A transition-metal-free Heck-type reaction between alkenes and alkyl iodides enabled by light in water

Article abstract of DOI:10.1039/c5ob00515a

A transition-metal-free coupling protocol between various alkenes and non-activated alkyl iodides has been developed by using photoenergy in water for the first time. Under UV irradiation and basic aqueous conditions, various alkenes efficiently couple with a wide range of non-activated alkyl iodides. A tentative mechanism, which involves an atom transfer radical addition process, for the coupling is proposed.

Full text of DOI:10.1039/c5ob00515a

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A transition-metal-free Heck-type reaction
between alkenes and alkyl iodides enabled
Cite this: DOI: 10.1039/c5ob00515a
by light in water†
Received 15th March 2015,
Accepted 1st May 2015
Wenbo Liu, Lu Li, Zhengwang Chen and Chao-Jun Li*
DOI: 10.1039/c5ob00515a
www.rsc.org/obc
A transition-metal-free coupling protocol between various alkenes ling of the substrates bearing β-H by employing diverse metals
and non-activated alkyl iodides has been developed by using including Pd,8 Ni,9 Co,10 Zr11 and Cu.12
photoenergy in water for the first time. Under UV irradiation and
Pioneered by Fu’s group, the palladium-catalyzed Heck-type
basic aqueous conditions, various alkenes efficiently couple with a couplings involving alkyl halides were initially only successful
wide range of non-activated alkyl iodides. A tentative mechanism, for the intramolecular reactions, in which alkene insertion was
which involves an atom transfer radical addition process, for the expected to be faster than β-H elimination.8a In 2014, Alexa-
coupling is proposed.
nian’s group8c and Zhou’s group8d both developed a general
protocol to conduct the Heck coupling related to alkyl halides
through a palladium catalyst at the same time. However, in
their protocols, a special solvent (PhCF3) and a high tempera-
ture were required (>100 °C), which could limit the application
of these methods. Besides palladium, nickel was also
employed to mediate the Heck-type reaction related to alkyl
halides. In 2011, Jamison’s group9c reported a method to
directly couple benzyl chloride with simple olefins. The reac-
tion conditions were mild (room temperature) but the scope of
this reaction was restricted to benzyl chloride and required a
stoichiometric amount of a Lewis acid. In 2013, Lei’s group13
reported a nickel-catalyzed Heck-type reaction related to alkyl
halides, in which only activated secondary and tertiary bro-
mides (α-carbonyl bromide type compounds) could be success-
fully coupled. In 2006, Oshima’s group10d reported a cobalt-
catalyzed trimethylsilylmethylmagnesium-promoted radical
alkenylation of alkyl halides, one drawback of which was that a
stoichiometric amount of Grignard’s reagent was required to
activate the cobalt catalyst. In 2011, Carreira’s group14 reported
a cobalt-mediated protocol to couple alkenes with alkyl halides
without Grignard’s reagent, which was only applicable to intra-
molecular coupling. Besides transition metal catalysts, the
photo-redox catalysts were also brought into this area by Lei’s
group.15 Although this visible light-initiated investigation con-
tributed a new pathway to the Heck chemistry, the photo-redox
strategy was only capable of coupling alkenes with activated
halides such as benzyl bromide and α-carbonyl bromides,
which would pose some limitation expanding this protocol to
non-activated halides. Therefore, a more general, green, and
economical protocol to couple alkenes with alkyl halides
would be highly desirable.
Concern over synthetic efficiency and the increased reco-
gnition on sustainable green chemistry have provoked che-
mists to seek novel approaches for producing chemicals more
efficiently, cleanly, under milder conditions, and in an envir-
onmentally favourable fashion.1 Although applications of tran-
sition-metal-catalysis have generally been considered the most
salient breakthrough in modern synthetic chemistry in the
20th century, the issues related to removal of metal residues
and consumption of non-renewable expensive metals have
aroused misgivings in pharmaceutical and electronics indus-
tries. Transition-metal (depleting and precarious)2,3 free coup-
lings in water (a greener solvent)4 promoted by photons (a
cleaner energy input)5 provide tremendous opportunities
towards more sustainable synthetic chemistry.
