Intermolecular C(sp3)?H Amination of Complex Molecules

Article abstract of DOI:10.1002/anie.201713225

A general and operationally convenient method for intermolecular amination of C(sp³)?H bonds is described. This technology allows for efficient functionalization of complex molecules, including numerous pharmaceutical targets. The combination o

Full text of DOI:10.1002/anie.201713225

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Accepted Article
Title: Intermolecular sp3 C-H Amination of Complex Molecules
Authors: Nicholas Derek Chiappini, James B. C. Mack, and Justin Du
Bois
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201713225
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10.1002/anie.201713225
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COMMUNICATION
Intermolecular sp3 C–H Amination of Complex Molecules
Nicholas D. Chiappini, James B. C. Mack and J. Du Bois*
Dedication ((optional))
method from our lab[2b] (entries 1, 2, Table 1), each giving < 50%
of the desired product 2a.[6] Switching to alternative reaction
solvents such as DMA and DMF was, unsurprisingly, found to
arrest the Rh-catalyzed process (entries 3, 4, Table 1). We were
encouraged, however, that other high dielectric solvents, including
sulfolane, propylene carbonate, and CH3CN, afforded reasonable
levels of conversion to the sulfamate product 2a (entries 6–8). The
reaction performed in sulfolane also produced a side product,
which was identified as the C3-sulfonamidated sulfolane. This
result prompted us to consider other solvents that would be
impervious to oxidation. From this analysis, t-BuCN and PhCN
were revealed as superior solvents for C–H amination reactions,
providing a substantial increase in the formation of 2a (entry 10,
11). Interestingly, the combination of i-PrOAc with 10% t-BuCN,
propylene carbonate, or sulfolane (entries 12–14) showed evident
improvement over the reaction conducted in neat i-PrOAc,
suggesting that the ability of these agents to coordinate [Rh2(esp)2]
might have some role in improving catalyst turnover numbers.
Abstract:
A
general and operationally convenient method for
intermolecular amination of sp3 C–H bonds is described. This technology
allows for efficient functionalization of complex molecules, including
numerous pharmaceutical targets. The combination of pivalonitrile as
solvent, Al2O3 as an additive, and phenyl sulfamate as a nitrogen source
affords differential reaction performance and substrate scope. Mechanistic
data strongly implicate a pathway for catalyst decomposition that initiates
with solvent oxidation, thus providing rationale for the marked influence of
pivalonitrile on this reaction process.
Due to the ubiquity of nitrogen containing molecules in Nature,
pharmaceuticals, and agrochemicals, the development of reaction
technologies for the construction of C–N bonds remains a problem
of central importance.[1a-f] As a general process, the selective
oxidation[2a,b] of C–H bonds to form amine derivatives offers
numerous salient features, not the least of which is the ability for
late stage diversification of existing molecular architectures.[3a-r]
Arguably, the full potential of this technology has not been realized
owing to the limited substrate scope and performance of available
intermolecular C–H amination reactions. Here, we disclose a
general and efficient method for the single step amination of
complex molecules, a process that uses one equivalent of substrate,
minimal reaction additives, and a convenient nitrogen source
(Figure 1). Mechanistic studies identify a link between solvent
Table 1. Optimizing conditions for Rh-catalyzed C–H amination of 1a
NHSO2OPh
1 mol % [Rh2(esp)2]
PhOSO2NH2
Me
Me
i-Pr
i-Pr
OTroc
1a
PhI(OPiv)2, Al2O3
OTroc
solvent
2a
oxidation and catalyst stability, and provide
understanding improved turnover numbers under the new protocol.
