Ir(III)-Catalyzed Stereoselective Haloamidation of Alkynes Enabled by Ligand Participation

Article abstract of DOI:10.1021/jacs.8b08134

Described herein is the application of a strategy of ligand participation for the Ir-catalyzed imido transfer into alkynes. On the basis of a stoichiometric [3 + 2] cycloaddition of Cp?Ir(III)(κ²-N,O-chelate) with alkynyl dioxazolone, a catalyt

Full text of DOI:10.1021/jacs.8b08134

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Communication
Ir(III)-Catalyzed Stereoselective Haloamidation
of Alkynes Enabled by Ligand Participation
Seung Youn Hong, Junsoo Son, Dongwook Kim, and Sukbok Chang
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Ir(III)-Catalyzed Stereoselective Haloamidation of Alkynes Enabled
by Ligand Participation
Seung Youn Hong,†,‡ Junsoo Son,†,‡ Dongwook Kim,‡,† and Sukbok Chang*,‡,†
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†Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
‡Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea
Supporting Information Placeholder
pation for the development of Ir-catalyzed stereoselective
ABSTRACT: Described herein is to apply a strategy of ligand
haloamidation of alkynes by using NaX (X = Cl / Br) as prac-
tical halide sources (Scheme 1c).
participation for the Ir-catalyzed imido transfer into alkynes.
Based on stoichiometric [3+2] cycloaddition of
a
Cp*Ir(III)(κ2-N,O-chelate) with alkynyl dioxazolone, a cata-
lytic haloamidation has been developed for the first time by
employing [Cp*IrCl2]2 precatalyst and NaX salts (X = Cl or
Br) as practical halide sources to furnish synthetically versa-
tile Z-(halovinyl)lactams with excellent stereoselectivity.
Scheme 1. Metal-Mediated Nitrenoid Transfer to
Alkynes
S
ince the seminal study by Breslow et al. on the Rh(II)- or
Fe(III)-catalyzed oxidation of C–H bonds,1 transition metal-
mediated amino group transfer has received a great attention
as a powerful tool for the direct C–N bond formation.2 Key to
success in this approach relies on the deliberate combination
of electrophilic nature of metal nitrenoids with nucleophilic
substrates. While C–H amidation and aziridination have
been extensively studied,2-3 only a few examples are known
on the relevant reaction with alkynes. For instance, Blakey
and Panek groups independently showed that Rh catalysts
can mediate cascade cyclization of alkynylsulfonamides teth-
ered with nucleophiles (Scheme 1a, top).4 Recently, this path
was extended to an intermolecular reaction with external
nucleophiles.5
Another approach of utilizing in situ generated metal
nitrenoids is based on open-shell catalysis, wherein an ami-
nyl radical initiates a homolytic cleavage of triple bonds. The
resultant vinyl radical intercepts a nucleophile to afford func-
tionalized azacyclic products (Scheme 1a, bottom).6 For ex-
ample, Fe-catalyzed chloroamination of azidoformates6a and
Cu-catalyzed alkyne functionalization by using PhI=NTs6b
were described by Bach and Pérez, respectively. Despite the-
se notable advances, the reaction of acylnitrenes with alkynes
has not been developed. This is mainly due to the intrinsic
instability of the presumed reactive intermediates, acylnit-
renoid, readily being converted to isocyanates via the Cur-
tius-type rearrangement (Scheme 1b, left).7
In order to challenge this issue in reaction of metal
acylnitrenoids with alkynes, we envisioned to apply a strate-
gy of ligand participation, wherein a chemically non-
innocent moiety of catalysts may cooperate with the metal
center likely via a [3+2] cycloaddition mode (Scheme 1b,
right). This was motivated by the anticipation that a stable
metallacycle would be generated more readily with concomi-
tant suppression of the undesired isocyanate path, thus even-
tually allowing the ligand-participated vinyl lactam for-
mation. Herein, we present a utilization of the ligand partici-
To verify our working hypothesis, we first planned to test
Cp*Ir(III)(κ2-N,O-chelate) species since its variants bearing
stronger chelators (κ2-N,N’) were shown to be highly effective
in generating Ir(V)-nitrenoids in our recent C(sp3)–H ami-
dation to afford γ-lactams.3e In particular, we chose 8-
hydroxyquinoline (8-HQ) as a model κ2-N,O-chelate to vali-
date the proposed ligand participation, and its iridium com-
plex I, readily prepared according to our own procedure,3e
was allowed to react with an γ-alkynyl dioxazolone 1 (Scheme
2).8 It needs to be mentioned that Love and Schafer recently
illustrated a cooperative behavior between 1,3-N,O-chelating
phosphoramidate ligand and Cp*Ir(III) metal center in a
stoichiomtertic anti-Markovnikov O-phosphoramidation of
1-alkynes via a vinylidene intermediate.9
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When alkynyl dioxazolone 1 was treated with an iridium
Concerted-Cl) is located with the CN and C−Cl bond for-
mation taking place in a concerted asynchronous manner
with barrier of 10.0 kcal/mol. At the final stage, the resultant
VIII will undergo protonation to release the desired product
2 with the regeneration of catalytically active species IV.
