A manganese catalyst for highly reactive yet chemoselective intramolecular C(sp 3)-H amination

Article abstract of DOI:10.1038/nchem.2366

C-H bond oxidation reactions underscore the existing paradigm wherein high reactivity and high selectivity are inversely correlated. The development of catalysts capable of oxidizing strong aliphatic C(sp³)-H bonds while displaying chemoselecti

Full text of DOI:10.1038/nchem.2366

ARTICLES
PUBLISHED ONLINE: 5 OCTOBER 2015 | DOI: 10.1038/NCHEM.2366
A manganese catalyst for highly reactive yet
chemoselective intramolecular C(sp3)–H amination
Shauna M. Paradine†‡, Jennifer R. Griffin†, Jinpeng Zhao, Aaron L. Petronico, Shannon M. Miller
and M. Christina White
*
C–H bond oxidation reactions underscore the existing paradigm wherein high reactivity and high selectivity are inversely
correlated. The development of catalysts capable of oxidizing strong aliphatic C(sp3)–H bonds while displaying
chemoselectivity (that is, tolerance of more oxidizable functionality) remains an unsolved problem. Here, we describe a
catalyst, manganese tert-butylphthalocyanine [Mn(tBuPc)], that is an outlier to the reactivity–selectivity paradigm. It is
unique in its capacity to functionalize all types of C(sp3)–H bond intramolecularly, while displaying excellent
chemoselectivity in the presence of π functionality. Mechanistic studies indicate that [Mn(tBuPc)] transfers bound
nitrenes to C(sp3)–H bonds via a pathway that lies between concerted C–H insertion, observed with reactive noble metals
such as rhodium, and stepwise radical C–H abstraction/rebound, as observed with chemoselective base metals such as
iron. Rather than achieving a blending of effects, [Mn(tBuPc)] aminates even 1° aliphatic and propargylic C–H bonds,
demonstrating reactivity and selectivity unusual for previously known catalysts.
igh-valent metal heteroatom species (that is, oxos and mechanism1. Conversely, base metal iron catalysts access mechanis-
nitrenes) oxidize inert C–H bonds with tunable site-selectiv- tically distinct single-electron pathways for nitrene transfer, afford-
H
ity and stereospecificity, but typically do not tolerate more ing excellent chemoselectivity with diminished reactivity for
readily oxidizable π functionality1–6. Intramolecular metallo- stronger C–H bond types11–14. We hypothesized that a metal catalyst
nitrene-based C(sp3)–H amination of sulfamate esters, which installs capable of transferring bound nitrenes to C(sp3)–H bonds via a
medicinally important amino alcohol motifs, showcases the inverse stepwise mechanism with attenuated radical character of the metal-
correlation between reactivity and chemoselectivity for such cataly- lonitrene oxidant relative to iron would achieve higher reactivity
sis7–10. Noble metal rhodium catalysts that stereospecifically func- while maintaining chemoselectivity20. The low reactivity observed
tionalize robust aliphatic C–H bonds (secondary, 2°; tertiary, 3°) under iron catalysis with aliphatic C(sp3)–H bonds coupled with
lack chemoselectivity due to the competitive oxidation of π bonds reports that sulfamate ester N-centred free radicals are unreactive
(Fig. 1a)1,7–10. Conversely, base metal iron catalysts that chemoselec- towards intramolecular aminations of 3° C(sp3)–H bonds21
tively aminate allylic C–H bonds over competing aziridination are suggested to us that a metallonitrene with diminished radical char-
only moderately reactive toward stronger aliphatic C–H bonds acter would be more reactive. Although nature rarely uses manga-
(Fig. 1a)11–15. Here, we describe the discovery of an outlier catalyst, nese metal species to mediate oxidations, early studies using
manganese tert-butylphthalocyanine [Mn(tBuPc)] (3), which is the synthetic metalloporphryins as models for cytochrome P450
first to achieve both high reactivity and chemoselectivity for a C–H demonstrated that manganese and iron oxos react via mechanisti-
oxidation reaction. Catalyst [Mn(tBuPc)] preparatively aminates all cally analogous one-electron pathways, with manganese exhibiting
C(sp3)–H bond types encompassed by rhodium, and maintains the significantly higher C–H hydroxylation reactivity22. Importantly,
high chemoselectivity for allylic C–H amination observed with iron, the manganese catalysts were found to have smaller kinetic
all while demonstrating stereospecificity, site selectivity and high isotope effects (KIE) than their iron counterparts, suggestive of
functional group tolerance (Fig. 1b). Additionally, [Mn(tBuPc)] attenuated radical behaviour23. Moreover, well-characterized
aminates primary (1°) aliphatic and propargylic C–H bonds, nitridomanganese(V) porphyrin complexes have been shown to stoi-
demonstrating reactivity and selectivity that is typically difficult to chiometrically transfer nitrenes when the nitrogen is rendered
achieve with metallonitrene-based catalysis. Importantly, we show electron-deficient, much like with iron24–26
this reaction enables rapid and scalable late-stage diversification of
.
