Enantioselective intramolecular C-H amination of aliphatic azides by dual ruthenium and phosphine catalysis

Article abstract of DOI:10.1039/C9SC00054B

The catalytic enantioselective intramolecular C(sp³)-H amination of aliphatic azides represents an efficient method for constructing chiral saturated cyclic amines which constitute a prominent structural motif in bioactive compounds. We report a dual catalytic system involving a chiral-at-metal bis(pyridyl-NHC) ruthenium complex and tris(4-fluorophenyl)phosphine (both 1 mol%), which facilitates the cyclization of aliphatic azides to chiral α-aryl pyrrolidines with enantioselectivities of up to 99% ee, including a pyrrolidine which can be converted to the anti-tumor alkaloid (R)-(+)-crispine. Mechanistically, the phosphine activates the organic azide to form an intermediate iminophosphorane and transfers the nitrene unit to the ruthenium providing an imido ruthenium intermediate which engages in the highly stereocontrolled C-H amination. This dual catalysis combines ruthenium catalysis with the Staudinger reaction and provides a novel strategy for catalyzing enantioselective C-H aminations of unactivated aliphatic azides.

Full text of DOI:10.1039/C9SC00054B

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ARTICLE
Enantioselective Intramolecular C-H Amination of Aliphatic Azides
by Dual Ruthenium and Phosphine Catalysis
Jie Qin,a Zijun Zhou,a Tianjiao Cui,a Marcel Hemminga and Eric Meggersa*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The catalytic enantioselective intramolecular C(sp3)-H amination of aliphatic azide represents an efficient method for
constructing chiral saturated cyclic amines which constitute a prominent structural motif in bioactive compounds. We
www.rsc.org/
report
a dual catalytic system involving a chiral-at-metal bis(pyridyl-NHC) ruthenium complex and tris(4-
fluorophenyl)phosphine (both 1 mol%), which in combination achieve the cyclization of aliphatic azides to chiral -aryl
pyrrolidines with enantioselectivities of up to 99% ee, including a pyrrolidine which can be converted to the anti-tumor
alkaloid (R)-(+)-crispine. Mechanistically, the phosphine activates the organic azide to form an intermediate
iminophosphorane and transfers the nitrene unit to the ruthenium providing an imido ruthenium intermediate which
engages in the highly stereocontrolled C-H amination. This dual-catalysis combines ruthenium catalysis with the
Staudinger reaction and provides a novel strategy for catalyzing enantioselective C-H aminations of unactivated aliphatic
azides.
a) Chiral -aryl pyrrolidine-containing bioactive compounds

MeO
Introduction
N
N
N
O
N
MeO
Pyrrolidines constitute a prominent structural motif in bioactive
compounds such as natural products and pharmaceuticals (Figure
1a).1,2 Their synthesis through a direct intramolecular C(sp3)-H
amination is particularly appealing due to the lacking necessity for
preinstalled functional groups which provides the prospect of an
efficient synthesis with high atom economy.3 In this respect, organic
azides are attractive functionalities for metal-mediated nitrene
C(sp3)-H insertion reactions4,5 because no additional oxidant is
required and molecular nitrogen is the only by-product. Whereas
the amination of saturated C(sp3)-H bonds with aryl, sulfonyl, acyl
and phosphoryl azides has been well established,6 the use of non-
activated, aliphatic azides is only a recent accomplishment.7,8 In
addition to their lower reactivity, a major pitfall for C(sp3)-H
aminations of primary aliphatic azides constitutes a competing
unproductive 1,2-hydride shift of the intermediate alkyl nitrenoid
intermediate leading to the irreversible formation of undesirable
imines.9 Betley introduced an elegant dipyrrinato-iron(II)-catalyzed
ring-closing C(sp3)-H amination of aliphatic azides but the reported
turnover numbers were modest with TON < 10.8b,c Subsequently
reported MOF-functionalized Fe(II)--diketiminate,8d iron(III)-
coordinated redox-active pyridine-aminophenol,8e and cobalt(II)
porphyrin8g catalysts by Lin, van der Vlugt, and de Bruin,
respectively, provided improved catalytic performances for this
challenging tranformation. Finally, Che very recently reported an
N
nicotine
(+)-crispine A
(S)-ABT-418
Cl
F
O
Cl
N
N
O
F
O
NH2
N
N
N
H
(S)-CERC-501
BMS-394136
b) Catalytic enantioselective cyclization with aliphatic azides
Boc
Ar
H
N
[M], Boc2O
N3
Ar
-N2
State of the art (de Bruin, 2017):
Mes
O
R
R
R
R
N
N
N
N
O
O
R =
Ph
Co
O
Mes
4 mol%
Boc
N
N3
80 °C
22% yield, 46% ee
Ph
This study:
(PF6)2
Ar
F
P
N
N
Ru
N
Me
C
C
N
N
N
N
Mes
Mes
&
Me
N
F
F
Ar
Boc
N
(each 1 mol%)
N3
Ar
Boc2O, 95 °C
Ar
up to 84 TON, up to 99% ee
Unique catalyst system (Ru & phosphine catalysis)
