Iron- or Palladium-Catalyzed Reaction Cascades Merging Cycloisomerization and Cross-Coupling Chemistry

Article abstract of DOI:10.1002/chem.201803360

A conceptually novel reaction cascade is presented, which allows readily available enynes to be converted into functionalized 1,3-dienes comprising a stereodefined tetrasubstituted alkene unit; such compounds are difficult to make by conventional means. The overall transformation is thought to commence with formation of a metallacyclic intermediate that evolves via cleavage of an unstrained C?X bond in its backbone. This non-canonical cycloisomerization process is followed by a cross-coupling step, such that reductive C?C bond formation regenerates the necessary low-valent metal fragment and hence closes an intricate catalytic cycle. The cascade entails the formation of two new C?C bonds at the expense of the constitutional C?X entity of the substrate: importantly, the extruded group X must not be a heteroelement (X=O, NR), since activated β-C?C bonds can also be broken. This concern was reduced to practice in two largely complementary formats: one procedure relies on the use of alkyl-Grignard reagents in combination with catalytic amounts of Fe(acac)_3, whereas the second method amalgamates cycloisomerization with Suzuki coupling by recourse to arylboronic acids and phosphine-ligated palladium catalysts.

Full text of DOI:10.1002/chem.201803360

A Journal of
Accepted Article
Title: Iron- or Palladium Catalyzed Reaction Cascades Merging
Cycloisomerization and Cross Coupling Chemistry
Authors: Alois Fürstner, Filipe Gomes, and Pierre-Georges Echeverria
This manuscript has been accepted after peer review and appears as an
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to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201803360
Link to VoR: http://dx.doi.org/10.1002/chem.201803360
Supported by

Chemistry - A European Journal
10.1002/chem.201803360
Iron- or Palladium Catalyzed Reaction Cascades Merging Cycloisomerization and Cross Coupling
Chemistry
[
a]
Filipe Gomes, Pierre-Georges Echeverria, and Alois Fürstner*
[
a]
Dr. F. Gomes, Dr. P.-G. Echeverria, Prof. A. Fürstner
Max-Planck-Institut für Kohlenforschung
4
5470 Mülheim/Ruhr (Germany)
E-mail: fuerstner@kofo.mpg.de
Supporting Information and the ORCHID identification number(s) for the author(s) of this article can
be found under:
https://doi.org/10.1002/chem.201803360.
1
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Abstract: A conceptually novel reaction cascade is presented, which allows readily available enynes
to be converted into functionalized 1,3-dienes comprising a stereodefined tetrasubstituted alkene
unit; such compounds are difficult to make by conventional means. The overall transformation is
thought to commence by formation of a metallacyclic intermediate that evolves via cleavage of an
unstrained CX bond in its backbone. This non-canonical cycloisomerization process is followed by a
cross coupling step, such that reductive CC-bond formation regenerates the necessary low-valent
metal fragment and hence closes an intricate catalytic cycle. The cascade entails the formation of
two new CC bonds at the expense of the constitutional CX entity of the substrate: importantly, the
extruded group X must not be a heteroelement (X = O, NR), since activated -CC bonds can also be
broken. This manifold was reduced to practice in two largely complementary formats: one procedure
relies on the use of alkyl-Grignard reagents in combination with catalytic amounts of Fe(acac)3,
whereas the second method amalgamates cycloisomerization with Suzuki coupling by recourse to
arylboronic acids and phosphine-ligated palladium catalysts.
Introduction
Enyne derivatives A react with various low-valent metal fragments [M] via oxidative cyclization to
[
1, 2]
give metallacyclic intermediates B in the first place (Scheme 1).
This reactivity mode is a common
entry point into the rich cycloisomerization and cycloaddition chemistry developed during the last
[
3-12]
decades that exploits the different possibilities by which a metallacycle can evolve.
-Hydride
elimination is arguably the most fundamental of these downstream processes, which leads to dienes
of type C or D; only in rare cases can reductive elimination with formation of a formal [2+2]
[
13-15]
cycloadduct of type E compete.
