Direct functionalization of benzylic C-Hs with vinyl acetates via Fe-catalysis

Article abstract of DOI:10.1039/b911031c

Direct cross-coupling to construct sp³ C-sp³ C bonds via Fe-catalyzed benzylic C-H activation with 1-aryl vinyl acetate was developed.

Full text of DOI:10.1039/b911031c

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Direct functionalization of benzylic C–Hs with vinyl acetates
via Fe-catalysiswz
Chun-Xiao Song,a Gui-Xin Cai,a Thomas R. Farrell,b Zhong-Ping Jiang,a Hu Li,a
Liang-Bing Gan*a and Zhang-Jie Shi*ac
Received (in Cambridge, UK) 4th June 2009, Accepted 12th August 2009
First published as an Advance Article on the web 7th September 2009
DOI: 10.1039/b911031c
Direct cross-coupling to construct sp3 C–sp3 C bonds via
Fe-catalyzed benzylic C–H activation with 1-aryl vinyl acetate
was developed.
Transition metal-catalyzed cross-coupling reactions, such as the
Heck reaction, have been well developed and become some of the
most powerful methods to construct C–C bonds.1 Other
developments have included coupling aliphatic halides, instead
of aryl/alkenyl halides, with the functionalized olefins.2 Recent
advances in approaching this goal have indicated that aryl C–H
bonds could be applied to C–C bond formation by coupling with
functionalized alkenes via Pd(II) catalysis under oxidative
conditions, avoiding the use of aryl halides.3 Undoubtedly, direct
olefination of sp3 C–H bonds is more difficult due to their
intrinsic properties. To the best of our knowledge, only two
examples have been reported so far. Sames et al. first reported
intramolecular C–C formation of the N-adjacent sp3 C–H bond
of pyrroline, followed by isomerization with a tethered olefin,
catalyzed by Ir complexes.4 The other example, reported by
Li et al., showed direct olefination of sp3 C–H bonds, which
was activated by both an adjacent N atom and an aryl group,
presumably through an oxidation–Baylis–Hillman sequence.5
Compared to late transition metal-catalyzed processes, early
transition metal-catalyzed transformations have unique features
due to their cost effectiveness and different mechanistic insights.6
Among all the first row transition metals, iron draws much
attention due to its high abundance, low price and low toxicity.7
Recently, Fe catalysis has been widely expanded,8 and in
particular, iron catalysts have led to great advances in the direct
oxidation8n,9 of C–H bonds, as well as in C–C bond formation.10
Herein, our developments offer a novel and useful method to
construct C–C bonds via iron-catalyzed direct benzylic C–H
transformations with functionalized olefins.
Scheme 1
Original design of the cross-coupling via sp3 C–H
activation with alkenes.
We originally planned to explore direct olefination through
a Heck-type process via sp3 C–H activation (Scheme 1). The
initial efforts were made to search for the solution of this
design from diphenyl methane 1a, which showed good activity
in various transformations.11 Different substituted olefins were
tested in the presence of various transition metal catalysts and
oxidants. Under different conditions, acrylate derivatives,
which showed high reactivity in traditional Heck reactions,1
were not efficient. Electron-rich olefins, such as 1-hexene,12
n-butyl vinyl ether13 and 3,4-dihydropyran,14 also failed.
To our delight, when styrene was used in the presence of
FeCl2 as a catalyst and di-tert-butyl peroxide (DTBP) as an
oxidant, the coupling product was observed by GC-MS
and confirmed by crude 1H NMR, accompanied by other
undetermined byproducts (Scheme 2). Unfortunately, the
efficiency could not be significantly improved, although
various reaction parameters were screened. To our surprise,
when other substituted styrenes were surveyed, the reaction
was highly inhibited. Although this reaction demonstrated the
first example of direct olefination of sp3 C–H bonds as a
Heck-type transformation, the low efficiency and limited
substrate scope hardly made this transformation applicable.
Further tests opened a new channel to approach our original
design. Interestingly, when 1-phenyl vinyl acetate 2a was submitted
to the aforementioned conditions, a new product 3aa was observed.
To optimize this transformation, different conditions were screened
(ESI, Table S1z) and we found that in the absence of either FeCl2
or DTPE, the reaction was terminated. The results also indicated
that other common metal salts, such as Co, Cu, Mn and Pd, were
not suitable for this transformation. Due to its availability, low
price, catalytic efficiency and tolerance of environments, FeCl2 was
determined to be the most effective catalyst. DTPE was found as
the best oxidant and the desired product was isolated in 74% yield
(ESI, Table S1, entry 7z). Other peroxides, such as TBHP and
a Beijing National Laboratory of Molecular Sciences (BNLMS) and
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education, Peking University, Beijing, China.
E-mail: zshi@pku.edu.cn; Fax: +86 010-62760890;
Tel: +86 010-62760890
b Department of Chemistry, University of Rochester, Rochester,
NY 14627, USA
c State Key Laboratory of Organometallic Chemistry Chinese
Academy of Sciences, Shanghai 200032, China
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experimental
details, analytical and spectral data, and NMR spectra of compounds.
See DOI: 10.1039/b911031c
Scheme 2 Direct olefination of benzylic C–H bonds with styrene.
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This journal is The Royal Society of Chemistry 2009
6002 | Chem. Commun., 2009, 6002–6004