Enantioselective catalysis
Primary aliphatic azides as substrates
a. Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse 4,
35043 Marburg, Germany.
* E-mail: meggers@chemie.uni-marburg.de
Electronic Supplementary Information (ESI) available: Characterization data and
experimental procedures. See DOI: 10.1039/x0xx00000x
Figure 1. Previous and this work on asymmetric ring-closing C(sp3)-
H aminations of aliphatic azides to provide non-racemic pyrrolidines.
This journal is © The Royal Society of Chemistry 20xx
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Table 1. Initial C-H amination experiments.a
N-heterocyclic carbene iron(III) porphyrin complex exibiting
high activity for this transformation under microwave
conditions.8h However, pyrrolidines as part of bioactive
compounds are typically chiral2 but only a single example of a
catalytic enantioselective reaction has been reported using a
chiral cobalt(II) porphyrin achieving low yields and very low
enantiomeric excess (Figure 1b).8g,10
Ruthenium complexes are well-established for catalyzing
C(sp3)-H activation11 and C(sp3)-H aminations of organic azides
such as aryl, acyl, and sulfonyl azides,6a,d,f,l-n,12 but applying
simple primary aliphatic azides has remained elusive and this
has been attributed at least in parts to a very efficient 1,2-
hydrogen shift of the intermediate Ru-imido complexes.9c-e
Our group recently reported a new class of “chiral-at-metal”
ruthenium catalysts in which two bidentate N-(2-pyridyl)-
substituted N-heterocyclic carbenes and two acetonitrile
ligands are coordinated to a central ruthenium in a C2-
symmetric fashion.13 Despite all ligands being achiral, overall
helical chirality originates from a stereogenic ruthenium
center.14,15 We recently demonstrated that such complexes
can indeed serve as catalysts for activating aliphatic azides
View Article Online
DOI: 10.1039/C9SC00054B
tBu
Me
(PF6)2
Me
R
H
N
N
N
Ru
N
C
C
N
N
tBu
Me
N
Mes
Mes
R =
Ru4
Ru3 -
Ru1
Ru2
-
-
-
N
Me
N3
SiMe3
CF3
tBu
Ru5
Ru7
-
-
Ru6
-
R
Boc
Ph
Ru-cat (1 mol%)
N
Ph
additive
1a
Boc2O (1 equiv)
2a
(R)-
1,2-dichlorobenzene
95 °C
+
H
N
Ph
Boc
3
NMR yield (%)b
Entry Cat.
Additive
Conv. (%)b
ee (%)c
2a
26
3
1d
2d
3d
4
no
57
79
81
77
79
75
70
65
77
65
45
<3
14
17
18
18
16
20
17
18
18
16
14
0h
81
82
82
89
90
87
89
80
95
94
95
n.a.i
-Ru1
-Ru1
-Ru1
-Ru2
-Ru3
-Ru4
-Ru5
-Ru6
-Ru7
-Ru7f
-Ru7
-Ru7
P(Ph)3
44
46
P(4-F-Ph)3
P(4-F-Ph)3
P(4-F-Ph)3
P(4-F-Ph)3
P(4-F-Ph)3
P(4-F-Ph)3
P(4-F-Ph)3
P(4-F-Ph)3
no
towards
enantioselective
C-H
amination,
however,
46
unfortunately, only in a very restricted structural context of
converting 2-azidoacetamides into chiral imidazolidin-4-ones.16
By discovering a novel ruthenium and phosphine dual catalysis
scheme to activate aliphatic azides towards C-H amination, we
here report the highly enantioselective ring-closing C(sp3)-H
amination of simple 4-azidobutylarenes to provide chiral -aryl
pyrrolidines with enantioselectivities of up to 99% ee (Figure
1b).
