Palladium-Catalyzed Regioselective C-H Iodination of Unactivated Alkenes

Article abstract of DOI:10.1021/jacs.9b03998

A palladium-catalyzed C-H iodination of unactivated alkenes is reported. A picolinamide directing group enables the regioselective functionalization of a wide array of olefins to furnish iodination products as single stereoisomers. Mechanistic investigations suggest the reversible formation of a six-membered alkenyl palladacycle intermediate through a turnover-limiting C-H activation.

Full text of DOI:10.1021/jacs.9b03998

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Communication
Palladium-Catalyzed Regioselective C–H Iodination of Unactivated Alkenes
Benedikt Schreib, and Erick M Carreira
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 14 May 2019
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Palladium-Catalyzed Regioselective C–H Iodination of Unactivated
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Benedikt S. Schreib, Erick M. Carreira*
ETH Zꢀrich, Vladimir-Prelog-Weg 3, HCI, 8093 Zꢀrich, Switzerland
Supporting Information Placeholder
simplest class of precursors for alkenyl iodides would be the corre-
ABSTRACT: A palladium-catalyzed C–H iodination of unacti-
sponding olefin. However, only few examples for the direct C–H
iodination of olefins have been reported in the literature (Scheme
2A).10-13 Synthetically useful methods of this type are limited to the
functionalization of Michael acceptors, and the most commonly
employed approach is the nucleophile-catalyzed iodination of cy-
clic enones. More recently, Glorius and co-workers have reported
the rhodium- or cobalt-catalyzed alkenyl C–H iodination of acryla-
mides.11 However, general methods for the direct and regioselec-
tive C–H iodination of unactivated olefins remain elusive, yet
highly desirable.
vated alkenes is reported. A picolinamide directing group enables
the regioselective functionalization of a wide array of olefins to fur-
nish iodination products as single stereoisomers. Mechanistic in-
vestigations suggest the reversible formation of a six-membered
alkenyl palladacycle intermediate through a turnover-limiting
C–H activation.
The selective transformation of C–H bonds has been a long-
standing goal in organic synthesis.1 The functionalization of unbi-
ased and unactivated hydrocarbons with high positional selectivity
remains a challenging problem, and possible overfunctionalization
often necessitates use of substrates in excess, even as solvent.2a Co-
ordinating groups which direct a metal to the desired site of func-
tionalization have emerged as a powerful tool to overcome these
issues.2 While palladium-catalyzed, direct activation of aromatic
and aliphatic C–H bonds has been at the forefront of this develop-
ment,3 reports of olefinic C–H functionalization have not enjoyed
the same level of development.4,5 Herein, we report a palladium-
catalyzed, picolinamide directed alkenyl C–H functionalization to
access the corresponding alkenyl iodides with excellent regio- and
stereoselectivity (Scheme 1).
Scheme 2. Prior Art and Challenges
Scheme 1. Palladium-Catalyzed Alkenyl C–H Iodination
Palladium catalysis offers a powerful tool for the halogenation
of hydrocarbons, and it has been explored for the iodination of
arenes and aliphatic hydrocarbons.14 Yet, a palladium-catalyzed C–
H iodination of olefins has not been documented. The use of palla-
dium for the direct iodination of alkenes is complicated by compet-
ing reactivity, such as palladium-catalyzed allylic oxidation,15
Wacker-type nucleopalladation,16 or Heck-type reactions17
(Scheme 2B). Additionally, significant undesired background reac-
tivity, such as olefin diiodination or competing electrophilic aro-
matic iodination can take place under the oxidizing conditions typ-
ically employed for iodination reactions. To address these reactiv-
ity challenges, we envisioned a chelation assisted cyclopalladation
strategy, which would enable the direct selective iodination of un-
activated olefins. We surmised that picolinamides may function as
Alkenyl iodides constitute a valuable class of building blocks
that are routinely used in organic synthesis.6,7 Commonly employed
methods for the synthesis of alkenyl iodides include Barton or
Takai olefination of the corresponding carbonyl compounds, metal-
lation-iodination sequence of acetylenes, or the Hunsdiecker reac-
tion on α,β-unsaturated carboxylic acids.8,9 However, the success-
ful implementation of these established methods can be hampered
by poor regio- and stereoselectivity, and it often necessitates the
use appropriately functionalized starting materials. Arguably the
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a suitable directing group, owing to their ability to facilitate the for-
electron deficient 2,6-dichlorostyrene 1k undergoing iodination
with comparable yields (83 and 85%).
