Iron-Enhanced Reactivity of Radicals Enables C-H Tertiary Alkylations for Construction of Functionalized Quaternary Carbons

Article abstract of DOI:10.1021/acscatal.8b04872

Iron is one of the most attractive catalysts, especially for aromatic C-H functionalizations. However, stoichiometric amounts of oxidants and strong carbanions are required, and C-H tertiary alkylation, especially with electron-deficient alkyl groups, is unexplored. In this paper, we describe the development of iron-catalyzed selective C-H tertiary alkylations with heteroaromatics, in which an iron salt acts as a single-electron source and enhances the reactivity of a tertiary alkyl radical generated from α-bromocarbonyl compounds. Our established methodology was demonstrated in the efficient synthesis of various quaternary carbon atoms under very simple conditions.

Full text of DOI:10.1021/acscatal.8b04872

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Article
Iron-Enhanced Reactivity of Radicals Enables C–H Tertiary
Alkylations for Construction of Functionalized Quaternary Carbons
Yu Yamane, Kohei Yoshinaga, Michinori Sumimoto, and Takashi Nishikata
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 15 Jan 2019
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Iron-Enhanced Reactivity of Radicals Enables C–H
Tertiary Alkylations for Construction of
Functionalized Quaternary Carbons.
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Yu Yamane, Kohei Yoshinaga, Michinori Sumimoto, and Takashi Nishikata*
Graduate School of Science and Engineering, Yamaguchi University, Ube, Yamaguchi, 755-
8611, Japan
Iron• SET • C-H alkylation • Tertiary-alkyl group • Radical
ABSTRACT. Iron is one of the most attractive catalysts, especially for aromatic C–H
functionalizations. However, stoichiometric amounts of oxidants and strong carbanions are
required, and C–H tertiary alkylation, especially electron deficient alkyl groups, is unexplored. In
this paper, we describe the development of iron-catalyzed selective C–H tertiary alkylations with
heteroaromatics, in which an iron salt acts as a single-electron source and enhances the reactivity
of a tertiary alkyl radical generated from α-bromocarbonyl compounds. Our established
methodology was demonstrated in the efficient synthesis of various quaternary carbon atoms under
very simple conditions.
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INTRODUCTION
The synthesis of quaternary carbon atoms is one of the central issues in organic synthesis because
the reaction to construct quaternary carbon atoms suffers from the problem of steric hindrance.
Although many challenges in the synthesis of complex molecules have been studied so far,1,2 the
reported methods do not allow the efficient synthesis of functionalized quaternary carbon atoms.
In this context, transition-metal-catalyzed reactions are one of the most attractive methodologies
to synthesize carbon quaternary centers.2 For these reactions, iron catalysts have received
considerable attention3 owing to their environmentally benign nature, their inexpensive cost, and
the abundance of elemental iron.4
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Although the possible iron-catalyzed C–H transformations employ excess Grignard reagent and/or
an oxidant,3 iron [Fe(0)]5 and some Fe(II) complexes6 have been known to promote redox-type
radical addition reactions through the activation of carbon–halogen bonds. On the other hand, iron-
catalyzed reactions involving a redox system are widely used in atom-transfer radical
polymerization chemistry,7 but the chemistry to construct all carbon quaternary centers through
C–H bond transformation has not yet been established.8 Generally, a radical species generated
from the reaction of an alkyl halide and an iron salt has limited reactivity or too much reactivity
for the substrates; specific organic halides, such as poly-halogenated compounds, are applicable
to the reaction.8 Therefore, the possible variations of the reaction and the structures of the products
are limited. This subtle phenomenon is still somewhat controversial3,8 but could be one explanation
for the limited development of iron-catalyzed organic reactions. Overall, a number of issues in
iron-catalyzed C–H bond transformations remain to be addressed, including (1) functional group
tolerance, (2) reaction varieties, (3) C–C formations via single-electron transfer (SET) process,
and (4) the synthesis of quaternary carbon atoms.
