Stereodefined Access to Lactams via Olefin Difunctionalization: Iridium Nitrenoids as a Motif of LUMO-Controlled Dipoles

Article abstract of DOI:10.1021/jacs.9b04317

Reported herein is a general platform of a stereodefined access to Γ-lactams via Cp*Ir-catalyzed olefin difunctionalization, where in situ generated Ir-nitrenoid is utilized as a key motif of 1,3-dipoles to enable amido transfer in a syn-selective manner.

Full text of DOI:10.1021/jacs.9b04317

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Article
Stereodefined Access to Lactams via Olefin Difunctionlization:
Iridium Nitrenoids as a Motif of LUMO-Controlled Dipoles
Seung Youn Hong, and Sukbok Chang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b04317 • Publication Date (Web): 10 Jun 2019
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Stereodefined Access to Lactams via Olefin Difunctionlization: Iridium
Nitrenoids as a Motif of LUMO-Controlled Dipoles
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Seung Youn Hong†,‡ and Sukbok Chang*,‡,†
† Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
‡ Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science, Daejeon 34141, Korea
Supporting Information
ABSTRACT: Reported herein is a general platform of a stereodefined access to γ-lactams via Cp*Ir-catalyzed olefin difunctionalization, where
in situ generated Ir-nitrenoid is utilized as a key motif of 1,3-dipoles to enable amido transfer in a syn-selective manner. Computational studies
suggested that the stereodefined process can be attributed to the proposed working mode of concerted [3+2] cyclization. Frontier molecular
orbital (FMO) analysis implied that a low-lying LUMO of the Ir-imido fragment engages in the olefin interaction. Mechanistic understanding
on the nitrene transfer process led us to develop mild catalytic protocols of stereoselective difuctionalization of alkenyl dioxazolones to furnish
-(haloalkyl)- or (oxyalkyl)lactam products which are of high synthetic and medicinal utility. Product stereochemistry (threo and erythro) was
found to be designated by the olefin geometry (E/Z) of substrates.
Scheme 1. Difunctionalization of alkenes via nitrene transfer
■ INTRODUCTION
a) Previous studies: stereoconvergent nitrene transfer to olefins (Bach, Xu)ref.8
O
Olefin difunctionalization is an attractive approach for introducing
O
R
N
H
O
two functional groups in alkene substrates.1 Especially when the
installed moieties have high synthetic utility for further
transformations, it can offer a unique opportunity to build molecular
complexity and functional diversity which are highly sought after in
organic synthesis and pharmaceutical chemistry.2,3 Among those
methods, reactions initiated by an amino transfer into double bonds
are particularly appealing to obtain synthetically versatile amine
products.4 In this context, a two-step sequence of olefin aziridination
and subsequent ring-opening with proper nucleophiles has been
well-established in synthesis.5 In parallel, a direct difunctionalization
of alkenes has also been actively pursued. Representatively, the
osmium-catalyzed alkene aminohydroxylation is already at its high
synthetic standard pioneered by Sharpless.6,7 The intrinsic
oxophilicity of osmium, however, suffers from developing other
types of difunctionalization approaches with this catalyst system.
On the other hand, open-shell catalysis has significantly
extended the entries of functional groups that can be installed at the
double bonds (Scheme 1a). For instance, Bach and Xu groups,
independently, reported Fe-catalyzed cyclization reactions with
organic azides or hydroxylamines as the nitrene sources to obtain
halogenated (Cl, Br, or F) and oxygenated carbamate products.8
The salient feature of this approach is the formation of one type of
stereoisomeric products regardless of double bond geometry (E/Z)
in olefin-tethered substrates. This stereo-convergence was
attributed to the intermediacy of readily rotatable alkyl radical
species generated in situ by the exo cyclization of a putative Fe-
nitrenoid. This synthetically attractive olefin difunctionalization has
been advanced even in an asymmetric manner.9
Fe, Nu
Fe, Nu
O
Nu
N
X
R
O
N
O
X
(Nu= Cl/Br/F/O)
E-sub.
Z-sub.
H
R
(X= N2, OR)
N
H
N
N
Fe
N
Fe
Fe
fast
Nu
Nu
R
R
H
R
R
alkyl radical
Fe-nitrene
specific isomer
b) Working hypothesis: metal nitrenoids
1,3-dipoles
as a motif of
alkene difunctionalization
1,3-dipolar cycloaddition
O
O
Y
M
M
mimic
concerted
X
Z
X
N
X
N
R2
R1
metal nitrenoid
R2
R1
R4
R3
R2
R1
stereo-determination by
Z/E
stereospecific
c) This work:
Stereodefined access to lactams via olefin difunctionalization
O
O
O
O
Cp*Ir(LX)
(L)X / H+
Cp*Ir(LX)
(L)X / H+
N
H
N
H
R
O
X
(L)
X
(L)
N
- CO2
- CO2
R
H
H
R
N-precursor
diastereomers
threo-lactam
(from E-olefin)
erythro-lactam
(from Z-olefin)
Continuing our research efforts toward the development of
efficient and selective amidiation reactions via the nitrenoid
intermediacy,10 we wondered whether this mechanistic approach
can serve as a motif in the olefin difunctionalization via a formal 1,3-
dipolar cycloaddition manner (Scheme 1b).11 We envisaged to take
advantage of a presupposed concerted pathway in this case, thereby
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(a)
O
O
BArF
achieving high stereoselectivity in a stereodefined manner where
4
O
3
4
5
6
7
8
9
each diastereomeric product (threo and erythro) can be generated
depending on the olefin geometry (E/Z).
