Iron-Catalyzed Cyclotrimerization of Terminal Alkynes by Dual Catalyst Activation in the Absence of Reductants

Article abstract of DOI:10.1002/anie.201705087

Catalyzing C?C bond-forming reactions with earth-abundant metals under mild conditions is at the heart of sustainable synthesis. The cyclotrimerization of alkynes is a valuable atom-efficient reaction in organic synthesis that is enabled by several metal catalysts, including iron. This study reports an effective iron-catalyzed cyclotrimerization for the regioselective synthesis of 1,2,4-substituted arenes (1 mol % catalyst, toluene, 20 °C, 5 min). A dual activation mechanism (substrate deprotonation, reductive elimination) renders the simple Fe^II precatalyst highly active in the absence of any reductant.

Full text of DOI:10.1002/anie.201705087

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Accepted Article
Title: Iron-Catalyzed Cyclotrimerization of Terminal Alkynes by Dual
Catalyst Activation in the Absence of Reductants
Authors: Axel Jacobi von Wangelin, Davide Brenna, Matteo Villa, Tim
N. Gieshoff, Marko Hapke, and Fabian Fischer
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705087
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10.1002/anie.201705087
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Cyclotrimerization
Iron-Catalyzed Cyclotrimerization of Terminal Alkynes by Dual Catalyst
Activation in the Absence of Reductants
Davide Brenna,[a] Matteo Villa,[a] Tim N. Gieshoff,[a] Fabian Fischer,[b] Marko Hapke,[b] and Axel
Jacobi von Wangelin[a],*
Abstract: Catalysis of C-C bond forming reactions by earth
abundant metals under mild conditions is at the heart of sustainable
synthesis. The cyclotrimerization of alkynes is a valuable atom-
efficient tool of organic synthesis which operates with several metal
catalysts, including iron. This study reports an effective iron-
catalyzed cyclotrimerization for the regioselective synthesis of 1,2,4-
substituted benzenes (1 mol% cat., toluene, 20°C, 5 min). A dual
activation mechanism (substrate deprotonation, reductive
elimination) enables high catalytic activity of a simple Fe(II) pre-
catalyst in the absence of any reductant.
lipophilic (solubility in organic solvents). With these framework
conditions, we investigated various ferrous salts and identified
Fe(hmds)2, iron(II) bis(1,1,1,3,3,3-hexamethyldisilazan-2-ide), as
active catalyst. Documented herein are the benefits of this simple
catalytic system that presents tangible advances over the current
state-of-the-art: The pre-catalyst is activated by the substrate; no
reductant is required. Instantaneous and highly regio-selective
cyclotrimerization of terminal alkynes proceeds under very mild
conditions. A most user-friendly protocol can be adopted by
preparing the catalyst from the simple salts FeCl2 and Li(hmds).
Metal-catalyzed cyclotrimerizations of alkynes constitute a key
technology for the construction of substituted aromatics and have
been developed to great maturity since its first discovery in the mid-
19th century and the early studies of Reppe in 1948.[1] Today, several
transition metals display good catalytic activity in this highly atom-
efficient, redox-neutral, complexity-generating reaction.[2] The
search for sustainable base metal technologies has recently
prompted the development of iron-catalyzed protocols.[3] High
activities were especially observed with low-valent iron catalysts
which can be generated from iron(0) precursors or by reactions of
Fe(II) complexes with suitable reductants. The first report utilized
iron carbonyl catalysts at high temperatures.[4] Recently, various
combinations of iron complexes, ligands, and zinc were shown to
exhibit high catalytic activity and wide applicability.[5]
Alternatively, elaborate iron complexes in low oxidation states (+1,
0) were also applied.[6] The majority of catalyst developments was
fueled by the notion that a low-valent iron species would engage in
coordinative activation of the softly Lewis basic alkyne, facilitate
the iron-centered oxidative cyclization step, and is regenerated upon
reductive elimination. However, these protocols require the
preparation and handling of highly reactive iron complexes or the
presence of suitable reductants. The conceptual relation between
reductants and bases led us to postulate a mechanistically distinct
approach to the design of effective iron(II) pre-catalysts in which a
simple internal base would mimic the role of an external reductant.