a basis for
Entry
Yielda,b
RSMb
Solvent
1
2
47
45
5
13
22
60
75
57
61
59
45
47
10
12
22
23
31
i-PrOAcc
i-PrOAc
Me
Me
Me NHSO2OAr
3
N,N-dimethylacetamide
N,N-dimethylformamide
2,2,2-trifluoroethanol
sulfolane
[N]
prior method: 27%
new protocol: 68%
5:1 dr
4
0
H
O
H
5
25
35
33
37
35
80
75
64
60
58
Me
Me
AcO
AcO
O
Me
O
6
O
7
propylene carbonate
CH3CN
Figure 1. General method for sp3 C–H amination.[2b]
8
9
i-PrCN
10
11
12
13
14
t-BuCN
Previously disclosed reports of intermolecular C–H amination
demonstrate good to excellent performance on substrates bearing a
limited number of heteroatom groups.[2b],[3d,m,n,p-r] These processes,
however, often fail to show comparable efficacy on densely
functionalized complex molecules and polar substrates such as
salts of basic amines and azacycles. Intent to solve these problems,
we became interested in testing amination reactions in polar
solvent media to facilitate dissolution of nitrogen-rich substrates
and amine salts. Exploratory reactions were conducted utilizing a
substrate derived from isomenthol 1a and PhOSO2NH2 (PhsNH2)
as the nitrogen source. This sulfamate was selected for its ease of
synthesis and the chromatographic stability of the sulfonamidated
products.[4] Different base additives, including MgO, molecular
sieves, and Al2O3, were also examined as part of this study.[5]
PhCN
9:1 i-PrOAc/t-BuCN
9:1 i-PrOAc/propylene carbonate
9:1 i-PrOAc/sulfolane
[a] Reactions were performed at ambient temperature for 6 h in the indicated
solvent with 1 mol % [Rh2(esp)2], 1.0 equiv of 1, 1.3 equiv of PhOSO2NH2, 1.5
equiv of PhI(OPiv)2, and 4.0 equiv Al2O3. [b] Percent recovered starting
material (RSM) estimated by 1H NMR integration against methyl benzoate as a
standard. [c] Reaction performed with 1.3 equiv 2,6-difluorophenyl sulfamate
(DfsNH2) in place of PhOSO2NH2, 2.0 equiv PhI(OAc)2, 0.5 equiv
PhMe2CCO2H, 4 equiv MgO, and 5Å molecular sieves, providing product as
corresponding DfsNH2 derivative.[2b]
Using our new protocol, we have examined reaction performance
with an array of functionally diverse starting materials (Table 2,
Table S1). Archetypal substrates for atom-transfer C–H oxidation
reactions such as cycloheximide (2b), estrone (2c), and sclareolide
(2d), in addition to numerous active pharmaceutical ingredients
(2g, 2k, 2o, 2p) can be successfully functionalized in synthetically
useful yields (40–75%). The reaction generally delivers product
and recovered starting material, and shows exceptional selectivity
for oxidation of benzylic and tertiary C–H bonds. Substrates
bearing stereogenic centers proximal to the site of amination
demonstrate modest levels of diasteroselectivity (cf, 2c, 2d, 2m).
With i-PrOAc as solvent, the effectiveness of 1 mol% [Rh2(esp)2],
PhOSO2NH2, and Al2O3 closely matched a previously disclosed
[*]
N. D. Chiappini, J. B. C. Mack, Prof. J. Du Bois
Department of Chemistry, Stanford University
Stanford, CA 94305-5080 (USA)
E-mail: jdubois@stanford.edu
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As expected for a reaction of this type, electron-deficient, and
sterically encumbered substrates generally afford lower product
coordination to dirhodium complexes and the use of t-BuCN as
solvent seemingly removes this ambiguity.[10]
UV-visible
yields;[1f],[2c] however, if limiting substrate is not
a
strict
spectroscopy of the [Rh2(esp)2] complex indicates that CH3CN,
t-BuCN, and PhCN have similar σ-donating strengths and are, not
surprisingly, more electron-donating than i-PrOAc, sulfolane, and
requirement, use of 2–3 equivalents typically leads to product
conversions that are nearly quantitative with respect to the nitrogen
source. Importantly, the sulfamate products can be unmasked to the
corresponding 1° amines by heating with pyridine in aqueous
CH3CN (Figure 2).[2b,7] These conditions are tolerant of other
hydrolytically sensitive functional groups, including aryl acetates,
β-acyloxy ketones, lactones, and methyl esters.