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The main strategy to transform C–H bonds by using an iron catalyst requires directed oxidative
addition or a concerted metalation–deprotonation (CMD) process in the presence of excess
Grignard reagent and oxidant (Figure 1a).9,10 On the other hand, our strategy is to use a radical
process by single-electron transfer, in which quaternary carbon atoms can be synthesized without
special additives (Figure 1b). Recently, there have been some reports of C–H radical alkylation
reactions in the presence of Ru or Cu catalysts with/without photoirradiation, but related iron-
catalyzed reactions to load tertiary alkyl groups for the synthesis of quaternary carbon atoms
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a. Previous strategy
"Fe"
DG
R
DG
R-X
DG
H
Ar
Ar
Ar
RMgX
Oxidant
"Fe"
DG
DG
Y=[N], O
Ar=
Y
C-H transformation process
CMD, Oxidative addition
Additives (RMgX)
Enhanced
reactivity
b. This work
FeIII
FeII
CO2R
HetAr H
CO2R
X
HetAr
CO2R
SET
Our strategy
Enhanced radical process
4° carbon
No additives
Figure 1. Strategies for the transformation of C–H bonds. DG: directing group.
are rare.11,12 During the course of our copper-catalyzed transformation studies using α-
bromocarbonyl compounds,13 we found that an iron catalyst is also effective to generate tertiary
alkyl radicals from α-bromocarbonyl compounds for C–H tertiary alkylation reactions.14 In this
reaction, FeII abstracts Br from the α-bromocarbonyl compound, resulting in the formation of an
alkyl radical and a higher oxidation state FeIII complex. We expect that the FeIII complex could
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enhance the radical reactivity due to the coordination to the carbonyl group of the resulting alkyl
radical. As the result, efficient C–H tertiary alkylation could be accomplished. Herein, we disclose
the iron-enhanced reactivity of tertiary alkyl radicals for heteroaromatic or vinylic C–H alkylations
to construct all carbon quaternary centers.
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RESULTS AND DISCUSSION
Heteroaromatic C-H Tert-Alkylations. Optimization studies employed the combination of
ethyl 2-bromoisobutyrate (1a, 1 equiv) and benzofuran (2a, 1.5 equiv) in the presence of an Fe
catalyst (5 mol%), and a base (2 equiv) at 110 °C (Table 1). The reaction with iPr2NEt gave 2-
alkylated product 3a in 45% yield, but the reaction without the Fe catalyst did not proceed (Table
1, entries 1 and 2). Other catalysts, such as Fe(OAc)2, Fe(OTf)2, CuI and PdCl2, were not effective.
The reaction was selective and no regioisomers were obtained, unlike the results in previous
reports.11,12 We expected that ligands would be very important to generate the reactive iron species
in situ, but the yields were not improved in the presence of nitrogen or phosphorus ligands (Table
1, entries 3–6). A theoretical study revealed that the coordination of the iron species to the ester
group of the generated alkyl radical is important to enhance the reactivity; therefore, ligands
retarded the reaction (see mechanism section). We next screened various bases. The reaction did
not proceed without a base or with inorganic bases (Table 1, entries 7 and 8). NEt3 decreased the
yield, and iPr2NH strongly retarded the reaction (Table 1, entries 9 and 10). As a result, iPr2NEt
gave the best yield of product 3a. When the reactions were carried out in various solvents,
including MeCN, EtOH, 1,4-dioxane, and toluene, the best result was obtained with 1,4-dioxane
(Table 1, entries 11–13). Finally, the reaction with 3 equivalents of 2a in 1M solution resulted in
75% yield of 3a (Table 1, entries 14 and 15). Several methods for direct C−H alkylation of
aromatic compounds with alkyl halides have been reported.13,14 However, the alkylation of
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heteroaromatic compounds is quite challenging due to slow C–H substitution and the undesired β-
H elimination of alkyl intermediates.15 Our strategy using reactive radical species can avoid the
above-mentioned issues.
