Iron-catalyzed stereospecific activation of olefinic C-H bonds with grignard reagent for synthesis of substituted olefins

Article abstract of DOI:10.1021/ja2017202

The reaction of an aryl Grignard reagent with a cyclic or acyclic olefin possessing a directing group such as pyridine or imine results in the stereospecific substitution of the olefinic C-H bond syn to the directing group. The reaction takes place smoothly and without isomerization of the product olefin in the presence of a mild oxidant (1,2-dichloro-2-methylpropane) and an aromatic cosolvent. Several lines of evidence suggest that the reaction proceeds via iron-catalyzed olefinic C-H bond activation rather than an oxidative Mizoroki-Heck-type reaction.

Full text of DOI:10.1021/ja2017202

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pubs.acs.org/JACS
Iron-Catalyzed Stereospecific Activation of Olefinic CꢀH Bonds with
Grignard Reagent for Synthesis of Substituted Olefins
Laurean Ilies, Sobi Asako, and Eiichi Nakamura*
Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S Supporting Information
b
Scheme 1. Control of Selectivity in the Iron-Catalyzed Oxi-
dative Phenylation of 1-Substituted Vinylpyridines
ABSTRACT: The reaction of an aryl Grignard reagent with
a cyclic or acyclic olefin possessing a directing group such as
pyridine or imine results in the stereospecific substitution of
the olefinic CꢀH bond syn to the directing group. The
reaction takes place smoothly and without isomerization of
the product olefin in the presence of a mild oxidant (1,2-
dichloro-2-methylpropane) and an aromatic cosolvent. Sev-
eral lines of evidence suggest that the reaction proceeds via
iron-catalyzed olefinic CꢀH bond activation rather than an
oxidative MizorokiꢀHeck-type reaction.
mong numerous methods for the stereoselective synthesis of
A
olefins,1 an attractive but undeveloped methodology is the
stereospecific substitution of a CꢀH bond, as represented by the
stereoselective coupling of an olefin possessing a directing group
with an aromatic compound bearing an electro- or nucleofugal
group2,3 or with alkene, alkyne, carbonyl, or carbon monoxide.4
These recently reported reactions have been catalyzed by pre-
cious metals such as Ru, Rh, and Pd and require an elevated
reaction temperature. The MizorokiꢀHeck reaction5 formally
belongs to this class of reactions but lacks the stereospecificity,
because of the intermediacy of a metal hydride species. We report
herein a new synthetic transformation for the coupling of an aryl
Grignard reagent with an olefin bearing a directing group such as
pyridine or imine, in which a hydrogen atom syn to the directing
group can be replaced stereospecifically with an aryl group
(Scheme 1). Attractive features include the use of a catalytic
amount of inorganic iron complex6,7 and a convenient Grignard
reagent, mild conditions (0 °C), and a short reaction time
(<5 min). The reaction adds to the rapidly increasing repertoire
of CꢀH bond activation reactions using a first-row group 8 or 9
metal as the catalyst.8,9
(2 equiv), Fe(acac)3 (10 mol %), and dtbpy (15 mol %) in
chlorobenzene afforded the syn-arylated product (Z)-2 and its
isomer (E)-2 in 91% overall yield with an E:Z ratio of 3:97. It
should be noted that 1 equiv of PhMgBr accepted the hydrogen
atom removed from the olefin.11 The dtbpy ligand and the slow
addition of the Grignard reagent retarded the otherwise fast iron-
catalyzed homocoupling of PhMgBr.12 The ratio dropped to
10:90 (92% yield) when chlorobenzene was used as the solvent
for the Grignard reagent, after solvent exchange from a solution
of PhMgBr in THF. When THF was used for both the Grignard
preparation and the coupling reaction, we predominantly ob-
tained (E)-2 (E:Z = 95:5) in 94% overall yield. To date we have
been unable to introduce alkyl (methyl, n-butyl, or cyclohexyl) or
alkenyl groups (vinyl, 2-propenyl, or 2-methylpropenyl) under
the present conditions.
Without the 1,2-dichloro-2-methylpropane oxidant, the reac-
tion was not catalytic in Fe(acac)3, and olefin isomerization (see
below) became the major reaction. The phenylation reaction
took place only at the 2-position of the olefin. When the
vinylpyridine substrate had a tert-butyl group at the 1-position
(substrate 3), the reaction was entirely syn-selective, giving 4 in
99% isolated yield.
