Iridium-Catalyzed Hydrochlorination and Hydrobromination of Alkynes by Shuttle Catalysis

Article abstract of DOI:10.1002/anie.201912803

Described herein are two different methods for the synthesis of vinyl halides by a shuttle catalysis based iridium-catalyzed transfer hydrohalogenation of unactivated alkynes. The use of 4-chlorobutan-2-one or tert-butyl halide as donors of hydrogen halides allows this transformation in the absence of corrosive reagents, such as hydrogen halides or acid chlorides, thus largely improving the functional-group tolerance and safety profile of these reactions compared to the state-of-the-art. This method has granted access to alkenyl halide compounds containing acid-sensitive groups, such as tertiary alcohols, silyl ethers, and acetals. The synthetic value of those methodologies has been demonstrated by gram-scale synthesis where low catalyst loading was achieved.

Full text of DOI:10.1002/anie.201912803

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Iridium-Catalyzed Hydrochlorination and Hydrobromination of
Alkynes via Shuttle Catalysis
Authors: Peng Yu, Alessandro Bismuto, and Bill Morandi
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201912803
Angew. Chem. 10.1002/ange.201912803
Link to VoR: http://dx.doi.org/10.1002/anie.201912803
http://dx.doi.org/10.1002/ange.201912803

10.1002/anie.201912803
Angewandte Chemie International Edition
RESEARCH ARTICLE
Iridium-Catalyzed Hydrochlorination and Hydrobromination of
Alkynes via Shuttle Catalysis
Peng Yu,[a,b] Alessandro Bismuto[a] and Bill Morandi*[a,b]
Abstract: Herein, we describe two different methods for the
synthesis of vinyl halides via a shuttle catalysis-based iridium-
catalyzed transfer hydrohalogenation of unactivated alkynes. The
use of 4-chlorobutan-2-one or tert-butyl halide as donors of
hydrogen halides has allowed to perform this transformation in the
absence of corrosive reagents, such as hydrogen halides or acid
chlorides, thus largely improving the functional group tolerance and
safety profile of these reactions compared to the state-of-the-art.
This, has granted access to alkenyl-halide compounds containing
acid sensitive groups, such as tertiary alcohols, silyl ethers and
acetals. The synthetic value of those methodologies has been
demonstrated by gram-scale synthesis where low catalyst loading
could be achieved.
Hammond, Xu and co-workers have recently employed HCl (as
a DMPU/HCl adduct) in a gold-catalyzed reaction (Scheme 1b).
[10]
However, the use of HCl as a reagent inherently limits the
functional group tolerance of these methods. A palladium-
catalyzed directed anti-hydrochlorination of unactivated alkynes
has recently been realized by Engle and co-workers (Scheme
1c).[11] Through the introduction of a bidentate directing group,
they could efficiently control the regioselectivity of the
transformation. This method is, however, limited to the synthesis
of vinyl chloride products that have a suitably positioned amino
group for the introduction of the directing group. The use of an
acid chloride as HCl precursor also limits the functional group
tolerance of this reaction. Thus, the discovery of a functional
group tolerant catalytic hydrochlorination still remains
a
challenge in organic synthesis. Herein, we report an iridium-
catalyzed transfer hydrochlorination and hydrobromination of
Introduction
alkynes
using
4-chlorobutan-2-one
and
tert-butyl
chloride/bromide as a formal HX donor, a feature that allows for
an unusually broad functional group tolerance in the synthesis of
vinyl halide species (Scheme 1d). Furthermore, it also
Alkenyl halides have found widespread application in organic
synthesis.[1] Among them, vinyl chlorides have gained increasing
attention in recent years due to their significant synthetic utility
and occurrence in natural products, pharmaceuticals and
agrochemicals.[2] Moreover, vinyl chlorides have emerged as
efficient coupling partners in cross-coupling reactions, such as
represents
a rare example of hydro functionalization of
unactivated internal alkynes by a simple iridium catalyst.
the
Suzuki−Miyaura
coupling
reaction[3]
and
the
Buchwald−Hartwig amination.[4] Thus, the development of
methods for the preparation of vinyl chlorides is of great
synthetic significance. Vinyl chlorides are generally accessed
from carbonyl compounds[5] or alkynes.[6] Although a catalytic
process using carbonyl compounds as starting materials has
been realized,[5h] the requirement for toxic phosphorus reagents
like PCl5[5a,5b] or POCl3[5d] or a large excess of CrCl2[5c] limits their
applications in complex molecule synthesis.
