A General Catalyst for Site-Selective C(sp3)-H Bond Amination of Activated Secondary over Tertiary Alkyl C(sp3)-H Bonds

Article abstract of DOI:10.1021/acs.orglett.6b01392

The discovery of transition metal complexes capable of promoting general, catalyst-controlled and selective carbon-hydrogen (C-H) bond amination of activated secondary C-H bonds over tertiary alkyl C(sp³)-H bonds is challenging, as substrate co

Full text of DOI:10.1021/acs.orglett.6b01392

Letter
pubs.acs.org/OrgLett
A General Catalyst for Site-Selective C(sp3)−H Bond Amination of
Activated Secondary over Tertiary Alkyl C(sp3)−H Bonds
Ryan J. Scamp, James G. Jirak, Nicholas S. Dolan, Ilia A. Guzei, and Jennifer M. Schomaker*
Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, United States
S
* Supporting Information
ABSTRACT: The discovery of transition metal complexes capable of
promoting general, catalyst-controlled and selective carbon−hydrogen
(C−H) bond amination of activated secondary C−H bonds over tertiary
alkyl C(sp3)−H bonds is challenging, as substrate control often
dominates when reactive nitrene intermediates are involved. In this
letter, we report the design of a new silver complex, [(Py5Me2)AgOTf]2, that displays general and good-to-excellent selectivity for
nitrene insertion into propargylic, benzylic, and allylic C−H bonds over tertiary alkyl C(sp3)−H bonds.
arbon−nitrogen bonds are ubiquitous in molecules of
Scheme 1. A General Catalyst for the Amination of Secondary,
Activated C−H Bonds over Competing Tertiary Alkyl C−H
Bonds
C
biological and therapeutic importance. Metal-catalyzed
nitrene insertion into C−H bonds1 represents a streamlined
process for the preparation of amine functionality; however, high
and predictable chemoselectivity and site selectivity in nitrene
transfer are largely a result of substrate control. Thus, there
remains strong interest in the development of more versatile
catalysts for C−H amination. Despite the broad array of
transition metals known to catalyze nitrene transfer,2−8 a general
catalyst for the selective amination of diverse activated secondary
C(sp3)−H bonds in the presence of competing tertiary C(sp3)−
H sites has not yet been identified, particularly when propargylic
C−H activation is desired. To address this need, we have
designed a new silver complex, [(Py5Me2)AgOTf]2 (Py5Me2 =
2,6-bis[1,1-bis(2-pyridyl)ethyl]pyridine), that exhibits good-to-
excellent selectivity for the amination of activated secondary C−
H bonds, including propargylic, allylic, and benzylic, even in the
presence of competing electron-rich, tertiary C(sp3)−H sites.
Two features of Ag(I) complexes make them amenable to
development as general and selective amination catalysts.9 The
first is the ability of Ag(I) to accommodate diverse coordination
geometries at the metal center, from linear to octahedral.10
Changes in the coordination geometry at Ag can be manipulated
through ligand choice, counteranion, solvent, and Ag/ligand
ratio to impact the behavior of nitrene transfer. A second feature
is the dynamic behavior of Ag(I) complexes in solution. While
this was advantageous in achieving highly chemoselective nitrene
transfer,9a dynamic behavior caused significant complications in
our efforts (Scheme 1A)9b to attain broad site selectivity for the
amination of propargylic, benzylic, and allylic C−H groups over
tertiary alkyl C(sp3)−H bonds. Unfortunately, both steric and
electronic modifications to our previous (tpa)AgOTf 1 (tpa =
tris(2-pyridylmethyl)amine) catalyst did not improve the
selectivities. We surmised these failures were due to dissociation
of one or more of the pyridine ‘arms’ from the metal center of 1,
resulting in the presence of multiple potential catalytic species in
solution, including 1 and 1a (Scheme 1A). In addition, the
conformational mobility of 1 could limit its ability to
productively discriminate between two competing reactive C−
H bonds. Indeed, VT-NMR studies in CD2Cl2 over a range of
+24 °C to −90 °C supported the presence of dynamic behavior
between 1 and 1a (see the Supporting Information (SI) for more
details).