bioactive molecules. The unique generality of [Mn(tBuPc)] is par- Results
tially attributed to its mechanistically distinct pathway for nitrene Reaction development. We first compared a series of manganese
transfer that lies between the stepwise mechanism of iron and the complexes with their iron counterparts for the C–H amination of
concerted mechanism of rhodium. Discovery of an Earth-abundant challenging 3° aliphatic substrate 4 (bond dissociation energy
base metal catalyst that is capable of aminating all types of C(sp3)–H (BDE) of ∼96 kcal mol–1)27. Improved yields of aminated product
bonds, including those challenging to access with precious noble 5 were observed with the manganese complexes across all
metals, underscores the potential benefits in the continued develop- ligand classes (Table 1, entries 1–8). The previously reported
ment of these inexpensive, underexplored metals as catalysts for phthalocyanine ligand was most effective11, so catalyst 2 was used
important synthetic reactions5,6,11–14,16–19
Noble metal rhodium catalysts functionalize strong aliphatic porphyrin catalysts, among the first catalysts shown to be
C–H bonds via
concerted asynchronous C–H insertion competent for metallonitrene-based C–H amination28, exhibited
.
for further optimization. Notably, both iron and manganese
a
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA. ‡Harvard University, Cambridge, Massachusetts, USA.
†These authors contributed equally to this work. e-mail: mcwhite7@illinois.edu
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2366
ARTICLES
a
Previous work
H3C
H3C
CH3
N
O
O
N
O
O
O
CH3
CH3
CH3
N
N
N
N
N
O
O
Cl
Rh
O
Ru
Rh
O
O
N
Fe
X
N
H3C
O
Rh
N
Ru
O
Rh
O
O
O
H3C
H3C
O
O
N
O
O
O
N
CH3
CH3
CH3
Rh2(esp)2
Rh2(OAc)4
[Ru2(hp)4]Cl
[FePc]·SbF6
Reactivity
Selectivity
O
O
O
O
O
O
N
Cat.
above
Cat.
above
H
S
S
S
O
HN
O
HN
O
R
Strong
aliphatic
C–H
R
OSO2NH2
Weak
allylic
C–H
R
R
C–H
insertion (ins.)
Aziridine
(azir.)
C–H
insertion (ins.)
Rh cat.
Rh cat.
Fe/Ru cat.
b
This work
tBu
tBu
N
O
O
O
O
[Mn(tBuPc)]
N
N
N
H
S
S
N
Mn
X
N
HN
O
HN
O
High reactivity and
chemoselectivity
R
OSO2NH2
N
R
R
N
tBu
C–H insertion
[Mn(tBuPc)]
X = SbF6
tBu
Figure 1 | The C–H oxidation reactivity/selectivity paradigm. a, Reactivity and chemoselectivity of existing C–H amination catalysts with sulfamate ester
substrates. Rhodium catalysts aminate strong 2° C–H bonds in aliphatic substrates but aziridinate reactive π functionality in allylic substrates. Iron and
ruthenium catalysts aminate weak allylic bonds with high chemoselectivity, but demonstrate limited reactivity towards strong aliphatic C–H bonds. b, Novel
[Mn(tBuPc)] catalyst demonstrates both high reactivity and chemoselectivity. It is capable of aminating strong aliphatic C–H bonds while tolerating reactive π
functionality in allylic substrates.
significantly lower reactivity with this challenging substrate (entries of aminated products 6 and 7 (entries 1 and 2). Catalyst 3
3 and 4). The enhanced reactivity for an electrophilic C–H exhibited good reactivity across all bond types with 2° (8, BDE
amination reaction may be attributed to an electronic difference of ∼98 kcal mol–1) and even 1° (9, BDE of ∼101 kcal mol–1)27
between these ligands, as evidence suggests that phthalocyanines C–H bonds being readily intramolecularly aminated (entries 3
are significantly better π-acceptor ligands and may lead to and 4). Significantly, 1° C–H bonds are at the lowest end of the
enhanced electrophilicity at the metal centre29,30. The addition of reactivity spectrum under rhodium catalysis, and amination of
molecular sieves significantly improved reactivity with both 10 this bond type is rare (vide infra)31. Moreover, despite the high
and 5 mol% catalyst 2, affording 60% and 58% of 5, respectively intramolecular reactivity of 3, excellent chemoselectivity (>20:1
(entries 9 and 10). Catalyst 3, in which tert-butyl groups were insertion (ins.)/aziridine (azir.)) was maintained for allylic C–H
introduced into the periphery of the phthalocyanine ligand, amination, as compared to 1:1 ins./azir. observed for rhodium catalyst
further improved the yield to 75% (entry 11). This modification [Rh2(esp)2] (bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic
was not similarly beneficial for the corresponding iron complex acid)]; ref. 31) (entry 2).
