Hydroalkylation of Alkenes Using Alkyl Iodides and Hantzsch Ester under Palladium/Light System

Article abstract of DOI:10.1021/acs.orglett.5b03238

The hydroalkylation of alkenes using alkyl iodides with Hantzsch ester as a hydrogen source occurred smoothly under a Pd/light system, in a novel, tin-free Giese reaction. A chemoselective reaction at C(sp³)-I in the presence of a C(sp²)-X (X = Br or I) bond was attained, which allowed for the stepwise functionalization of two types of C-X bonds in a one-pot procedure.

Full text of DOI:10.1021/acs.orglett.5b03238

Letter
pubs.acs.org/OrgLett
Hydroalkylation of Alkenes Using Alkyl Iodides and Hantzsch Ester
under Palladium/Light System
Shuhei Sumino and Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
S
* Supporting Information
ABSTRACT: The hydroalkylation of alkenes using alkyl iodides with Hantzsch ester as a hydrogen source occurred smoothly
under a Pd/light system, in a novel, tin-free Giese reaction. A chemoselective reaction at C(sp3)−I in the presence of a C(sp2)−X
(X = Br or I) bond was attained, which allowed for the stepwise functionalization of two types of C−X bonds in a one-pot
procedure.
focused on the use of Hantzsch ester, which has been used
successfully in radical reductions9 and glycosylations10 based on
photoredox catalysts such as Ir(ppy)3 and [Ru(bpy)3](BF4)2. In
this paper, we report that a palladium/light system worked well
to achieve the Giese-type reaction of alkyl iodides with
electron-deficient alkenes by introducing Hantzsch ester as a
hydrogen source.
As expected, under photoirradiation (SolarBox; 1500 W of
xenon lamp in a box, for details see the Supporting
Information) the reaction of iodocyclohexane 1a, ethyl acrylate
2a, and Hantzsch ester 3 in benzene in the presence of Et3N
and a catalytic amount of PdCl2 and PPh3 proceeded to give the
desired Giese addition product 4aa in a 30% yield (Scheme 2).
Without Hantzsch ester 3, the Giese product would not form.
he addition of radicals to alkenes is among the most basic
1
2−4
Tof radical reactions. The Kharasch and Giese reactions
both proceed with a radical chain composed of radical addition
to alkenes followed by SH2 reaction delivering halogen and
hydrogen, respectively. There has been a recent renewal of
interest in palladium-assisted radical reactions using alkyl
iodides5−7 whereby a SET (single electron transfer) process
from Pd(0) to alkyl iodides is typically proposed for the
generation of alkyl radicals/PdI radical pair as a first event.
Based on this concept, we previously developed a series of
cascade carbonylation reactions using alkyl iodides, CO, and
coupling reagents using a Pd/light combined system6 in which
CO trapping by alkyl radicals ultimately leads to the formation
of acylpalladium intermediates.8
We expected that such a Pd/light combined system would be
applicable even to a tin-free Giese reaction, as outlined in
Scheme 1. A key issue here was deciding what reagent would
work as a hydrogen source in the presence of a Pd complex. We
Scheme 2. Photoinduced Reductive Radical Addition of
Iodocyclohexane 1a to Ethyl Acrylate 2a
Scheme 1. Concept: Pd/Photoirradiation System for Tin-
Free Giese Reaction
Received: November 10, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b03238
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Letter
Changing the ligand from PPh3 to t-BuNC11 in benzene
improved the yield of 4aa to 71%. In the absence of a Pd
catalyst, t-BuNC, or LiCl, only a trace amount of 4aa was
observed. No reaction took place under thermal conditions (80
°C).
Table 1. Reaction of Alkyl Iodides 1 and Alkenes 2 under the
Pd/hν System
Table 1 demonstrates the general nature of the present
reductive alkylation of alkenes 2 by iodoalkanes 1 and Hantzsch
ester 3. A series of substituted α,β-unsaturated esters 2b−f were
examined (entries 2−6). The reaction of 1a with ethyl
crotonate 2b, dimethyl maleate 2d, and Me- and Ph-substituted
ethylidene malonate 2e and 2f gave the corresponding addition
products 4ab−af in moderate to good yields. In contrast, the
reaction of 1a with methyl methacrylate 2c gave 4ac in a rather