With one equivalent of a terminal alkyne, a dual activation
mechanism of the inactive FeX2 involving sequential alkyne
deprotonation and reductive alkyne elimination would result in an
overall reduction in the absence of an actual reductant (Scheme 1).
We believed that FeX2 complexes constitute most simple pre-
catalysts with cheap, easily accessible ligands X that are bulky
(facile dissociation), strongly basic (alkyne deprotonation),
Scheme 1. Modes of catalyst formation in iron-catalyzed cyclotrimerization.
We commenced our studies with the employment of various simple
ferrous salts in the cyclotrimerization of phenylacetylene at room
temperature (Table 1). FeCl2, FeCl2(thf)1.5, Fe(OAc)2, Fe(OTf)2 and
Fe(acac)2 gave no turnover; the starting material was recovered
(entries 1-5). The postulated catalyst activation by alkyne deproto-
nation (pKa (PhCCH): 28, DMSO)[7a] would require a sufficiently
basic substituent Y in the pre-catalyst FeY2 for attaining high
catalytic activity. Indeed, excellent yields and exclusive formation
of 1,2,4-triphenylbenzene was observed with Fe(hmds)2 (entry 6).
The even more basic Fe2(mes)4 (mes = mesityl) gave lower regio-
selectivity (entry 8). Reactions in THF and diethylether gave
identical yields; hexane as solvent was slightly inferior (90%, 95/5).
The optimized set of conditions involved reaction of a 1 M solution
of phenylacetylene in toluene at 20°C for 1 min under argon with 1
mol% Fe(hmds)2 and afforded 1,2,4-triphenylbenzene as a single
regio-isomer in >99% yield. Importantly, a mixture of the simple
salts FeCl2 and Li(hmds) (ratio 1/2) exhibited nearly identical
activity (entry 9); other transition metal salts proved inactive (entries
10-12). After 2 sec reaction with 1 mol% catalyst loading, an
impressive turnover frequency (TOF) of 180,000 h-1 was recorded.
To the best of our knowledge, this is the most active catalyst system
that operates under such mild conditions. This protocol constitutes
the first application of an Fe(II) catalyst to the cyclotrimerization of
[a]
[b]
D. Brenna, M. Villa, T. N. Gieshoff, Prof. Dr. A. Jacobi von
Wangelin*
Institute of Organic Chemistry, University of Regensburg
Universitaetsstr. 31, 93040 Regensburg (Germany)
E-mail: axel.jacobi@ur.de
F. Fischer, Prof. Dr. M. Hapke
Johannes Kepler University of Linz (Austria) and
Leibniz Institute of Catalysis, Rostock (Germany)
alkynes in the absence of
a
common reducing reagent.
1
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10.1002/anie.201705087
Angewandte Chemie International Edition
Table 1. Evaluation of MY2 pre-catalysts.
Entry Pre-catalyst MY2
pKa (HY) a
Yield [%] b
Selectivity c
1
Fe(OTf)2
0
0
-
2
FeCl2
2
0
-
4
FeCl2(thf)1.5
Fe(OAc)2
2
0
-
3
11
0
-
5
Fe(acac)2
13
0
-
6
Fe(hmds)2
30/26 d
96
99
90
98
0
100/0
Scheme 2. Synthesis of other 1,2,4-trisubstituted benzenes: 1 M alkyne,
PhMe, 1 mol% Fe(hmds)2, 20 °C, 1 h, Ar. Yields were identical to
conversion; no other side products formed. Ratios of 1,2,4/1,3,5-isomer in
parentheses.