The catalytic synthesis of vinyl chlorides from broadly
accessible alkynes is a powerful alternative to the traditional
synthetic methods. A first approach, carbochlorination, the
addition of a C–Cl bond across an alkyne, mostly involves acid
chlorides as reagents.[6] The second approach, alkyne
hydrochlorination,[7] a reaction which requires otherwise harsh
conditions in the absence of a catalyst, provides a powerful and
complementary strategy to transform alkynes into vinyl chlorides.
However, most of the catalytic hydrochlorination methods rely on
corrosive and acidic HCl as a reagent,[8] leading to a limited
functional group tolerance (Scheme 1). For example, Dérien and
co-workers
have
reported
a
ruthenium-catalyzed
hydrochlorination of alkynes with HCl (Scheme 1a),[9] and
Scheme 1. Context of the work.
[a]
[b]
Dr. Peng Yu, Dr. A. Bismuto, Prof. Dr. B. Morandi
Laboratorium für Organische Chemie ETH Zꢀrich
Vladimir-Prelog-Weg 3, HCI, 8093 Zꢀrich, Switzerland
Results and Discussion
Dr. Peng Yu, Prof. Dr. B. Morandi
Evaluation of the halide donor. Recently, our group reported
several reactions that addressed safety problems associated
with the use of hazardous and toxic reagents, such as HCN-free
hydrocyanation,[12] cyanide-free cyanation of aryl chloride[13] and
CO/HCl-free hydrochlorocarbonylation.[14] These reactions
Max-Planck-Institut für Kohlenforschung
Kaiser-Wihelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
E-mail: bill.morandi@org.chem.ethz.ch
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.
[†]
This article is protected by copyright. All rights reserved.

10.1002/anie.201912803
Angewandte Chemie International Edition
RESEARCH ARTICLE
proceed via a shuttle catalysis[15] paradigm wherein a chemical
moiety is transferred between two stable organic molecules.
Accordingly, we sought a suitable catalytic system that could
enable an HCl molecule to be formally transferred between a
simple alkyl chloride and an alkyne without any direct use of
corrosive HCl. We initially explored reagents that are similar in
structure to those we employed in previous examples of shuttle
catalysis by reacting with a simple aliphatic terminal alkyne 1.[15]
We started our investigations with iridium catalysts because of
their expected high reactivity toward the oxidative addition of
C‒X bonds.[16] Unfortunately, both isobutyl chloride (table 1,
entry 1) and butyl chloride (table 1, entry 2) did not show any
reactivity probably due to the inertness of the C–Cl bond.
Interestingly, the use of tert-butyl chloride (2c) as the donor of
HCl was found to give trace amount of vinyl chloride product (3)
under these conditions (table 1, entry 3), however together with
some decomposition product. We next reasoned that the
installation of a polar group at a neighbouring position on the
reagent backbone could possibly facilitate the initial activation
step through either coordination of a metal and/or
electronic activation of the C–Cl bond. Through the evaluation of
several reagents and catalysts (see SI for the optimization), we
found 4-chlorobutan-2-one (2d), which contains an acyl group
on the β carbon relative to the chlorine atom, as a suitable donor
of HCI for the transfer hydrochlorination of pent-4-yn-1-
ylbenzene (1).
The ideal catalytic system for this transformation emerged as
a combination of [IrCl(cod)]2 as precursor and CPhos as a ligand
o
at 80 C in toluene, giving rise to 3 as a single regioisomer in
85% yield (table 1, entry 4). To the best of our knowledge, this is
the first example of an iridium-catalyzed hydrochlorination
reaction. Moreover, the alkene by-product, methyl vinyl ketone,
was obtained in 87% yield, a result which strongly suggests that
the reaction proceeds through shuttle catalysis. A similar
reagent 1-chloropentan-3-one (2e) also showed high reactivity
under the same conditions, leading to the vinyl chloride (3) in
75% yield (table 1, entry 5). Among those reagents bearing
various carbonyl groups, only the one containing a carboxylic
acid (2g) showed limited reactivity in this hydrochlorination
reaction, delivering the vinyl chloride (3) in 15% yield (table 1,
entry 7). As expected, the reagent which lacks β hydrogens did
not react under the conditions (table 1, entry 8). A reagent
bearing the acyl group on the γ carbon to the chlorine atom (2h)
was also tested in the reaction. However, only trace amount of
product was detected, which further demonstrated the beneficial
effect of the acyl group on the reactivity of the chloride reagent
(table 1, entry 9).