O
Ph
N
Ir
N
N
1
H
N
R
Herein, we present a general platform of a stereodefined access
to γ-lactams via Cp*Ir-catalyzed olefin difunctionalization (Scheme
1c). Model studies with Cp*Ir(III)(κ2-chelate) species laid a
mechanistic basis for this strategy especially on the use of metal
nitrenoids as a motif of 1,3-dipoles in a stereoselective cycloaddition
with double bonds. Computational studies suggested that the
stereodefined process can be attributed to a concerted [3+2]
cyclization where a low-lying LUMO of the Ir-imido fragment
engages in the olefin interaction. Based on the mechanistic
understanding of the nitrene transfer, catalytic protocols of
stereoselective difuctionalization of olefin-tethered dioxazolones
were developed to give -(haloalkyl)- or (oxyalkyl)lactam products.
- CO2
H
Ph
II
, >95%
NaBArF
diastereomer
4
N1
Ir
O
Cl
N2
DCM, rt
-NaCl
BArF
OMe
Ph
O
4
O
O
O
N
N
Ir
N
I
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2
H
R
N
(Ir-N2: 2.107(2) Å)ref.10g
- CO2
H
Ph
III
, >95%
(R= methyloxycarbonyl)
(c)
(b)
Ir
Ir
■ RESULTS AND DISCUSSION
N1
N1
N2
N2
N3
N3
C1
C1
C2
We recently demonstrated that pentamethylcyclopentadienyl
(Cp*)-based Ir(III) complexes are highly effective in generating a
putative acylnitrenoid to enable a catalytic haloamidation of
alkynes.12 Key to this achievement was to utilize a strategy of ligand
participation with effective suppression of the Curtius-type
decomposition path although detailed mechanistic description is
still lack. Motivated by this result, we wondered if Cp*Ir(III)
complexes can also facilitate an acylnitrene transfer to alkenes in a
stereoselective manner.13
C2
II
III
X-ray of
X-ray of
IrN2
2.283(3) Å
1.580(5) Å
IrN2C1C2 27.4(4)
IrN2
N2C1
2.323(3) Å
1.576(4) Å
N2C1
IrN2C1C2 23.1(3)
Figure 1. (a) Stoichiometric olefin diamination. Solid state structure
of (b) II and (c) III with selected data.
To validate our working hypothesis, we commenced our present
study by testing Cp*Ir(III)(κ2-N,N’-chelate) species with a model
substrate, γ-alkenyl dioxazolones. In fact, this type of complexes was
shown to readily generate high valent Ir-imido species which are
subsequently engaged in C(sp3)−H amidation in our recent
report.10f Firstly, an iridium complex I was prepared from
[Cp*IrCl2]2 and 8-(methyloxycarbonyl)aminoquinoline ligand.10f
When a neutral complex I was treated with (E-alkenyl)dioxazolone
(a)
BArF
4
O
1
Ir
N
N
H
O
- CO2
MeO
H
Ph
NaBArF
4
V
, >95%
diastereomer
Ir
N
DCM, rt
-NaCl
Cl
O
BArF
4
1 in the presence of NaBArF , a 5-membered cationic iridacycle II
MeO
(b)
O
4
Ir
2
IV
N
N
was formed in quantitative yield (Figure 1a). Significantly, a reaction
of I with isomeric (Z-alkenyl)dioxazolone 2 also furnished an
amino-lactam Ir species (III) in excellent yield. A notable difference
in chemical shifts of benzylic protons between II and III was seen in
1H NMR spectroscopy: δ 3.0 ppm (doublet, J = 11.1 Hz) and 5.1
ppm (doublet, J = 5.9 Hz) in CD2Cl2, respectively. This observation
suggested that the olefin geometry critically influences on the
product configuration.
Solid state structure of II and III was subsequently obtained by
an X-ray crystallographic analysis to reveal that indeed they are
diastereomers each other (Figure 1b and 1c). While the benzylic
proton of II was shown to be more shielded by quinolinyl and lactam
moieties, this anisotropic effect is reduced in III. The Ir−N2 bond
length increases from 2.107(2) Å (I10f) to 2.283(3) Å in II and
2.323(3) Å in III, suggesting that putative Ir-nitrenoid transfer was
accompanied with the addition of the ligand N2 atom into double
bonds in both cases. Most importantly, the structure of II and III
clearly indicates that the presupposed 1,3-dipole of (amino)Ir-
nitrenoid inserts into the pendant double bond in a syn manner.
Ph
O
- CO2
H
H
MeO
VI
, >95%
V
X-ray of
Ir
IrO
OC1
IrOC1C2 27.2(7)
2.258(4) Å
O
1.53(1) Å
C2
C1
(c)
VI
X-ray of
Ir
O
IrO
2.258(2) Å
1.525(4) Å
OC1
C1
IrOC1C2 -38.9(2)
C2
Figure 2. (a) Stoichiometric olefin oxyamidation. Solid state
structure of (b) V and (c) VI with selected data.
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Encouraged by the above promising result of the stereodefined
to be kinetically favorable with only negligible barrier of 2.1
3
4
5
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8
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diamination, we also examined oxyamidation as another entry of
olefin difunctionalization. In this context, Cp*Ir(III)(κ2-N,O-
chelate) species was first considered, and iridium complexes bearing
5-methoxy-8-hydroxyquinoline ligands were accordingly applied.10g
When a representative complex IV was reacted with γ-alkenyl
dioxazolones (1 and 2), the expected oxyamidation took place
readily to give single diastereomers V and VI in excellent yields,
respectively (Figure 2a). Their structures were again unambiguously
confirmed by X-ray analysis to reveal that an oxyamidated product V
is a structural analogue of the diaminated complex II (Figure 2b).