+
NHPhs
CO2Me
NH3
I
I
CO2Me
20 equiv C5H5N
MeO
MeO
aq. CH3CN, 70 °C
I
I
3i (89%)
Me NH3
2i
Table 2. C–H amination of complex molecule substrates[a]
O
+
O
O
OAc
NH
H
Me
+H3N
O
Me
H
O
Me
Me
AcO
Me
O
+
Me
Me
Me
NH3
O
3b (86%)
3d (93%)
3q (81%)
Figure 2. Deprotection of N-alkyl phenylsulfamates. Products were obtained
as trifluoroacetate salts following preparative reversed-phase HPLC
purification (see Supporting Information for details).
propylene carbonate (Figure 3).[9-11] As we and others have
demonstrated previously, intermolecular C–H amination reactions
result in one-electron catalyst oxidation to furnish the red-colored
Rh(II)/Rh(III) dimer.[12] The stability and lifetime of this complex
is critical for achieving high reaction turnover numbers. It is
possible that the nitrene-bound Rh(II)/Rh(III) dimer itself functions
as a competent oxidant for C–H functionalization.[8] A strongly
coordinating solvent such as t-BuCN could help to stabilize the
oxidized complex, thus enabling increased turnover numbers.
Such an explanation, however, is incomplete, as the reaction is
decidedly more effective in t-BuCN and PhCN than in CH3CN.
*
Figure 3. UV-visible spectra of [Rh2(esp)2] in t-BuCN !, MeCN !, PhCN !, i-
PrOAc !, sulfolane !, and propylene carbonate ! are shown above. The
axial ligand donor strength of these solvents if reflected in the λmax (*) of the
lower energy π*→σ* band.[10d,11]
[a] All reactions were conducted at ambient temperature under air with non-
anhydrous solvent for 6 h on 0.15 mmol scale using 1.0 equiv substrate in
t-BuCN with 1 mol % [Rh2(esp)2], 1.3 equiv PhOSO2NH2, 1.5 equiv PhI(OPiv)2,
and 4 equiv Al2O3. Percent yield of recovered starting material is shown in
parentheses. [b] Isolated as 5:1 mixture of diastereomers; [c] Isolated as 1:1
inseparable mixture of regioisomers; [d] Ar = p-C6H4F, isolated as 1.25:1
We have noted previously that C–H amination reactions performed
in CH2Cl2 can result in solvent oxidation to liberate chloride ion.[2a]
Based on these insights, we have evaluated performance
differences in protio- and deuterio- solvents for the oxidation of 1a
(Table 3). Deuterated solvents, particularly CD3CN, clearly
outperform the corresponding protiated forms. These data give
weight to the proposal that solvent oxidation, even in CH3CN, is
deleterious to reaction turnover.[13]
inseparable mixture of regioisomers; [e] Ar
= 1,3-benzodioxol-5-yl, 20:1
diastereomer ratio; [f] 20:1 diastereomer ratio. Further exposition of substrate
scope and limitations can be found in Supporting Information.
We have conducted a series of experiments to understand the
origin of the marked performance enhancement imparted by
t-BuCN in intermolecular C–H amination reactions. A long-
standing question in our lab has been the identity and role of the
ligand coordinated to the distal Rh-center in the putative metal-
nitrene oxidant.[8,9] The affinity of nitrile groups for axial
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Interestingly, quantitative 19F NMR analyses of spent reaction
mixtures reveal a substantial deficit in the mass balance of F-esp-
derived material. We have discovered that a considerable amount
of free ligand (~25%) is associated with the Al2O3 solids;
nevertheless, the mass balance remains incomplete. Current efforts
are aimed at identifying the fate of this missing material and
associated catalyst decomposition products.
Table 3. Effect of solvent deuteration on C–H amination performance.