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Table 1. Optimizationa
FeCl2 (5 mol%)
Ligand (10 mol%)
Base (2.0 equiv)
CO2Et
Br
+
EtO2C
Run
O
O
solvent, 110 °C
24h
1a
2a
3a
: 1.5 equiv
Base
Yield (%)b
Ligand
Solvent (M)
None
None
2,2-bipyridyl
TPMA
PPh3
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
None
Toluene (0.5)
Toluene (0.5)
Toluene (0.5)
Toluene (0.5)
Toluene (0.5)
Toluene (0.5)
Toluene (0.5)
Toluene (0.5)
Toluene (0.5)
Toluene (0.5)
MeCN (0.5)
45
0
1
2c
32
22
46
44
0
3
4
5
PCy3
6
None
None
None
None
None
None
None
None
None
7
Cs2CO3
NEt3
0
8
28
0
9
iPr2NH
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
10
11
12
13
14
15d
0
EtOH (0.5)
trace
1,4-dioxane (0.5) 50
1,4-dioxane (1)
1,4-dioxane (1)
57
75e
a Reaction conditions: 1a (0.50 mmol), 2a (0.75 mmol), FeCl2 (5 mol%), ligand (10 mol%), base
(1.0 mmol) in solvent at 110 °C for 24 h. b NMR spectroscopy yield. C Without FeCl2. d Using 3
equiv of 2a. e Isolated yield.
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Under the optimal conditions, we tried various bromides 1 and heteroaromatic compounds (2 or
3) (Table 2). Our optimized conditions can be applied to gram scale C-H alkylation (4a), which
shows that our reaction conditions are reliable. The bromides 1 possessing alkyl-Br bond and aryl
ester gave the corresponding products in good yields (4b-4e). The reaction occurred with not only
2-bromoesters but also 2-bromoamides to produce 4f and 4g in 64% and 60% yields, respectively.
In those cases, the increased amount of 2 was effective to obtain better yields. 2-Bromomalonate
ester also reacted with benzofuran to give 4h but the yield was low due to the decomposition of 2-
bromomalonate. 2-Bromoesters possessing various carbon functionalities at α–position resulted in
moderate to good yields (4i-4l). These results reflect that highly congested quaternary carbons can
be synthesized by our methodology. But the corresponding primary- and secondary-alkyl radicals
were not reactive due to the radical stabilities (4m, 4n). Substituted benzofuran and furan
derivatives possessing bromine, alkyl group, ketone, and even aldehyde gave alkylated products
in moderate to good yields without loss of the functional groups (4o-4v). We also tried the reaction
of thiophens and the corresponding quaternary carbons of thiophens were obtained under the
modified conditions (5a, 5b). The reaction did not occur with benzoxazole and benzothiazole.
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Table 2. Heteroaromatic C–H substitutionsa
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a Reaction conditions: 1 (0.50 mmol), 2 or 3 (1.5 mmol), FeCl2 (5 mol%), iPr2NEt (1.0 mmol) in
1,4-dioxane at 110 °C for 24 h. b 5 equiv of 2 was used. c Run at 150 °C.
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Mechanistic Consideration. While the exact reaction mechanism is currently unclear, one
possibility involves a radical pathway (Scheme 1). The reaction starts with the generation of
tertiary-alkyl radical species A from the reaction between Fe(II) and 1. An evidence of this step is
the reaction in the presence of radical scavenger such as BHT or TEMPO. This reaction with BHT
or TEMPO did not result in the formation of product 4. After the generation of A, addition of A to
2 takes place to give the radical intermediate B. Then, intermediate B reacts with an iron bromide
species to produce intermediate C with concomitant formation of a Fe(II) species to complete the
catalytic cycle. The intermediate C undergoes elimination with the amine to give the desired
product 4. During the reaction, there are a few possibilities to produce homocoupling product of
A and B. But such products were not detected.
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Scheme 1. Proposed mechanism.
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The formation of cation species from the oxidation of B with FeIII cannot be ruled out. The smooth
radical addition of A to 2 can be explained by comparing the transition states (Scheme 1 bottom).
To support the reaction mechanism, we carried out DFT calculations (See supporting information).
During the reaction, iron-coordinated species (TYPE I or II) could be generated and favored
transition state is to be TYPE I (ΔG‡=16.8 kcal/mol). Free radical process (radical chain reaction)
is another possibility but energy level was high compared with them. Iron Lewis acidity could
enhance the electrophilicity of A, in which the life time of the radical might be long enough to
react with aromatic C-H bonds. NBO atomic charge of radical carbon in TYPE I was calculated to
be 0.135 e which showed higher density than that of TYPE II (0.090 e). We also calculated the
relative Fukui indices, which are calculated by NBO analysis for carbon atoms of 2. Calculated
relative Fukui indices showed that the nucleophilicity of C2 is the highest of all carbons in 2. This
result explains the importance of reactivity enhancement of A with iron, in which an electrophilic
radical could be generated.