(29% yield, entry 12). The enhanced productivity of 3 enables the
Catalyst 3 is capable of aminating 3°, 2° and 1° aliphatic C–H
catalyst loading to be reduced to 5 mol% (72%, entry 13) and in bonds in a broad range of substrates with good functional group tol-
some cases to 2.5 mol% (71%, entry 14). Additionally, the oxidant erance and site-selectivity (Table 3). Adjacent functionality, such as
loading can be reduced to 1.2 equiv. while still maintaining good protected nitrogen (10, 79%) and silyl ethers (11, 71%), is well
reactivity (68%, entry 15).
tolerated. In the presence of proximally equivalent C–H bonds,
catalyst 3 discriminates according to BDE, functionalizing at the
Reaction generality. This new catalytic method was examined with all weaker β 3° C–H bond of an isopinocampheol derivative in the pres-
other major sp3 C–H bond types (benzylic, allylic, 2° and 1° aliphatic) ence of a β 2° C–H bond (12, 63%; vide infra Fig. 2c). Amination of
using unsubstituted linear sulfamate esters, among the most difficult 3° C–H bonds is also effective for the formation of azaspirocycles
substrate classes for intramolecular C–H amination (Table 2). In all (13, 52%) and fused bicycles (14, 86%). Additionally, 3 exhibits
cases, a significant improvement in yield was observed in switching sensitivity to substrate electronics (that is, inductive effects) in the
from the iron to the manganese phthalocyanine catalyst, with the amination of 2° C–H bonds. A remote electron-withdrawing
benzylic and allylic substrates affording synthetically useful yields ester moiety has limited impact on amination at the γ position
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2366
ARTICLES
similarly high chemoselectivity (7:1 ins./azir.) but poor reactivity
(22%), whereas a noble metal ruthenium catalyst [Ru2(hp)4]
(tetrakis-(2-oxypyridinato)diruthenium(II, III) chloride), designed to
be highly chemoselective, is less selective for insertion (2:1 ins./azir.)15
and Rh2(esp)2 favours π functionalization (1:1.5 ins./azir.)31.
Additionally, [Mn(tBuPc)] exhibits diminished sensitivity to sub-
strate electronics relative to its iron predecessor with weaker
C(sp3)–H bond types (Fig. 2b, vide infra). Catalyst 3 readily functio-
nalizes C–H bonds proximal to an α,β-unsaturated ester (21, 77%),
while other chemoselective catalysts 1 and [Ru2(hp)4] are less reac-
tive (12 and 25%, respectively)11,15. This electronic insensitivity is
further highlighted by the tolerance of electron-withdrawing nitro-
gen functionality (22, 73%) introduced via palladium-catalysed
intermolecular allylic C–H amination33. A cyclohexene derivative
readily cyclizes to form bicycle 23 in 69% yield with excellent dia-
stereoselectivity (>20:1 anti/syn). The high chemoselectivity for
allylic C–H amination over aziridination with [Mn(tBuPc)] 3 is
maintained even in cases where aziridination is geometrically pre-
ferred. The homoallylic sulfamate derivative of terpene (–)-nopol
undergoes facile allylic C–H amination with catalyst 3 at the
β-position to furnish the five-membered heterocycle (24, 60%) with
no observed aziridine. This bias of 3 toward allylic C–H amination
versus aziridination persists even in an acyclic styrenyl homoallylic
sulfamate ester substrate (25, 62%, 7:1 ins./azir.). In contrast, both
reactivity and chemoselectivity are lower with typically chemoselective
chiral rhodium catalysts34 ([Rh2(S-nap)4], 48%, 2:1 ins./azir.), and for-
mation of the aziridine product is strongly favoured (1:20 ins./azir.)
with standard Rh2(OAc)4 (ref. 1).
Table1 | Reaction development with [Mn(tBuPc)] catalyst.
O
O
Fe/Mn cat. (10 mol%)
2 equiv. PhI(OPiv)2
S
HN
O
H
Additive
9:1 C6H6/MeCN
rt, 8 h
OSO2NH2
3
3
4
5
Entry
Catalyst
Additive
% yield (% rsm)
1
2
3
[FePc]·SbF6 (1)*
[MnPc]·SbF6 (2)*
Fe(TPP)·SbF6*
–
–
–
29 (32)
43 (27)
4 (85)
4
5
6
7
8
9
10
11
12
13
14
15
Mn(TPP)·SbF6*
–
–
–
–
18 (62)
<1 (85)
4 (78)
<1 (91)
7 (82)
60 (11)
58 (20)†
75 (<5)
29 (34)
72 (14)†
71 (13)‡
68 (16)†.§
Fe(R,R-salen)·SbF6*
Mn(R,R-salen)·SbF6*
Fe(R,R-PDP)(SbF6)2
Mn(R,R-PDP)(SbF6)2
[MnPc]·SbF6 (2)*
[MnPc]·SbF6 (2)*
–
4 Å MS
4 Å MS
[Mn(tBuPc)]·SbF6 (3)*
[Fe(tBuPc)·SbF*6
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
[Mn(tBuPc)]·SbF6 (3)*
[Mn(tBuPc)]·SbF6 (3)*
[Mn(tBuPc)]·SbF6 (3)*
Isolated yields are an average of three runs with recovered starting material (rsm) in parentheses.
Pc, phthalocyanine; TPP, tetraphenylporphyrin; salen, N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-
cyclohexanediamine; PDP, [N,N′-bis(2-pyridylmethyl)]-2,2′-bipyrrolidine. *Active catalyst formed
via in situ metathesis using equimolar AgSbF6 and chloride pre-catalyst. †5 mol% each Mn
catalyst and AgSbF6. ‡2.5 mol% each Mn catalyst and AgSbF6. §1.2 equiv. PhI(OPiv)2. Piv, pivaloyl.
