa)AgOTf in water
as compared to dichloromethane, favoring benzylic insertion to
5a. The nonpolar substrate 6, featuring two very similar tertiary
CAH bonds, resulted in minimal selectivity to favor insertion at
the isopropyl CAH bond 6b. The preferred insertion into the allylic
CAH bond of 7 in water matched the previous results in dichloro-
methane; 8–13 were similarly well-behaved. Overall, these results
indicate that although there is a slight sensitivity of (tpa)AgOTf to
water, overall, the reactions are surprisingly similar to those car-
ried out in organic solvents.
Catalyst activity in aqueous solvent.
Intermolecular nitrene transfer presents a greater challenge as
compared to intramolecular reactions. However, water proved to
be an effective solvent for the intermolecular amination of
Following initial catalyst screening, further optimization was
carried out to determine if water enabled the use of less solvent,
less oxidant and lower catalyst loadings, as compared to standard
conditions (Table 4). The oxidant could be lowered to 2 equiv from
the standard 3.5 equiv, but cutting the PhIO to 1 equiv resulted in
incomplete conversion, even with longer reaction times (entries 1–
3). The stronger PhIO oxidant (entry 4) gave superior results to
both PhI(OAc)2 and PhI(OPiv)2 (entries 5–6). Solvent concentration
did not have a significant effect on selectivity or reactivity (com-
pare entry 2 vs. 4, 7–8). However, the substitution of water for
dichloromethane did allow reactions to be run at higher concentra-
Table 5
Examples of intramolecular amination in water.
Table 4
Reaction optimization.
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J.M. Alderson et al. / Bioorganic & Medicinal Chemistry xxx (2018) xxx–xxx
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.bmc.2018.04.002.
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This work was funded by NSF Award 1664374 and the Wiscon-
sin Alumni Research Foundation to JMS. The NMR facilities at UW-
Madison are funded by the NSF (CHE-9208463, CHE-9629688) and
NIH (RR08389-01). The National Magnetic Resonance Facility at
Madison is supported by the NIH (P41GM103399, S10RR08438
and S10RR029220) and the NSF (BIR-0214394). The purchase of
the Thermo Q ExactiveTM Plus in 2015 for mass spectrometry was
funded by NIH Award 1S10 OD020022-1 to the Department of
Chemistry.
15. Dolan NS, Scamp RJ, Yang T, Berry JF, Schomaker JM.
2016;138:14658.
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Please cite this article in press as: Alderson J.M., et al. Bioorg. Med. Chem. (2018), https://doi.org/10.1016/j.bmc.2018.04.002