The Z-selective formation of 2 and 4 when chlorobenzene was
used as a cosolvent suggests that the CꢀH bond activation is
intrinsically stereospecific. Indeed, as illustrated in Scheme 2, the
reaction of PhMgBr with (Z)-2-(1-phenylprop-1-en-2-yl)pyridine
[(Z)-2], which lacks the syn hydrogen atom, did not give any of
the expected CꢀH bond activation product 5 but instead gave a
trace amount of (E)-2 because of in situ E/Z isomerization of the
Scheme 1 describes the reaction conditions that allowed us to
achieve the stereospecific arylation of an olefin, as illustrated by
the reaction of 2-isopropenylpyridine (1) with 3 equiv of
PhMgBr in the presence of 10 mol % Fe(acac)3 and 15 mol %
4,40-di-tert-butyl-2,20-bipyridyl (dtbpy). Application of the con-
ditions that we previously developed9a for the iron-catalyzed
CꢀH bond activation of 2-phenylpyridine with in situ-prepared
Ph2Zn resulted in a very slow and low-yielding reaction (see the
Supporting Information) despite the use of a large amount of
zinc halide (3 equiv) and Grignard reagent (6 equiv). Therefore,
we carefully reoptimized10 the catalytic system and found that
slow addition (during 5 min) of a diethyl ether solution of
PhMgBr (3 equiv) to a mixture of 1, 1,2-dichloro-2-methylpropane
Received: February 24, 2011
Published: April 27, 2011
r
2011 American Chemical Society
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Scheme 2. Different Reactivities of the Z and E Isomers of 2
Table 1. Iron-Catalyzed Oxidative Arylation of Alkenylpyr-
idines and Ketimines with Aryl Grignard Reagentsa
starting material. On the other hand, (E)-2 gave the desired
product 5 in 35% yield with no (Z)-2. The observed stereo-
specificity is a signature of CꢀH bond activation, as opposed to
the expected lack of stereospecificity in the Heck-type reaction
involving carbometalation and metal hydride elimination.
The in situ isomerization of (Z)-2-styrylpyridine [(Z)-6, 100%Z]
was briefly probed using a 4-MeOC6H4MgBr reagent. A congener
of 6 without a nitrogen atom [i.e., (Z)-stilbene] did not isomerize at
all under the conditions in Scheme 1. Using (Z)-6 and THF as
the solvent under otherwise similar conditions, we obtained an
E/Z mixture of 89:11, as opposed to the 42:58 ratio (100:0 with
PhMgBr) obtained when chlorobenzene/THF was used. When
we did not add the oxidant (1,2-dichloro-2-methylpropane),
the E:Z ratio became 100:0, suggesting that a reduced iron
species catalyzes the isomerization. Indeed, no isomerization
took place in the absence of the Grignard reagent, which
presumably serves as a reducing agent to generate a reactive
iron species from Fe(acac)3.
This low-valent iron species is not likely to be iron hydride,
because we detected no hydrogenation products in any of the
reactions reported here, even when the reaction was performed in
the absence of an oxidant. This observation stands in contrast to a
seemingly similar iron-catalyzed oxidative Heck reaction13 that
produces a large amount of reduced products unless suitable
measures are taken. In the light of the stability of isolated ironꢀ
arene π complexes,14 we speculate that the aromatic solvent acts as
a ligand for the low-valent iron species, thereby inhibiting its
interaction with the olefin product and thus the E/Z isomerization.
The scope of the arylation reaction is illustrated in Table 1.
The reaction of 2-(cyclohex-1-en-1-yl)pyridine with phenyl
(entry 1) and p-biphenyl (entry 2) Grignard reagents proceeded
in quantitative yield. Aryl Grignard reagents possessing an
electron-withdrawing (entries 3 and 7) or electron-donating
(entries 4 and 5) group also reacted well. Meta-substituted
Grignard reagents (entries 6 and 7) reacted in high yield, whereas
ortho substitution suppressed the reaction (entry 8).
A variety of cyclic and acyclic olefins possessing a 2-pyridyl
directing group took part in this reaction (entries 9ꢀ16).
Cyclopentenyl to cycloheptenyl pyridines illustrate the general-
ity (entries 1, 9, and 10). Notably, the reaction did not produce
any of the olefin regioisomers known to form in the palladium-
catalyzed Heck reaction of cyclohexene substrates.15 2-Vinylpyr-
idine took part in the reaction, but the product was found to have
isomerized in situ to an E isomer (entry 11). Careful monitoring
of the reaction after 1, 3, and 5 min of addition of the Grignard
reagent allowed us to observe the in situ isomerization quantitatively
(E:Z = 35:65, 65:35, and 96:4, respectively). This isomerization
a Reaction conditions: olefin (0.4 mmol), Fe(acac)3 (10 mol %), dtbpy
(15 mol %), and 1,2-dichloro-2-methylpropane (2 equiv) in PhCl with
slow addition of PhMgBr in THF (3.2 equiv) at 0 °C over 5 min.