In contrast, various intra- as well as intermolecular insertion
reactions of -systems are fast enough to outperform -hydride elimination; a few prototype
[
3-10]
structures within reach are shown in Scheme 1.
2
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Scheme 1. Top: A representative set of canonical transformations of enynes proceeding via
metallacyclic intermediates; bottom: outline of a conceptually novel transformation in which a
metallacycle evolves by cleavage of a constitutional CX bond in its backbone.
In an attempt to further increase the portfolio of accessible structural motifs, our group has
[
16]
recently proposed a non-canonical reaction manifold.
Specifically, we conceived that a
metallacyclic intermediate of type L comprising a potential leaving group X in its backbone should
favor ring opening over -hydride elimination because the antibonding CX * orbital is well aligned
with the electron rich C[M] bond; this preference is amplified by the rigidity of the bicyclic core
which impedes puckering of the metallacycle as necessary for cleavage of the annular CH
[
17, 18]
bond.
In contrast to -hydride elimination, however, the rupture of the CX bond does not
regenerate a catalytically active low-valent metal species [M]; therefore the reaction must come to a
3
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hold unless a separate process is juxtaposed that ensures turnover. Cross coupling was deemed
adequate for this purpose, in that the reductive CC-bond forming step would adjust the redox state
of the metal fragment as necessary for entertaining a catalytic cycle.
This conceptually novel cycloisomerization/cross coupling cascade has been successfully
reduced to practice with the aid of bare iron catalysts in combination with alkyl-Grignard reagents as
[
16]
the nucleophilic reaction partners. Iron was chosen because it is cheap and benign and had proven
[
19]
effective in many different cross coupling and cycloisomerization reactions.
Moreover, its
[
20-22]
propensity to form ate-complexes
could provide an additional driving force since alkylation at
the stage of the ferracycle to give a charged intermediate of type L (M = Fe) renders the metal more
electron rich. The escorting magnesium cation might engage with the leaving group; in so doing, it
might well activate the CX bond and, at the same time, relieve the transition state from possible
geometric constrains. These factors are thought to synergize and hence render the overall
transformation fast, facile and productive.
In fact, the many excellent results obtained with Fe(acac) cat./RMgX concur with this
3
[
16]
mechanistic rationale. From a conceptual viewpoint, however, the net cycloisomerization/cross
coupling cascade should not be limited to the use of iron catalysts and organomagnesium
compounds; other catalyst/nucleophile combinations might increase the substrate scope and could
[
23]
bear advantages in terms of functional group compatibility. As outlined below, we have in fact
been able to develop an alternative manifold using palladium catalysis, which nicely complements
the original iron-based protocol.
Results and Discussion
Iron catalyzed reaction cascades of enynes with heteroatom tethers: The readily available enyne 1
served as model compound for reaction optimization. This substrate was deemed particularly
adequate since the electron deficient alkene unit will favor oxidative cyclization with formation of a
metallacycle 2, which in turn should benefit from the partial enolate character that the ester does
[
24]
impose. At the same time, this substituent serves as a chemical probe: it shows whether or not the
iron catalyzed reaction is fast enough to outperform uncatalyzed attack of the organomagnesium
reagent onto the ester. Finally, the good leaving group properties of a phenolate are thought to
expedite the envisaged bond cleavage.
4
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Table 1. Optimization of the Reaction Conditions.
[
a]
[b]
Entry
Precatalyst
Loading
mol%]
Additive
[mol%]
t [min]
Conversion Yield
[%, NMR]
E:Z
[
1
2
3
4
5
6
7
8
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
FeBr2
20
20
20
10
5
---
 20
quant.
96
86 %
91 %
82 %
91 %
84 %
90 %
55 %
nd
97:3
97:3
97:3
97:3
98:2
98:2
98:2
98:2
tmeda (20) 10
dppe (20)
80
quant
quant
93
---
---
---
---
---
50
60
5
120
1140
600
quant
93
1
20
quant
9
20
20
---
---
120
120
quant
quant
nd
nd
95:5
97:3
10
11
20
---
180
0
---
---
[
a] Isolated yield of pure product. [b] Isomer ratio at the tetrasubstituted alkene unit; nd = not
determined.