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Miscellaneous Reactions. Iron-enhanced alkyl radical species can be applied to various
reactions. For example, when the reaction ran in the presence of BHT (6a) without benzofuran 2,
the resulting alkyl radical added directly to the aromatic ring to produce dearomatized product 7a
in 73% yield. The reaction of 6b gave C-H tert-alkylated product 7b in 61% yield (Scheme 2).
These results supported the existence of radical species A in Scheme 1. On the other hand, the
reaction of 8a-c underwent similar intramolecular reactions (Scheme 3). The reaction of 8a
possessing a phenol fragment gave dearomatized adduct 9a and C-H cyclized products (9b, 9c)
were obtained from the reaction of 8b and 8c. Generally, BHT generates benzyl radical from a
phenoxy radical and the resulting benzyl radical could couple with other radical species16. Those
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results showed that the α-radicals generated under our optimized conditions could have broad
reactivities.
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Scheme 2. The reaction of BHT and its derivatives.
Scheme 3. Intramolecular reaction.
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We next applied our iron-catalyzed conditions to cascade C-H cyclization reactions to produce
oxindoles possessing two quaternary carbons which are partly core structure of Indolidan (Table
3). Although intramolecular C-H cyclizations to produce oxindoles have been well studied by
using a Pd catalyst17, the corresponding Fe-catalyzed reactions have not yet been established. The
generated α-radicals possessing an ester or an amide under the conditions reacted with the C-C
double bond of acrylamide 10 followed by intramolecular C-H radical cyclization radical
cyclization to provide the functionalized oxindoles 11 in the yield ranging from 75-94%.
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Table 3. Cascade C–H cyclization reactions.
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Moreover, our conditions were effective for tert-alkylation of olefins (vinylic C-H substitutions)
(Table 4). Unlike previous Fe-, Ni- and Cu-catalyzed related tert-alkylations18, our reaction system
can employ simple styrene derivatives, α-methylstyrene, and β-substituted styrene. The reaction
of 1 and styrenes 12 under our iron catalyzed conditions provide Heck like olefination products
(13a-13f) in moderate to good yields. The reaction of α-methylstyrene and 1 selectively produced
exo-methylene product 13e. In Pd-catalzed reaction, it is very difficult to control exo- and endo-
selectivity19. When substrate 12 possessing an internal C-C double bond was employed, the
corresponding (E)-tert-alkylated product 13f was obtained as a single stereoisomer.
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Table 4. Vinylic C–H substitutions.
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CONCLUSION
In conclusion, we found universal iron-catalyzed conditions for 1) heteroaromatic C-H
alkylations, 2) C-H cyclizations, 3) dearomative additions of phenols and 4) vinylic C-H
alkylations. From the natural resource points of view, finding new aspects of iron chemistry is very
important20 and iron is one of the most attractive catalysts. Iron-catalyzed C-H functionalization
chemistry have been succeeded with Grignard reagents for the synthesis of substituted arenes, but
new iron chemistry for the synthesis of quaternary carbons has not yet been established. Our iron
catalyzed radical research revealed that α-radicals generated from the reaction of 2-
bromocarbonyls and iron salt can react with various C-H bonds. The theoretical study revealed
that iron catalyst enhanced the reactivity of generated alkyl radicals, which enables smooth C-H
tertiary-alkylations. Further investigations, including other type of reactions and mechanistic
studies, are currently underway.
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ASSOCIATED CONTENT
Experimental procedures and spectroscopic data for all new compounds are available free of
charge via the Internet at http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
nisikata@yamaguchi-u.ac.jp
ACKNOWLEDGMENT
We warmly thank YU and JSPS KAKENHI Grant Number JP 18H04262(TN) in Precisely
Designed Catalysts with Customized Scaffolding.
REFERENCES
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Y.; Linbin, L.; Pan, Z.; Wang, Y.; Li, J.; Wang, K.; Wang, X.; Zhang, Y.; Hu, T.; Zhang, Y. Protecting-Group-
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R1 COR3
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COR3
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Cl Fe
Cl
Br
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X= O, S
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