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

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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 J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 14 Sep 2018 Downloaded from http://pubs.acs.org on September 15, 2018

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Journal of the American Chemical Society

Ir(III)-Catalyzed Stereoselective Haloamidation of Alkynes Enabled by Ligand Participation Seung Youn Hong,†,‡ Junsoo Son,†,‡ Dongwook Kim,‡,† and Sukbok Chang*,‡,† †

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 ABSTRACT: Described herein is to apply a strategy of ligand participation for the Ir-catalyzed imido transfer into alkynes. Based on a stoichiometric [3+2] cycloaddition of 2 Cp*Ir(III)(κ -N,O-chelate) with alkynyl dioxazolone, a catalytic 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 versatile Z-(halovinyl)lactams with excellent stereoselectivity.

Since the seminal study by Breslow et al. on the Rh(II)- or 1 Fe(III)-catalyzed oxidation of C–H bonds, transition metalmediated amino group transfer has received a great attention 2 as a powerful tool for the direct C–N bond formation. 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 2-3 been extensively studied, 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 teth4 ered with nucleophiles (Scheme 1a, top). Recently, this path was extended to an intermolecular reaction with external 5 nucleophiles. Another approach of utilizing in situ generated metal nitrenoids is based on open-shell catalysis, wherein an aminyl radical initiates a homolytic cleavage of triple bonds. The resultant vinyl radical intercepts a nucleophile to afford func6 tionalized azacyclic products (Scheme 1a, bottom). For ex6a ample, Fe-catalyzed chloroamination of azidoformates and 6b Cu-catalyzed alkyne functionalization by using PhI=NTs were described by Bach and Pérez, respectively. Despite these 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, acylnitrenoid, readily being converted to isocyanates via the Cur7 tius-type rearrangement (Scheme 1b, left). In order to challenge this issue in reaction of metal acylnitrenoids with alkynes, we envisioned to apply a strategy of ligand participation, wherein a chemically noninnocent 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 concomitant suppression of the undesired isocyanate path, thus eventually allowing the ligand-participated vinyl lactam formation. Herein, we present a utilization of the ligand partici-

pation for the development of Ir-catalyzed stereoselective haloamidation of alkynes by using NaX (X = Cl / Br) as practical halide sources (Scheme 1c).

Scheme 1. Metal-Mediated Nitrenoid Transfer to Alkynes

To verify our working hypothesis, we first planned to test 2 Cp*Ir(III)(κ -N,O-chelate) species since its variants bearing 2 stronger chelators (κ -N,N’) were shown to be highly effective 3 in generating Ir(V)-nitrenoids in our recent C(sp )–H ami3e dation to afford γ-lactams. In particular, we chose 82 hydroxyquinoline (8-HQ) as a model κ -N,O-chelate to validate the proposed ligand participation, and its iridium com3e plex I, readily prepared according to our own procedure, was allowed to react with an γ-alkynyl dioxazolone 1 (Scheme 8 2). 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 9 1-alkynes via a vinylidene intermediate.

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When alkynyl dioxazolone 1 was treated with an iridium F complex I in the presence of NaBAr 4, a vinyl-lactam Ir species (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 10 of I [2.091 Å]. 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).

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Concerted-Cl) is located with the CN and C−Cl bond formation 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.

Scheme 3. Development of Chloroamidation a) Design principle of catalytic haloamidation H+

O

+

HN

O

Scheme 2. Model Study of Ligand Participation

O

Bis(κ 1-X)

Ir N

N

X

Ir N

X

catalytic + Cp*IrX n

X

O

more labile

Isolable, but inert (κ 3-N,N',O)

catalyst regeneration

(κ 2-N,X-κ1-X)

b) Proposed catalytic cycle of haloamidation O

L [Cp*IrX2 ]2

NH Ph L,

X-,

(L = sol. or additive) (X = Cl or Br)

X 2

H+

Ir

X

X

Product release

Ir

L

O

O

O X

1

L IV

N

Ir

X

N

X

X

X VIII Ph

O N

O

X

VII Ph

Ph ∆G = 18.8 kcal/mol (X = Cl)

Ligand participation

likely via

Ir

V

O

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 whereas 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 isocyanate was calculated to lie 3.6 kcal/mol higher in energy (see SI for details). All attempts to locate other meaningful intermediates such as vinyl cation, frequently proposed in the 4a,4b,5 related chemistry, were unfruitful, but just being converged to II. As a result, we tentatively propose that the involvement of a vinyl cation intermediate traversing a stepwise 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 2 replacing the κ -N,O bidentate with two monodentate (X) ligands in the iridium center might provide a catalysis platform for the desired ligand-participated alkyne insertion (Scheme 3a). It was foreseen to generate a key labile Ir in1 2 termediate bearing κ -X and κ -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 participation 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-

X 2.22 Å

Ir

N

CO2

X

∆G = 10.0 kcal/mol (X = Cl)

Ph

3.13 Å

VI

ts-Concerted-Cl c) Test reaction as a proof of concept O O O N 1

presumably via

Ph Cl

Ir Cl 2

AcOH CH2 Cl2, r.t.