As evident from the results compiled in Table 1, addition of cyclohexylmagnesium chloride to
a solution of enyne 1 and catalytic amounts of Fe(acac) (20 mol%) in THF furnished dienoate 3c in
3
excellent yield; the reaction proceeded within minutes at low temperature. Importantly, the central
tetrasubstituted alkene unit of 3c was formed with impeccable regio- and stereoselectivity (E:Z 
9
7:3). This outcome is consistent with intervention of a metallacyclic intermediate of type 2, the
[
25-30]
alkenyliron unit of which eventually succumbs to cross coupling
whereas the alkyliron side
5
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triggers ring opening. In any case, the cascade process engenders a highly selective formation of two
vicinal CC bonds at the expense of the CO bond of the former enol ether that is cleaved during the
reaction.
In practical terms, it is rewarding that the simple and ligand-free system comprising non-
hygroscopic Fe(acac) and RMgCl gave optimal results; additives such as tmeda or dppe are neither
3
necessary nor beneficial. The catalyst loading could be lowered to 5 mol% without compromising the
outcome, except that the reaction proceeded more slowly; the same was noticed on replacement of
0
Fe(acac) by FeBr . It is mechanistically relevant that the structurally well-defined Fe complex
3
2
[
31, 32]
[
(dippp)Fe(C H ) ] was also found to be catalytically competent (entry 9).
Since Grignard
2
4 2
I
0
reagents readily reduce the analogous Fe complex [(dippp)FeBr(C H )] to the Fe species, this
2
4
0
precatalyst was similarly effective (entry 10). Surprisingly though, the bimetallic Fe complex
[
[
CpFe(C H ) ][Li(tmeda)], which had previously been used as catalyst for Alder-ene type reactions,
2
4 2
[
32, 33]
4+2], [2+2+2] and [5+2] cycloadditions,
failed to afford product 3c under otherwise identical
conditions for reasons that are currently not clear (entry 11).
Our group has recently shown that the reaction of FeX (n = 2, 3) with cyclohexylmagnesium
n
chloride is a highly involved process, in which disproportionation of the transient organoiron species
[
31, 34]
and/or allylic C-H activation processes will eventually interfere.
It was for this reason that this
particular nucleophile had been chosen for reaction optimization. The fact that the cyclohexyl group
was transferred almost quantitatively augured well for the scope of the reaction with regard to the
nucleophilic partner. Indeed, a range of (functionalized) alkyl-Grignard reagents performed nicely
(Table 2); even the isopropyl group was successfully transferred, although cross coupling reactions of
secondary alkyl donors in general are often plagued by isomerization to the linear isomers via rapid
[
35]
MH elimination/re-addition (entry 4);
of the primary Grignard reagents investigated, only
TMSCH MgCl failed to participate in the cascade, most likely for the -silicon effect that is thought to
2
[
36]
stabilize the transient organoiron species. The alkyl substituent delivered by the Grignard reagent
and the relocated alkenoate group were invariably found to reside on the same side of the newly
formed tetrasubstituted alkene unit of the resulting major isomer. This stereochemistry was assigned
by numerous NOE experiments (Figure 1) and confirmed by crystallographic data. The structure of
compound 3f in the solid state (Figure 2) is representative for a number of other cases that were
6
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equally ascertained (for three additional X-ray structures, see the Supporting Information). As an
important limitation of this iron catalyzed procedure, however, we note that aryl-Grignard reagents
proved largely inadequate; the expected products were obtained in low yields and proved difficult to
separate from biaryl derivatives formed as by-products by competitive homo-coupling of ArMgBr;
the examples shown in entries 8 and 21 are representative.
Figure 1. Representative example for the NOE-based stereochemical assignment.
Figure 2. Structure of one of the two independent molecules of compound 3f in the unit cell.
7
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[
a]
Table 2. Iron catalyzed cycloisomerization/cross coupling cascade.