mation of 6-membered alkenyl-palladacycles 3 through a concerted
metallation-deprotonation (CMD) pathway,18 as demonstrated by
He5h and Engle4 (Scheme 2C). Subsequent reaction with an elec-
trophilic iodine source is envisioned to afford alkenyl iodide 2 with
retention of olefin configuration, either through a redox-neutral
electrophilic cleavage pathway or a stepwise oxidative addition/re-
ductive elimination mechanism.19
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Table 1. Selected Optimization Resultsa
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We set out to identify optimal reaction conditions using (Z)-5-
phenylpent-4-en-1-amine derived olefin 1a as model substrate,
which bears the bidentate picolinamide directing group. Originally
introduced by Daugulis, picolinamides are conveniently prepared
from inexpensive picolinic acid, and can be readily cleaved through
hydrolytic or reductive procedures.20,21 After evaluating a wide ar-
ray of reaction parameters, we found that a system comprising of
palladium acetate (10 mol%), pivalic acid (1.0 equiv), and the com-
bination of tetrabutylammonium iodide (1.3 equiv) and di-(pivalo-
yloxy)iodobenzene (1.3 equiv) as oxidative iodinating agent in
aqueous acetonitrile afforded the desired alkenyl iodide 2a in 64%
isolated yield (Table 1, entry 1). The olefin configuration was re-
tained, as evidenced by NOESY experiments. The major side prod-
ucts included the formation of a regioisomeric mixture of the cor-
responding enol pivalates, which may form either through oxida-
tion of palladacycle 3 or Wacker-type pathways. The combination
of an iodide salt and an oxidizing agent proved to be more efficient
than common electrophilic iodinating reagents such as N-iodosuc-
cinimide (entries 2 and 3). Initial attempts to achieve bromination
or chlorination under similar conditions were unsuccessful.
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Variation from “standard condi-
Entry
Yieldb
tions”
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6
None
70 (64c)
<10
63d
<15e
56c,e
60c,e
NIS, MeCN, 70 °C
Oxone, MeCN, 70 °C
Directing group B-E
Directing group F
Directing group G
Complex
mixture
26c,e
7
Directing group H
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9
Directing group I
No Pd
0
10
No water, 70 °C
60
A screening of picolinamide derivatives showed that substitution
adjacent to the aromatic nitrogen is not tolerated (entry 4). Of note,
quinoline containing directing group B showed modest selectivity
for the undesired C–H oxidation products (ca 60% NMR yield).
Only traces of the iodination product were formed when pyridine
N-oxide-containing directing group E – a potential side-product
under the oxidizing reaction conditions – was employed (entry 4).
Using pharmaceutically relevant pyrazine F and β-carboline G5j as
directing groups furnished the corresponding alkenyl iodides in
56% and 60% isolated yields, respectively (entries 5, 6). When the
corresponding 4-pentenoic acid derived substrate bearing well-es-
tablished 8-aminoquinoline directing group H20 was subjected to
our standard conditions, a complex mixture of products was ob-
tained (entry 7). Employing Shi’s PIP directing group I22 allowed
for isolation of the desired vinyl iodide in 26% yield (entry 8),
demonstrating that the iodination of 4-pentenoic acids is possible.
a Reactions conducted on 0.2 mmol scale. b Determined by 1H NMR
analysis of the unpurified reaction mixture. c Isolated yield after pu-
rification. d 15 mol% Pd(OAc)2. e 0.1 mmol scale.
As a control experiment, in the absence of palladium catalyst
alkenyl iodide 2a was not observed (entry 9). The reactions de-
scribed in Table 1 are conducted in aqueous acetonitrile as solvent
under ambient atmosphere, and execution of the reaction under in-
ert atmosphere (dry N2) has no impact on the yield. The use of an-
hydrous acetonitrile decreases slightly the yield of 2a (70 vs 60%)
and leads to an increased amount of enol pivalate formation, as de-
termined by NMR (entry 10).