On the other hand, the structural feature of VI is distinctive to that
of III in that the dihedral angles of Ir−X−C1−C2 are quite differed:
23.1° for III (X= N2) and -38.9° for VI (X= O). It should be noted
that, irrespective of structural discrepancy between two sets of
complexes obtained from diamination and oxyamidation, both types
of olefin difunctionalization were found to proceed in a syn-selective
manner to afford diastereoisomeric products depending on the
olefin geometry.
15
kcal/mol.
On the other hand, a two-step path involving an aziridine
intermediate iii was found to require higher barrier by 3.7 kcal/mol.
Moreover, the subsequent ring-opening process was calculated to be
kinetically demanding (G = 19.6 kcal/mol, red line). In addition,
a radical cyclization was found to kinetically less favorable at 5.3
kcal/mol (black line) when compared to the concerted pathway,
and the resulting alkyl radical iv traverses TS-6 with activation
barrier of 23.5 kcal/mol via the interception with an oxygen atom
embedded in ligand.16 Moreover, the concerted pathway was also
calculated to be most accessible when a less nucleophilic alkene was
employed (see Supporting Information for details).
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(a)
dipolarophile
1,3-dipole
O
Ir
Ir
N
N
N
O
O
Ph
(alkene)
(Ir-imido)
ii
(Z)-
Ph
LUMO+14
-0.021 eV
O
O
Ir
O
O
G = 2.1
N
N
O
Ir
Ir
N
L
LUMO
N
N
O
Ph
concerted
O
O
-0.220 eV
Ph
-i
(Z)
Ph
H
H
H
TS-1
H
(0.0)
VI
(-64.0)
-CO2
G = 18.0
HOMO
O
HOMO-1
-0.307 eV
G = 5.8
G = 19.6
Ir
VI
-0.315 eV
N
N
O
N
aziridination
ring opening
O
Ir
Ph
N
TS-2
TS-5
)
(via
)
(via
(b)
iii
(-55.3)
O
Ph
O
O
O
-ii
(Z)
Ir
Ir
Ir
N
N
N
N
N
(-12.3)
N
G = 5.3
G = 23.5
TS-6
Ph
O
Ph
O
O
O
VI
Ir
N
Ph
N
radical
cyclization
(via
)
H
H
O
Ph
-ii
iv
(-31.2)
symmetry-allowed
TS-3
VI
(via
)
(Z)
Figure 4. (a) Quantitative FMO analysis of Ir-nitrenoid (Z)-ii. (b)
Conceptual MO interaction describing the proposed concerted
pathway.
Figure 3. Plausible working modes of a putative Ir-nitrenoid (Z)-ii.
Energy profiles for the proposed pathways were calculated at
PCM(dichloromethane)-M06/SDD+6-
311++G**//M06/Lanl2dz+6-31G** level of theory.
Having identified the energy landscape of the reaction progress,
another theoretical insight was obtained by an FMO analysis to see
how Ir-nitrenoids engage in the kinetically most accessible
concerted [3+2] cyclization pathway.17 Figure 4a shows a MO
diagram partitioned into two fragments as a function. The carbon-
carbon double bond in substrate is denoted as an olefinic
dipolarophile, and its π molecular orbitals pertain to HOMO-1 at -
0.315 eV and LUMO+14 at -0.021 eV. On the other hand, the
fragment of Ir-nitrenoid species reveals a 1,3-dipole character as seen
by the three-centered LUMO and HOMO at -0.220 and -0.327 eV,
respectively. Indeed, as shown in Figure 4b, LUMO of Ir-imido and
HOMO-1 of the olefin moiety overlap in a symmetry-allowed
manner. Although an inverse electron-demand combination
between HOMO and LUMO+16 can also be considered (dashed
line), the former interaction is predicted to be dominant in that a
smaller energy gap of 0.095 eV is involved in this combination
between LUMO and HOMO-1. Moreover, the corresponding
To better understand the underlying origin of the observed
excellent stereoselectivity in the olefin insertion, putative
intermediates were evaluated by DFT calculation under the
plausible working modes (Figure 3). Representatively, Ir complex
IV and Z-alkenyl dioxazalone 2 were selected for this theoretical
study (for others, see Supporting Information). The reaction will be
initiated by an oxidative decarboxylation of an Ir complex-substrate
adduct (Z)-i.10f It requires 18.0 kcal/mol of energy to generate a key
Ir-imido intermediate (Z)-ii. Based on the literature regarding the
reactivity of presupposed metal-nitrenes toward olefins,14 we
evaluated three plausible pathways in our case to lead to an
oxyamidation product VI from (Z)-ii: concerted cycloaddition,
aziridination-ring opening, and radical cyclization. Among those, the
concerted [3+2] cyclizative pathway (blue line) was calculated to be
energetically most downhill by 51.7 kcal/mol, and it was also found
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intermediates derived from Cp*Ir(III)(κ2-N,N’-chelate) also
equiv each), (-chlorobenzyl)lactam 3 was obtained (11%) in
3
4
5
6
7
8
9
showed a similar behavior as a three-centered LUMO according to
the analogous FMO analysis (see Supporting Information for
details).
hexafluoroisopropanol (HFIP) solvent by the action of [Cp*IrCl2]2
(2.5 mol %) catalyst (entry 1). Subsequently, an acid additive was
found to have significant influence on the reaction efficiency. For
instance, acetic acid, benzoic acid, or binaphthyl-2,2′-diyl hydrogen
phosphate (BNDHP) displayed significant improvements (entries
2−4). While the use of p-toluenesulfonic acid (p-TsOH) or HCl
were found to have more pronounced effects (entries 5−6), a slight
erosion in diastereoselectivity was accompanied in these cases
mainly due to the olefin isomerization induced by the acid.21
Pleasingly, product 3 was obtained quantitatively with excellent
Transition state analysis offered an additional information on
the working mode of the putative Ir-imido in the concerted process.