Entry
Solvent
TONa,b
1 mol% [Rh2(esp)2]
PhOSO2NH2
1
2
3
4
CH3CN
CD3CN
CH2Cl2
CD2Cl2
37
55
22
33
1a
2a
PhI(OPiv)2, Al2O3
solvent
[a] Reactions were conducted with 1.0 equiv substrate in solvent with 1 mol %
[Rh2(esp)2], 1.3 equiv PhOSO2NH2, 1.5 equiv PhI(OPiv)2, 4 equiv neutral Al2O3. [b]
Turnover numbers (TON) were determined by 1H NMR integration against methyl
benzoate as a standard.
We have developed a general method for intermolecular C–H
amination capable of generating sulfamate derivatives of complex
molecules, including APIs and natural products. The streamlined
process utilizes limiting quantities of substrate, 1 mol % of
commercially available [Rh2(esp)2], PhI(OPiv)2, and Al2O3. The
identification of t-BuCN as solvent affords substantial
improvements in catalyst turnover and unprecedented reaction
scope. Hallmarks of this method also include product selectivity
and outstanding mass balance. Mechanistic investigations have
shown that a larger fraction of the dirhodium catalyst remains
intact for reactions performed in t-BuCN. Additional studies
comparing amination performance in protio- and deuterio- solvents
intimate a correlation between solvent oxidation and catalyst
decomposition. Future studies are aimed at understanding stepwise
details of the mechanism(s) for catalyst decomposition with the
goal of informing subsequent efforts in catalyst design and reaction
development.
To examine whether solvent has an influence on [Rh2(esp)2]
stability, we have developed an assay to quantify the amount of
intact catalyst at a given time point over the course of the reaction.
Due to the low catalyst loading employed in this process and the
paramagnetic nature of the Rh(II)/Rh(III) dimer, we have modified
the H2(esp) ligand to include a 19F-label (Figure 4). The sensitivity
of 19F NMR allows us to perform the amination reaction under our
standard protocol and to record a strong F-signal of the [Rh2(F-
esp)2] adduct. Attempts to follow the reaction progress in real-time
by 19F NMR, however are complicated by paramagnetic line-
broadening. We have thus resorted to quenching the reaction by
addition of Zn powder at a fixed time point. The red color of the
Rh(II)/Rh(III) dimer is extinguished upon addition of the reducing
agent, and the blue-green color of [Rh2(F-esp)2] is restored. 19F
NMR allows us to quantify against an internal standard (1,3-
dbromo-2,5-difluorobenzene) the percentage of Rh(II)/Rh(II)
dimer remaining in solution.
Acknowledgements
F
We are grateful to Professor Hemamala Karunadasa, Dr. Carmen
Leal-Cervantes, and Kurt Lindquist for generous use of equipment
and for assistance with UV/vis experiments. We also wish to thank
Dr. Stephen Lynch for his assistance with two-dimensional NMR
spectroscopy, Dr. Mark Smith (MCKC, ChEM-H Stanford
University) for use of LC-MS instrumentation, and the Vincent
Coates Foundation Mass Spectrometry Laboratory, Stanford
University Mass Spectrometry for HRMS data collection. The
National Science Foundation through the CCI Center for Selective
C−H Functionalization (CHE-1700982) and Novartis have
graciously provided financial support of this work.
1 mol%
Me
[Rh2(F-esp)2]
Me
Me
NHPhs
PhOSO2NH2
O
O
Me
Me
Me
OBz
Me
OBz
O
L
O
L
Rh
Me
PhI(OPiv)2, Al2O3;
Rh
1r
2r
then Zn, EtOAc
[Rh2(F-esp)2]
Keywords: oxidation • sulfamate • [Rh2(esp)2] • t-BuCN
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Entry for the Table of Contents
COMMUNICATION
Nicholas D. Chiappini, James B. C.
Mack, J. Du Bois*
Page No. – Page No.
Title
Intermolecular sp3 C–H
Amination of Complex
Molecules
Text for Table of Contents
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