[
b]
Entry Substrate
RMgX
Product
Yield (E/Z)
%]
[
1
2
3
4
MeMgBr
nPentMgCl
3a
3b
3c
3d
93
84 (93:7)
90 (98:2)[
76 (94:6)
C H MgCl
6
11
c]
[
iPrMgCl
c]
5
3e
73 (90:10)
6
7
3f
3g
9 ( 99:1)
94 ( 99:1)
8
40a < 25 (99:1)
PhMgBr
MeMgBr
9
5a
5b
90 ( 99:1)
72 ( 99:1)
1
0
1
1
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeMgBr
7
93 ( 99:1)
[
e]
e]
1
1
2
3
9a
9b
95[
74
[
c]
c]
14
15
16
11
13
15
89
[
94
64 (90:10)
[
f]
1
7
8
17
74 (99:1) + 22
[
c, g]
1
19a 81 (95:5)
[
c, g]
19
20
21
19b 64
19c 72 (73:27)
MeMgBr
[
c, g]
C H MgCl
6
11
[
c ,d, g]
19d 37 (92:8)
PhMgBr
[
a] Unless stated otherwise, all reactions were carried out with Fe(acac) (5 mol%) in THF at 30 °C. [b] Yield of
3
isolated pure product; E/Z ratios as determined by NMR. [c] Using 20 mol% of Fe(acac) as precatalyst. [d]
3
8
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Considerable homocoupling of PhMgBr was noticed; the resulting biphenyl proved difficult to separate from
the product. [e] The E/Z ratio changes significantly with reaction time, see Text. [f] The minor product is the
oxa-Michael adduct formed by 1,4-additon of the phenol –OH group to the alkenyl sulfone. [g] At 0 °C; Ms =
methanesulfonyl.
Different substituents on their alkyne terminus of the enyne substrates were tolerated,
including a silyl group that allows for further functionalization. In this context, it is emphasized that
formation of products 9 was accompanied by a gradual but substantial loss of isomeric purity on
prolonged stirring; specifically, the Z/E ratio for 9a decreased from an appreciable 96:4 after 10 min
to 41:59 after 90 min reaction time. We tentatively ascribe this secondary process to a high degree of
charge delocalization and a certain steric congestion in the product. This major exception
notwithstanding, the highly selective course of the cycloisomerization/cross coupling cascade allows
isomeric pairs of products to be obtained by permutation of the alkyne terminus and the substituent
R delivered by the Grignard reagent; dienoate 3b and its stereoisomer 5a illustrate the point.
Compounds 11 and 13 indicate that even significant changes in the electronic character of
the central aryl ring are largely inconsequential. In accord with previous experiences with iron
[25-28, 37]
catalyzed cross coupling,
the compatibility of the additional ester group in 12 further
illustrates the kinetic selectivity of the process, in that the organomagnesium reagent is consumed
before it gets a chance to attack the electrophilic substituent. Moreover, variations of the acceptor
site (alkenyl sulfone) and of the leaving group (anilide) are possible (entries 16, 17): the fact that
product 17 is prone to undergo a secondary Michael addition of the phenol to the alkenylsulfone
forecasts further opportunities for reaction development. Finally, a much more dramatic structural
change is manifest in substrate 18 featuring an aliphatic backbone: the increased conformational
flexibility is expected to lower the propensity for metallacycle formation; likewise, an alkoxide is a
much less favorable leaving group than a phenolate. Despite these arguments, enyne 18 was readily
transformed into dienoates 19 under standard conditions, except that the reaction was best carried
out at 0 °C rather than 30 °C.
Iron catalyzed cascades involving CC bond cleavage: The concept of letting a metallacycle of type L
evolve by the cleavage of a constitutional bond rather than a peripheral CH group is not limited to
the extrusion of phenolates, alkoxides or anilides. As manifest in the examples shown in Scheme 2,
9
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[
38-41]
unstrained but activated CC bonds can be cleaved analogously.