As enumerated in Figure 5a, the transition state TS-1 reveals that
formation of the C−N bond (2.47 Å) takes place early whereas C−O
bond remains to be developed at 3.02 Å. Considering that the bond
lengths of C−N and C−O bond in VI are 2.258(2) Å and 1.525(4)
Å, respectively (see Figure 2c), the cyclization is rationalized to be
concerted but asynchronous. This aspect may be reflected in the
nature of LUMO of ii that is mainly composed of Ir−N π* orbital
whereas contribution of the oxygen p orbital is relatively small
(Figure 5b). Once again, this orbital analysis strongly supports that
the putative Ir-nitrenoids will behave as a motif of LUMO-
controlled dipoles to participate in the olefin difunctionalization
being mechanically reminiscent of 1,3-dipolar cycloaddition
reactions.18 In fact, certain electrophilic dipoles such as ozone (O3)
and nitrous oxide (N2O) were shown to display analogous
molecular orbital interactions, referred as a Sustmann type III.17b,19
While the synthetic utility of metal-involved [3+2] cycloadditions
have been reported,20 to our best knowledge, our current study
represents the first example how FMOs of metal-nitrenoids govern
their reactivity and selectivity toward the olefin difunctionalization.
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diastereoselectivity
when
HCl
was
added
in
dichloromethane/trifluoroethanol (DCM/TFE, 1:1) co-solvent
(entry 7).22 Significantly, an almost same outcome was obtained
when HCl was employed alone in the absence of NaCl/15-crown-5
(entry 8), suggesting that HCl can serve as a source of both proton
and chloride.
Scheme 2. Proposed catalytic cycle
O
O
AgNTf2, LX-
N
H
N
H
[Cp*IrCl2]2
H
H
X
H
(L)
or
X
(L)
Ph
erythro-
-AgCl
Ph
ix
H
ix
threo-
1
2
(E)- or (Z)-
(L)X-, H+
L
Ir
L
L
X
likely via
v
LUMO of ( )-ii
TS-1
(b)
Z
(a)
O
[Ir]
O
N
O
O
N
Ir
Ir
X
O
(L)
L
N
L
X
X
H
R
2R1
Ir
Ph
R1
viii
R2
O
"1,3-dipolar
cycloaddition"
vi
3.02 Å
C
N
R1=H, R2= Ph
O
Ir
1
L
N
from (E)-
2.47 Å
CO2
X
R1=Ph, R2= H
C
2
from (Z)-
Ph
vii
Table 1. Selected reaction parameters in chloroamidation
Figure 5. (a) DFT-computed structures of TS-1 and (b) LUMO of
(Z)-ii (isovalue: 0.05).
[Cp*IrCl2]2 (2.5 mol%)
NaCl/15-crown-5 (1.5/1.5 equiv)
O
O
N
H
O
additive (2.0 equiv)
Ph
O
On the basis of the above rationale, we next wondered whether
the mechanistic motif of 1,3-dipolar cycloaddition can be developed
into a catalytic version as depicted in Scheme 2. A deliberate
combination of pre-catalyst [Cp*IrCl2]2 and nucleophile (L)X- is
anticipated to form an active species v that can bind to an alkenyl
dioxazolone (1 or 2) leading to an adduct vi. A putative Ir-nitrenoid
vii, generated upon the oxidative coupling of vi to release CO2, will
undergo the postulated concerted cycloaddition onto tethered
double bond to give an iridium-lactam species viii. It should be noted
that this cyclization will be a stereodefined process affording
diastereomeric isomers viii depending on the olefin geometry. The
final protonation with a concomitant ligand exchange from viii was
predicted to be also crucial for the overall catalytic performance.
Along with our previous work on the Ir-catalyzed haloamidation
of alkynes,12 the above described mechanistic rationale on the olefin
difunctionalization led us to screen reaction parameters by using an
alkenyl dioxazolone substrate 1 (Table 1). When NaCl was
employed as a chloride source in the presence of 15-crown-5 (1.5
Ph
N
HFIP, rt, 1 h
- CO2
Cl
1
3
entry
1
additive [pKa(H2O)]23
none (HFIP= 9.3)24
acetic acid (4.8)
o-nitrobenzoic acid (2.2)
BNDHP (-)
3 (%)a
11
d.r.b
>19:1
>19:1
>19:1
>19:1
9.0:1
2
50
3
41
4
60
5
p-TsOHc (-2.8)
90
6
HCl (-8.0)
>95
>95
>95
7.1:1
7d
8d,e
HCl
>19:1
HCl
>19:1
aH NMR yields using 1,1,2,2,-tetrachloroehtane as an internal
b
1
standard. Diastereomeric ratio (d.r.), determined by H NMR of
the crude mixture. cMonohydrate form was used. dRun in
DCM/TFE (1:1) co-solvent. 1.0 equiv of HCl was used without
e
NaCl/15-crown-5.