The palladium-catalyzed Heck reaction is an important
organic synthetic tool to couple alkenes with aryl/vinyl halides
(or sulfonates), and plays an essential role in constructing C–C
bonds in modern organic chemistry. However, the seminal
Heck protocol is not applicable for the alkyl halides mainly
due to two reasons: the difficult oxidative addition and the
facile β-H elimination.6 Therefore, early Heck-type couplings
related to alkyl halides were focused on the alkyl halides
without β-H, such as benzyl halides.7 Despite these intrinsic
challenges, the last decade has witnessed the progress in coup-
Department of Chemistry and FQRNT Centre for Green Chemistry and Catalysis
(CCVC), McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8,
Canada. E-mail: cj.li@mcgill.ca
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob00515a
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Table 1 Optimization of the model reaction
Entry
Variation from standard conditions
Yielda
1
2
No change
No UV at 50 °C
99% (84%)
0%
3
No UV at 100 °C
0%
4b
5
Commercial photoreactor
NaOH instead of NaOtBu
NaHCO3 instead of NaOtBu
K3PO4 instead of NaOtBu
K2CO3 instead of NaOtBu
LiClO4 instead of water
8 equiv. cyclohexyl iodide
Distilled cyclohexyl iodide
60 mg (8 equiv.) NaOtBu
Triethylamine
TFE instead of H2O
CH3CN instead of H2O
MeOH instead of H2O
tBuOH instead of H2O
DMF instead of H2O
DMSO instead of H2O
0.5 mL H2O
<5%
74%
26%
57%
18%
17%
90%
98%
77%
23%
0%
40%
10%
<5%
<5%
0%
6
7
8
9c
10
11
12
13
14d
15
16
17
18
19
20
21
22
23
24
25
26
Scheme 1 (1) Classical Heck reaction involving aryl halides; (2) Heck
reaction involving alkyl halides catalyzed by various metals; (3) our work
on the coupling of alkenes and alkyl iodides without any transition
metals in water promoted by ultraviolet light.
40%
86%
8%
39%
<5%
0%
2.5 mL H2O
1 equiv. CuI
280 nm Optical filter
320 nm Optical filter
360 nm Optical filter
Under O2 atmosphere
Recently, we have reported a transition-metal-free protocol
to couple terminal alkynes with non-activated alkyl iodides in
water promoted by using UV light.16 Inspired by this work,
herein, we wish to report a transition-metal-free protocol to
couple alkenes with various non-activated alkyl iodides in
water promoted by UV under mild conditions. Our protocol
was greener (water was the sole solvent), efficient (most of the
substrates were consumed over 1 h) and mild (temperature was
<50 °C). More importantly, our protocol is transition-metal-
free, which not only avoids the consumption of expensive
palladium, toxic nickel or other transition metals, but also
eliminates the transition metal residue problem (Scheme 1).3
0%
a The reaction yield (combined yield of E/Z isomers) was determined
through GC analysis by using dodecane as an internal standard; the
isolated yield is in parentheses. b See the ESI for the details of this
photoreactor and the setup of the apparatus. c 1.3 mL saturated LiClO4
solution and 0.2 mL distilled water. LiClO4 was added to increase
the polarity of the solvent, which might affect the reaction. d TFE:
trifluoroethanol.
the base and the iodide. Therefore, to obtain a decent yield,
To commence our investigation, we selected 4-methoxy- we decided to use 10 equivalents of bases and iodides in the
styrene and cyclohexyl iodide for the model reaction. All the current study20 (entries 10 and 12). The concentration, as a key
parameters that have an impact on the reaction are listed in factor for a photochemical reaction, affected this reaction dra-
Table 1. Entries 2 and 3 showed the indispensability of UV. No matically. Either a very high concentration or very low concen-
product could be detected in the absence of UV even at a tration was detrimental to the yield (entries 20 and 21). To
higher temperature (100 °C). Use of various optical filters further exclude the potential influence of transition metals,
(entries 23–25) further validated that UV was crucial for this distilled cyclohexyl iodide21 was subjected to the standard con-
reaction and that the effective wavelength should be <320 nm. ditions, which did not bring any discrepancy in the reaction
A commercial photoreactor17 was not efficient enough to yield (entry 11). Furthermore, when 1 equivalent of CuI was
promote this reaction (entry 4). Screening of different in- added, the reaction yield decreased distinctively probably
organic bases demonstrated that NaOtBu was the optimum because the formed precipitate, i.e. Cu(OH), would disturb the
one18 (entries 5–8). Use of an organic base could also produce absorption of UV by the reactants. Finally, we found that O2
the desired coupling product although the yield was lower was pernicious to this reaction (entry 26), perhaps because O2
(entry 13). The addition of inorganic salt was not helpful to can initiate the styrene polymerization especially in the pres-
increase the reaction yield (entry 9). Concerning the solvent ence of UV light.