5
44
6
44
7
43
8
23
9
54 (51)e
42
Results and discussion
Initial optimization
10
11
12g
12
We initiated our study by investigating the intramolecular C-H
amination of 4-azidobutylbenzene (1a) to Boc-protected 2-
phenylpyrrolidine (2a). Unfortunately, despite extensive
screening of the reaction conditions, the results were
unsatisfactory (see details in Tables S1-4). For example,
heating 1a under optimized conditions in 1,2-dichlorobenzene
at 95 °C for 40 hours using -Ru1 (1 mol%) in the presence of
Boc2O (1 equiv) provided the desired pyrrolidine 2a only in 26%
NMR yield at a conversion of 57% but at least with an
encouraging enantioselectivity of 81% ee (Table 1, entry 1). At
the same time, the Boc-protected amine 3 was detected as a
side-product in 14% yield. To our surprise, we finally
discovered that the reaction was fastly improved when
performed in the presence of catalytic amounts of PPh3,
providing 2a in 44% yield with 79% conversion at an
enantioselectivity of 82% ee (entry 2). Even slightly better
yields were obtained with tris(4-fluorophenyl)phosphine (entry
3), while other phosphines provided inferior results (Table S5).
The amount of the phosphine was also investigated, and it was
found that 1 mol% provided the optimal results (Table S6).
Next, we optimized the ruthenium catalyst for this
transformation to improve the enantioselectivity. Our initial
P(4-F-Ph)3
0h
aStandard conditions: 1a (0.2 mmol), Boc2O (0.2 mmol, 1 equiv), catalyst (0.002
mmol, 1 mol%), and additive (0.002 mmol, 1 mol%) in 1,2-dichlorobenzene (0.5
mL) at 95 oC for 60 h under N2 unless otherwise noted. bDetermined by 1H NMR
of crude products using Cl2CHCHCl2 as internal standard. cDetermined by HPLC of
crude main product on a chiral stationary phase. d40 h was used. eIsolated yield in
parentheses. f0.5 mol% -Ru7 was used. gWithout Boc2O. hRefers to cpds without
Boc-protection. in.a. = not applicable.
experiments were performed with the chiral-at-ruthenium catalyst
-Ru1 which bears two very bulky 3,5-di(tert-butyl)phenyl
substituents at the coordinating pyridine ligands. Interestingly, -
Ru2 with less bulky 3,5-(dimethyl)phenyl substituents at the pyridyl
moieties provided an even higher enantioselectivity of 89% ee
(entry 4). The phenyl-modified catalyst -Ru3 afforded a further
slightly increased enantioselectivity of 90% ee (entry 5), whereas
the plain catalyst devoid of additional substituents (-Ru4) yielded
the Boc-protected pyrrolidine with reduced 87% ee (entry 6).
Furthermore,
a trimethylsilyl (TMS)-functionalized ruthenium
complex -Ru5, which is the optimal catalyst in our previous work
on enantioselective C-H aminations of 2-azidoacetamides,16 did not
2 | J. Name., 2012, 00, 1-3
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Ru7
-
(1 mol%)
provide better results here (entry 7). Adding a tBu-moiety at the 4-
position of the phenyl groups (-Ru6) decreased the
enantioselectivity to 80% ee (entry 8). However, the best result was
obtained with a 4-(CF3)Ph modification (-Ru7) which afforded (R)-
2a in 54% NMR yield at 77% conversion and with 95% ee (entry 9).
Interestingly, even at a catalyst loading of just 0.5 mol%, the Boc-
protected pyrrolidine (R)-2a was still formed with 42% yield (65%
conversion) and 94% ee, reflecting a turnover number of 84 (entry
10). Thus, a careful optimization of steric and electronic effects
provided a ruthenium catalyst (-Ru7) which, in the presence of
tris(4-fluorophenyl)phosphine, effectively discriminates between
the two benzylic C-H bonds of 4-azidobutylbenzene to provide the
corresponding chiral pyrrolidine with modest yield but outstanding
enantioselectivity.17,18
Boc
View Article Online
P(4-F-Ph)3 (1 mol%)
N
N3
DOI: 10.1039/C9SC00054B
Ar
1,2-dichlorobenzene (0.4 M)
Boc2O (1 equiv)
95 °C
Ar
2b u
1b u
-
-
OMe
Me
Me
Me
2b
2c
2d
2e
52% yield (19%) 50% yield (21%)
15% yield (57%) 53% yield (24%)
93% ee
91% ee
90% ee
99% ee
Ph
N
OMe
OMe
SMe
2f
2g
2h
2i
50% yield (17%) 51% yield (11%)
51% yield (21%) 55% yield (19%)
94% ee
94% ee
94% ee
77% ee
Control experiments revealed that tris(4-fluorophenyl)phosphine is
crucial for obtaining a satisfactory yield. In its absence, the yield
diminished to merely 12% even after an extended reaction time,
while the enantioselectivity was not affected, thus implying that the
phosphine is not involved in the stereocontrolling step (entry 11).
