Cyclotrimerization for the Synthesis of Cyclopropanes

Article abstract of DOI:10.1002/anie.201600807

The synthesis of small rings by functionalization of C(sp³)-H bonds remains a great challenge. We report for the first time a copper-catalyzed [1+1+1] cyclotrimerization of acetophenone derivatives under mild reaction conditions. The reaction has a broad scope for the stereoselective synthesis of cyclopropanes by trimerization of acetophenone. The developed transformation is based on an extraordinary copper-catalyzed cascade process that allows saturated carbocycles to be obtained for the first time by cyclotrimerization through functionalization of C(sp³)-H bonds. The cascade of sixfold C(sp³)-H bond functionalization allows the synthesis of cyclopropanes in a highly stereoselective approach. Give it a tri: Copper-catalyzed oxidative [1+1+1] cyclotrimerization of acetophenone derivatives under mild reaction conditions and with a broad reaction scope has been developed. This transformation is a radical cascade process that allows saturated carbocycles to be obtained by cyclotrimerization through functionalization of C(sp³)-H bonds.

Full text of DOI:10.1002/anie.201600807

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201600807
German Edition: DOI: 10.1002/ange.201600807
Cyclotrimerization Very Important Paper
[1+1+1] Cyclotrimerization for the Synthesis of Cyclopropanes
Srimanta Manna and Andrey P. Antonchick*
Abstract: The synthesis of small rings by functionalization of
3
À
C(sp ) H bonds remains a great challenge. We report for the
first time a copper-catalyzed [1+1+1] cyclotrimerization of
acetophenone derivatives under mild reaction conditions. The
reaction has a broad scope for the stereoselective synthesis of
cyclopropanes by trimerization of acetophenone. The devel-
oped transformation is based on an extraordinary copper-
catalyzed cascade process that allows saturated carbocycles to
be obtained for the first time by cyclotrimerization through
3
À
functionalization of C(sp ) H bonds. The cascade of sixfold
3
À
C(sp ) H bond functionalization allows the synthesis of
cyclopropanes in a highly stereoselective approach.
I
ntermolecular cyclotrimerization reactions are among the
most efficient methods for the synthesis of complex products
in a single step from simple nonfunctionalized building
blocks.[1] The cyclotrimerization is expected to have out-
standing potential because of is high atom economy, high
product yields, and broad reaction scope. Efficient, selective,
and practical procedures based on the [2+2+2] cyclotrime-
rization of alkynes were developed for the synthesis of
polysubstituted benzenes (Figure 1a).[2] Achievements in the
regioselective formation of various benzenes resulted in the
broad application of [2+2+2] cyclotrimerization for the
synthesis of materials, drugs, and bioactive compounds.[2,3]
The [2+2+2] cyclotrimerization of acetophenones provides
a regioselective approach to polysubstituted aromatic com-
pounds.[4] Those processes occur under mild reaction con-
ditions and produce water as a by-product. However, known
methods of cyclotrimerization only allow the synthesis of
unsaturated carbocyclic compounds and the synthesis of fully
saturated carbocycles has not been reported. The biggest
problem for the synthesis of saturated carbocycles is associ-
ated with the possible formation of stereocenters, which
Figure 1. Cyclotrimerization. a) [2+2+2] Cyclotrimerization of acety-
lenes for the synthesis of benzene derivatives. b) [2+2+2] Cyclotrime-
rization of acetophenones for the synthesis of benzene derivatives.
c) Present work: [1+1+1] cyclotrimerization of acetophenones for the
synthesis of cyclopropane derivatives.
approach for the synthesis of target compounds. Here we
demonstrate the first catalytic approach for the synthesis of
small strained cyclopropanes by an unprecedented [1+1+1]
cyclotrimerization of simple ketones. A notable feature of our
approach is its high stereoselectivity and its extraordinary
cascade of regioselective sixfold functionalization of unreac-
3
À
tive C(sp ) H bonds. Our results reveal a new method for the
synthesis of cyclopropanes[5] and an unparalleled cascade
reaction mechanism in which a single catalyst is used in
several steps.
would require
a regio-, diastereo-, and stereoselective
Having an interest in the development of novel oxidative
coupling methods,[6,7] we envisaged that a novel approach for
the synthesis of cyclopropanones could be realized through
the cyclotrimerization of acetophenone under radical reac-
tion conditions[6] (Figure 1c). A radical addition of acetophe-
none to unsaturated diketone A could provide the desired
cyclopropane. Intermediate A could be obtained from 1,4-
diketone B under oxidative reaction condition. Furthermore,
diketone B can be obtained by the oxidative coupling of
ketones.[8] Therefore, we would need three molecules of
ketones to create a small cycle.