The variability in coordination geometry at the metal center
and the dynamic behavior of (tpa)AgOTf 1 prompted us to
consider other ligand designs. Efforts to rigidify 1 did not result in
general selectivity; thus, we sought a bridging, modular ligand
scaffold that could support a potential dimeric silver complex
with decreased conformational flexibility. With this design
principle in mind, a series of multidentate nitrogenated ligands
for Ag(I) were explored, leading to the discovery of a new Ag
complex, [(Py5Me2)AgOTf]2 2 (Scheme 1B and Table 1,
bottom).12 In contrast to 1, 2 is dimeric in its resting state in both
the solid and solution states, as judged by X-ray and DOSY NMR
Received: May 12, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01392
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Table 1. X-ray and DOSY NMR Studies of 2
Scheme 2. Site-Selective Propargylic C−H Amination
complex
molecular weight (g/mol) diffusion constant (×10−10 m2/s)
a
lMesAuCl
536.85
11.15
8.436
6.976
8.763
a
Rh2(esp)2
758.47
b
Rh2(TPA)4
1355.16
c
1
547.30 monomeric
1094.60 dimeric
700.49 monomeric
c
2
7.074
1400.98 dimeric
a
b
c
0.025 M in CD2Cl2. 0.0125 M solution in CD2Cl2. 0.025 M
solution based on AgOTf.
studies, respectively (Table 1, top). Each of the Ag atoms in the
dimer exhibits a seesaw geometry; the 3.9 Å distance between the
two Ag atoms, in combination with the ligand scaffold, forms a
restricted ‘pocket’ where the nitrene precursor could bind. We
hypothesized the bridging pyridines of 2 would provide sufficient
steric discrimination between activated methylene C−H bonds
and sterically hindered, yet more electron-rich, tertiary alkyl
C(sp3)−H bonds.
Complex [(Py5Me2)AgOTf]2 2 was tested against a panel of
alkynes (Scheme 2) to determine if it was a competent catalyst
for the competitive amination of propargylic C−H bonds. The
primary sulfamates 3−5 furnished 3a−5a as the major products,
showing heteroatom-containing alkynes, including methoxy-
methyl (4) and nitrile (5) groups, could tolerate the reaction
conditions. Reaction of 6 gave complete preference for
amination of the propargylic C−H bond over an unactivated
2° C−H bond, a result expected to display broad scope.
Substrates where a tertiary alkyl C(sp3)−H bond competes with
the propargylic C−H bond (Scheme 2, 7−14) have posed
difficulties for other nitrene transfer catalysts; Rh-based
complexes usually engage with the alkyne, while first-row
transition catalysts show approximately statistical selectivitie-
s.7a,13 For example, 7 yielded preferred amination of the tertiary
C−H bond to furnish 7b using Rh2(esp)2. Our initial
(tpa)AgOTf catalyst delivered the desired 7a as the major
product, albeit in a poor 1.4:1 selectivity. An Fe catalyst
supported by a phthalocyanine ligand (FePc), in combination
with an equimolar amount of AgSbF6, increased this to 2:1.7a To
our delight, 2 proved to be superior for aminating the propargylic
C−H bond, delivering 7a:7b in a ratio of 8.5:1. The scope of the
amination with 2 encompassed alkyl, aryl, and silyl substitution at
the alkyne, as well as a range of tertiary alkyl substitutions to yield
8a−14a in good-to-excellent selectivities. In general, selectivity at
the propargylic C−H site increased as steric bulk around the
tertiary C−H bond was increased (compare 8a to 10a and 9a to
11a). Useful silyl functionalities were tolerated in the reaction, as
demonstrated by the syntheses of 13a and 14a. The steric bulk of
the bridging ligands may also exhibit a remote effect on the
a
10 mol % AgOTf, 12 mol % Py5Me2, 3.5 equiv of PhIO, 0.05 M
b
c
CH2Cl2, 4 Å MS, rt, 30 min. Determined by crude NMR. 2 mol %
Rh2esp2, 1.1 equiv of PhI(OAc)2, 0.16 M CH2Cl2, 4 Å MS, reflux, 24 h.
