Iron catalyzed methylation and ethylation of vinyl arenes

Article abstract of DOI:10.1039/c6sc04274k

Short alkyl chain Heck (type) reactions, especially methyl Heck reactions, are a difficult aspect of the alkyl Heck reaction. To provide a solution to this problem, iron-catalyzed methyl, ethyl and propyl Heck reactions were developed using readily available alkyl peroxides as alkyl sources. The reaction conditions were mild, clean, and easy to handle. No additive was needed, and no hazardous waste was generated. The products were obtained in up to 99% yield of one isomer for most situations. This reaction works for many types of olefin and tolerates a variety of functional groups. Several late-stage functionalizations of natural products and drug molecules were conducted to demonstrate the synthetic applications of this reaction.

Full text of DOI:10.1039/c6sc04274k

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Iron catalyzed methylation and ethylation of vinyl
arenes†
Cite this: DOI: 10.1039/c6sc04274k
*
Nengbo Zhu, Jianguo Zhao and Hongli Bao
Short alkyl chain Heck (type) reactions, especially methyl Heck reactions, are a difficult aspect of the alkyl
Heck reaction. To provide a solution to this problem, iron-catalyzed methyl, ethyl and propyl Heck
reactions were developed using readily available alkyl peroxides as alkyl sources. The reaction conditions
were mild, clean, and easy to handle. No additive was needed, and no hazardous waste was generated.
The products were obtained in up to 99% yield of one isomer for most situations. This reaction works for
many types of olefin and tolerates a variety of functional groups. Several late-stage functionalizations of
natural products and drug molecules were conducted to demonstrate the synthetic applications of this
reaction.
Received 24th September 2016
Accepted 15th November 2016
DOI: 10.1039/c6sc04274k
www.rsc.org/chemicalscience
The methyl group, which is so oen considered to be chemically stage methylation of heterocycles with peresters as methyl
inert, is able to signicantly alter the pharmacological proper- sources.31 Both examples mentioned above worked on the
ties of a molecule.1 The methyl group affects micromolecules methylation of arenes or heterocycles,34,35 rather than double
and biomacromolecules through stereoelectronic effects to bonds.
increase their potency against enzyme metabolism or changes
Many peresters and OO-tert-butyl (or pentyl) O-alkyl
in the physiochemical properties of bioactive compounds.2 The monopercarbonates (B) are commercially available. It would be
importance of the methyl group on arenes or heteroarenes is synthetically useful if a methyl Heck reaction based on these
widely recognized, whereas the importance of the methyl group non-ordinary methylation reagents was developed. Iron is one
in alkyl or vinyl chains is less well understood. In fact, methyl of the most important metals in nature.36–41 Many iron
groups in the alkyl chain or vinyl chain can profoundly affect compounds are observed to be essential components of
a bioactive compound's properties.2,3
The Heck reaction is
a powerful tool in chemical
synthesis.4–12 Aryl Heck reactions are well established whereas
alkyl Heck and alkyl Heck type reactions (for brevity, all Heck
reactions including Heck-type reactions are referred to as Heck
reactions), especially methyl Heck reactions are still chal-
lenging.13–23 Methyl hydrazine,24 methyl halides,13,14,25 and
silanes26 have been applied to solve this problem (Scheme 1).
Unfortunately, the methyl Heck reaction remains challenging
and there is no practical solution to this problem using readily
available methylation reagents.
Perester (A) and OO-tert-butyl (or pentyl) O-alkyl monop-
ercarbonate (B) are inexpensive chemical feedstocks commonly
used in industry as oxidants or radical initiators. These perox-
ides are rarely seen as alkylation reagents.27–33 Li and co-
workers29 developed a procedure for the methylation of aryl C–H
bonds using dicumyl peroxide as the methylation reagent, and
DiRocco and co-workers developed a procedure for the late-
State Key Laboratory of Structural Chemistry, Key Laboratory of Coal to Ethylene
Glycol and Its Related Technology, Fujian Institute of Research on the Structure of
Matter, University of Chinese Academy of Sciences, 155 Yangqiao Road West,
Fuzhou, 350002, P. R. China. E-mail: hlbao@irsm.ac.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6sc04274k
Scheme 1 Short chain alkylation of olefins.