Although chemoselective propargylic C–H amination with car-
bamates to furnish 1,2-amino alcohols is precedented35, amination
using sulfamate esters to afford the 1,3-amino alcohol motif is
(15, 57%), but will attenuate reactivity when made more proximal
(Supplementary Table 3 and Supplementary compound S36). A
distal tosylate group is tolerated under the reaction conditions to
afford 16 in 54% yield; this functionality can be subsequently dis-
placed intramolecularly to generate a heterobicycle in 80% yield
(Supplementary compound S37). In addition, 2° C–H amination
in cyclohexanes can occur across the ring in a 1,3-fashion, functio-
nalizing adjacent to a bulky tert-butyl group in a cis relationship (17,
90%), which would be challenging to accomplish with traditional
synthetic methods.
Table 2 | Manganese versus iron catalyst comparison with
unsubstituted linear substrates.
O
O
Catalyst • SbF6 (5 mol%)
PhI(OPiv)2 (2 equiv.)
S
H
OSO2NH2
HN
O
R
R
Under [Mn(tBuPc)] 3 catalysis, amination of γ C–H bonds to
form six-membered oxathiazinanes is generally preferred over β
C–H bonds to form five-membered oxathiazoles, regardless of the
relative bond strength. For example, in the functionalization of a
borneol derivative, amination selectively occurs at the stronger γ 1°
C–H bond of the adjacent methyl group to afford 18 in 53% yield.
Competitive C–H amination at the β 2° C–H bond is geometrically
possible with this substrate and is observed in 27% yield. This ring-
size selectivity has been noted with rhodium catalysis and is based on
the geometric constraints imposed by the favoured N–S–O bond
angles of the sulfamate tether1. However, the ability to aminate effec-
tively at 1° methyl groups with metallonitrenes is rare, and the
reported examples with iron12,14 and rhodium31,32 are low yielding.
A limitation to this trend can be observed when amination to
form a six-membered heterocycle requires functionalization of an
exceptionally strong γ C–H bond over a much weaker β C–H
bond. Amination of a cyclopropane-containing substrate occurs
exclusively at the stereoelectronically activated β 2° C–H bond
(BDE of ∼97 kcal mol–1) to form five-membered sulfamidate 19
(51%) as opposed to the six-membered oxathiazinane, which
would require abstraction of a much stronger 3° cyclopropane
C–H bond (BDE of ∼106 kcal mol–1)27.
4 Å MS, 9:1 C6H6/MeCN
rt, 8–24 h
6–9
Entry Product
Yield (%, based on catalyst)
[FePc] (1) [MnPc] (2) [Mn(tBuPc)] (3)
Benzylic
O
O
1
S
S
HN
O
(6)
(7)
22
10
71
61
74
61
Ph
Allylic
O
O
2
HN
O
>20:1 ins./azir.
O
O
2° C–H
S
S
3
HN
O
(8)
(9)
5†
39†
37†
57†
64†
nPr
1° C–H
O
O
4
HN
O
Catalyst 3 successfully aminates at the allylic position in a variety
of molecules, in all cases maintaining the excellent chemoselectivity
previously observed with [FeIIIPc] for olefin-containing substrates
(Table 3)11. For example, with a challenging linear terminal olefin
substrate, catalyst 3 affords C–H amination product 20 in 50%
yield and in 7:1 excess over the aziridine. Iron catalyst 1 exhibits
3†
Isolated yields are average of three runs. *Conditions: 5 mol% [FePc]Cl, 5 mol% AgSbF6, 2 equiv.
PhI(OPiv)2, 4:1 PhMe/MeCN (0.5 M), rt, 8 h. †10 mol% catalyst.
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Table 3 | Substrate scope of [Mn(tBuPc)]-catalysed C–H amination.
tBu
tBu
N
[Mn(tBuPc)]Cl (5 mol%)
O
O
N
N
N
N
AgSbF6 (5 mol%)
S
Mn
X
N
N
R1
OSO2NH2
R3
HN
O
PhI(OPiv)2 (2 equiv.)
H
R1
γ
R2
R3
N
4 Å MS, 9:1 C6H6/MeCN
rt, 8-24h
R2
tBu
β
[Mn(tBuPc)] (3)
tBu
X = SbF6
Aliphatic
O
O
O
O
O
O
O
O
O
O
O
O
H
2°
S
S
S
S
S
S
HN
O
HN
O
O
HN
O
HN
O
O
HN
O
HN
Me
H
3°
Me
MeO
Me
3
NPhth
OTBDPS
15, 57%†
10, 79%
(–)-11, 71%
(–)-12, 63%†
13, 52%†
(+)-14, 86%
O
O
O
O
O
O
S
S
S
HN
O
HN
HN
O
2°
O
TsO
(+)-18, 53%
(+27% 2°)
2:1 1°/2°
4
1°
NH
O
O
O
19, 51%†
16, 54%†
17, 90%
>20:1 d.r.
S
Allylic
O
O
O
O
O
O
O
O
O
O
O
O
S
S
S
S
S
S
HN
HN
HN
O
HN
O
Ts
N
HN
O
HN
O
O
O
EtO
MeO2C
O
20, 50%†, 7:1‡
[FePc]: 22%*†, 7:1‡
[Ru2(hp)4]: 2:1‡,§
Rh2(esp)2: 1:1.5‡,§
25, 62%, 7:1‡
21, 77%†
[FePc]: 12%*,†
[Ru2(hp)4]: 25%§
22, 73%†
23, 69%
>20:1 d.r.