Specifically, enyne 20 was
converted into diene 21 in good yield by an overall process in which two CC bonds are formed while
another CC bond is concomitantly broken; changing the alkyl-Grignard reagent did not affect the
course (20  23). Once again, the transformation turned out to be highly regio- and stereoselective
with regard to the newly formed tetrasubstituted alkene. In contrast, the configuration of the
migrating enoate proved irrelevant, since E-20 and Z-20 led to the exact same isomer 21 as the only
detectable product.
Scheme 2. a) C H MgCl, Fe(acac) (20 mol%), THF, 30 °C, 70 % (E:Z = 99:1). b) C H MgCl, Fe(acac)
6
11
3
6
11
3
(
20 mol%), THF, 30 °C, 70 % (E:Z = 99:1). c) 22, Fe(acac) (20 mol%), THF, 15 °C, 63 % (E:Z = 98:2). d)
3
MeMgBr, Fe(acac) (20 mol%), THF, 30 °C, 67 %; E = COOMe.
3
The comparison with substrate 24 indicates that the malonate leaving group in 20 is
mandatory for the full cascade to be passed through. While enyne 24 obviously engaged in
metallacycle formation and iron catalyzed cross coupling, cleavage of the less activated CC bond
embedded into the bicyclic skeleton of the putative intermediate 25 has not taken place. The densely
decorated dihydroindene derivative 26 was obtained in diastereomerically pure form upon hydrolytic
work-up.
1
0
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Mechanistic considerations: Although formation of ferracycles of type L is plausible and consistent
with all available experimental data, it is not the only conceivable mechanistic scenario. Rather, a
[
42-45]
stepwise process commencing with an iron catalyzed carbometalation of the alkyne in N,
followed by a Michael addition of the resulting alkenylmetal species O could be envisaged (Scheme
); in this case, the resulting (C- or O-metalated) enolate P could be prone to elimination to give the
3
final product Q. Various pieces of evidence, however, speak against such a pathway (Scheme 4).
Scheme 3. Conceivable but unlikely alternative mechanism comprising an iron catalyzed
carbometalation followed by 1,4-addition/elimination.
1
1
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Scheme 4. Control experiments of mechanistic relevance.
First and foremost, aryl alkynes 27 and 28  without or with a potentially directing oxygen
atom at the arene ortho position  both failed to undergo iron catalyzed carbomagnesiation under
the chosen conditions, even when the mixtures were allowed to reach ambient temperature.
Moreover, a literature report had shown that the iron catalyzed carbolithiation of the related
[
42]
substrate 29 is regio-unselective, furnishing the isomers 30 and 31 in a 82:18 ratio. Even if one
assumes that it is the assistance provided by the flanking alkene in 6 which entails facile
[
46]
carbometalation without participating in metallacycle formation, the directing effect of the silyl
[
47]
group would almost certainly counteract any try to place the incoming [MgBr]-unit next to it; as a
consequence, formation of product 7 would almost certainly be unselective. Taken together, these
data speak against carbometalation as the triggering event.
1
2
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Scheme 5. a) C H MgCl, Fe(acac) (20 mol%), THF, 30 °C, 53 % (34:35 = 3.8:1). b) MeMgBr, Fe(acac)
6
11
3
3
(1 equiv.), THF, 30 °C  RT, quant. (NMR, 39:40 = 69:31).
The examples compiled in Scheme 5 show that a Michael acceptor unit is not needed either
for the cascade to proceed. Specifically, compound 32 bearing a terminal alkene rather than an
enoate entity did engage in the full cascade. As expected, the activated malonate unit allowed even
CC-bond cleavage to occur, although the slower overall reaction rate (compared to 20) allowed
[
48]
hydride transfer to compete with cross coupling of the cyclohexyl unit. In line with the results
outlined above, the reaction of the unactivated substrate 37 stopped prior to bond cleavage.