Table 1 C–C formation via FeCl2-catalyzed benzylic sp3 C–H activationa
Ar1
R
Entry
1
Yield (%)
1
2
3
4
5
6
7
8
Ar1 = R = Ph
1a
3aa (74)
3ba (62)
3ca (73)
3da (63)
3ea (77)
3fa (45)
3ga (13)
3ha (69)
Ar1 = R = 4-FPh
1b
1c
1d
1e
1f
4-FPh
Ph
Scheme 3 Fe-catalyzed direct olefination of toluene 1k and derivatives
1l with 1-phenyl vinyl acetate 2a.
4-CIPh
4-PhPh
4-MeOPh
2-MeOPh
2-Nap
Ph
Ph
Ph
Ph
Ph
Table
activation with different vinyl estersa
2
C–C formation via FeCl2-catalyzed benzylic sp3 C–H
1g
1h
9
1i
1j
3ia (77)
3ja (59)
10
Entry
1
R
3
Yield (%)
a
The reaction was carried out in 4.0 mmol of 1 and 0.5 mmol of 2a, in
the presence of 0.6 mmol of DTBP and 0.05 mmol of FeCl2 under N2
at 100 1C for 24 h and isolated yields were obtained after column
chromatography if without further note.
3aa (74)
2
3
4
5
6
7
3ab (65)
3ac (68)
3ad (52)
3ae (52)
3af (69)
3ag (70)
tBuOOCOPh could also promote the reaction, but with lower
efficiencies. Notably, stable poly-tert-butylperoxylated fullerene
was first observed to show partial reactivity.15
Different benzylic substrates were explored (Table 1), and we
found that various derivatives of diphenylmethane were suitable.
Electronic effects seemingly played an important role. Electron-
withdrawing groups partially promoted the yields (entries 2–4),
but in contrast, electron-donating groups decreased the
efficiency. For example, the presence of a methoxyl group on
the phenyl ring decreased the yield obviously (entry 6). Steric
effects in ortho-substituted substrate 1g also dramatically lowered
the yield (entry 7). Aside from substituted phenyls, naphthyl and
seven-membered cyclic diphenyl methane derivatives were
suitable substrates, and the desired products were isolated in
good yields (entries 5, 8 and 9). The reaction could be extended to
the isochroman and the desired product 3ja was obtained in 59%
yield, with functionalization at the highly reactive benzylic
position adjacent to the O-atom (entry 10).
Further exploration extended the substrate scope to the
benzylic C–H of substituted toluene. When toluene 1k was
submitted, the desired product was obtained in a moderate
yield (eqn (1), Scheme 3). The benzylic methyl group of 1l
showed excellent reactivity, which may arise from stabilization
of the proposed radical intermediate (eqn (2), Scheme 3).16
Different substituted 1-aryl vinyl acetates were also explored
(Table 2). We found that steric effects affected the efficiency:
ortho-tolyl substitution lowered the yield to 52% from 65%
and 68% with para- and meta-tolyl substitutions, respectively
(cf. entry 4 with entries 2 and 3). Electronic effects similarly
favored the electron withdrawing groups (cf. entry 5 with
entries 6 and 7). It is noteworthy that C–X (X = Br or F)
and ester groups tolerated the conditions well, and these
groups could be transformed into different functionalities
(3af, 3ag and 3ah, entries 6–8). Unfortunately, 2-propenyl
acetate is not suitable and only a small amount of desired
product was observed by GC-MS.
8
3ah (59)
a
The reaction was carried out in the 4.0 mmol of 1 and 0.5 mmol of
2 in the presence of 0.6 mmol of DTBP and 0.05 mmol of FeCl2 under
N2 at 80 1C for 24 h and isolated yields were obtained after column
chromatography if without further note.
Considering the safety problem arising from the possible
explosion of peroxide in the presence of transition metal
species, we further experimentally modified this transformation
(Scheme 4). When both vinyl acetate 2a and DTBP was mixed
and added dropwise in a half hour, 3aa was isolated in 61%
yield. To our delight, a better efficiency was obtained with the
addition of only DTBP in 0.5 h. The length of the adding time
to 10 h did not affect the yield significantly. Thus, this
operation reduced the hazard by the decrease of the DTBP
concentration.
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Chem. Commun., 2009, 6002–6004 | 6003

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5 Proposed mechanism on direct C–C formation via
Fe-catalyzed benzylic C–H activation via either radical (path A) or
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This journal is The Royal Society of Chemistry 2009
6004 | Chem. Commun., 2009, 6002–6004