To test our hypothesis, we began our study on the [1+1+1]
cyclotrimerization of 4-fluoroacetophenone (1a) using CuI
(10 mol %) in the presence of 2,2’-bipyridine-based ligands
(Table 1, entries 1–6, and see Table S1 in the Supporting
Information). To our delight, we observed a ligand-induced
[*] S. Manna, Dr. A. P. Antonchick
Abteilung Chemische Biologie
Max-Planck-Institut fꢀr Molekulare Physiologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
and
Fakultꢁt Chemie und Chemische Biologie
Technische Universitꢁt Dortmund
Otto-Hahn-Strasse 4a, 44227 Dortmund (Germany)
E-mail: andrey.antonchick@mpi-dortmund.mpg.de
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201600807.
ꢂ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial NoDerivs License, which
permits use and distribution in any medium, provided the original
work is properly cited, the use is non-commercial, and no
modifications or adaptations are made.
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Table 1: Screening of reaction conditions.[a]
the cyclotrimerization product was reduced when various
copper(I) salts were used. The application copper(II) salts as
the precatalyst led to a further decrease in the product yield.
Thus, subsequent cyclotrimerization reactions were per-
formed in the presence of CuI. The effect of temperature
was next examined. The yield of the desired product 2a was
increased to 86% on reduction of the reaction temperature
from 1008C to 908C (entry 13). However, a further decrease
or increase in temperature led to a lower yield of 2a (see
Table S4). No formation of the target product was observed
when polar solvents such as H2O, tert-AmOH, or DMSO were
used (entries 14–17 and see Table S5). Only the formation of
trace amounts of product was observed in nonpolar solvents
such as toluene and p-xylene. Aromatic halogenated solvents
were found to be suitable for the [1+1+1] cyclotrimerization
of acetophenones, with chlorobenzene found to be the best
solvent for the synthesis of cyclopropanes.
Entry Cu salt
(mol %)
Ligand
(mol %)
Solvent Oxidant
(equiv)
Yield [%]
1
2
3
4
5
6
7
8
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (5)
CuBr (10)
CuCl (10)
Cu(OAc)2
(10)
L1 (20)
L2 (20)
L3 (20)
L4 (20)
L5 (20)
L6 (20)
L5 (20)
L5 (20)
L5 (20)
L5 (20)
L5 (20)
L5 (20)
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DCP
TBHP
DTBP
DTBP
DTBP
DTBP
traces
traces
traces
41
73
55
55
15
48
68
With the optimized reaction conditions in hand, we next
investigated the scope of the unprecedented copper-catalyzed
[1+1+1] cyclotrimerization. We found that various acetophe-
nones can be transformed into the corresponding products in
moderate to good yields (Table 2). Interestingly, a wide array
of functional groups such as halogens, carbonyl, sulfonamide,
nitryl, alkoxy, and alkyl were tolerated under the optimized
conditions (Table 2, entries 1–19). To our delight, various
electron-withdrawing groups as well as electron-donating
groups on the aryl moiety were tolerated. However, aceto-
phenones with electron-withdrawing groups reacted faster
than electron-rich derivatives. Furthermore, substitutions in
the ortho-, meta-, and para- positions give comparable results
under the developed reaction conditions. Polysubstituted
acetophenones were also tested for the formation of the
desired products. It is remarkable that heterocyclic deriva-
tives such as 2-acetylthiophene were found to form the
desired product in 52% yield under the developed oxidative
reaction conditions (Table 2, entry 20). It is interesting that
although the bond dissociation energies (BDEs) of all the
methyl groups in 3,4-dimethylacetophenone are similar
(BDE = 89–91 kcalmolÀ1), the reaction occurs by functional-
ization of the methyl group attached to the carbonyl group
(Table 2, entry 15). Moreover, the reaction with allyl 4-
acetylbenzoate (Table 2, entry 6) gave the desired cyclopro-
pane 2 f in moderate yield, despite a methylene group with
a dramatically lower BDE being present (BDE = 81 kcal
9
10
11
12
72
traces
13[b] CuI (10)
14[b] CuI (10)
15[b] CuI (20)
16[b] CuI (20)
17[b] CuI (20)
L5 (20)
L5 (20)
L5 (20)
L5 (20)
L5 (20)
PhCl
PhMe DTBP
DMF
PhF
PhBr
DTBP
86
traces
43
68
74
DTBP
DTBP
DTBP
[a] Reaction conditions: 1a (0.5 mmol), oxidant (3 equiv), copper salt
(10 mol%), ligand (20 mol%) in solvent (2.0 mL) at 1008C for 8 h under
argon [b] Reaction carried out at 908C for 8 h. DTBP=di-tert-butyl
peroxide, DCP=dicumyl peroxide, TBHP=tert-butyl hydrogen peroxide.