Table 1: Exploring the reagent for the transfer hydrochlorination of alkynes.[a]
Hydrochlorination using 4-chlorobutan-2-one. With 4-
chlorobutan-2-one (2d) as the optimized reagent, we then
moved to explore the substrate scope of this iridium-catalyzed
transfer hydrochlorination reaction. As illustrated in table 2, a
wide variety of alkyne derivatives could successfully undergo
hydrochlorination reaction using our system to give the
corresponding vinyl chlorides in good yield. Initially, we focused
on the evaluation of aliphatic terminal alkynes. A broad range of
functional groups including nitriles (8), chlorides (9), esters (10),
amines (12), nitro (16), aryl chloride (17) or aryl iodide (19),
fluorides (18), aldehyde (22) and ketone (29) were tolerated.
Likewise, α, β-unsaturated esters, which serve as an important
building block in organic synthesis, were tolerated under the
reaction conditions (15). Interestingly, a substrate bearing two
terminal
alkyne
moieties
could
undergo
successful
hydrochlorination reaction giving the product containing two vinyl
chloride moieties (7). To our delight, acid sensitive functional
groups such as tertiary alcohols (13), silyl ethers (14) and
acetals (23), which are usually not tolerated by other methods
employing hydrochloric acid as a reagent, remained untouched
during the reaction, showcasing the excellent functional group
tolerance of our methodology. Alkynes containing heterocycles
such as pyridine and thiophene reacted smoothly, leading to the
corresponding vinyl chlorides in 83% and 78% yield respectively
(20, 21). It is worth noting that alkynes derived from natural
products such as estrone and cholic acid could also be
efficiently converted to the corresponding vinyl chlorides in high
yields (29, 30), further demonstrating the diversity and
practicality of this novel protocol. An aromatic terminal alkyne
was subsequently evaluated and improved yield of product were
obtained using Ruphos as the ligand (24). Next, we were
pleased to find that slightly modifying our protocol, both a
[a] 1 (0.1 mmol), 2 (0.2 mmol), [IrCl(cod)]2 (2.5 mol%), CPhos
(7.5 mol%), toluene (0.25 mL) at 80 oC, 5 h. [b] NMR yields
using dibromomethane as an internal standard. [c] 2c (1.0
mmol), toluene (0.5 mL) at 110 oC, 12 h.
This article is protected by copyright. All rights reserved.

10.1002/anie.201912803
Angewandte Chemie International Edition
RESEARCH ARTICLE
symmetric diarylethyne (25) and an asymmetric internal alkyne
(26, 28) could be converted to the corresponding vinyl chlorides
in good selectivity. In the case of symmetric aliphatic internal
alkynes, excellent yield of product was obtained, but in a low Z/E
ratio of 64:36 (27). In contrast, an ester-substituted alkyne led to
product formation with high yield, regio- and stereoselectivity
(26).
synthetic applicability. Thus, the discovery of more sustainable
donors of HCl still remains highly significant. As shown in table 1,
the use of tert-butyl chloride as a donor of HCl can produce the
vinyl chloride product in trace amount under the conditions with
more equivalents of the reagent, higher temperature and longer
reaction time (table 1, entry 3). Encouraged by this result, we
moved to explore the reactivity of tert-butyl chloride in the
hydrochlorination of alkynes due to its higher availability and
lower price than 4-chlorobutan-2-one. Furthermore, the use of
tert-butyl chloride as a donor of HCl produces a non-toxic and
benign by-product, isobutene. After screening of reaction’s
conditions (see details in SI), we found the optimal system for
hydrochlorination reaction of internal alkynes using tert-butyl
chloride under ligand-free conditions with [IrCl(cod)]2 as a
Table 2: Scope of iridium-catalyzed transfer hydrochlorination of alkynes with
4-chlorobutan-2-one.[a]
o
catalyst at 110 C. A range of internal alkynes, either symmetric
or asymmetric, aliphatic or aromatic, activated or unactivated,
were successfully converted to the corresponding vinyl chlorides
in good to excellent yields even without using any external
ligands (Table 3, 26, 27, 31-37). Regarding the symmetric
internal alkynes, diarylethynes bearing either electron-donating
(32, 33) or electron-withdrawing groups (25, 34, 35, 36) were
well tolerated, reacting with tert-butyl chloride to give vinyl
chlorides in excellent yields with good E/Z selectivity. The
symmetric aliphatic internal alkyne also reacted to afford the
corresponding vinyl chlorides with high efficiency and moderate
Z/E ratio (27). Besides, some asymmetric internal alkynes also
showed good reactivity in the transformation, being converted to
the vinyl chlorides in good yields and selectivity (26, 28, 37).