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biological systems and have low toxicity in living systems. The reaction conditions and 65% of the isolated product was ob-
application of nontoxic iron catalysts in pharmaceutical related tained (entry 19). The product was obtained in 34% yield in the
chemistry is highly desired as it could reduce the risk of presence of HOTf (entry 20). There was no product generated
contamination by metal catalysts. Here, we report our work on without Fe(OTf)3 or under photoredox catalysis conditions
the methylation of double bonds with an iron catalyst. This iron (entries 21–22). The reaction conditions were mild, clean and
catalyzed unprecedented short alkyl chain Heck reaction of easy to handle, used a nontoxic catalyst and required no addi-
olens applies readily available peroxides (A, B, C) as the tives. This method is potentially useful due to its low cost and
alkylation reagents (Scheme 1). Type B peroxides are shown to environmental advantages.
be valuable alkyl electrophiles for the rst time.
Having identied the optimal conditions, we investigated
We commenced our study by screening metal catalysts for the reactivity of thirteen methylation reagents (Table 2, 6–18).
the reaction of p-tert-butyl-styrene 1 with commercially available The methylation product was obtained in up to an 87% yield.
tert-butyl peroxybenzoate (2) as the methylation reagent. Effective methylation reagent 13 is commercially available, and
Copper, nickel and palladium catalysts did not deliver the reagents 10–12 and 14–18 were easily made from t-butyl
methylation product in an effective way. Styrene 1 and benzoic hydroperoxide. Encouraged by these results, six ethylation
acid were the two major peaks observed using GC-MS (Table 1, reagents (19–24) and one propylation reagent (26) were
entries 1–4). To our delight, Fe(OTf)3 (10 mol%) promoted the synthesized and examined. Up to a 99% yield for ethylation and
reaction and afforded the product in 85% yield (entry 8). Study a 90% yield for propylation were obtained. Interestingly, an 81%
of the reaction temperature revealed that 80 ꢀC was optimal yield of an ethylation product was achieved with commercially
(entries 8–12). Solvent screening showed that THF and dioxane available reagent 26 (TMTETPN). It is worth noting that trans
were both suitable for this reaction (entry 16). When reducing olen was the only isomer observed. We found that peresters (A)
the usage of the catalyst from 10 mol% to 5 mol% in dioxane, are more reactive, while monopercarbonates (B) are milder and
the yield increased slightly (entry 17, 90% yield). The yield thus important for sensitive substrates (Table 3).
dropped to 36% when one equivalent of the catalyst was
Having established the reactivity of these three types of
employed (entry 18). Fe(OTf)2 was examined under the optimal peroxides in the presence of iron, we investigated the scope
Table 1 Reaction condition screeninga
Table 2 Scope of methylation, ethylation and propylation reagentsa
Entry
Metal (mol%)
Solvent
Temp. (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
Cu(OTf)2/10
CuBr/10
Pd(TFA)2/10
NiCl2/10
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
PhCH3
CH3CN
DMF
80
80
80
80
80
80
80
80
rt
40
60
80
80
80
80
80
80
80
80
80
80
rt
Trace
Trace
Trace
Trace
Trace
Trace
Trace
85
46
56
69
6
FeSO4$7H2O (10)
Fe(OAc)2 (10)
Fe(acac)3 (10)
Fe(OTf)3 (10)
Fe(OTf)3 (10)
Fe(OTf)3 (10)
Fe(OTf)3 (10)
Fe(OTf)3 (10)
Fe(OTf)3 (10)
Fe(OTf)3 (10)
Fe(OTf)3 (10)
Fe(OTf)3 (10)
Fe(OTf)3 (5)
Fe(OTf)3 (100)
Fe(OTf)2(5)
HOTf (15)
9
10
11
12
13
14
15
16
17
18
19
20
21
22d
—
21
70
80
DME
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
90 (85)c
36
65c
34
Trace
Trace
—
White LED light
a
Reactions were conducted with styrene (0.5 mmol), 2 (1.0 mmol),
b
catalyst and solvent (2 mL) at 80 ꢀC for 12 h. Yield of product
detected using GC.
c
d
Yield of isolated product.