d
10 mol % AgOTf, 12 mol % tpa, 3.5 equiv of PhIO, 0.05 M CH2Cl2, 4
e
Å MS, rt, 30 min. 10 mol % [FePc]Cl, 10 mol % AgSbF6, 2.0 equiv of
PhI(OPiv)2, 4:1 PhMe/MeCN, ratio of isolated products. Average of
two runs. 10 mol % [MnPc]Cl, 10 mol % AgSbF6, 2.0 equiv of
PhI(OPiv)2, 100 mg of 4 A MS, 9:1 C6H6/MeCN, ratio of isolated
products. 10 mol % AgBF4 found to effect less deprotection of TMS
than AgOTf. Reference 7a: dr unreported.
f
g
h
i
selectivity; the TMS group of 13 resulted in better selectivity
than the bulky TIPS group of 14.
[(Py5Me2)AgOTf]2 2 was then tested for the selective
amination of benzylic C−H bonds over tertiary alkyl C(sp3)−
H bonds (Table 2). The sensitivity of 2 to the steric environment
of the tertiary alkyl C(sp3)−H bond was apparent in the
increased preference for benzylic C−H amination as the bulk of
substituents at the tertiary carbon was increased (compare entry
1 with entries 6, 11, and 13−15). Even in cases where the steric
hindrance at the tertiary alkyl C(sp3)−H was lessened due to a
‘pinning back’ of the alkyl groups, as in 18 and 19, the use of 2
essentially doubled the selectivity compared to 1 (entries 7 vs 8
and 10 vs 11). Interestingly, both 1 and 2 exhibit similar behavior
in the presence of a radical inhibitor (see Table 4, entries 3−4),
suggesting that benzylic selectivity is not a result of forming a
long-lived radical intermediate, as is the case with most Fe-based
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DOI: 10.1021/acs.orglett.6b01392
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Table 2. Selectivity for Benzylic C−H Amination with 2
Table 3. Selectivity for Allylic C−H Amination with 2
a
Unless otherwise indicated, the reaction conditions were 5 mol %
b
catalyst 2, PhIO, 4 A MS, CH2Cl2, rt. Syn:anti ratio for allylic
insertion as determined by crude NMR. 2.5 mol % [M2Ln],
PhI(OPiv)2, 5 A MS, CH2Cl2, 40 °C, NMR ratios. 2.5 mol %
[M2Ln], PhI(OPiv)2, 5 A MS, CH2Cl2, 40 °C. lsomerization from 9:1
c
d
e
f
Z:E to 3:1 was noted. 10 mol % [FePc]Cl, 10 mol % AgSbF6, 2.0
a
equiv of PhI(OPiv)2, 4:1 PhMe/MeCN.
Unless otherwise indicated, the reaction conditions were 5 mol %
b
catalyst 2, PhIO, 4 A MS, CH2Cl2, rt. 2.5 mol % [M2Ln], Phl(OPiv)2,
5 A MS, CH2Cl2, 40 °C. 10 mol % [FePc]Cl, 10 mol % AgSbF6, 2.0
equiv of PhI(OPiv)2, 4:1 PhMe/MeCN. 10 mol % (tpa)AgOTf 1 was
employed instead of catalyst 2.