poor yield of 38% (entry 3). Other alkenes with an electron-
deficient group, such as ethyl vinyl ketone 2g, acrylonitrile 2h,
and phenyl vinyl sulfone 2i, also gave the alkylation products
4ag−ai in good yields (entries 7−9). The reaction of 1a with
cyclohexenone 2j gave the desired product 4aj in a modest
yield of 48% (entry 10). Irrespective of whether the alkyl
moiety of RI 1 was primary, secondary, or tertiary, the reaction
worked quite well (entries 11−16).
To confirm the intervention of radical species,12 radical
cascade reactions were examined (Scheme 3). The reaction of
Scheme 3. Radical Cascade Reactions Using 6-Iodo-1-
hexene 1g and (Iodomethyl)cyclopropane 1h
6-iodo-1-hexene 1g and 2a gave ethyl 4-cyclopentylbutanoate
4ga in 53% yield by way of 5-exo radical cyclization (Scheme 3,
eq 1). (Iodomethyl)cyclopropane 1g reacted with 2a to give
1,2-disubstituted cyclopentane 4ha in a 40% yield. In this
reaction, an initially formed cyclopropylcarbinyl radical under-
goes ring-opening to give a homoallyl radical,13 which then
adds to 2a to form an α-carbonyl radical. The 5-exo cyclization
and the addition of the resultant radical to the second molecule
of 2a followed by hydrogen abstraction from Hantzsch ester
gives the product 4ha (Scheme 3, eq 2). The syn/anti ratio of
4ha was nearly the same as that of a previously established
radical cyclization.4c
We then examined the chemoselectivity of the reaction using
alkyl iodides 1i and 1j with a haloaryl moiety (Scheme 4). The
alkylation reactions of 1i or 1j with 2a proceeded chemo-
lectively at the C(sp3)−I bond, leaving C(sp2)−X bonds for the
next functionalization (Scheme 4, eq 3). The crude products
4ia and 4ja were exposed to the standard conditions of
Suzuki−Miyaura raection without additional Pd, which gave the
a
Reaction conditions 1 (1 mmol), 2 (1.5 equiv), 3 (1.2 eqiuv), PdCl2
(5 mol %), t-BuNC (20 mol %), LiCl (20 mol %), Et3N (1.5 equiv),
C6H6 (10 mL), 16 h, hν (SolarBox (Xe, 1000 W/m2), Pyrex).
B
DOI: 10.1021/acs.orglett.5b03238
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Scheme 4. Chemoselective Reaction of 1i and 1j with Alkyl−
I and Aryl−X Moieties (X = Br, I)
Scheme 5. Proposed Reaction Mechanism
arylated products 5ia and 5ja, respectively (Scheme 4, eq 4).
Although the chemoselective reaction was achieved, moderate
yields of 4ia and 4ja, which are due to the side reactions of key
alkyl radicals to add to two molecules of ethyl acrylate and H-
abstraction from α-position to ether oygen, requires further
optimization of the reaction conditions. On the other hand, it
should be noted that GC−MS analysis of the crude reaction
mixture indicated that the reduction of the yields of 5 is partly
because of Pd-catalyzed aromatic reduction of 4ia and 4ja with
Hantzch ester remaining in the one-pot procedure.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03238.
■
S
Typical experimental procedure and characterization for
all products (PDF)
Whereas an appreciable byproduct of the reaction of 1b with
2a (Table 1, entry 11) was diester 7 (>10%), which
incorporated two molecules of ethyl acrylate 2a, octane 6, a
simple reduction product, was detected in only a trace amount
(Figure 1). This suggests that while a reduction of the adduct
α-carbonyl radical by Hantzsch ester is sluggish, that of the
parent octyl radical is far more sluggish.10a
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ryu@c.s.osakafu-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work has been supported by a Grant-in-Aid for Scientific
Research from the MEXT. S.S. acknowledges a Research
Fellowship of the Japan Society for the Promotion of Science
for Young Scientists.
Figure 1. Byproducts.
REFERENCES
■
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A plausible reaction mechanism is illustrated in Scheme 5.
First, alkyl radicals are generated by the reaction of alkyl iodides
and Pd(0) under photoirradiation via a SET process, which is
then added to olefins. The resultant radicals abstract hydrogen
at the 4-position of Hantzsch ester to give the products and a
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