24, 60%
2:1 d.r.
[Rh2(S-nap)4]: 2:1‡,§
Rh2(OAc)4: 1:20‡,§
Propargylic, ethereal, benzylic
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
S
S
S
S
S
S
HN
O
HN
O
HN
O
HN
O
HN
O
HN
O
HN
O
OEt
Ph
Ph
O
TsO
OTBS
O
Me
TMS
O
X
X
S
(–)-27, 48%†
1:1 d.r.
29, X = H, 69%
31, X = Br, 68%
[FePc]: 30%*
33, 64%†
>20:1 d.r.
26, 64%
(–)-28, 64%
>20:1 d.r.
34, 68%
>20:1 d.r.
[FePc]: 43%*,†
30, X = OBoc, 69%
32, X = CF3, 58%†
O
O
O
O
O
O
O
O
O
O
O
O
O
S
S
S
S
S
HN
O
HN
O
HN
O
HN
HN
O
HN
O
O
Ph
O
Ph
N
N
N
PhO2SN
PhO2SN
N
O
Ph
O
35, 63%¶
36, 69%
7:1 d.r.
37, 71%
12:1 d.r.
38, 56%†
39, 63%†
40, 63%
oxaprozin derivative
Isolated yields are average of three runs. *Conditions: 5 mol% [FePc]Cl, 5 mol%AgSbF6, 2 equiv. PhI(OPiv)2, 4:1 PhMe/MeCN (0.5 M), rt, 8 h. †10 mol% catalyst. ‡Ins./azir. ratio. §For Rh2(esp)2 see ref. 31.
For Rh2(OAc)4 and [Rh2(S-nap)4] see ref. 1. For [Ru2(hp)4] see ref. 15. ¶10% of 1° C–H amination also isolated.
challenging as the alkyne typically undergoes alternative oxidation for a streamlined synthesis of saxitoxin37. Alternatively, ethereal C–H
pathways36. Instead, two-step sequences have been developed that amination can be performed in good yield and diastereoselectivity
involve amination of activated ethereal C–H bonds to furnish N, (64%; >20:1 d.r.) with catalyst 3 to furnish the sensitive oxathiazinane
O-acetals followed by Lewis acid-promoted alkylations to generate N,O-acetal 28, a known precursor to alkyne 27.
propargylic amines1. Further underscoring the high chemo-
Catalyst 3 functionalizes benzylic C–H bonds in a variety of aro-
selectivity achieved with manganese catalysis, a trimethylsilyl matic and heterocyclic compounds, further demonstrating the gen-
(TMS)-protected terminal alkyne sulfamate ester readily undergoes erality of this method (Table 3). Phenolic sulfamate esters cyclize
propargylic C–H amination (26, 64%). α-Substituted alkyne 27 with iron catalyst 1 in modest yields due to deleterious substrate
functionalizes in moderate yields and serves as a viable intermediate decomposition (29, 43%), but these substrates are functionalized
4
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2366
ARTICLES
a
Iminoiodinane
formation
Metallonitrene
formation
b
Hammett
analysis
O
O
O
O
O
O
O O
O
O
OSO2NH2
S
S
S
PhI(OPiv)2
S
S
+
[MLn]
O
NH
HN
O
IPh
[MLn]
H
O
NH2
H
O
N
H
O
N
Ar
Ph
Standard
conditions
Ar
Ph
PivOH
Ph
Ar
R1
R3
R1
R3
2
R1
R3
2
PhI
R2
R2
R2
Ar =
C–H
cleavage
1: ρσ+ = –1.12
3: ρσ+ = –0.88
R
R
X
N
X = OMe, Me, CF3, NO2
N
N
N
Radical
rebound
O
O
O
O
M
X
N
N
N
S
S
HN
O
O
N
[MLn]
N
Fast
Allylic
Benzylic
c
R
H
X = SbF6
OSO2NH2
OSO2NH2
R1
R3
R
R1
R3
R2
R2
1 R = H; M = Fe
2 R = H; M = Mn
3 R = tBu; M = Mn
[MLn]
Ph
γ
γ'
γ
γ'
41
42
γ:γ
1: <1:20
3: <1:20
1: 1:14
3: 1:3
'
O
S
O
O
O
d
Y
X
Kinetic
isotope
S
HN
O
HN
O
+
Propargylic
OSO2NH2
Ph
OSO2NH2
45: X=H, Y=D
46: X=Y=H or X=Y=D (46-d2)
Secondary
Standard
conditions
Ph
Ph
OSO2NH2
D
H
γ
γ'
Parallel reactions (46 or 46-d2)
2: kH/kD = 1.9 0.2
3: kH/kD = 1.7 0.1
γ
γ'
43
Intramolecular competition (45)
1: kH/kD = 4.8 0.1
2: kH/kD = 4.5 0.1
3: kH/kD = 4.2 0.1
Rh2(OAc)4: kH/kD = 3.8 0.1
TMS
44
Intermolecular competition (46 and 46-d2)
2: kH/kD = 1.9 0.1
3: kH/kD = 1.6 0.1
1: 1:3
3: 1:2
1: >20:1
3: 5:1
O
O
O
O
O
O
e
Olefin
isomerization
f
H
S
S
S
HN
O
Stereoretention
HN
O
HN
O
+
OSO2NH2
OSO2NH2
Standard
Standard
conditions
conditions
(+)-49
47
>20:1 Z:E
(+)-48
99% e.e.