complex I in the presence of NaBArF , a vinyl-lactam Ir spe-
1
2
3
4
5
6
7
4
cies (II) was isolated in good yield, and its structure of II was
confirmed by X-ray analysis. The bond length of Ir–O is 2.235
Å, being significantly longer than that of reported Ir–O bond
of I [2.091 Å].10 Indeed, this result clearly shows that a ligand
participation of 8-HQ in I occurred simultaneously during
the alkyne insertion into a postulated Ir-imido intermediate
III in a [3+2] cycloaddition manner (Scheme 2b).
Scheme 3. Development of Chloroamidation
a) Design principle of catalytic haloamidation
H+
O
+
HN
8
9
O
O
X
Bis( 1-X)
κ
Ir
Scheme 2. Model Study of Ligand Participation
catalytic
Ir
N
O
N
X
N
+
X
10
11
12
13
14
15
16
17
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26
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Cp*IrXn
more labile
κ2-N,X-κ1-X)
catalyst
regeneration
Isolable, but inert
κ3-N,N',O)
(
(
b) Proposed catalytic cycle of haloamidation
O
L
[Cp*IrX2]2
NH
(L = sol. or additive)
(X = Cl or Br)
X
Ph
2
1
Ir
X
L, X-, H+
L
X
L
IV
Product release
O
O
O
O
O
Ir
Ir
Ir
N
N
N
X
X
X
X
X
X
VII
Ph
Ph
Ph
VIII
V
ꢀ
G
= 18.8 kcal/mol
(X = Cl)
Ligand
participation
likely via
O
Ir
X
N
CO2
The postulated cooperative process was validated by a
computational study (density functional theory, DFT) to
reveal that the alkyne insertion step of III is energetically
downhill by 65 kcal/mol with a barrier of only 6.4 kcal/mol
to furnish II. This path was calculated to be concerted but
asynchronous: the C−N bond (2.34 Å) is formed early where-
as the C−O bond formation (3.42 Å) is not developed yet at
the transition state. On the other hand, a transition state for
the undesired Curtius-type decomposition of III to isocya-
nate was calculated to lie 3.6 kcal/mol higher in energy (see
SI for details). All attempts to locate other meaningful inter-
mediates such as vinyl cation, frequently proposed in the
related chemistry,4a,4b,5 were unfruitful, but just being con-
verged to II. As a result, we tentatively propose that the in-
volvement of a vinyl cation intermediate traversing a step-
wise pathway is not considered for further discussions.
The above promising result motivated us to see whether
this strategy of ligand participation can be applicable for the
development of a catalytic reaction. We hypothesized that
replacing the κ2-N,O bidentate with two monodentate (X)
ligands in the iridium center might provide a catalysis plat-
form for the desired ligand-participated alkyne insertion
(Scheme 3a). It was foreseen to generate a key labile Ir in-
termediate bearing κ1-X and κ2-N,X ligands which could give
a chance to operate a catalytic cycle by proper protonation.
A designed mechanistic cycle for the haloamidation (X =
Cl or Br) is outlined in Scheme 3b. An alkynyl dioxazlone
substrate 1 will coordinate to the Ir center of monomeric
species IV to afford an adduct V which then undergoes an
oxidative coupling to generate the postulated acylnitrene VI
with CO2 extrusion. As described above, a ligand participa-
tion is proposed to involve in the subsequent imido transfer
to alkyne to give a metallacycle intermediate VIII. This
pathway was predicted to be plausible by DFT calculations,
wherein a [3+2]-cycloaddition type transition state (ts-
2.22 Å
X
ꢀG = 10.0 kcal/mol
Ph
(X = Cl)
3.13 Å
VI
ts-Concerted-Cl
c) Test reaction as a proof of concept
O
presumably via
O
O
O
N
1
NH
Ph
O
Ir
Ir
N
Cl
Cl
AcOH
CH2Cl2, r.t.