c
Our previous catalysts, including 1, promote nitrene transfer
through concerted or rapid H atom abstraction (HAA)/radical
rebound pathways;9a,b evidence for this same behavior was noted
in reactions of 12, 15, and 24 with 1 (see the SI for details). In
contrast, reactions catalyzed by [(Py5Me2)AgOTf]2 2 in the
presence of dihydroanthracene (DHA) as a radical inhibitor
(Table 4) showed a significant decrease in the yields 12a and 24a
d
catalysts giving better selectivity, but lower yields (entries 4, 9).4
If the tertiary alkyl C−H bond was hindered enough, as in 20−22
(entries 13−15), the selectivity for benzylic amination with 2 was
excellent, in contrast to the 1:1 mixture observed with
[Rh2(esp)2] (entry 12). The observed dr was high in all cases,
favoring the syn diastereomer in ratios >20:1 and was attributed
to the larger size of the Ph group as compared to the alkyne. This
steric bulk enforces a transition state where both the Ph group
and the side chain occupy pseudoequatorial positions, leading to
preferred formation of the syn diastereomer.
a
Table 4. Radical Inhibitor Studies of Catalysis Promoted by 2
Substrates containing an alkene moiety present the additional
test of chemoselectivity (Table 3). Our previous strategy of
increasing the ratio of ligand/AgOTf to favor allylic amination
over aziridination was not successful for sulfamates containing
competing reactive C−H bonds.9a Achieving both chemo-
selectivity and site selectivity is also challenging for dinuclear Rh
and Ru catalysts (entries 1−3); however, [Ru2(hp)4Cl] (entry 4)
was successful for amination of 23.3a Catalyst 2 showed better
chemoselectivity for 23a, with no trace of aziridine products
(entry 5). The lowered preference for allylic C−H amination in
cis-substituted alkenes (23 and 24 in entries 5−6), compared to
the >20:1 selectivity for the amination of trans alkene 25 (entry
7), again highlights the sensitivity of [(Py5Me2)AgOTf]2 to steric
effects. Catalyst 2 also provided a surprising reversal in site
selectivity compared to [Rh2(esp)2] and 1 (entries 8 and 10),
favoring the difficult amination of the electron-deficient allylic
C−H bond of 26 in much better yield (entry 11) compared to
PcFeCl/AgSF6 (entry 9).
a
Conditions: standard: 10 mol % AgOTf, 12 mol % ligand, 3.5 equiv
of PhIO, 1 g/mmol 4 Å MS, CH2Cl2. DHA: 10 mol % AgOTf, 12 mol
% ligand, 50% DHA, 3.5 equiv of PhIO, 1 g/mmol 4 Å MS, 0.05 M
CH2Cl2. Average of two runs.
b
with DHA (entries 2 and 6) compared to those observed under
the standard conditions (entries 1 and 5), suggesting an HAA
pathway. Interestingly, 15 furnished similar results in the absence
and presence of DHA (entries 3−4), highlighting the subtle
interplay between substrate and catalyst in determining the
probable mechanism of the nitrene transfer event.
In summary, [(Py5Me2)AgOTf]2 2 was identified as a new
catalyst that exhibits a broad preference for the selective
amination of propargylic, benzylic, and allylic C−H bonds over
C
DOI: 10.1021/acs.orglett.6b01392
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more electron-rich tertiary alkyl C(sp3)−H bonds. The dimeric
nature of [(Py5Me2)AgOTf]2, coupled with increased steric bulk
around the metal center, was the key design principle driving the
design of this inexpensive and general amination catalyst. Future
efforts will focus on continuing to explore the generality of 2, as
well as mechanistic studies to understand the influence of catalyst
structure on the pathway of nitrene transfer.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01392.
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NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: schomakerj@chem.wisc.edu.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded through the NSF-CAREER Award
1254397 and the Wisconsin Alumni Research Foundation to
J.M.S. Dr. Charles Fry (University of WisconsinMadison) is
thanked for assistance with NMR spectroscopy. Professor Robert
Bergman (University of CaliforniaBerkeley) is thanked for
helpful comments. 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, S10RR029220) and the NSF (BIR-0214394).
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D
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