(Z)-7
(E)-7
1: 99% e.e.
3: 99% e.e.
1: 10:1 Z:E
3: 10:1 Z:E
Figure 2 | Mechanistic studies of manganese and iron C–H amination catalysts. a, Proposed stepwise mechanism for manganese and iron catalysis.
b, Intramolecular Hammett analysis (σ+) reveals that 3 is less sensitive to the electronics of the C–H bond than 1, but more so than reported for rhodium
(ρ = −0.55). c, C–H bond reactivity trends for 3° aliphatic C–H bonds relative to other bond types show that 3 reacts according to relative C–H BDE but is
less discriminating than 1, indicating attenuated radical character in C–H cleavage. d, KIE values for intramolecular competition experiments for catalysts 1, 2,
3 and Rh2(OAc)4 (quantitative 13C NMR spectroscopy) suggest manganese catalysis proceeds via a transition structure where C–H bond breakage occurs
to a greater extent than with rhodium but less than with iron. Intermolecular KIE studies with catalysts 2 and 3 suggest C–H cleavage contributes to the
reaction rate but is not solely rate-determining. e, Partial isomerization of Z-olefin substrate 47 with catalysts 3 and 1 support a stepwise mechanism.
f, Complete stereoretention in C–H amination of enantiometrically enriched (+)-48 with catalysts 3 and 1 supports a rapid radical rebound of the nitrogen
from the base metal catalyst versus a free radical intermediate.
with manganese catalyst 3 in improved yields (29, 69%; 30, 69%). conditions (38, 56% and 39, 63%, respectively). Exemplifying the
Catalyst 3 promotes benzylic C–H amination on substrates with potential application of this method to late-stage diversification
varying degrees of electronic deactivation, such as para-Br- and of pharmaceuticals, an oxazole-based substrate derived from
para-CF3-substituted benzylic substrates (31, 68% and 32, 58%, the commercial nonsteroidal anti-inflammatory drug (NSAID)
respectively). In contrast, iron catalyst 1 is less reactive for electroni- oxaprozin furnished oxathiazinane 40 in 63% yield.
cally deactivated benzylic substrates (31, 30%). Both α- and
β-branched sulfamates readily undergo benzylic C–H amination Mechanistic studies. We sought to investigate our hypothesis that
with excellent diastereoselectivity (>20:1), favouring the confor- the unique generality of catalyst 3 can be attributed to the
mationally preferred syn and anti oxathiazinane, respectively attenuated radical character of the manganese metallonitrene
(33, 64%; 34, 68%)1. Sterically encumbered benzylic substrates oxidant relative to iron. Intramolecular competition experiments
with quaternary centres adjacent to the site of functionalization were conducted to probe the C–H amination steps of the catalytic
still aminate in good yields (35, 63%). Given the prevalence of het- cycle independently from the reaction kinetics (Fig. 2a). The
erocycles in medicinally relevant compounds, we evaluated the toler- electronic nature of the transition state for C–H cleavage was
ance of this method to aromatics with varying degrees of heteroatom assessed by way of Hammett analysis with a series of sulfamate
incorporation. Pyrrole and indole substrates both afforded good ester substrates having two electronically dissimilar benzylic sites
yields and diastereoselectivities of the desired C–H amination pro- (Fig. 2b and Supplementary Fig. 1). Plotting log(kAr/kH) against
ducts (36, 69%, 7:1 d.r. and 37, 71%, 12:1 d.r., respectively). substituent parameter σ+ gave linear correlations, with manganese
N-aryloxazolidinones and oxadiazoles, which contain both nitrogen showing less sensitivity to the electronics of the C–H bond
and oxygen heteroatoms, proceeded smoothly under the reaction relative to iron (ρ = –0.88 for 3, –1.12 for 1), but significantly
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ARTICLES
Allylic
Benzylic
a
3° aliphatic
O
O
S
O
O
R
H2NO2SO
H
O
NH
H
H
Mn(tBuPc)
amination
O
OH
(–)-51,
55%
H
H
R =
O
S
CO2Me
O
O
H
NH
H
S
O
O
N
(–)-52,
66%
NO2PhthN
O
H
NO2PhthN
(+)-50, 57%
(–)-53
(–)-54, 70%
2° aliphatic
O
O
O
Mn(tBuPc)
amination
(i) CBzCl, Et3N, DMAP,
THF, 2 h, 83%.