Cl
Cl
Ph
Cl
2
Ph
2,
(X-ray)
64% (Z/E=>20:1)
VIII
(X = Cl)
Based on the above considerations, the Cp*Ir system was
explored to develop a ligand-participated chloroamidation
reaction. To our delight, the desired chloroamidation indeed
did proceed when [Cp*IrCl2]2 was treated with alkynyl dioxa-
zolone 1 in the presence of AcOH. Significantly, the vinyl
lactam product 2 was formed as a single stereoisomer (Z),
confirmed by X-ray analysis.11 The proposed [3+2] cyclizative
chloride participation is believed to be associated with this
excellent stereoselective generation of Z-vinyl lactam. Given
that vinyl chloride is a versatile synthetic building unit,12-13
the development of catalytic procedure is highly desirable.
With the promising result on the stoichiometric chloro-
amidation, we accordingly endeavored to search for optimal
conditions for the catalytic reaction of 1 by examining NaCl
as the practical chloride source (Table 2). Pleasingly, quanti-
tative product yield was obtained with excellent Z-selectivity
o
by using 1.25 mol% of [Cp*IrCl2]2 at 40 C in a co-solvent
system [CH2Cl2/CF3CH2OH, 2:1] (entry 1). In different solvent
systems examined, lower efficiency and/or decreased Z/E-
selectivity were observed (entries 2−4).14 In addition, acids
other than AcOH were found to be less effective (entries 5−7)
while this additive is essential for the catalytic turnovers (en-
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try 8). The presence of 15-crown-5 was crucial as seen in en-
H bonds, and the corresponding γ-lactams 22’ and 24’ were
1
2
3
4
5
6
7
8
try 9. (n-Bu4N)Cl was equally effective as the chloride source
(entry 10). However, isoelectronic catalysts like Rh(III) and
Ru(II)-complexes displayed poorer performance (entries
11−12).
not formed, respectively.
We were pleased to see that the present protocol could
successfully be extended to bromo-amidation by employing
NaBr instead of NaCl. When dioxazolone 25 was allowed to
cyclize in the presence of NaBr/15-crown-5 and NaBArF , the
4
Table 1. Optimization Table
corresponding bromoalkenyl lactam 26 was formed quantita-
tively (Z/E = 8.2:1), which was immediately dehydrobromin-
ated upon isolation leading to 27 (eq 1). In contrast, a sub-
strate derived from benzoic acid (28) furnished Z-bromovinyl
isoindolinone 29 in high yield (eq 2).
O
O
O
O
[Cp*IrCl2]2 (1.25 mol%)
AcOH (2.0 equiv)
NH
O
NH
N
NaCl/15-crown-5
(1.5/1.5 equiv)
+
Ph
Cl
CH2Cl2/TFE (2:1)
40 oC, 12 h
'standard conditions'
9
Cl
E-2'
Ph
Z-2
Ph
10
11
12
13
14
15
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23
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1
Table 2. Substrate Scopea
En
try
1
Variations from ‘standard conditions’
2+2’ 2:2’b
(%)a
none
>95 >20:1
2
3
CH2Cl2 only (DCM, solvent)
CF3CH2OH only (TFE, solvent)
(CF3)2CHOH only (HFIP, solvent)
PhCOOH (additive)
40
86
90
66
85
77
11
>20:1
10.2:1
5.9:1
>20:1
4.7:1
4
5
6
7
o-NO2C6H4COOH (additive)
CF3COOH (additive)
2.9:1
>20:1
>20:1
8
w/o AcOH
9
10
11
12
w/o 15-crown-5
33
(n-Bu4N)Cl (chloride source)
[Cp*RhCl2]2 (catalyst)
>95 >20:1
<5
-
[RuCl2(p-cymene)]2 (catalyst)
36
>20:1
a1H NMR yields. Ratio of Z/E-isomers (2:2’), determined by
b
1H NMR of the crude reaction mixture.
Next, the generality of the Ir(III)-catalyzed chloroami-
dation was investigated by applying various types of sub-
strates at 25~40 oC (Table 1). γ-(Aryl)alkynyl dioxazlones
bearing a range of substituents at the phenyl side smoothly
underwent the desired cyclization with excellent Z-selectivity
(2–6). Replacement of the phenyl with heterocycles such as
benzofuran or benzothiophene was no problem (7–8).
Notably, the nitrenoid insertion took place exclusively at
the γ-position even in case of a conjugated dialkynyl sub-
strate (9).15 The position of an alkyl substituent in the linker
between dioxazolone and alkynyl group was observed to in-
fluence the reaction efficiency to some extents, but Z-
selectivity was excellent in both cases (10–11). Isoindoline
derivatives could be obtained through the present method by
applying dioxazolones prepared from ortho-acetylene benzo-
ic acids substituted with phenyl, cyclohexenyl, and cyclopro-
pyl groups (12–14). However, the presence of a sterically de-
manding group (t-Bu) resulted in moderate cyclization effi-
ciency (15). Notably, the reaction proceeded smoothly even
for a more complex molecule, a derivative of Mestranol (16).