Terminal alkynes, 5-phenyl-1-pentyne could also undergo
hydrochlorination to give the vinyl chloride in 42% yield (table 3,
3), albeit tris(pentafluorophenyl)phosphine is required to
successfully promote this transformation.
Table 3: Scope of iridium-catalyzed transfer hydrochlorination of alkynes with
tert-butyl chloride.[a]
[a] alkyne (0.2 mol), 2d (0.4 mmol, 2.0 eq.), [IrCl(cod)]2 (2.5
o
mol%), CPhos (7.5 mol%), toluene (0.5 mL) at 80 C, 5 h, given
as isolated yields. [b] 2d (4.0 eq.). [c] CPhos (15 mol%). [d]
[IrCl(cod)]2 (5 mol%), t-Bu-Xantphos (20 mol%), 12h. [e] Ruphos
(7.5 mol%), 12h. [f] 110 oC, 12h.
Hydrochlorination using tert-butyl chloride. Although the
method using 4-chlorobutan-2-one showed broad applicability
and enabled the hydrochlorination without the use of corrosive
reagent, its high price and the generation of highly reactive
methyl vinyl ketone as a by-product can possibly limit its
[a] alkyne (0.2 mol), 2c (2.0 mmol, 10.0 eq.), [IrCl(cod)]2 (2.5
This article is protected by copyright. All rights reserved.

10.1002/anie.201912803
Angewandte Chemie International Edition
RESEARCH ARTICLE
mol%), toluene (1.0 mL) at 110 oC, 12 h, given as isolated yields.
[b] tris(pentafluorophenyl)phosphine (7.5 mol%). [c] 5 h.
the amount of catalyst loading to 0.2 mol% with a TON of at
least 480. This demonstrates the simplicity, efficiency and the
synthetic value of this protocol.
Hydrobromination using tert-butyl bromide. Catalytic
hydrobromination of alkynes represents an efficient approach to
synthesize vinyl bromides. However, current conditions for this
process mainly rely on the use of corrosive and gaseous HBr or
in situ generated HBr,[17] which is not ideal for laboratory-scale
synthesis. Recently, an alternative method using a transfer
hydrofunctionalization strategy was reported by Lautens[18] and
Oestreich.[19] They achieved the hydrobromination of 1,6-enynes
or alkynes through the transfer of HBr from Et3N·HBr or 1-(2-
bromoethyl)-1,4-dihydro-1,1'-biphenyl. In this context, we were
delighted to see that our protocol for the transfer
hydrochlorination using tert-butyl chloride could also be applied
to the transfer hydrobromination using tert-butyl bromide as the
source of HBr. We then decided to evaluate the scope and the
potential of this transformation. As shown in table 4, an aliphatic
terminal alkyne could successfully undergo hydrobromination
reaction to give the branched vinyl bromide (48) in moderate
yield. Internal alkynes, including symmetric diarylethynes and
dialkylethynes and several asymmetric substrates, were also
converted to the corresponding vinyl bromides (38-47) in good to
excellent yield.
Scheme 2. Gram-scale experiments.
Mechanistic study
The lack of previously reported examples of iridium-
catalyzed hydrohalogenation reactions raises questions
regarding the mechanism of our processes. Thus, we became
interested in investigating the mechanism of our novel
methodologies performing both stoichiometric and catalytic
experiments. We started evaluating the reactivity of the iridium
catalyst, the phosphine ligand and the first reagent, 4-
chlorobutan-2-one (2d). After forming the Ir-phospine in situ,
which was confirmed by NMR spectroscopy, we added a
stoichiometric amount of 4-chlorobutan-2-one and monitored the
reaction over time and at different temperatures (see SI). Upon
heating at 80 oC, trace amount of methyl vinyl ketone was
Table 4: Scope of iridium-catalyzed transfer hydrobromination of alkynes with
tert-butyl bromide.[a]
observed together with formation of
a new phosphorous
compound which became the major product after 24 hours.