Finally, Boc2O is also required for this reaction to proceed (entry
12).16
O
F
O
O
Cl
P
OEt
EtO
Ph
2j
2k
2l
2m
32% yield (45%) 42% yield (35%)
40% yield (27%) 45% yield (24%)
92% ee
92% ee
94% ee
95% ee
S
O
S
Substrate scope investigation
2n
2o
2p
2q
57% yield (19%) 49% yield (22%)
51% yield (20%) 50% yield (23%)
With the optimized catalyst -Ru7 and optimized reaction
conditions in hand, we investigated the substrate scope of this
transformation. As shown in Figure 2, methyl groups in para or
meta position of the benzene moiety are well tolerated
(pyrrolidines 2b,c), but a sterically demanding ortho-methyl group
leads to vastly diminished yields of 15%. Both electron-donating
(leading to pyrrolidines 2e-k) and electron-accepting substituents
(leading to pyrrolidines 2l, m) are tolerated, although electron-
accepting substituents led to decreased yields. The phenyl moiety
can also be replaced by a naphthyl (pyrrolidine 2n) and by
heteroaromatic moieties (pyrrolidines 2o-s). For example, a
carbazole moiety provides the Boc-protected pyrrolidine 2s in 52%
yield and 93% ee. However, replacing the aryl group with alkyl,
alkenyl, or alkynyl groups suppresses the C-H amination reaction
(Table S8, entries 1-3). Further substrates including bridging aryl
groups could also be transformed to their pyrrolidine products
(2t,u). Finally, a racemic substrate with a tertiary C-H group only
provided a very modest kinetic resolution (Table S8, entry 4).
Overall, enantioselectivities of 76-99% ee were observed and
isolated yields of 15-57%. However it has to be noted that none of
the reactions proceed to full conversion and thus allow to
reisolated unreacted starting materials (Figure 2). Despite the
modest yields it is remarkable that chiral α-aryl pyrrolidines with
outstanding enantioselectivities of up to 99% ee can be obtained
through this challenging ring-closing C(sp3)-H amination of aliphatic
azides.19 Importantly, chiral α-aryl pyrrolidines are prominent
structural motifs in bioactive compounds.2 For example, pyrrolidine
2g can be converted to the anti-tumor alkaloid (R)-(+)-crispine in 4
steps using a Pummerer cyclization (Figure S1).2c
96% ee
95% ee
80% ee
90% ee
Me
N
Ph
Ph
O
N
Boc
N
Boc
2t
2ub
2r
2s
47% yield (29%) 45% yield (26%)
80% ee
94% ee
36% yield (45%)
76% ee
52% yield (21%)
93% ee
Figure 2. Substrate scope with isolated yield.a
aRecovered starting materials are shown in parentheses. Lower
b
substrate concentration (0.1 M) and 85 oC was used instead.
Mechanism study
We performed experiments to gain insight into the reaction
mechanism and started with the unusual function of the phosphine.
The role of the phosphine as a co-catalyst to activate the organic
azide is advocated by the well-established reactivity of azides
towards phosphines.20 Indeed, P(4-F-Ph)3 starts to react with (4-
azidobutyl)benzene already at room temperature and full
conversion is obtained at 95 °C for 2 hours to form the
corresponding iminophosphorane 4 (Figure 3a). We also confirmed
that iminophosphorane 4 is catalytically competent itself (Figure
3b). Interestingly, although such a role of phosphines in the
activation of organic azides towards C-H amination has not been
reported to our knowledge, the opposite reaction namely the
phosphine-induced extraction of a nitrene from a metal imido
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a) Formation of iminophosphorane
compared with electron-deficient substrates. The C-H amination
DOI: 10.1039/C9SC00054B
with mono-deuterated substrate 1a' using racemic catalyst
provided an intramolecular kinetic isotope effect (KIE) of 1.3 (Figure
3e), which is much lower than the value reported for iron8b,e and
cobalt8g catalytic systems. This might suggest that the C-H
amination appears to occur by a concerted-insertion mechanism or
View Article Online
P(4-F-Ph)3
N3
N
Ph
Ph
P(4-F-Ph)3
95 °C, 2 h
1a
4
quantitative
b) Iminophosphorane as co-catalyst
4
(1 mol%)
Boc
N
instead of P(4-F-Ph)3
a
hydrogen abstraction mechanism with fast radical
N3
Ph
recombination.8h However, the interpretation of the intramolecular
KIE is complicated by the fact that the ruthenium catalyst is
intrinsically chiral, although used as a racemic mixture for this
experiment, and the monodeuterated substrate 1a' as well. Indeed
the cyclization of the chiral substrate (R)-5 to (R)-6 but not (S)-5 to
(S)-6 demonstrates the high stereospecificity of the C-H amination
(Figure 3f). Finally, we determined a pronounced (noncompetitive)
intermolecular KIE value of 3.1 by measuring initial C-H amination
rates of non-deuterated (1a) and bis-deuterated (1a'') substrates
(Figure 3e). Using alternatively a 1:1 mixture of non-deuterated (1a)
and bis-deuterated substrate (1a'') provides a (competitive)
intermolecular KIE of 3.9 (see Figure S6). An observation of a
significant intermolecular KIE reveals that the C-H amination is the
rate limiting step in the overall process.