Diastereomeric substrates 17 and 19 underwent the desired
cyclization in a stereo-retentive manner leading to 18 and 20
respectively, albeit with slightly differed efficiency.
aUnless otherwise indicated, reactions were run with 1.25 mol
% of catalyst at 25 oC for 12 h (ratio of Z/E-isomers, measured
Given that the putative iridium nitrenoid was also shown
to efficiently transfer to a wide range of C–H bonds,3e we
were intrigued to observe any distinctive chemoselectivity
between two reactive sites: alkynyl vs sp3 C–H bonds. Im-
portantly, γ-alkyne insertion was found to be exclusive lead-
ing to 22 and 24 in the presence of γ-aliphatic or benzylic C–
1
b
o
c
by H NMR of the crude reaction mixture). At 40 C. 2.5
d
Mol% of catalyst was used. Isolated as a N-benzyl protected
product.
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Synthetic utility of the obtained products was briefly
demonstrated (Scheme 4). Product 8, easily obtained even in
a gram scale, smoothly underwent a Pd-catalyzed cross-
coupling reaction with phenyl boronic acid to afford 30 with
excellent stereoselectivity. Nucleophilic substitution of vinyl
chloride with morpholine occurred under metal-free condi-
tions to give 31 as an isomeric mixture. Bromoamidated
product 29 also underwent Pd-catalyzed couplings to afford
conjugated Z-dienyl and Z-enynyl products in a stereoreten-
tive manner (32 and 33, respectively).
Scheme 4. Synthetic Applicationsa
(7) Lebel, H.; Leogane, O. Org. Lett. 2005, 7, 4107.
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11147; (h) Park, J.; Lee, J.; Chang, S. Angew. Chem. Int. Ed.
2018, 57, 5202; (i) Zhou, Y.; Engl, O. D.; Bandar, J. S.; Chant,
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aSee SI for detailed reaction conditions (ratio of Z/E-isomers
is given in parentheses).
In conclusion, we have successfully utilized an intuitive
strategy of ligand participation towards the first development
of Ir-catalyzed imido transfer into alkynes. Based on a stoi-
chiometric [3+2] cycloaddition of Cp*Ir(III)(κ2-N,O-chelate)
with alkynyl dioxazolone, a catalytic haloamidation protocol
is now established by employing [Cp*IrCl2]2 precatalyst and
NaX salts (X= Cl or Br) as a practical halide source to afford
synthetically versatile Z-(halovinyl)lactams in high efficiency
and stereoselectivity.
(10) Thai, T.-T.; Therrien, B.; Süss-Fink, G. Inorg. Chem.
Commun. 2009, 12, 806.
(11) Brahmchari, D.; Verma, A. K.; Mehta, S. J. Org. Chem.
2018, 83, 3339.
ASSOCIATED CONTENT
Supporting Information
Corresponding Author
(12) (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.
Chem. Int. Ed. 2005, 44, 4442; (b) Evano, G.; Blanchard, N.;
Toumi, M. Chem. Rev. 2008, 108, 3054; (c) Jana, R.; Pathak, T.
P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417.
(13) (a) Saputra, M. A.; Ngo, L.; Kartika, R. J. Org. Chem. 2015,
80, 8815; (b) Xu, Y.; McLaughlin, M.; Chen, C.-y.; Reamer, R.
A.; Dormer, P. G.; Davies, I. W. J. Org. Chem. 2009, 74, 5100;
(c) Le, C. M.; Sperger, T.; Fu, R.; Hou, X.; Lim, Y. H.;
Schoenebeck, F.; Lautens, M. J. Am. Chem. Soc. 2016, 138,
14441; (d) Derosa, J.; Cantu, A. L.; Boulous, M. N.; O’Duill, M.
L.; Turnbull, J. L.; Liu, Z.; De La Torre, D. M.; Engle, K. M. J.
Am. Chem. Soc. 2017, 139, 5183; (e) Trost, B. M.; Pinkerton, A.
B. J. Am. Chem. Soc. 2002, 124, 7376.
sbchang@kaist.ac.kr
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This research was supported by the Institute of Basic Science
(IBS). Single crystal x-ray diffraction experiment with syn-
chrotron radiation were performed at the BL2D-SMC in Po-
hang Accelerator Laboratory.
(14) When a pre-isolated product Z-2 was subjected to the
present catalyst system, an isomerization was observed to
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occur leading to Z/E = 2.7:1 in HFIP. See the supporting
information for details.
dioxazolone and triple bond was subjected to the present
reaction conditions. See the SI for details.
1
2
3
(15) On the other hand, 6-membered lactam was not formed
when a substrate having three methylene linkers between the
4
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ACS Paragon Plus Environment

Journal of the American Chemical Society
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ACS Paragon Plus Environment