7 e
8
Fe(hmds)2
100/0
½ Fe2(mes)4
FeCl2 / 2 Li(hmds)
MCl2 / 2 Li(hmds)
CuCl2 / 2 Li(hmds)
CoBr2 / 2 Li(hmds)
44
94/6
9 f
10 f,g
11 f
12 f
99/1
-
-
-
<5
<5
Internal alkynes did not undergo cyclotrimerizations under standard
conditions which is consistent with the postulated mechanism of
initiating alkyne deprotonation. However, a competent catalyst
activation would only require catalytic amounts of terminal alkyne
as the cyclotrimerization does not involve alkynyl anions (see
deuteration, Scheme 2). Consistent with this hypothesis, the
standard reaction of phenylacetylene with catalytic Fe2mes4 afforded
trace amounts of mesityl-2,4,5-triphenylbenzene (beside the major
homo-cyclotrimer) via co-cyclization with the in situ formed 2-
mesityl phenylacetylene. 1-Phenyl-1-propyne showed no reactivity
under standard conditions but was converted at elevated temperature
to give 1,2,4-trimethyl-3,5,6-triphenylbenzene in 85% yield
(Scheme 3, top). However, mixtures of internal alkynes and terminal
alkynes could be cleanly reacted at 20 °C and afforded the co-
cyclotrimers in good yields (Scheme 3). Intramolecular and inter-
molecular reactions were successful.
Conditions: 5 mol % cat., 0.48 mmol alkyne (1 M), toluene, 20 °C, 3 h,
Ar. a in DMSO.[7b] b Combined isolated yields of regioisomers. c Ratio
1,2,4/1,3,5-regioisomer (GC-FID). d in THF[8]. e 1 mol% Fe(hmds)2, 5
mmol scale, 1 min. f MX2 and Li(hmds) in toluene were stirred for 12 h
at 20 °C prior to alkyne addition. g M = Zn, Mn, Pd, respectively.
The scope of the cyclotrimerization was then extended to other
terminal alkynes. Generally, good to excellent yields and
regioselectivities were observed under the standard conditions with
1 mol% Fe(hmds)2 at 20 °C after 1 h (Table 2). The bulky mesityl-
acetylene showed very little conversion (entry 10). Alkynes bearing
non-aryl substituents were also competent substrates and gave clean
conversions to the benzene derivatives (Scheme 2). High regio-
selectivities were observed with t-butyl, i-propenyl, carboxymethyl,
and deuterium substituents. Tris(cyclopropyl)benzenes were formed
in good yields but low regioselectivity.[9] The deuterium content of
d1-phenylacetylene was fully conserved in the product.
Table 2. Scope of iron-catalyzed cyclotrimerization of terminal alkynes. a
Entry Aryl substituents
Yield [%] b
95
Selectivity c
96/4
1
4-NMe2
4-OMe
2
95
100/0
n.d.
100/0 d
99/1
3
4-OPh
94
4
4-Me
98
5 e
6
4-Cl
99
4-F
94
96/4
7
4-CF3
98
100/0 c
96/4
8
2-Me
90
9
2,4,5-Me3
2,4,6-Me3
2-Me-4-OMe
3-OMe
98
100/0 d
n.d.
10
11
12
13
14
15
<5
95
98/2
98
96/4
3-OBn
98
98/2
3,4-(OMe)2
98
98/2
6-Methoxy-2-naphthyl
93
98/2
Scheme 3. Fe(hmds)2-catalyzed co-cyclizations with internal alkynes.
a Conditions: 0.48 mmol alkyne (1 M), toluene, 1 mol% Fe(hmds)2,
20 °C, 1 h, Ar. b Combined isolated yields of both regioisomers. c Ratio
1,2,4/1,3,5-regioisomer (1H-NMR). d Ratio 1,2,4/1,3,5-regioisomer
(GC-FID). e 5 mol% cat.
2
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10.1002/anie.201705087
Angewandte Chemie International Edition
The catalyst solutions prepared by treatment of Fe(hmds)2 with
2 equiv. phenylacetylene in toluene resulted in a rapid colour change
to brownish and were highly stable over extended periods of time.