effect, aprotic polar and protic organic solvents were all less
With the optimized conditions in hand, the scope of
effective than H2O (entries 14–19). The amounts of cyclohexyl various alkenes and non-activated alkyl iodides was investi-
iodide and base were crucial to guarantee a good yield since gated. Regarding the alkenes, various types of styrene
the elimination reaction of alkyl iodides in water could be tre- derivatives could be coupled successfully, including styrene
mendously accelerated by UV light,19 which would consume derivatives with strong electron donating groups (3c, 3d, EDG,
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such as –OMe), strong electron withdrawing groups (3e, 3k, 3q,
EWGs, such as –CF3 and –F) as well as electron neutral groups
(3a, 3l, 3m). The styrene derivatives with EDGs (3c, 3d) pro-
duced better yields than those with EWGs (3e, 3k) due to the
fact that some reduction products could be formed for the
EWG bearing substrates (15–25%, please see the ESI†) besides
the desired Heck coupling products. Diverse functional groups
including –OMe (3a), –Cl (3o), –F (3q), –CF3 (3k) and –CN (3p)
on the styrene rings could be tolerated but aldehyde, ketone,
ester and –NO2 were not compatible with our current con-
ditions (not shown here) probably because of the interference
of UV as well as the strong basicity of the reaction conditions.
It was worthwhile to note that a non-styrene type conjugated
linear alkene (3g) could result in the desired product albeit
with a lower yield. Internal alkenes rather than terminal
alkenes show a more complex reactivity depending on the
steric hindrance of the substituents on the double bond. More
sterically hindered internal alkenes (please see ESI Fig. S5†)
could not give the desired products, while the less sterically
hindered internal alkenes (3n) could produce the desired
coupling products in a low yield under the standard con-
ditions. Moreover, 1-vinyl naphthalene (3i) could also work
efficiently. For the heterocyclic styrene type alkenes, although
4-vinylpyridine (3f) could result in a 10% yield, 2-vinylpyridine
and 1-vinylimidazole failed to couple with the iodides (please
see the ESI Fig. S5†). As to the scope of the alkyl halides, our
current protocol was only applicable to alkyl iodides instead of
alkyl chlorides and bromides. Among diverse alkyl iodides,
Table 3 Scope of the various alkyl iodides
both primary alkyl iodides and secondary alkyl iodides could
be coupled successfully while tertiary alkyl iodides failed. Gen-
erally speaking, secondary alkyl iodides behaved better than
primary iodides and cyclic secondary alkyl iodides produced
the best yields among all the alkyl iodides (Tables 2 and 3).
To gain more insight into the reaction mechanism, we con-
ducted further mechanistic investigations. When cyclopropyl-
methyl iodide was subjected to the standard conditions, only
the cyclopropyl ring opening product (2a in Scheme 2a) could
be isolated, while the direct coupling product (2e in
Scheme 2a) could not be detected at all. This radical clock
control experiment clearly confirmed the existence of a radical
intermediate. Besides the radical clock investigation, we also
attempted to use (2,2,6,6-tetramethylpiperidin-1-yl)oxyl
(TEMPO) to trap the radial intermediates. After carefully scruti-
nizing the GC trace, we were able to detect the signal of the
trapped radical intermediate (2b in Scheme 2b). Besides these,
the formation of the reduced byproduct 2d along with the
desired coupling product could shed more light on the mech-
anism (vide infra).
Table 2 Scope of the various alkenes
Combining all the observations mentioned above, we pro-
posed the following mechanism in Scheme 3 to rationalize
this reaction. The C–I bond underwent homolytic cleavage
under the irradiation of UV, resulting in a radical pair of
carbon and iodine.22 Addition of the carbon radical (4b) to the
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Conclusions
In summary, we have developed a transition-metal-free metho-
dology to couple alkenes with non-activated alkyl iodides (the
Heck-type reaction) in water induced by UV for the first time,
although there are still some limitations in our protocol such
as the requirement of a large amount of base and alkyl iodides
as well as the narrow scope of alkenes (mainly suitable for
styrene derivatives). Further efforts will be devoted to reduce
the amount of base and alkyl iodides, and to expand the sub-
strate scope.
Acknowledgements
We are grateful to the Canada Research Chair (Tier 1) Foun-
dation, FQRNT (CCVC), CFI and NSERC for supporting our
research.
Scheme 2 Some control experiments conducted to probe the
mechanism.
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17 Please see the ESI† for the details of the photoreactor and 23 The H source may be the alkyl iodides or the styrene while
the 300 Watts Xenon Lamp we used in the research.
18 We are not totally clear why NaOBu is better than NaOH
since NaOBu would be converted into NaOH in water. One
it is not likely to be the solvent water given the fact that
H–O bond energy (119 kcal mol−1) is higher than that of
C–H (104 kcal mol−1).
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