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2
3
4
5
6
7
8
9
Table 2. Substrate scope in the haloamidation of alkenyl dioxazolones
Condition Bb
Cl
2]2 (2.5 mol%)
Conditon Aa
[Cp*Ir
O
Cl
[Cp*Ir
Cl
]
2 2 (2.5 mol%)
O
O
Cl
Na /15-crown-5 (1.5/1.5 equivs)
HOAc (2.0 equiv)
H
(1.0 equiv)
O
N
H
or
X
N
DCM/TFE = 1:1 or HFIP, rt
- CO2
HFIP, rt
- CO2
syn-product, (d.r.)c
E-
A a
]
from olefin [
O
O
O
O
O
O
O
Me
Br
Me
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
H
F
N
H
N
N
H
H
N
N
N
H
H
H
threo
Ph
Ph
Br
Ph
Ph
Cl
Cl
Cl
Cl
Cl
Cl
(bromoamidation)
d
e
f
3
4
5
6 6'
+
6 6'
7
8
, 88%
(>19:1 d.r.)
, 72%
(>19:1 d.r.)
, 93%
(>19:1 d.r.)
, 85%
(>19:1 d.r.)
Z-
, (96%:
(>19:1 d.r.)
:
= 1:1)
, 72%
(X-ray)
(9.1:1 d.r.)
B b
from olefin [
]
O
O
O
O
O
N
H
O
O
N
H
N
H
Cl
Cl
N
H
N
H
N
N
H
H
Cl
Br
Cl
Ph
, 80%
Cl
erythro
Cl
Ph
Me
(bromoamidation)
CF3
, 79%
OMe
Cl
a,e
g
f
9
10
(19:1 d.r.)
11
12
, 69%
(17:1 d.r.)
13
14
15
, 78%
(19:1 d.r.)
, 61%
, 81%
(9.7:1 d.r.)
, 70%
(X-ray)
(15:1 d.r.)
(8.9:1 d.r.)
(>19:1 d.r.)
terminal
A a,h
trisubstituted
B b,i
from
olefin [
]
olefin [ ]
O
H
H
H
H
H
H
O
O
O
O
Cl
Cl
O
Cl
N
N
O
Cl
N
N
Ph
Ph
Cl
N
N
N
H
PhthN
Cl
(dechlorination)
19
, 97%
(1.9:1 d.r.)
j
k
16
18
20
N
21
, 56%
, 97%
O
, 87%
, 75%
O
17
, 71%
22
, 60%
O
H
H
O
O
O
Ph
N
Cl
N
O
B
O
Condition
A
Condition
- CO2
N
threo
Cl
Ph
- CO2
Ph
erythro
(X-ray)
(>19:1 d.r)
(17:1 d.r) Ph
26
Ph
, 75%
23
25
Ph
24
, 93%
(>19:1 d.r.)
(X-ray)
Ph
(>19:1 d.r.)
.
aSubstrate (0.2 mmol), [Cp*IrCl2]2 (2.5 mol%) and HCl (1.0 equiv) in DCM/TFE (1:1) at 25 C for 1 h. Substrate (0.2 mmol),
o
b
o
c
[Cp*IrCl2]2 (2.5 mol%), NaCl (1.5 equiv), 15-crown-5 (1.5 equiv) and acetic acid (2.0 equiv) in HFIP at 25 C for 2 h. Ratio of
diastereoisomers, determined by 1H NMR analysis of the crude reaction mixture. dConducted on 1.0 mmol scale. e5 mol% of [Cp*IrCl2]2 was
used. fBromoamidation using NaBr as a bromide source (see Supporting Information for details). gSubstrate was added using a syringe pump
over 1 h. hHFIP was used as solvent. iHCl (1.0 equiv) was used instead of HOAc. jRun at 80 C. kIsolated as a dechlorinated product.
The Ir-catalyzed olefin haloamidation was found to have broad
scope under mild conditions (Table 2). Dioxazolones bearing E-
(aryl)alkenyl groups at the γ-position smoothly underwent the
desired chloroamidation by using HCl (1.0 equiv) as both chloride
and proton source to afford threo-lactams with excellent
diastereoselectivity (3−5). The reaction was readily scaled up
without difficulty, and the relative stereo stereochemistry of 3 was
unambiguously determined based on the NMR and X-ray
crystallographic analysis. Again, the observed selectivity can be
rationalized as a consequence of the proposed [3+2] cycloaddition
mode. The presence of a methyl group  to the dioxazolone moiety
resulted in an equal mixture of two diastereoisomeric products
(6/6’), but the relative stereochemistry of the newly formed
neighboring C−N and C−Cl bonds were determined to be threo
exclusively. When a cyclopropyl group is present at the alkenyl
moiety, the corresponding lactam 7 was furnished with good
diastereoselectivity. This protocol was successfully extended to the
bromoamidation by using NaBr as the bromide source (8).
We were pleased to observe that, as anticipated,
chloroamidation of Z-alkenyl dioxazolones provided erythro-
products. However, when HCl alone was employed as in case of E-
olefinic substrates, a decrease in diastereomeric ratio (4.8:1, major
product 9) was observed from a reaction of Z-alkene 2 (see
Supporting Information for details). We assume that this is due to a
partial isomerization of Z-olefin under these conditions.25 In
contrast, when NaCl and acetic acid were employed together as the
chloride and proton sources respectively, excellent erythro-
selectivity was obtained from Z-alkenyl dioxazolones (9−12).