Unfortunately, despite our efforts, this product could not be
isolated. Interestingly, after 3 hours, trace amount of an Ir–H
species was observed (see SI) which, however, subsequently
disappeared upon further heating. Next, we investigated whether
a different behavior was taking place with the other class of
reagents, tert-butyl chloride and bromide. Reacting these
o
species at 80 C with [IrCODCl]2 led, this time, to a significant
formation of isobutene (see SI). In all the cases, no significant
amounts of Ir–H species were observed, raising questions about
the possible intermediacy and stability of such species under our
reaction conditions.
[a] alkyne (0.2 mol), 2j (2.0 mmol, 10.0 eq.), [IrCl(cod)]2 (2.5
mol%), toluene (1.0 mL) at 110 oC, 12 h, given as isolated yields. stoichiometric experiments, we wondered whether the reagent
As we could not gather further information from the
could just serve as a donor of HCl which then could be
oxidatively added to the iridium and generate the active
intermediate. Replacing our reagents, 4-chlorobutan-2-one or
tert-butyl chloride, with an HCl solution in ether, led to product
formation with similar conversion and yield (Scheme 3a).
Besides being a new synthetic method on its own, this result
suggests that both reactions could proceed through a similar Cl–
Ir–H intermediate. Interestingly, and in contrast to the normal
[b] tris(pentafluorophenyl)phosphine (7.5 mol%).
Application on preparative scale. To demonstrate the
robustness and applicability of those methodologies, we
performed several scale-up experiments (Scheme 2). To our
delight, both methods can be applied to a gram-scale synthesis
with high efficiency. Furthermore, in the specific case of the
methodology based on tert-butyl halide, we were able to reduce
This article is protected by copyright. All rights reserved.

10.1002/anie.201912803
Angewandte Chemie International Edition
RESEARCH ARTICLE
reaction conditions, the reaction with HCl could even be run at
room temperature in the absence of the phosphine ligand.
These results suggest that the most challenging (and slower)
part of the catalytic cycle in the shuttle process, the one which
requires higher temperature and an electron-rich phosphine
ligand or only higher temperature, is the activation of 4-
chlorobutan-2-one or tert-butyl halide by the iridium catalyst
(Scheme 3b). In order to test the thermal stability of those halide
reagents and any possible in situ formation of HCl, we
performed the reaction in the absence of the catalyst which
showed no significant conversion of either chlorobutan-2-one or
the tert-butyl halide as well as no formation of the desired vinyl
halide product. This result, combined with the high tolerance of
the reaction to acid-sensitive groups, makes the in situ
generation of significant amounts of free HCl highly unlikely
(Scheme 3c).
synthesized and subjected to the reaction conditions (Scheme
4a). Interestingly, a nearly equimolar mixture of the two possible
isomers was obtained with both methodologies. This result was
later confirmed by another labelling experiment wherein DCl was
employed with a non-labelled alkyne substrate, which led to the
formation of a similar ratio of both isomers. However, as
expected, the other isomer was formed as the major product
(Scheme 4b). While an initial Ir–H migratory insertion cannot be
excluded at this stage, the results obtained, combined with the
known propensity of Rh(III)–Cl and Ir(III)–Cl species to undergo
rapid M–Cl insertion into unsaturated substrates,[6t] support a
mechanism where an initial chloroiridation step occurs through
competing syn and anti-addition pathways. In further support of
this rationale, we treated the reaction with an exogenous source
of Cl anion (Scheme 4a). As expected, a significant change in
the observed ratio in favor of the anti-addition product was
observed.
Scheme 4. Deuterium-labelling experiments.
Finally, we performed an experiment using a fully deuterated
tert-butyl chloride (98% D) as the reagent to determine the level
of deuterium incorporation in the product (scheme 5a).