standard conditions
Ph
1a
2a
40% NMR yield, 94% ee
c) Facilitation of 1,2-hydride shift
Ru1
(15 mol%)
NH
P(4-F-Ph)3 (2 mol%)
N3
Ph
Ph
50 °C, CH2Cl2
(sealed Schlenk)
1a
0% conv.
Ru1
(15 mol%)
P(4-F-Ph)3 (2 mol%)
Ph
N3
NH
15% conv.
Ph
50 °C, CH2Cl2
(sealed Schlenk)
d) Reaction rate of electronically distinct substrates
N3
Boc
N
Ru1
rac-
MeO
1e
1l
Based on previous work8b-h on the ring-closing C-H amination of (4-
azidobutyl)arenes and our mechanism study, the following
mechanism is proposed (Figure 4). P(4-F-Ph)3 activates the organic
azide to form an intermediate iminophosphorane (I) through the
well-known Staudinger reaction which then transfers a nitrene to
the ruthenium center to afford a ruthenium imido complex
(intermediate II), followed by a stereo-controlled insertion of the
nitrene moiety into the -C-H bond (transition state III) to provide a
ruthenium-coordinated pyrrolidine (intermediate IV). Alternatively,
a stepwise process through H-atom transfer cannot be excluded at
this point. Finally, the product is released after Boc-protection.
or
standard
conditions
N3
R
2e 2l
or
k1e/k1l = 1.7
F
e) Kinetic isotope effects
D
KIE = 1.3
N3
Ph
1a'
Boc
Boc
Ph
Ru7
rac-
under
N
N
D
and/
or
standard conditions
Ph
X
X
H
N3
Ph
2a
2a(D)
1a''
1a
(X = D) or
(X = H)
KIE = k1a/k1a'' = 3.1
N2
f) Stereospecificity
N3
N
Ar
Boc
N
Ar
PAr3
Boc
Me
I
standard conditions
N
N3
Ar
[Ru]
Ph
Ph
PAr3
N
Me
Boc2O
5
(R)- (94% ee)
6
6
(R)- : 22% NMR yield, 96% ee
(S)- : <5% NMR yield, 94% ee
5
(S)- (97% ee)
H
[Ru]
[Ru]
IV
N
Figure 3. Mechanistic experiments.
Ar
II
H
Ar
complex was disclosed independently by McElwee-White21a and
Sundermeyer.21b
[Ru]
N
H
III
Next, we attempted to gain insight into the competing 1,2-hydride
shift by comparing (4-azidobutyl)benzene and benzyl azide as
substrates at a temperature where C-H amination does not yet
occur. As a result, only benzyl azide provided significant amounts of
the imine product which can be traced back to the higher activity of
the benzylic C-H group in the ruthenium imido intermediate
towards 1,2-H shift (Figure 3c). This is consistent with a recent
report by Park who showed that the degree of 1,2-H shift correlates
with the nature of the -C-H bond.9c
To understand the electronic nature of the proposed ruthenium
nitrenoid intermediate, initial C-H amination rates of electronically
distinct substrates 1e and 1l were determined. As a result, the
cyclization rate of electron-rich 1e was 1.7 times faster than
electron-deficient 1l suggesting the electrophilic nature of the
ruthenium nitrene (Figure 3d). This is consistent with the substrate
scope in which electron-rich substrates provided better yields
Ar
Figure 4. Proposed mechanism.
Conclusions
We here presented a highly enantioselective catalytic ring-
closing benzylic C(sp3)-H amination of primary aliphatic azides
to provide chiral 2-aryl pyrrolidines by combining of chiral-at-
metal transition metal catalysis with nucleophilic phosphine
catalysis. In this unique dual catalysis system, the phosphine
activates the organic azide and transfers a nitrene to the
ruthenium complex, which then executes the enantioselective
C-H amination. This combination of ruthenium catalysis and
Staudinger reaction introduces a novel direction for C-H
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Lett., 2007, 9, 4889; (f) S. Fantauzzi, E. Gallo,ViAew. ACrtaicsleelOlin,linFe.