Dialkyl-substituted internal olefins were also readily chloroamidated
in a syn-selective manner (13 and 14) as evidenced by the solid
structure of 14. Moreover, bromoamidation could also be achieved
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by using NaBr instead of NaCl to afford erythro-
mentioned that dioxazolone substrates can be prepared in high
3
4
5
6
7
8
9
(bromoalkyl)lactam (15).
yields from the corresponding carboxylic acids in two steps: (i)
conversion to hydoxamic acids with hydroxylamine, and (ii)
carbonylation with carbodiimidazole (see Supporting Information
for details).
The current procedure of Ir-catalyzed haloamidation was
successfully applied to dioxazolones tethered with terminal olefins.
For instance, 3-propenyldioxazolone was readily cyclized by the
action with HCl (1.0 equiv) alone to afford the corresponding
chlorinated lactam 16 in excellent yield.26 The reaction efficiency
was not much decreased by the presence of - or -dimethyl
substituents between dioxazolone and terminal olefinic moieties (17
and 18). A reaction of L-allylglycine derivative was highly facile, but
producing two diastereomers in low selectivity (19). Notably, (3-
chloromethyl)isoindolinone (20) was synthesized in 3 steps starting
from (ortho-vinyl)benzoic acid. On the other hand, the reaction
efficiency became rather moderate when dioxazolone substrates
bearing trisubstituted double bonds were subjected (21 and 22).
The fact that the presupposed Ir-nitrenoid was proven to
efficiently insert into sp3  C−H bonds10f or at  arene carbons10g
motivated us to interrogate plausible chemoselective reactivity in the
presence of such competing reactive sites. Pleasingly, when a
substrate 23 was subjected, chloroamidation occurred exclusively to
afford erythro-lactam 24 in excellent diastereoselectivity confirmed
by an X-ray crystallographic analysis. Notably, the corresponding
insertion at the benzylic  C−H bond (blue colored) did not occur
at all. In addition, a substrate 25 smoothly underwent
chloroamidation to furnish threo-lactam 26 exclusively (>19:1 d.r.).
No spirocyclization at the ipso phenyl carbon (blue colored) was
observed which is potentially competitive according to our previous
study.10g
Table 3. Selected reaction parameters in oxyamidationa
O
[CpArFIrCl2]2
O
O
[Cp*IrCl2]2 (2.5 mol%)
AgNTf2 (10 mol%)
CF3
CF3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
N
H
N
OAc
H
Ph
OAc
+
HFIP
60 oC, 12 h
-CO2
Ir
Cl
Cl
31
(>19:1 d.r.)
1
(1.5 equiv)
Ph
2
entry
1
2b
3b
4
variation from entry 1
none
31 (%)a
31
77
73
68
72
92
-
AgOAc (additive, 1.0 equiv)
AgOAc (additive, 40 mol%)
CsOAc (additive, 40 mol%)
NaOAc (additive, 40 mol%)
[CpArFIrCl2]2 (catalyst) + NaOAc
[Cp*RhCl2]2 (catalyst) + NaOAc
[Cp*CoCl2]2 (catalyst) + NaOAc
5
6c
7c
8c
-
aH NMR yield using 1,1,2,2,-tetrachloroehtane as an internal
b
c
standard. Without AgNTf2 (10 mol%). 40 mol% of NaOAc was
used.
While (α-oxyalkyl)-γ-lactams could be obtained from
chloroamidated compounds in an additional step (Scheme 3a), we
wondered whether the current catalyst system could be applied to a
direct oxyamidation by optimizing proper oxygen sources. Given
that (α-oxyalkyl)-γ-lactams are broadly present in natural products
and medicinal compounds as a bio-relevant pharmacophore,27 the
development of a catalytic route to this privileged scaffold is highly
desirable. In this aspect, we first envisaged to use acetic acid as a
convenient oxygen source for the following considerations: (i) the
required catalytically active species Cp*Ir(OAc)+ (v in Scheme 2)
was elucidated to be accessible according to our previous
studies;10c,28 and (ii) the olefin insertion will be benefited by the κ2-
chelate nature of acetate to lead to an oxyamidated intermediate
more readily (viii in Scheme 2).
We accordingly examined optimal conditions for the envisioned
catalytic oxyamidation of 1 by employing acetic acid (1.5 equiv) as
an oxygen source (Table 3). To our delight, [Cp*IrCl2]2 catalyst
with AgNTf2 displayed reactivity to some extents for the desired
lactamization at 60 oC (entry 1). The use of silver acetate (1.0 equiv)
resulted in a notable improvement in the reaction efficiency, giving
the corresponding product 31 in 75% yield (entry 2). Moreover, a
catalytic amount of AgOAc (40 mol%) was sufficient to obtain a
similar level of reaction efficiency (entry 3). While CsOAc and
NaOAc were also equally effective as an acetate additive (entries 4
and 5), further improvement was not achieved.