Interestingly, only 85% incorporation of deuterium in the product
was observed, probably as a result of a side reaction with the
COD ligand on the iridium catalyst. This side reaction might
proceed through rapid and reversible Cl–Ir–D insertion into the
alkene groups of COD, a process that could result in the loss of
deuterium. To get evidence for the side reaction, an experiment
using an equimolar mixture of diphenylacetylene and
cyclooctene as the substrate was performed (scheme 5b). As
expected, the deuterated cyclooctene was detected by
deuterium NMR, a result which suggests the presence of a short
lived Ir–D species under the catalytic reaction conditions.
Scheme 3. Control experiments.
In order to gain more information regarding the actual alkyne
addition step,
a deuterium-labelled alkyne substrate was
This article is protected by copyright. All rights reserved.

10.1002/anie.201912803
Angewandte Chemie International Edition
RESEARCH ARTICLE
Pathak, M. S. Sigman, Chem. Rev. 2011, 111, 1417; d) A. B. Dounay, L.
E. Overman, Chem. Rev. 2003, 103, 2945
[2]
[3]
a) K. C. Engvild, Phytochemistry 1986, 25, 781; b) G. W. Gribble, Acc.
Chem. Res. 1998, 31, 141; c) J. Kim, Y. Zhang, C. Ran, L. M. Sayre,
Bioorg. Med. Chem. 2006, 14, 1444.
a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457; b) A.Thakur, K.
Zhang, J. Louie, Chem. Commun. 2012, 48, 203; c) L. M. Geary, P. G.
Hultin, J. Org. Chem. 2010, 75, 6354; d) A. B. Lemay, K. S. Vulic, W. W.
Ogilvie, J. Org. Chem. 2006, 71, 3615; e) J. Choi, G. C. Fu, Science
2017, 356, DOI: 10.1126/science.aaf7230.
[4]
[5]
a) J. F. Hartwig, Acc. Chem. Res. 2008, 41, 1534; b) P. Ruiz-Castillo, S.
L. Buchwald, Chem. Rev. 2016, 116, 12564.
Scheme 5. Deuterium-labelling experiments.
a) S. Hirsl-Starcevic, Z. Majerski, J. Org. Chem. 1982, 47, 2520; b) J.
Kagan, S. K. Arora, M. Bryzgis, S. N. Dhawan, K. Reid, S. P. Singh, L.
Tow, J. Org. Chem. 1983, 48, 703; c) K. Takai, K. Nitta, K. Utimoto, J.
Am. Chem. Soc. 1986, 108, 7408; d) R. S. Al-awar, S. P. Joseph, D. L.
Comins, J. Org. Chem. 1993, 58, 7732; e) C. Muthiah, K. P. Kumar, S.
Kumaraswamy, K. C. Kumara Swamy, Tetrahedron 1998, 54, 14315; f)
K. Kamei, N. Maeda, T. Tatsuoka, Tetrahedron Lett. 2005, 46, 229; g)
A. Spaggiari, D. Vaccari, P. Davoli, G. Torre, F. Prati, J. Org. Chem.
2007, 72, 2216; h) W. Su, C. Jin, Org. Lett. 2007, 9, 993.
Conclusion
In conclusion, we have presented an iridium-catalyzed transfer
hydrohalogenation reaction which proceeds through a shuttle
catalysis strategy. The method uses chlorobutan-2-one as an
HCl surrogate, enabling this milder protocol to tolerate the
widest range of functional groups reported to date in a
[6]
a) H. Brown, T. Hamaoka, N. Ravindran, C. Subrahmanyam, V.
Somayaji, N. G. Bhat, J. Org. Chem. 1989, 54, 6075; b) S. Ma, X. Lu, Z.
Li, J. Org. Chem. 1992, 57, 709; c) K. Kokubo, K. Matsumasa, M. Miura,
M. Nomura, J. Org. Chem. 1996, 61, 6941; d) Z. Wang, X. Lu, Chem.
Commun. 1996, 535; e) R. Hua, S. Shimada, M. Tanaka, J. Am. Chem.
Soc. 1998, 120, 12365; f) A. Sun, X. Huang, Synthesis 2000, 2000,
1819; g) W. Yu, Z. Jin, J. Am. Chem. Soc. 2000, 122, 9840; h) M. Su,
W. Yu, Z. Jin, Tetrahedron Lett. 2001, 42, 3771; i) J. A. Mulder, K. C. M.
Kurtz, R. P. Hsung, H. Coverdale, M. O. Frederick, L. Shen, C. A.