H
H
H
3
H
CBzN
HN
(ii) NaN3, DMF, 40 °C
or KOAc, DMF, 80 °C
H
H
H
H
H
O
S
Nuc
OSO2NH2
O
O
(–)-57: Nuc = N3, 56%
(–)-58: Nuc = OAc, 76%
(–)-55
(–)-56, 92% (5 mol% 3)
Gram scale: 75% (2.5 mol% 3, 1.5 equiv. [O])
1° aliphatic
b
1 regioisomer
1 stereoisomer
AcO
AcO
1 regioisomer
H
H
O
O
S
O
O
OMe
Mn(tBuPc)
amination
Mn(tBuPc)
amination
OMe
O
H
H
1o
O
H
N
16
H
O
H
H
2
O
O
O
H
H
H2NO2SO
O
6
H
H
O
S
8
H2NO2SO
H
H
H
H
O
O
H
N
1o
23 24
O
O
H
(+)-59
(–)-60, 76%
(+)-61
(–)-62, 84%
Figure 3 | Late-stage diversification of complex molecules via [Mn(tBuPc)]-catalysed C–H amination. Amination of native oxygen-containing complex
molecules picrotoxinin, pregnenolone, stigmasterol, isosteviol and betulinic acid, as well as those where hydroxyl functionality is readily installed, leelamine
and dihydropleuromutilone. a, Predictably selective C–H amination occurs on allylic, benzylic and 3° and 2° aliphatic C–H bonds in the presence of alternative
reactive functionality. Isosteviol derivative (−)-55 undergoes C–H amination on a gram scale and the resulting oxathiazinane (−)-56 is derivatized to reveal
1,3 diamine and amino alcohol motifs. DMAP, 4-dimethylaminopyridine. b, Site- and diastereoselective 1° aliphatic C–H amination of betulinic acid (+)-59 and
dihydropleuromutilone (+)-61 sulfamate ester derivatives in the presence of alternative, accessible 2° and 3° C–H bonds to furnish geometrically favoured
six-membered oxathiazinanes.
more than that reported for rhodium catalysts (ρ = –0.55)1,15. These same degree as with iron catalyst 1, affording a 10:1 Z/E mixture of 7
data are consistent with the reactivity trends observed between (Fig. 2e). Characteristic of a reaction proceeding via a concerted
manganese and iron with electronically deactivated substrates and C–H amination mechanism, an analogous substrate has been
suggest a transition structure in which C–H cleavage for reported to proceed with no isomerization under rhodium cataly-
manganese is less pronounced than for iron, but more so than the sis11. Importantly, C–H amination at a defined aliphatic stereocentre
related transition structure for the concerted rhodium-catalysed in 48 proceeds with complete stereoretention for manganese cata-
process15 We also systematically compared the C–H bond lysts 2 and 3 as well as for iron catalyst 1 (49, 99% enantiomeric
.
reactivity trends for γ 3° aliphatic C–H bonds relative to other excess (e.e.), Fig. 2f). These data further support a stepwise mechan-
bond types (γ′) (41–44, Fig. 2c). The reactivity trends correlate ism for manganese that proceeds through H atom abstraction fol-
with the homolytic C–H BDEs for both manganese and iron, but lowed by rapid radical rebound from the base metal catalyst. In
manganese shows less discrimination between the different bond contrast to aminations that proceed via free radical intermedi-
types, consistent with diminished electrophilic radical character in ates21,38,39, this mechanistic feature of metallonitrene chemistry
the C–H cleavage transition state. Additionally, benzylic amination allows C–H amination reactions to proceed stereospecifically with
of monodeuterated substrate 45 provides an intramolecular KIE for high functional group tolerance, and enables the prospect of
manganese catalyst 3 (4.2 0.1) that lies between iron catalyst 1 tuning the catalyst to control selectivity during functionalization6.
(4.8 0.1) and Rh2(OAc)4 catalyst (3.8 0.1) (Fig. 2d). Taken
together, these data support our hypothesis that catalyst 3 of manganese catalyst 3 on reaction kinetics. The reaction profile for
proceeds through stepwise mechanism with a transition a 2° aliphatic substrate suggested an overall reaction rate enhance-
To gain further mechanistic insight, we investigated the influence
a
structure in which C–H bond breakage occurs to a lesser extent ment with 3 relative to both 1 and 2, resulting in significantly
than with iron15. Notably, catalyst 3 behaved in a manner higher product yields with 3 (Supplementary Fig. 2). Initial rate
comparable to its unsubstituted manganese analogue 2, with the measurements for 2° and benzylic C–H amination with 3 quantitat-
exception that a slightly smaller intramolecular KIE was observed ively support catalyst involvement in the rate-determining step of
with 3 (4.2) relative to 2 (4.5), suggesting that this ligand the reaction, as changes in catalyst concentration (5–10 mol%)
modification results in further attenuation of radical character.
result in proportional changes in the initial rate (Supplementary
We next evaluated the recombination step for manganese catalyst Figs 3–5 and 10). This contrasts with rhodium catalysis, where
3. In the allylic C–H amination of Z-olefin substrate 47 (>20:1 Z/E), there is no rate dependence on catalyst concentration, and imino-
olefin isomerization was observed with manganese catalyst 3 to the iodinane formation is hypothesized to be rate-determining1,31
.