Scheme 3. Versatility of the product obtained in this study
16
(a) derivations of the chlorinated product
O
O
O
Ph
O
PhOH
K2CO3
PhCOOH
K2CO3
N
H
N
H
N
H
OPh
O
Cl
60%
70%
27
16
28
(b) stereospecific synthesis of functionalized lactams
O
std. condition
NaN3
O
N
H
Cl
N
H
DMSO
83%
N3
3
Ph
O
O
E
x=
Ph
30
O
O
threo-
N
Ph
N
H
x-alkenyl substrate
N3
O
Ph
N
H
Z
x=
NaN3
Cl
-29
erythro
DMSO
85%
std. condition
9
Ph
We next briefly examined the synthetic utility of chloroamidated
products as shown in Scheme 3. γ-(Chloromethyl)lactam 16 was
readily converted to its oxygenated derivatives 27 or 28 in good
yields when phenol and benzoic acid were reacted, respectively. By
taking advantage of the current stereoselective chloroamidation, a
set of diastereomeric derivatives could also be accessible. For
instance, both erythro-azido -lactam 29 and threo-isomer 30 were
easily obtained in two steps starting from alkenyl dioxazolone
substrates in E- and Z-olefinic geometry, respectively. It needs to be
At this stage, we hypothesized that Cp* derivatives bearing
electron-deficient substituents may provide lower-lying LUMOs on
the corresponding metal center, thereby enhancing the catalytic
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performance.29 Indeed, excellent product yield of 31 could be
instance, it proceeded in excellent syn-selective manner with a
substrate bearing an ortho-methoxy group (34) whereas it was
decreased a bit when the same substituent is at the para-position
(35). While a reaction with β-phenyl-substituted substrate gave a
mixture of 36 and 36’ (3:1), the oxyamidation proceeded with a syn-
addition manner exclusively. It needs to be mentioned that the
obtained compounds 36/36’ can serve as intermediates for the total
synthesis of natural product clausenamide or its derivatives.31 On the
other hand, Z-olefinic substrates were found to furnish oxyamidated
products with moderate diastereoselectivity. For instance, when 2
was subjected to the optimal conditions, lactam 37 was obtained as
a major product (erythro/threo, 3.0:1).
2
3
4
5
obtained when [CpArFIrCl2]2 was used as a catalyst (entry 6). In stark
contrast, group 9 isoelectronic species such as Rh(III) and Co(III)
were totally ineffective (entries 7 and 8).30
6
7
8
Table 4. Substrate scope in the oxyamidation of alkenyl
dioxazolonesa
9
[CpArFIrCl2]2 (2.5 mol%)
AgNTf2 (10 mol%)
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
N
H
NaOAc or NaOH (40 mol%)
OR
H
+
N
HFIP, 60 oC, 12 h
-CO2
OR
(1.5 equiv)
variation of
In addition to acetic acid, a range of additional carboxylic acids
were also successfully utilized for the olefin oxyamidation reaction.
Not only primary but also secondary carboxylic acids could be
applied to afford thero-lactams 38 and 39, respectively. When a
chiral carboxylic acid was employed, an equal mixture of two
diastereomeric products (40/40’) was obtained while the
oxyamidation took place with a complete syn-manner. In addition,
N-protected gabapentin also participated in the reaction leading to
41 albeit in moderate yield.
Interestingly, dialkyl-olefinic substrates, prepared from (E)- or
(Z)-4-hexenoic acids, underwent the oxyamidation to afford
erythro-43 and threo-45, respectively, with high diastereoselectivity
(equations 1 and 2). This anti-addition revealed that a tandem
process consisting of aziridination and ring-opening may also be
operative in these cases although the exact reason is not clear at this
stage.
dioxazolone
O
H
O
O
N
N
N
H
H
threo
AcO
AcO
AcO
Br
F
31
32
33
, 74%
(>19:1 d.r.)
, 90%
(>19:1 d.r.)
, 82%
(X-ray)
(>19:1 d.r.)
O
O
O
O
N
H
N
H
N
H
OMe
N
H
Ph
OAc
Ph
+
AcO
AcO
Ph
OAc
Ph
OMe
36+36'
36 36'
:
, 80% (
=3:1)
35
, 87%
34
, 86%
(>19:1 d.r.)
(6.5:1 d.r.)
(>19:1 d.r.)
O
H
O
N
2
O
R groupa,c
(from Z- )
variation of
O
OAc
'standard conditions'
O
O
(1)
O
+
OAc
H
MeO
N
H
N
N
Me
Me
Me
H
N
H
O
O
43
(16:1 d.r.)
, 60%
42
44
(1.5 equiv)
Ph
37
Ph
O
OAc
O
Ph
b
39
[CpArFIrCl2]2 (2.5 mol%)
, 60%
(>19:1 d.r.)
, 61%
O
O
38
, 55%
(>19:1 d.r.)
H
O
Me
OAc
Ag
(40 mol%)
N
(3.0:1 d.r.)
O
(2)
+
HOAc
O
N
O
O
OAc
, 53%
(8.9:1 d.r.)
HFIP
60 oC, 12 h
-CO2
O
O
O
O
O
45
N
H
N
N
H
H
(1.5 equiv)
+
*
*
O
Ph
Ph
Ph
Ph
Ph
PhthN
40 40
+
40 40
:
41
', 62% (
'=1:1)
, 40%
■ CONCLUSION
(>19:1 d.r.)
(>19:1 d.r.)
In conclusion, we have proved that the intermediacy of metal
nitrenoids can be harnessed as a mechanistic motif of LUMO-
controlled 1,3-dipoles for the olefin difunctionalization. In parallel
with a series of stoichiometric probes, DFT calculation suggested
that our working hypothesis on the concerted [3+2] cycloaddition
pathway is operative, wherein the postulated three-centered LUMO
of Ir-nitrenoids dictates its selectivity and reactivity with olefins via
symmetry-allowed orbital interactions. Our approach to utilize
dipole character in the imido transfer was successfully applied
toward the olefin difuctionalization of dioxazolones to furnish γ-
lactams in excellent syn-selectivity. In this line, haloamidation and
oxyamidation were able to achieve via Ir catalysis, and either threo-
or erythro-products were obtained in a stereodefined manner where
olefin geometry (E/Z) of substrates determines the stereochemistry
of products. We anticipate that the present analysis of the reactivity
of Ir-nitrenoids as a motif of 1,3-dipoles may serve as a general
a(E)-substrate (0.2 mmol), carboxylic acid (0.3 mmol),
[CpArFIrCl2]2 (2.5 mol%), AgNTf2 (10 mol%), and NaOAc (40
o
mol%) in HFIP at 60 C for 12 h; Ratio of diastereoisomers,
determined by 1H NMR analysis of the crude reaction mixture. b(Z)-
olefin was used with AgOAc (40 mol%) instead of AgNTf2 and
NaOAc. cNaOH (40 mol%) was used instead of NaOAc.