Zificsak, Org. Lett. 2003, 5, 1547; j) A. Coelho, H. Novoa, O. M. Peeters,
N. Blaton, M. Alvarado, E. Sotelo, Tetrahedron 2005, 61, 4785; k) R.
Hua, S.-Y. Onozawa, M. Tanaka, Chem. Eur. J. 2005, 11, 3621; l) J.-H.
Li, S. Tang, Y.-X. Xie, J. Org. Chem. 2005, 70, 477; m) T. Kashiwabara,
K. Fuse, R. Hua, M. Tanaka, Org. Lett. 2008, 10, 5469; n) L. Feray, P.
Perfetti, M. P. Bertrand, Synlett 2009, 01, 89; o) T. Iwai, T. Fujihara, J.
Terao, Y. Tsuji, J. Am. Chem. Soc. 2009, 131, 6668; p) T. Wada, M.
Iwasaki, A. Kondoh, H. Yorimitsu, K. Oshima, Chem. Eur. J. 2010, 16,
10671; q) B. Wang, S. Wang, P. Li, L. Wang, Chem. Commun. 2010,
46, 5891; r) T. Kashiwabara, M. Tanaka, Adv. Synth. Cat. 2011, 353,
1485; s) Z. Lu, W. Kong, Z. Yuan, X. Zhao, G. Zhu, J. Org. Chem. 2011,
76, 8524; t) T. Iwai, T. Fujihara, J. Terao, Y. Tsuji, J. Am. Chem. Soc.
2012, 134, 1268; u) G. Zhu, D. Chen, Y. Wang, R. Zheng, Chem.
Commun. 2012, 48, 5796.
hydrochlorination reaction. Alternatively,
a protocol using
inexpensive tert-butyl chloride can be used with decreased
catalyst loadings. The latter transformation can also be
efficiently extended to hydrobromination reactions. In a broader
context, this work highlights both the possibility to use the shuttle
catalysis concept to elude the use of mineral acids, and the
previously untapped potential of iridium complexes to catalyze
hydrohalogenation reactions. Despite our extensive efforts, the
isolation of relevant catalytic intermediates was hampered by the
short life of those iridium species. Thus, further studies will be
necessary to unravel the mechanism of these novel catalytic
reactions.
Experimental Section
Experimental details and compound characterization are provided in the
supporting information.
[7]
[8]
For a review on catalytic C–halogen formation, see: D. A. Petrone, J.
Ye, M. Lautens, Chem. Rev. 2016, 116, 8003.
Acknowledgements
For an example of HCl-free alkene hydrochlorination, see: B. Gaspar, E.
M. Carreira, Angew. Chem. 2008, 120, 5842; Angew. Chem. Int. Ed.
2008, 47, 5758.
We thank the ERC (ShuttleCat, Project ID : 757608). Generous
funding from the Max-Planck-Society and the Max-Planck-
Institut für Kohlenforschung is acknowledged. We thank Prof. Dr.
Benjamin List for sharing analytical equipment and X-ray
departments of ETH Zürich (Dr. Nils Trapp) for technical
assistance. We also thank Dr. Sayanti Chatterjee for fruitful
discussion. P.Y. thanks the China Scholarship Council for a
scholarship.
[9]
S. Dérien, H. Klein, C. Bruneau, Angew. Chem. 2015, 127, 12280;
Angew. Chem. Int. Ed. 2015, 54, 12112.
[10] R. Ebule, S. Liang, G. B. Hammond, B. Xu, ACS Catalysis 2017, 7,
6798.
[11] J. Derosa, A. L. Cantu, M. N. Boulous, M. L. O’Duill, J. L. Turnbull, Z.
Liu, D. M. De La Torre, K. M. Engle, J. Am. Chem. Soc. 2017, 139,
5183.
[12] X. Fang, P. Yu, B. Morandi, Science 2016, 351, 832.
[13] P. Yu, B. Morandi, Angew. Chem. 2017, 129, 15899; Angew. Chem. Int.
Ed. 2017, 56, 15693.
Keywords: Iridium • Hydrochlorination • Hydrobromination •
[14] X. Fang, B. Cacherat, B. Morandi, Nat. Chem. 2017, 9, 1105.