It is worth noting that the trans-isomer of 1j did not show any re-
activity under these conditions, with the starting material being re-
covered. Introduction of a branching substituent at the tether was
unfavourable to the reaction outcome and methyl substituted prod-
uct 2m was isolated in 45% yield. The robustness and scalability of
this protocol was demonstrated through the iodination of 1i on a
1 mmol scale, which afforded the desired product 2i in 75% yield,
even when the catalyst loading was lowered to 5 mol%.
With optimal conditions in hand, we explored the scope of the
directed C–H iodination reaction (Scheme 3). Changing the phenyl
substituent for a larger 2-naphthyl had a negligible effect on the
reaction outcome and 2b was afforded in 63% yield. Styrenes car-
rying electron-neutral or electron-withdrawing substituents in the
meta or para positon were well tolerated and furnished the desired
alkenyl iodide in 57 to 72% yield (2d–2h). Notably, substrates con-
taining an oxidation sensitive benzaldehyde (1d) or an aryl bromide
(1h) undergo iodination successfully in 66 and 72% yield, respec-
tively. Increasing steric bulk at the ortho-position of the arene
proved beneficial for the reaction, affording the desired products in
75 to 85% yield (2i–2l). The electronic nature of the arene only has
a minor influence, with electron rich 2,6-dimethylstyrene 1j and
During the investigations on the substrate scope of the directed
C–H iodination, cyclohexyl substituted olefin 1p was found to ox-
idize to a mixture of enol pivalate and ketone side-products. Thus,
re-evaluation of the reaction conditions revealed inexpensive Ox-
one to be an efficient oxidant in anhydrous acetonitrile, providing
2p in 67% isolated yield. Under these conditions the remaining ma-
terial was identified as starting material and enol-pivalate side-
products. A variety of aliphatic disubstituted olefins
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Scheme 3. Scope of the Alkenyl C–H Iodinationa
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a Reactions were conducted on 0.3 mmol scale unless indicated otherwise. Yields refer to the isolated product after purification. b Yield
determined by 1H NMR analysis of the unpurified reaction mixture. c Reaction was conducted in anhydrous acetonitrile at 70 °C, using 1.3
equiv of Oxone instead of PhI(OPiv)2 and 15 mol% Pd(OAc)2. d 20 mol% Pd(OAc)2. e Reaction was conducted in anhydrous acetonitrile at
70 °C. f Reaction was conducted on a 0.1 mmol scale.
underwent iodination in moderate yields under these conditions
(2n–2q, 55–67%). The yield of the reaction drops dramatically for
unbranched alkyl substituents. Boc-protected amines are tolerated
under the acidic reaction conditions and vinyl-piperidine 1q under-
went iodination in 55% yield. Substituted cyclohexene 2q show-
cases that selective iodination at the sterically less accessible C–H
of the olefin is possible in 48% yield. Switching the oxidant from
di-(pivaloyloxy)iodobenzene to Oxone also enabled the iodination
of electron rich styrene 1c in 60% yield, which had decomposed
under the previous conditions.
instead of exocyclic in the putatively operating palladacycle inter-
mediate 3. While an aqueous solvent system was found to be detri-
mental for the reaction outcome, the desired iodocyclohexene 2x
was obtained in 48% yield in anhydrous acetonitrile with di-
(pivaloyloxy)iodobenzene as oxidant. This result showcases that
trisubstituted olefins are suitable substrates for the reaction. Similar
to the styrenes discussed above, an increase in steric bulk around
the olefin proves beneficial, as demonstrated by the increased
yields for (R)-(–)-nopol derived product 2y (66%) and (1R)-(+)-
camphor derived product 2z (83%). No rearrangement of the vinyl-
cyclobutane 1y and the norbornene skeleton in 1z were observed
during the iodination reaction. This stands in contrast to the classi-
cal Barton vinyl iodide synthesis on camphor, where 1-iodocam-
phene is obtained after a Wagner-Meerwein rearrangement of the
proposed iodocarbonium intermediate.23
Importantly, all olefins subjected to iodination conditions af-
forded the alkenyl iodide as a single regioisomer, as determined by
1H-NMR analysis of the crude reaction mixture. To further assess
the selectivity imparted by the directing group, we evaluated sev-
eral substrates bearing additional olefins and alkynes. The C–H io-
dination reaction allows for a highly regioselective functionaliza-
tion of polyenes, as demonstrated by non-conjugated diene 2s and
phenylbutadiene derivative 2t, which were obtained in 56 and 49%
yield, respectively. In addition, (S)-(–)-perillaldehyde derived tri-
ene 2u (56%) and (1R)-(–)-myrtenal derived diene 2v (50%) were
obtained as single regio- and diastereoisomers.