6
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2366
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Moreover, measuring initial rates on parallel reactions with benzylic product 62 in 84% yield, a remarkably high level of reactivity for
substrate 46 and 46-d2 revealed a primary KIE of 1.7 for catalyst 3 1° aliphatic C–H bond amination under metallonitrene catalysis.
and 1.9 for catalyst 2. Consistent with this, an intermolecular com- These results establish that native alcohols present in a wide
petition experiment with 1 equiv. each of 46 and 46-d2 gave a KIE of range of readily available natural products, as well as those
1.6 for 3 and 1.9 for 2 from isolated product ratios (Fig. 2d). These that can be readily installed, serve as valuable handles to install
two KIE experiments with manganese catalysts 2 and 3 provide nitrogen into a broad range of sp3 C–H bonds in predictable
values that are larger than would be expected for a rate-determining 1,3- or 1,2-relationships.
step that did not involve C–H cleavage (kH/kD of ∼1), but smaller
than if C–H cleavage was solely rate-determining (kH/kD of
∼3.5–6)40. Ligand modification on the manganese catalyst results
in small differences in KIE (Fig. 2d), providing support for a manga-
nese-bound nitrene species in the C–H cleavage step. Collectively,
these data suggest that the C–H cleavage step contributes signifi-
cantly to the overall reactivity and selectivity observed with catalyst
3, a mechanistic feature that enables tunable control over selectivity
in oxidation.
Conclusion
We have reported a novel manganese C–H amination catalyst,
readily synthesized in one step from commercial materials (see
Supplementary Information), that is ten million times more abun-
dant than its noble metal predecessor45. While further development
of this reaction is required, [Mn(tBuPc)] 3 is unique in its capacity to
intramolecularly functionalize all types of C(sp3)–H bonds (includ-
ing 1° aliphatic and propargylic) while maintaining stereospecificity
and broad functional group tolerance in complex molecule settings.
Studies indicate that the mechanism of metallonitrene insertion into
sp3 C–H bonds for [Mn(tBuPc)] lies between that of the concerted
asynchronous C–H insertion observed with rhodium and the step-
wise radical C–H abstraction/rebound observed for iron. Rather
than demonstrating reactivity and selectivity between the two,
[Mn(tBuPc)] promotes intramolecular C–H amination with
higher reactivity than rhodium while maintaining the high chemo-
selectivity observed with iron. This finding challenges the bounds
of the reactivity/selectivity paradigm and informs an approach
to discover other highly reactive and selective C–H oxidation
reactions with catalysts that access tunable high-valent
metal–heteroatom species.
Late-stage C–H amination. The reactivity, site- and chemoselectivity
trends observed with catalyst 3 on relatively simple molecules are
maintained in more topologically and functionally complex natural
product settings (Fig. 3).
A functionally dense picrotoxinin
derivative, containing an unprotected 3° alcohol, reacted smoothly
under standard reaction conditions at a 3° C–H bond to produce
fused bicycle 50 in 57% yield (Fig. 3a). Allylic C–H amination of
sulfamate ester-derived steroids pregnenolone and stigmasterol
furnished five-membered heterocycles 51 and 52 in 55% and 66%
yields, respectively, as single diastereomers. A leelamine-derived
phenolic sulfamate ester 53 gave 70% yield of the 3° benzylic C–H
amination product 54. Isosteviol derivative 55 was functionalized
at the equatorial γ 2° aliphatic C–H bond to furnish 56 in 92%
yield as a single syn diastereomer. Importantly, this reaction is
high yielding (75%) with reduced catalyst (2.5 mol% 3) and
oxidant (1.5 equiv.) loadings, and scales readily. The versatile
oxathiazinane moiety can also be diversified easily41. For example,
reaction of N-carboxybenzyl (Cbz)-protected oxathiazinane 56
with NaN3 or KOAc affords 1,3-diamine (57, 56%) or amino
alcohol (58, 76%) precursors.
Received 1 July 2015; accepted 1 September 2015;
published online 5 October 2015
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Acknowledgements
Financial support for this work was provided by the NIH/NIGMS (GM112492). S.M.P. was
a NSF Graduate Research Fellow, J.R.G is a NSF Graduate Research Fellow and a
Springborn Graduate Fellow, J.P.Z. is a R.C. Fuson graduate fellow, and S.M.M. is a UIUC
Summer Undergraduate Research Fellow. The authors thank Bristol-Myers-Squibb for
generous support with an unrestricted ‘Freedom to Discover’ grant to M.C.W. and
acknowledge J.M. Howell, J.R. Clark and C.C. Pattillo for checking our experimental
procedure. The authors thank J. Bertke and D. Gray for crystallographic analysis of
compound 56, L. Zhu for assistance with NMR data analysis, and D. Loudermilk for
creative graphic assistance.
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Author contributions
S.M.P., J.R.G., J.P.Z., A.L.P. and S.M.M. conducted the experiments and analysed the data.
S.M.P., J.R.G. and M.C.W. conceived and designed the project, analysed the data and
prepared the manuscript.
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Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Metrical parameters for the structure of 56 are available free of
charge from the Cambridge Crystallographic Data Centre under reference CCDC-1421220.
Reprints and permissions information is available online at www.nature.com/reprints.
Correspondence and requests for materials should be addressed to M.C.W.
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Competing financial interests
The University of Illinois has filed a patent application on the [Mn(tBuPc)] catalyst for
general C–H functionalizations. The [Mn(tBuPc)] catalyst (prod # 799688) will be offered
by Aldrich through a licence from the University of Illinois.
8
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