General applicability of the Ir-catalyzed olefin oxyamidation was
subsequently scrutinized with [CpArFIrCl2]2 catalyst (Table 4). E-
(Aryl)alkenyl dioxazolones containing a range of substituents on the
arene moiety readily underwent the desired oxyamidation in
reaction with acetic acid to afford the corresponding lactams with
excellent syn-selectivity (31−33). Interestingly, the position of
substituents at the arene ring influenced the diasteoselectivity
although the exact reason is not understood at the present stage. For
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platform for the development of additional stereoselective olefin
Amino Lactonization and Amino Oxygenation of Alkenes Using O-
3
4
5
6
7
8
9
difunctionalization reactions.
Benzoylhydroxylamines. J. Am. Chem. Soc. 2016, 138, 5813; (i) Liu,
Z.; Zeng, T.; Yang, K. S.; Engle, K. M. β,γ-Vicinal
Dicarbofunctionalization of Alkenyl Carbonyl Compounds via
Directed Nucleopalladation. J. Am. Chem. Soc. 2016, 138, 15122;
(j) Liu, Y.-Y.; Yang, X.-H.; Song, R.-J.; Luo, S.; Li, J.-H. Oxidative
1,2-carboamination of alkenes with alkyl nitriles and amines toward
γ-amino alkyl nitriles. Nat. Commun. 2017, 8, 14720; (k) Shen, K.;
Wang, Q. Copper-Catalyzed Alkene Aminoazidation as a Rapid
Entry to 1,2-Diamines and Installation of an Azide Reporter onto
Azahetereocycles. J. Am. Chem. Soc. 2017, 139, 13110; (l) Conway,
J. H.; Rovis, T. Regiodivergent Iridium(III)-Catalyzed Diamination
of Alkenyl Amides with Secondary Amines: Complementary Access
to γ- or δ-Lactams. J. Am. Chem. Soc. 2018, 140, 135.
(3) (a) Fu, N.; Sauer, G. S.; Saha, A.; Loo, A.; Lin, S. Metal-catalyzed
electrochemical diazidation of alkenes. Science 2017, 357, 575; (b)
Nakafuku, K. M.; Fosu, S. C.; Nagib, D. A. Catalytic Alkene
Difunctionalization via Imidate Radicals. J. Am. Chem. Soc. 2018,
140, 11202; (c) Siu, J. C.; Sauer, G. S.; Saha, A.; Macey, R. L.; Fu, N.;
Chauviré, T.; Lancaster, K. M.; Lin, S. Electrochemical
Azidooxygenation of Alkenes Mediated by a TEMPO–N3 Charge-
Transfer Complex. J. Am. Chem. Soc. 2018, 140, 12511; (d) Fu, N.;
Shen, Y.; Allen, A. R.; Song, L.; Ozaki, A.; Lin, S. Mn-Catalyzed
Electrochemical Chloroalkylation of Alkenes. ACS Catal. 2019, 9,
746; (e) Tlahuext-Aca, A.; Garza-Sanchez, R. A.; Schäfer, M.;
Glorius, F. Visible-Light-Mediated Synthesis of Ketones by the
Oxidative Alkylation of Styrenes. Org. Lett. 2018, 20, 1546.
■ ASSOCIATED CONTENT
Supporting Information
Gibbs free energies for the optimized structures and transition states.
Additional crystallographic and NMR data
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
■ AUTHOR INFORMATION
Corresponding Author
* E-mail: sbchang@kaist.ac.kr
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENT
This research was supported by the Institute of Basic Science (IBS-
R010-D1). We thank Dr. Dongwook Kim for single-crystal X-ray
diffraction experiments with synchrotron radiation performed at the
BL2D-SMC in Pohang Accelerator Laboratory.
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(15) Of note, the formation of other complexes II, III and V also
implicates in analogous concerted processes, and the details are
described in Supporting Information.
(16) As an alternative process, the second radical cyclization of alkyl
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(30) Since starting material was mostly recovered intact from the
reactions with [Cp*RhCl2]2 or [Cp*CoCl2]2, these catalysts are
assumed to be ineffective in generating the putative nitrenoid
intermediates via decarboxylation.
LUMO/Dipolarophile-HOMO
Controlled
Asymmetric
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(25) When 2 (Z/E, >20:1) was treated with HCl in HFIP solvent, a
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material (Z/E, 2.8:1). See Supporting Information for details.
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stereodefined olefin insertion
7
8
9
O
O
O
(L)X-
N
(L)X-
H
N
H
R
O
X
(L)
O
Ir
X
(L)
Ir
N
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60
R
H
H
R
(E-olefin)
(Z-olefin)
threo
erythro
theoretical study
stoichiometric probe
O
N
Ir
X
O
O
Ir
Ir
X
L
N
L
N
R1
R2
H
X
R1 R2
R1
R2
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