Ragaini, N. Casati, P. Macchi and S. Cenini, Chem. Commun.,
2009, 3952; (g) K. Sun, R. Sachwani,DKO.I:J.10R.1ic0h39e/rCt9aSnCd00T0.54GB.
Driver, Org. Lett., 2009, 11, 3598; (h) H. Lu, V. Subbarayan,
J. Tao and X. P. Zhang, Organometallics, 2010, 29, 389; (i) H.
Lu, J. Tao, J. E. Jones, L. Wojtas and X. P. Zhang, Org. Lett.,
2010, 12, 1248; (j) M. Ichinose, H. Suematsu, Y. Yasutomi, Y.
Nishioka and T. Uchida, T. Katsuki, Angew. Chem. Int. Ed.,
2011, 50, 9884; (k) Q. Nguyen, K. Sun and T. G. Driver, J.
Am. Chem. Soc., 2012, 134, 7262; (l) W. Xiao, J. Wei, C.-Y.
Zhou and C.-M. Che, Chem. Commun., 2013, 49, 4619; (m)
Y. Nishioka, T. Uchida and T. Katsuki, Angew. Chem. Int. Ed.,
2013, 52, 1739; (n) K.-H. Chan, X. Guan, V. K.-Y. Lo and C.-M.
Che, Angew. Chem. Int. Ed., 2014, 53, 2982; (o) T. Kang, Y.
Kim, D. Lee, Z. Wang and S. Chang, J. Am. Chem. Soc., 2014,
136, 4141; (p) I. T. Alt, C. Guttroff and B. Plietker, Angew.
Chem. Int. Ed., 2017, 56, 10582; (q) C. Li, K. Lang, H. Lu, Y.
Hu, X. Cui, L. Wojtas and X. P. Zhang, Angew. Chem. Int. Ed.,
2018, 57, 16837.
amination of unactivated aliphatic azides which are very
desirable but challenging substrates for this transformation.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Support of this work by the Deutsche Forschungsgemeinschaft
is gratefully acknowledged (ME1805/15-1).
Notes and references
1
(a) D. O’Hagan, Nat. Prod. Rep., 2000, 17, 435; (b) R. D.
Taylor, M. MacCoss and A. D. G. Lawson, J. Med. Chem.,
2014, 57, 5845.
7
8
For an intermolecular C-H amination of 1-adamantylazide,
see: Y. M. Badiei, A. Dinescu, X. Dai, R. M. Palomino, F. W.
Heinemann, T. R. Cundari and T. H. Warren, Angew. Chem.
Int. Ed., 2008, 47, 9961.
2
For chiral α-aryl pyrrolidines-containing bioactive molecules,
see: (a) J. Lloyd, H. J. Finlay, W. Vacarro, T. Hyunh, A. Kover,
R. Bhandaru, L. Yan, K. Atwal, M. L. Conder, T. Jenkins-West,
H. Shi, C. Huang, D. Li, H. Sun and P. Levesque, Bioorg. Med.
Chem., 2010, 20, 1436; (b) C. H. Mitch, S. J. Quimby, N. Diaz,
C. Pedregal, M. G. de la Torre, A. Jimenez, Q. Shi, E. J.
Canada, S. D. Kahl, M. A. Statnick, D. L. McKinzie, D. R.
Benesh, K. S. Rash and V. N. Barth, J. Med. Chem., 2011, 54,
8000; (c) S. C. K. Rotte, A. G. Chittiboyina and I. A. Khan, Eur.
J. Org. Chem., 2013, 6355.
(a) G. He, Y. Zhao, S. Zhang, C. Lu and G. Chen, J. Am. Chem.
Soc., 2012, 134, 3; (b) M. Yang, B. Su, Y. Wang, K. Chen, X.
Jiang, Y.-F. Zhang, X.-S. Zhang, G. Chen, Y. Cheng, Z. Cao, Q.-
Y. Guo, L. Wang and Z.-J. Shi, Nat. Commun., 2014, 5, 4707;
(c) C. Q. O'Broin, P. Fernández, C. Martínez and K. Muñiz,
Org. Lett., 2016, 18, 436; (d) D. Meng, Y. Tang, J. Wei, X. Shi
and M. Yang, Chem. Commun., 2017, 53, 5744; (e) P.
Becker, T. Duhamel, J. C. Stein, M. Reiher and K. Muñiz,
Angew. Chem. Int. Ed., 2017, 56, 8004; (f) P. Becker, T.