b Isolated yield. The newly formed bond is shown in bold. c Determined
1
by H NMR analysis. d PhMgBr in Et2O was used. e THF was used
f
instead of PhCl. 2-Phenyl-1-(2-pyridyl)indene was also obtained in
18% yield as an inseparable mixture with the desired product. g 4 equiv of
PhMgBr was used. The imine product was hydrolyzed with HCl in
THF/H2O at 60 °C.
was suppressed by the presence of a substituent at the 1-position
of the olefin, as discussed in Scheme 1. It is also notable that the
product yield also increased as the 2-substituent became bulkier
(from H to Me to tert-butyl; entries 11ꢀ14). A substituent at the
2-position of the olefin appeared to be unfavorable for the
reaction (entry 15 and Scheme 2). An indene derivative, of
recent interest for materials science,16 could also be employed as
the starting material (entry 16).
Unsaturated imines also took part in this reaction. Under
similar conditions, an N-benzyl cyclic ketimine (entry 17) was
smoothly arylated, and after hydrolysis, the corresponding un-
saturated ketone was obtained in high yield. The imines derived
from substituted anilines and alkylamines served as modest
directing groups, while an N-diphenylphosphinylimine gave
none of the desired product (see the Supporting Information).
Acyclic ketimines reacted sluggishly (<20% yield) under these
conditions.
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COMMUNICATION
Scheme 3. Different Reaction Pathways: (a) CꢀH Bond
Cleavage Followed by Reductive Elimination (This Reaction)
and (b) Carbometalation Followed by β-Hydride
Elimination13
’ AUTHOR INFORMATION
Corresponding Author
nakamura@chem.s.u-tokyo.ac.jp
’ ACKNOWLEDGMENT
This paper is dedicated to Prof. Eun Lee on the occasion of his
65th birthday. We thank MEXT [KAKENHI Specially Promoted
Research 22000008 to E.N.] and the Global COE Program for
Chemistry Innovation.
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(10) The reaction proceeded with comparable yield using various
Fe(II) and Fe(III) salts having different purities. The presence of the
iron catalyst and of the diamine ligand was mandatory. Without the
oxidant, the reaction was stoichiometric in iron, and no reduction of the
double bond was observed. See the Supporting Information for details.
(11) The amount of PhMgBr could be reduced to 2.4 equiv without
an appreciable decrease in yield (73%).
It may be useful to consider briefly the reaction mechanism,
although the whole catalytic cycle appears to be too complex to
be studied at this time. On the basis of the necessary presence of a
directing nitrogen group and the favorable effects of the 1-sub-
stituent illustrated in Scheme 1, we surmise that the reaction
involves a five-membered metallacycle resulting from CꢀH
bond activation (Scheme 3a) and that this intermediate then
undergoes reductive elimination, perhaps after interaction with
1,2-dichloro-2-methylpropane, to give the syn-substituted olefin.
The oxidative Heck reaction that we reported recently
(Scheme 3b)13 formally resembles the present reaction; how-
ever, it is mechanistically different. Thus, the addition of an
aryliron species to the olefinic bond generates a five-membered
metallacycle, which undergoes β-hydride elimination to produce
the desired product (as the sterically more stable E isomer)
together with an iron hydride species. The latter competitively
reduces the starting material or the product, which was the major
side reaction. Such reductive products were never detected in the
present reaction, even when an oxidant was not present. We
therefore consider that the CꢀH bond activation reported here
and the oxidative Heck reaction are different reactions. The lack
of regioisomeric olefinic products in entries 1ꢀ10 (which are
inherent in the Heck-type reaction)15 and the fact that only the
(E)-2 isomer was arylated (Scheme 2) also suggest that the
present reaction does not involve the Heck-type carbometala-
tion/β-hydride elimination mechanism.
In conclusion, we have developed a directed substitution
reaction of an olefinic CꢀH bond with Grignard reagents using
iron catalysis under very mild conditions. The reaction takes
place in a syn-specific manner; however, the product may be
allowed to isomerize to the more stable isomer when possible. To
our knowledge, this is the first report of an iron-catalyzed olefin
functionalization via stereospecific CꢀH bond activation. In
view of the recent rush of reports on iron- and cobalt-catalyzed
CꢀH bond activation reactions,8,9 we suspect that the first-row
transition metals will soon secure an important position in CꢀH
bond activation chemistry, where only precious metals have
played the dominant role in the past decades.17,18
’ ASSOCIATED CONTENT
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Supporting Information. Experimental procedures and
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Org. Lett. 2005, 7, 1943–1946. (b) Nagano, T.; Hayashi, T. Org. Lett.
2005, 7, 491–493.
physical properties of the compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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