Cl

Ir

O NH

O N

Cl

Ph Ph

VIII (X = Cl)

Cl

2, 64% (Z/E=>20:1)

(X-ray)

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 dioxazolone 1 in the presence of AcOH. Significantly, the vinyl lactam product 2 was formed as a single stereoisomer (Z), 11 confirmed by X-ray analysis. The proposed [3+2] cyclizative chloride participation is believed to be associated with this excellent stereoselective generation of Z-vinyl lactam. Given 12-13 that vinyl chloride is a versatile synthetic building unit, the development of catalytic procedure is highly desirable. With the promising result on the stoichiometric chloroamidation, 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, quantitative 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/E14 selectivity were observed (entries 2−4). 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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Journal of the American Chemical Society try 8). The presence of 15-crown-5 was crucial as seen in entry 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).

Table 1. Optimization Table O O N

1

En try 1

O

O

O +

NaCl/15-crown-5 (1.5/1.5 equiv)

Ph

[Cp*IrCl2 ] 2 (1.25 mol%) AcOH (2.0 equiv)

NH

NH

Ph

Cl CH2 Cl2 /TFE (2:1) 40 o C, 12 h 'standard conditions '

Z-2

Variations from ‘standard conditions’ none

Cl

Ph

E-2'

’

2+2 a (%) >95

’b

2:2

CH2Cl2 only (DCM, solvent)

40

>20:1

3

CF3CH2OH only (TFE, solvent)

86

10.2:1

4

(CF3)2CHOH only (HFIP, solvent)

90

5.9:1

5

PhCOOH (additive)

66

>20:1

6

o-NO2C6H4COOH (additive)

85

4.7:1

7

CF3COOH (additive)

77

2.9:1

8

w/o AcOH

11

>20:1

9

w/o 15-crown-5

33

>20:1

10

(n-Bu4N)Cl (chloride source)

>95

>20:1

11

[Cp*RhCl2]2 (catalyst)

20:1

1

Table 2. Substrate Scopea

>20:1

2

a1

H bonds, and the corresponding γ-lactams 22’ and 24’ were 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 F cyclize in the presence of NaBr/15-crown-5 and NaBAr 4, the corresponding bromoalkenyl lactam 26 was formed quantitatively (Z/E = 8.2:1), which was immediately dehydrobrominated upon isolation leading to 27 (eq 1). In contrast, a substrate derived from benzoic acid (28) furnished Z-bromovinyl isoindolinone 29 in high yield (eq 2).

b

H NMR yields. Ratio of Z/E-isomers (2:2’), determined by H NMR of the crude reaction mixture.

Next, the generality of the Ir(III)-catalyzed chloroamidation was investigated by applying various types of subo strates at 25~40 C (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 sub15 strate (9). The position of an alkyl substituent in the linker between dioxazolone and alkynyl group was observed to influence the reaction efficiency to some extents, but Zselectivity was excellent in both cases (10–11). Isoindoline derivatives could be obtained through the present method by applying dioxazolones prepared from ortho-acetylene benzoic acids substituted with phenyl, cyclohexenyl, and cyclopropyl groups (12–14). However, the presence of a sterically demanding group (t-Bu) resulted in moderate cyclization efficiency (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. Given that the putative iridium nitrenoid was also shown 3e to efficiently transfer to a wide range of C–H bonds, we were intrigued to observe any distinctive chemoselectivity 3 between two reactive sites: alkynyl vs sp C–H bonds. Importantly, γ-alkyne insertion was found to be exclusive leading to 22 and 24 in the presence of γ-aliphatic or benzylic C–

a

Unless otherwise indicated, reactions were run with 1.25 mol o % of catalyst at 25 C for 12 h (ratio of Z/E-isomers, measured 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.



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 crosscoupling reaction with phenyl boronic acid to afford 30 with excellent stereoselectivity. Nucleophilic substitution of vinyl chloride with morpholine occurred under metal-free conditions 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 stereoretentive manner (32 and 33, respectively).

Scheme 4. Synthetic Applications

a

a

See 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 stoi2 chiometric [3+2] cycloaddition of Cp*Ir(III)(κ -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.

ASSOCIATED CONTENT Supporting Information Corresponding Author [email protected]

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 synchrotron radiation were performed at the BL2D-SMC in Pohang Accelerator Laboratory.

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Journal of the American Chemical Society occur leading to Z/E = 2.7:1 in HFIP. See the supporting information for details. (15) On the other hand, 6-membered lactam was not formed when a substrate having three methylene linkers between the

dioxazolone and triple bond was subjected to the present reaction conditions. See the SI for details.



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

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