Duhamel, C. Martínez and K. Muñiz, Angew. Chem. Int. Ed.,
2018, 57, 5166; (g) S. Herold, D. Bafaluy and K. Muñiz,
Green Chem., 2018, 20, 3191.
For intramolecular C-H aminations of alkylazides, see: (a) E. R.
King and T. A. Betley, Inorg. Chem., 2009, 48, 2361; (b) E. T.
Hennessy and T. A. Betley, Science, 2013, 340, 591; (c) D. A.
Iovan, M. J. T. Wilding, Y. Baek, E. T. Hennessy and T. A.
Betley, Angew. Chem. Int. Ed., 2017, 56, 15599; (d) N. C.
Thacker, Z. Lin, T. Zhang, J. C. Gilhula, C. W. Abney and W.
Lin, J. Am. Chem. Soc., 2016, 138, 3501; (e) B. Bagh, D. L. J.
Broere, V. Sinha, P. F. Kuijpers, N. P. van Leest, B. de Bruin, S.
Demeshko, M. A. Siegler and J. I. van der Vlugt, J. Am. Chem.
Soc., 2017, 139, 5117; (f) D. L. J. Broere, B. de Bruin, J. N. H.
Reek, M. Lutz, S. Dechert and J. I. van der Vlugt, J. Am. Chem.
Soc., 2014, 136, 11574; (g) P. F. Kuijpers, M. J. Tiekink, W. B.
Breukelaar, D. L. J. Broere, N. P. van Leest, J. I. van der Vlugt,
J. N. H. Reek and B. de Bruin, Chem. Eur. J., 2017, 23, 7945;
(h) K.-P. Shing, Y. Liu, B. Cao, X.-Y. Chang, T. You and C.-M.
Che, Angew. Chem. Int. Ed., 2018, 57, 11947.
3
9
(a) G. Albertin, S. Antoniutti, D. Baldan, J. Castro and S.
García-Fontán, Inorg. Chem., 2008, 47, 742; (b) G. Albertin, S.
Antoniutti and J. Castro, J. Organomet. Chem., 2010, 695,
574; (c) J. H. Lee, S. Gupta, W. Jeong, Y. H. Rhee and J. Park,
Angew. Chem. Int. Ed., 2012, 51, 10851; (d) H. K. Pak, J. Han,
M. Jeon, Y. Kim, Y. Kwon, J. Y. Park, Y. H. Rhee and J. Park,
ChemCatChem, 2015, 7, 4030; (e) J. Y. Park, Y. Kim, D. Y. Bae,
Y. H. Rhee and J. Park, Organometallics, 2017, 36, 3471; (f) L.
Hu, Y. A. Liu and X. Liao, Sci. Adv., 2017, 3, e1700826
4
Reviews on catalytic C(sp3)-H aminations, see: (a) F. Collet,
R. H. Dodd and P. Dauban, Chem. Commun., 2009, 5061; (b)
C.-M. Che, V. K.-Y. Lo, C.-Y. Zhou and J.-S. Huang, Chem. Soc.
Rev., 2011, 40, 1950; (c) F. Collet, C. Lescot and P. Dauban,
Chem. Soc. Rev., 2011, 40, 1926; (d) J. L. Roizen, M. E.
Harvey and J. Du Bois, Acc. Chem. Res., 2012, 45, 911; (e) G.
Dequirez, V. Pons and P. Dauban, Angew. Chem. Int. Ed.,
2012, 51, 7384; (f) J. L. Jeffrey and R. Sarpong, Chem. Sci.,
2013, 4, 4092; (g) Y. Park, Y. Kim and S. Chang, Chem. Rev.,
2017, 117, 9247; (h) B. Darses, R. Rodrigues, L. Neuville, M.
Mazurais and P. Dauban, Chem. Commun., 2017, 53, 493; (i)
J. C. K. Chu and T. Rovis, Angew. Chem. Int. Ed., 2018, 57, 62.
Reviews on C(sp3)-H aminations with organic azides, see: (a)
T. G. Driver, Org. Biomol. Chem., 2010, 8, 3831; (b) T.
Uchida and T. Katsuki, Chem. Rec., 2014, 14, 117; (c) D.
Intrieri, P. Zardi, A. Caselli and E. Gallo, Chem. Commun.,
2014, 50, 11440; (d) P. F. Kuijpers, J. I. van der Vlugt, S.
Schneider and B. de Bruin, Chem. Eur. J., 2017, 23, 13819.
(a) S.-M. Au, J.-S. Huang, W.-Y. Yu, W.-H. Fung and C.-M.
Che, J. Am. Chem. Soc., 1999, 121, 9120; (b) S. Cenini, E.