Identical yields and selectivities were observed after 1 min and 14 d
storage (Scheme 4). Poisoning studies with 0.5 equiv. trimethyl-
phosphine (PMe3) per Fe unambiguously resulted in inhibition of
catalysis (Figure 1).[10] No impact on catalyst activity was observed
upon addition of the selective homotopic poison dibenzo[a,e]cyclo-
octatetraene (dct) to the reaction mixture (Figure 1).[11] Based on the
collected mechanistic data and literature precedents,[2-6] we postulate
a reaction mechanism that is initiated by substrate-induced catalyst
formation via sequential alkyne deprotonation and reductive
elimination (Scheme 5). Both side products were observed by mass
spectrometry. The formal reduction event leads to a low-valent
catalyst species, presumably an iron(0) particle that is stabilized by
labile coordination to the amine, alkyne, or solvent.[12] The
mechanism presumably follows that of related protocols via π-
Scheme 5. Postulated mechanism involving dual catalyst activation and
heterotopic cyclotrimerization catalysis.
In summary, we have developed an iron-catalyzed cyclotrimeri-
zation protocol that displays unprecedented activity for terminal
alkynes under very mild reaction conditions with turnover
frequencies reaching 180,000 h-1. The pre-catalyst Fe(hmds)2 does
not require the addition of a dedicated reductant but undergoes rapid
substrate-induced activation. With such catalyst system, highly
regioselective cyclotrimerizations of alkynes to 1,2,4-trisubstituted
benzenes proceeded within short reaction times (<2 min) at 20°C in
1 M substrate solution. A most user-friendly procedure can be
adopted by simply mixing cheap FeCl2 with the base Li(hmds).
Mechanistic studies are indicative of a dual catalyst activation which
involves alkyne deprotonation and reductive elimination to a low-
valent heterotopic iron catalyst that exhibits long-term stability.
alkyne,
ferracyclopentadiene,
and
ferracycloheptatriene
intermediates.[5a,6a,6b] The high regioselectivity is determined at the
stage of the ferracyclopentadiene which might experience
significant steric repulsion in the 2,5-diaryl isomer by bulky ligands
(amine, alkyne, solvent) or the catalyst surface.
Acknowledgement
Scheme 4. Catalyst ageing studies document long-term stability and activity.
We thank the ERASMUS Student Mobility Program (D.B.), the Fonds
der Chemischen Industrie (M.V.), and the Evonik Foundation (T.N.G.)
for doctoral fellowships. D.B. is an exchange student from the
University of Milano (Italy). M.H. thanks the Leibniz Institute of
Catalysis for generous support.
100
b) poisoned reaction (inhibition)
75
1a
[%]
50
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
a) control reaction
c)
25
Keywords: iron · cyclotrimerizations · alkynes · arene synthesis ·
nanoparticles
dct
PMe3
0
0
120
240
360
3600
t [sec]
Figure 1. Catalyst poisoning. 4.8 mmol phenylacetylene (1 M in toluene),
1 mol% Fe(hmds)2, -30 °C. a) Control reaction; b) with 0.5 mol% trimethyl-
phosphine (PMe3); c) with 6 mol% dibenzo[a,e]cyclooctatetraene (dct).
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Angewandte Chemie International Edition
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4
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10.1002/anie.201705087
Angewandte Chemie International Edition
Entry for the Table of Contents
Cyclotrimerization
Davide Brenna, Matteo Villa, Tim N.
Gieshoff, Fabian Fischer, Marko Hapke,
and Axel Jacobi von Wangelin*
__________ Page – Page
Iron-Catalyzed Cyclotrimerization of
Terminal Alkynes by Dual Catalyst
Activation in the Absence of
Reductants
A new iron-catalyzed cyclotrimerization protocol has been developed. The
simple pre-catalyst Fe(hmds)2 does not require the addition of a dedicated
reductant but undergoes rapid substrate-induced activation. With such catalyst
system, highly regioselective cyclotrimerizations of alkynes to 1,2,4-tri-
substituted benzenes proceeded within a few min reaction times at 20°C in 1 M
solution.
A most user-friendly procedure can be adopted by using
FeCl2/LiN(SiMe3)2. Mechanistic studies are indicative of a dual catalyst
activation which involves alkyne deprotonation and reductive elimination to a
low-valent heterotopic iron catalyst.
5
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10.1002/anie.201705087
Angewandte Chemie International Edition
6
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