[15] a) B. N. Bhawal, B. Morandi, ACS Catalysis 2016, 6, 7528; b) B. N.
Bhawal, B. Morandi, Chem. Eur. J. 2017, 23, 12004; c) D. A. Petrone, I.
Franzoni, Y. Ye, J. F. Rodriguez, A. I. Poblador-Bahamonde, M.
Lautens, J. Am. Chem. Soc. 2017, 139, 3546; d) S. K. Murphy, J.-W.
Park, F. A. Cruz, V. M. Dong, Science 2015, 347, 56; e) X. Wang, M.
Nakajima, E. Serrano, R. Martin, J. Am. Chem. Soc. 2016, 138, 15531;
Vinyl chloride • Shuttle catalysis
[1]
a) K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. 2005, 117,
4516; Angew. Chem. Int. Ed. 2005, 44, 4442; b) G. Evano, N.
Blanchard, M. Toumi, Chem. Rev. 2008, 108, 3054; c) R. Jana, T. P.
This article is protected by copyright. All rights reserved.

10.1002/anie.201912803
Angewandte Chemie International Edition
RESEARCH ARTICLE
f) M. D. Greenhalgh, S. P. Thomas, J. Am. Chem. Soc. 2012, 134,
11900; g) L. Ilies T. Yoshida; E. Nakamura, J. Am. Chem. Soc. 2012,
134, 16951.
[16] a) F. Cusmano Priolo, V. Marsala, G. Rizzardi, P. Vitarelli, Inorg. Chim.
Acta 1983, 76, L193; b) M. A. Bennett, G. T. Crisp, Aust. J. Chem. 1986,
39, 1363.
[17] a) F. Gao, A. H. Hoveyda, J. Am. Chem. Soc. 2010, 132, 10961; b) R. J.
Van Hoveln, S. C. Schmid, M. Tretbar, C. T. Buttke, J. M. Schomaker,
Chem. Sci. 2014, 5, 4763; c) M. R. Uehling, R. P. Rucker, G. Lalic, J.
Am. Chem. Soc. 2014, 136, 8799; d) X. Ma, S. B. Herzon, Chem. Sci.
2015, 6, 6250; e) M. Das, T. Kaicharla, J. F. Teichert, Org. Lett. 2018,
20, 4926; f) S. Hara, H. Dojo, S. Takinami, A. Suzuki, Tetrahedron Lett.
1983, 24, 731; g) A. Bunrit, S. Ruchirawat, C. Thongsornkleeb,
Tetrahedron Lett. 2011, 52, 3124; h) X. Chen, T. Chen, Y. Xiang, Y.
Zhou, D. Han, L.-B. Han, S.-F. Yin, Tetrahedron Lett. 2014, 55, 4572; i)
Y. Nishio, R. Mifune, T. Sato, S. Ishikawa, H. Matsubara, Tetrahedron
Lett. 2017, 58, 1190; j) Z. Li, R. Ebule, J. Kostyo, G. B. Hammond, B.
Xu, Chem. - Eur. J. 2017, 23, 12739.
[18] D. A. Petrone, I. Franzoni, J. Ye, J. F. Rodríguez, A. I. Poblador-
Bahamonde, M. Lautens, J. Am. Chem. Soc. 2017, 139, 3546.
[19] a) W. Chen, M. Oestreich, Org. Lett. 2019, 21, 4531; b) P. Orecchia, W.
Yuan, M. Oestreich, Angew. Chem. Int. Ed. 2019, 58, 3579; Angew.
Chem. 2019, 131, 3617; c) W. Chen, J. C. L. Walker, M. Oestreich, J.
Am. Chem. Soc. 2019, 141, 1135; d) J. C. L. Walker, M. Oestreich
10.1002/anie.201909852; e) S. Keess, M. Oestreich, Org. Lett. 2017,
19, 1898.
This article is protected by copyright. All rights reserved.

10.1002/anie.201912803
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents (Please choose one layout)
Layout 2:
RESEARCH ARTICLE
Peng Yu, Alessandro Bismuto and Bill
Morandi*
Page No. – Page No.
Iridium-Catalyzed Hydrochlorination
and Hydrobromination of Alkynes via
Shuttle Catalysis
This article is protected by copyright. All rights reserved.