To demonstrate the synthetic versatility of the alkenyl iodides we
subjected 2a to a variety of transformations (Scheme 4). The pico-
linamide auxiliary can be easily removed through a one pot Boc-
activation/hydrolysis sequence, affording Boc-protected amine 4 in
89% yield. Intramolecular Ullman amidation using Buchwald’s
conditions24 yields pyrrolidine derivative 5 (93%). Despite the
strongly coordinating picolinamide auxiliary, palladium catalyzed
alkylation and alkynylation readily furnish 1,3-dioxane 6 and TMS-
alkyne 7 in 87 and 91% yield, respectively.
In order to explore substrates bearing a shorter tether (cyclohex-
enyl)ethylamine derived substrate 1x was subjected to the io-
dination conditions. This would require the olefin to be endocyclic
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To probe the mechanism of the reaction β-substituted styrene 1k
was treated with pivalic acid (1 equiv) and Pd(OAc)2 (10 mol%) in
CD3CN/D2O 4:1 at 90 °C. After 6 hours selective
(a) Pd(OAc)2 (10 mol%), PhI(OPiv)2 (1.3 equiv), [nBu4N+]I– (1.3
equiv), MeCN, 70 °C; see Supporting Information for detailed ex-
perimental procedures.
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Scheme 4. Derivatization of 2a
In summary, we developed a regio- and stereoselective palla-
dium catalyzed C–H iodination of unactivated alkenes tolerating a
wide variety of alkyl and aryl substituted olefins bearing various
functional groups. The robust and operationally convenient proce-
dure is enabled by a picolinamide auxiliary and mechanistic inves-
tigations demonstrate that the reaction proceeds via an alkenyl C–
H activation as turnover limiting step. This method complements
existing methods for the regio- and stereoselective synthesis of
highly functionalized olefins.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website. Experimental procedures and characteriza-
tion data (PDF).
Reagents and conditions: (a) Boc2O (8 equiv), DMAP (1 equiv),
MeCN, 50 °C, 24 h, then aq LiOH, 50 °C, 3 h; (b) CuI (20 mol%),
1,2-bis(methylamino)ethane (40 mol%), Cs2CO3 (1.5 equiv), THF,
50 °C, 90 min; (c) Pd(PPh3)4 (10 mol%), (2-(1,3-dioxan-2-
yl)ethyl)zinc(II) bromide (3 equiv, 0.5 M in THF), THF, 50 °C, 4
h; (d) Pd(PPh3)4 (10 mol%), ethynyltrimethylsilane (3 equiv), lith-
ium diisopropylamide (3 equiv), ZnBr2 (3.3 equiv), THF, 50 °C, 2
h.
AUTHOR INFORMATION
Corresponding Author
*erickm.carreira@org.chem.ethz.ch
deuterium incorporation at the β-carbon was observed (>95% D),
which is consistent with reversible formation of palladacycle 3
(Scheme 5). Notably, this result demonstrates the synthetically use-
ful, efficient and highly selective β-deuteration of styrenes enabled
through this method. Measurement of the initial rate constant for
the iodination of 1k and 1k-D1 in two parallel reactions, as well as
an intermolecular competition experiment, provided a kH/kD value
of 3.4 and 3.3 respectively, showing that C–H cleavage is the turn-
over-limiting step of the reaction.25 The magnitude of the observed
kinetic isotope effect is in the expected range for a C–H bond cleav-
age based on a CMD mechanism.26
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
ETH Zꢀrich is gratefully acknowledged for financial support. We
thank Dr. M.-O. Ebert, R. Arnold, R. Frankenstein, and S.
Burkhardt for NMR measurements. Simon L. Rössler and Dr. Da-
vid A. Petrone (all ETH Zürich) are thanked for helpful discus-
sions.
Scheme 5. Mechanistic Investigations
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