5 mol% of
a
Yield of isolated product.
RuCl3(bpy)3 6H2O as photocatalyst.
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of the olens, which proved to be broad. Alkyl substituents was examined (Scheme 3). The reaction did not reach full
on the phenyl ring increased the yield to 80–95%, whereas conversion and it delivered ethyl Heck product 70 as a mixture
halogen substituents decreased the yield to 70–88%. Func- of E/Z isomers (E/Z ¼ 1.9 : 1) in 30% yield (25% of the starting
tional groups such as acetate, methoxyl, free carboxylic acid, material was recovered). Other simple olens suffer with the
boronic acid and amine were all tolerated. 2-Vinyl- same conversion and E/Z selectivity problems. This reaction is
naphthalene afforded products in reasonable yields. Impor- less ideal for non-conjugated olens.
tantly, dienes and enynes were suitable substrates for this
reaction, delivering the corresponding products in moderate Nagashima, Nakamura, and Neidig,43–46 a single electron
yields. transfer catalytic cycle involving iron complexes, that differs
Inspired by Fenton's reaction42 and the work of Bedford,
To exemplify the synthetic application of this method we only in one oxidation state, is proposed. Fe(OTf)3 is reduced
examined this reaction with regard to natural products and to iron(II). Iron(II) complex T-A transfers an electron to the
drug molecules. The late-stage modication of exemestane perester to form an iron(III) compound (T-B) and a methyl
60, an aromatase inhibitor used in the treatment of breast radical. The methyl radical reacts with styrenes to form
cancer, delivered the double bond shi product 61a and the a benzylic radical (T-C). The benzylic radical (T-C) is oxidized
normal product 61b in 61% yield (Scheme 2). The function- by the iron(III) species (T-B) to a carbocation (T-D) and
alization of trenbolone acetate 62 afforded derivative 63 in reforms the iron(II) species (T-A). The carbocation (T-D) then
a 41% yield. Remarkably, vinylestrone 64 delivered the ethyl undergoes deprotonation to deliver the desired product. To
Heck product 65 in a 91% yield. Simvastatin derivative 67 was support this proposed mechanism a radical trapping exper-
examined in this reaction. The site selectivity was good iment was conducted using NHPI (N-hydroxyphthalimide).
and the ethylation product 68 was obtained in 48% yield. The reaction was stopped and no desired product was
These examples demonstrate that this reaction is a useful observed, while radical adduct 71 was observed using GC-MS.
method to functionalize complex molecules in the late Thereaer, MeOH was added to the reaction to see whether it
stages.
would capture the carbon cation. Fortunately, methyl
To learn more about the reactivity information of this reac- ether 72 was isolated from this reaction in a 30% yield
tion with non-conjugated olens, natural product betulin 69 (Scheme 4).
Table 3 Scope of olefinsa
a
Reactions were conducted on a 0.5 mmol scale with Fe(OTf)3 (2.5–5 mol%) and THF or dioxane (2 mL) at 80 ꢀC for 12 h. Please see ESI for more
details. b 3 equiv. of HOTf was added as an additive.
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Scheme 2 Synthetic applications of natural products and drug molecules.
Acknowledgements
We thank NSFC (grant no. 21402200 and 21672213), Strategic
Priority Research Program of the Chinese Academy of Sciences
(Grant No. XDB20000000) and the 100 Talents Program, “The
1000 Youth Talents Program” for nancial support. We also
thank Professor Weiping Su, Zhongning Chen and Daqiang
Yuan from our institute for suggestions and help.
Scheme 3 Example of a non-conjugated olefin.
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In summary, we have developed a practical method for the
short chain alkylation of olens using readily available
peresters and monopercarbonates as alkylation reagents.
Many of these reagents are commercially available and the
others are easy to synthesize. The simple reaction conditions
and environmental benets of this catalytic system open up
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dienes, enynes, and complicated natural products or drug
molecules.
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