Gallo, A. Penoni, F. Ragaini and S. Tollari, Chem. Commun.,
2000, 2265; (c) F. Ragaini, A. Penoni, E. Gallo, S. Tollari, C. L.
Gotti, M. Lapadula, E. Mangioni and S. Cenini, Chem. Eur. J.,
2003, 9, 249; (d) S. K.-Y. Leung, W.-M. Tsui, J.-S. Huang, C.-
M. Che, J.-L. Liang and N. Zhu, J. Am. Chem. Soc., 2005, 127,
16629; (e) J. V. Ruppel, R. M. Kamble and X. P. Zhang, Org.
10 For a review of asymmetric C-H functionalization, see: C.
Zheng and S.-L. You, RSC Adv., 2014, 4, 6173.
11 For
reviews
of
ruthenium
catalyzed
C(sp3)-H
functionalization, see: (a) F. Kakiuchi and N. Chatani,
Ruthenium-Catalyzed Reactions via sp C-H, sp2 C-H, sp3 C-H,
and C-Halogen Bond Activations. In Ruthenium in Organic
Synthesis, Murahashi, S.-I., ed. (Wiley-VCH Verlag GmbH),
2005, pp 219; (b) P. B. Arockiam, C. Bruneau and P. H.
Dixneuf, Chem. Rev., 2012, 112, 5879; (c) C. Bruneau, sp3 C–
H Bond Functionalization with Ruthenium Catalysts. In
Ruthenium in Catalysis, C. Bruneau, and P. H. Dixneuf, ed.
Springer, Top. Organomet. Chem., 2014, 48, 195.
5
6
12 For an example of ruthenium imido intermediate, see: S.-M.
Au, W.-H. Fung, M.-C. Cheng, C.-M. Che and S.-M. Peng,
Chem. Commun., 1997, 1655.
13 Y. Zheng, Y. Tan, K. Harms, M. Marsch, R. Riedel, L. Zhang
and E. Meggers, J. Am. Chem. Soc., 2017, 139, 4322.
14 L. Zhang and E. Meggers, Acc. Chem. Res., 2017, 50, 320.
15 L. Zhang and E. Meggers, Chem. Asian J., 2017, 12, 2335.
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ARTICLE
Journal Name
16 Z. Zhou, S. Chen, J. Qin, X. Nie, X. Zheng, K. Harms, R. Riedel,
K. N. Houk and E. Meggers, Angew. Chem. Int. Ed., 2019, 58,
1088.
View Article Online
DOI: 10.1039/C9SC00054B
17 Several other ruthenium catalysts were tested for this C-H
amination. However, none of them could catalyze this
reaction providing Boc-protected pyrrolidine product (see
Table S7). This indicated that ligand environment of
ruthenium complex was important for the success of C-H
amination.
18 Experiments in which we added fresh catalyst and
optionally also additional phosphine ligand after a reaction
time of 30 h did only slightly improve the yields (see Table
S6, entries 8-10).
19 For a different but very convenient method to prepare non-
racemic 2-aryl pyrrolidines, see: K. R. Campos, A. Klapars, J.
H. Waldman, P. G. Dormer and C. Chen, J. Am. Chem. Soc.,
2006, 128, 3538.
20 (a) H. Staudinger and J. Meyer, Helv. Chim. Acta., 1919, 2,
635; (b) Y. G. Gololobov and L. F. Kasukhin, Tetrahedron,
1992, 48, 1353.
21 (a) H. F. Sleiman, S. Mercer and L. McElwee-White, J. Am.
Chem. Soc., 1989, 111, 8007; (b) K. Korn, A. Schorm and J.
Sundermeyer, Z. Anorg. Allg. Chem., 1999, 625, 2125.
6 | J. Name., 2012, 00, 1-3
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ARTICLE
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F
P
Ar (PF6)2
Enantioselective Intramolecular C-H AminatDioOnI: 1o0f.1039/C9SC00054B
Aliphatic Azides by Dual Ruthenium and Phosphine
Catalysis
N
N
Ru
N
Me
C
N
N
Mes
Mes
N
N
F
F
Boc
Ar
C
N
Me
(each 1 mol%)
Ar
N
N3
Ar
Boc2O, 95 °C
J. Qin, Z. Zhou, T. Cui, M. Hemming, E. Meggers*
up to 84 TON, up to 99% ee
By combining a chiral-at-metal ruthenium catalyst with
catalytic amounts of tris(p-fluorophenyl)phosphine
(both 1 mol%) the challenging catalytic enantioselective
ring-closing C(sp3)-H amination of unactivated aliphatic
azides has been achieved with high enantioselectivities.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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