Arguably most telling in mechanistic term, however, is the fact that traces of product 40 were
detected in the crude material, in which two methyl groups derived from MeMgBr got incorporated,
one on either end of the original enyne -system; this compound accounted for up to 31 % when the
Fe(acac) loading was increased to one equivalent. This outcome speaks for a metallacyclic ate-
3
complex of type 38 as the key reactive intermediate, in which the iron center is already loaded with
[
20-22]
2
3
(at least) two methyl substituents.
Since Csp Me coupling is arguably easier than Csp Me
coupling, 39 is expected to be the major product after work-up, whereas 40 eventually accumulates
on prolonged reaction time and/or under more forcing conditions.
1
3
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Palladium catalyzed cycloisomerization/cross coupling cascade: Although many iron catalyzed cross
[
25-28, 37]
coupling reactions are distinguished by remarkable (kinetic) functional group compatibility,
the need for organomagnesium reagents RMgX as the preferred coupling partners implies certain
limitations. Another notable shortcoming is the fact that only alkyl-Grignard reagents will engage in
the iron catalyzed cascade, whereas their aryl counterpart gave rather poor results. Therefore we set
out to establish alternative procedures that accommodate alternative nucleophilic partners.
Scheme 6. Example of a chlorosilane-assisted, nickel catalyzed cycloisomerization/cross coupling
cascade.
Although some success was attained with organozinc reagents in the presence of nickel
[
49]
[50}
catalysts (Scheme 6),
the merger of the venerable Suzuki coupling
with the new enyne
cycloisomerization chemistry was more rewarding. To this end, however, the reaction conditions had
to be carefully optimized, not least because the active palladium catalyst proved rather unstable
under the quite forcing conditions that turned out to be necessary; rapid precipitation of Pd-black
was observed in most cases. Best results were secured with Pd(OAc) in combination with SPhos as
2
[
51]
the ligand, K PO as the base, and degassed 1,4-dioxane/water (1:2) at 90 °C; interestingly, it is
3
4
beneficial to complement the mixture with EtOAc as an additive (10 equiv.), whereas the use of
EtOAc as the solvent gave inferior results. It is also important to note that the use of the
corresponding arylboronic acid rather than the popular pinacol boronates was mandatory.
1
4
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Scheme 7. Palladium catalyzed cycloisomerization/cross coupling cascade. [a] The reaction has to be
stopped after  10 min to avoid (partial) Michael addition of the phenole to the enoate.
Under these conditions, the method allowed aryl groups of largely different character to be
[
52]
transferred with good to excellent yields (Scheme 7). If the aryl substituent is electron rich as in
compounds 40g and 40h, the reaction has to be stopped immediately once full conversion is
reached, since prolonged stirring results in oxa-Michael addition of the phenol unit to the enoate. As
expected, it proved unnecessary that the enyne substrate itself comprises an aromatic ring as
evident from the formation of products 43 and 44. The regio- and stereoselectivity of the palladium
catalyzed transformation were outstanding in all cases investigated in that a single geometric isomer
was formed within the limits of detection of NMR and GC/MS. We take this rewarding and consistent
pattern as an indication that the palladium catalyzed cascade follows a pathway similar to that of the
iron catalyzed process, even though a more thorough mechanistic investigation is needed to confirm
or disprove this notion.
1
5
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Scheme 8. a) 49, Pd(OAc) (20 mol%), SPhos (40 mol%), K PO , EtOAc (10 equiv.), H O/1,4-dioxane,
2
3
4
2
(
2:1), 90 °C, 63 %. b) 50, Pd(OAc) (20 mol%), SPhos (40 mol%), K PO , EtOAc (10 equiv.), H O/1,4-
2
3
4
2
dioxane, (2:1), 90 °C, 67 %. c) B (OH) , Pd(OAc) (20 mol%), SPhos (40 mol%), K PO , EtOAc (10
2
4
2
3
4
equiv.), H O/1,4-dioxane, (2:1), 90 °C, 69 %. d) 51, MeLi, then Pd (dba) (20 mol%), [Et OBF ], 0 °C 
2
2
3
3
4
RT, 70 %; dba = dibenzylideneacetone.
As expected, an alkenylboronic acid also performed well as the nucleophile (Scheme 8),
whereas attempted use of alkylboronic acids met with failure. This limitation is it overly grave since
alkyl groups transfer exceedingly well under iron catalysis (see above); if they carry substituents that
are incompatible with the use of Grignard reagents, the corresponding 9-alkyl-9-BBN reagent can be
[
53, 54]
used,
although removal of the extra boron residues tends to make the purification of the crude
[
55]
material more cumbersome. Moreover, product 48 shows that boryl transfer is possible:
interestingly though, the use of tetrahydroxydiboron resulted in selective reduction of the triple
bond of the substrate to give 47, without any borylative cyclization being detectable. This somewhat
[
56]
counterintuitive outcome has precedent in the literature. In contrast, activation of B (pin) with
2
2
MeLi generated a suitable boryl-transfer agent, although the purification of the resulting product
proved difficult, most likely because the released phenolate is non-innocent vis-à-vis the boron
1
6
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moiety. The problem was solved by in situ O-alkylation with Meerwein salt, which furnished the
[
57]
elaborate building block 48 in respectable yield.
Conclusions
Two different incarnations of a conceptually novel reaction cascade are presented herein, which
allow cycloisomerization to be merged with cross coupling chemistry in a non-canonical way. One
procedure makes use of cheap, benign and ligand-free iron catalysts in combination with alkyl-
Grignard reagents as nucleophiles, whereas the other protocol relies on phosphine-ligated palladium
catalysts in combination with arylboronic acids. The overall transformation opens a highly regio- and
stereoselective entry into dienoates comprising a tetrasubstituted double bond with up to four
different (functionalized) substituents as handles for further functionalization. Compounds of this
[
58]
and related types are exceedingly difficult to make in stereodefined format otherwise; therefore
their chemistry is underdeveloped, despite the many opportunities that the dense array of functional
groups may provide. Moreover, we note a possibility for parallel synthesis inherent to the new route,
which could be relevant given a certain structural relationship of the resulting products with
[
59]
compounds as important as the anticancer agent tamoxifen.
The two experimental procedures are largely complementary to each other, because they
make use of different nucleophilic reaction partners (RMgX versus ArB(OH) ). This rewarding aspect
2
notwithstanding, we cannot help but emphasize the enormous reactivity difference: whereas the
iron chemistry proceeds rapidly at temperatures as low as 30 °C, all palladium-based reactions
required heating to +90 °C to ensure reasonable rates and full conversion. The exceedingly high
driving force of the iron catalyzed process manifest in this differential is thought to indicate
considerable opportunity for discovery of yet other chemically unorthodox but synthetically enabling
transformations leading to the formation of one or more CC-bonds. Our laboratory has already
1
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Chemistry - A European Journal
10.1002/chem.201803360
encountered a few such cases in the past, wherein iron unlocks reactivity that is difficult or even
[
60]
impossible to harness otherwise; we plan to continue our quest into this promising chemical
territory.
Experimental Section
All experimental details can be found in the Supporting Information. This material includes
crystallographic abstracts, compound characterization data and copies of spectra of new compounds.
Acknowledgements
Generous financial support by the MPG is gratefully acknowledged. We thank Dr. B. Sherry for an
initial result, Mr. J. Rust and Dr. R. Goddard for solving the X-ray structure analyses, and all analytical
departments of our Institute for excellent support of our program.
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Chemistry - A European Journal
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10.1002/chem.201803360
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[
[
57] In this case, the use of Pd (dba) give slightly better results than Pd(OAc) used as precatalyst
2
3
2
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2
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For the Table of Contents
Non-Traditional: Iron as well as palladium catalysis allows cycloisomerization chemistry to be merged
with cross coupling via metallacyclic intermediates that evolve in an unorthodox fashion into highly
substituted 1,3-dienes. The overall reaction cascades entail formation of two new CC bonds, while
an unstrained CX bond (X = O, NR, C(COOR) ) in the substrate backbone is concomitantly broken.
2
Keywords: cross coupling  cycloisomerization  1,3-dienes  iron catalysis  metallacycles  palladium
2
6
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