formation of the desired cyclopropane[9] 2a in the presence of
di-tert-butyl peroxide (DTBP) as an oxidant in chlorobenzene
at 1008C under argon after 12 h. Pleasingly, we found that
4,4’-di-tert-butyl-2-2’-bipyridine (L5) was the best ligand for
the copper-catalyzed cyclotrimerization of acetophenone 1a.
It is notable that the product of the [1+1+1] cyclotrimeriza-
tion (2a) was formed as a single stereoisomer. Unfortunately,
other nitrogen-containing ligands did not give promising
results for the synthesis of 2a (see Table S1). We then
examined various oxidants. The yield of cyclopropane 2a was
reduced when dicumyl peroxide or tert-butyl hydroperoxide
were used (Table 1, entries 7 and 8, and see Table S2).
Furthermore, cyclotrimerization occurred when benzoyl per-
oxide, hydrogen peroxide, K2S2O8, or (diacetoxyiodo)ben-
zene were used as oxidants (see Table S2). The formation of
product 2a drastically decreased when air was used instead of
argon. The highest yield of the desired product 2a (73%) was
obtained using DTBP (3 equiv). A reduction in the loading of
CuI from 10 mol % to 5 mol % led to a decrease of 2a.
Various copper salts were examined to identify the best
precatalyst (Table 1, entries 10–12 and Table S3). The yield of
molÀ1). Therefore, the developed method allows the func-
3
À
tionalization of a strong C(sp ) H bond in the presence of
a weak one. Finally, we scaled-up the experiment using 1c
(6 mmol). Product 3c was formed smoothly in the scaled-up
experiment in a yield of 66%.
Following our synthetic studies, we performed a number
of experiments to gain insight into the reaction mechanism of
the copper-catalyzed [1+1+1] cyclotrimerization reaction.
Based on the reaction design, we carried out control experi-
ments using possible intermediates. Initially, we tested
diketone 3, which can be formed by the oxidative dimeriza-
tion of acetophenones (Figure 2a).[10] Under optimized reac-
tion conditions, diketone 3 reacts with acetophenone 1d to
afford cyclopropane 4 in good yield and regioselectivity.
Moreover, under the same reaction conditions but in the
2
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Table 2: Scope of the [1+1+1] cyclotrimerization.[a]
Entry
R
Product
2a
t [h]
8
Yield [%]
1
2
3
4
5
86
66
73
88
65
2b
8
2c
8
2d
8
2e
8
6
2 f
6
43
7
8
2g
2h
5
6
79
62
9
2i
8
35
10
2j
8
43
69
11[b]
2k
12
12
2l
8
46
68
77
53
13
2m
2n
2o
7
14
8
15[c]
18
16
2p
2q
2r
18
8
43
65
46
41
17
18[b]
12
19
20
2s
2t
8
8
Figure 2. Studies on reaction mechanism and plausible reaction mech-
anism. a) Control experiments. b) Reaction mechanism.
52
[a] Reaction conditions: 2 (0.5 mmol), DTBP (3 equiv), CuI (10 mol %),
L5 (20 mol%) in PhCl (2.0 mL) at 908C for 5–8 h under argon. Yields are
given for isolated products. All products were formed with d.r.>20:1.
[b] CuI (20 mol %), L5 (30 mol %) were used at 758C for 12 h under
argon. [c] Reaction was carried out in 1 mL DMF for 18 h.
[1+1+1] cyclotrimerization proceeds through the following
reaction sequence: 1) dimerization of ketones to 1,4-dike-
tones, 2) oxidation of 1,4-diketones to but-2-ene-1,4-dione,
and 3) annulation of but-2-ene-1,4-dione with a third equiv-
alent of acetophenone. The formation of cyclopropanes was
suppressed in the presence of radical scavengers such as
TEMPO under the optimized reaction conditions. Therefore,
cyclotrimerization involves the formation of radical inter-
mediates. However, the kinetic isotopic effect was the same at
absence of acetophenone 1d, the unsaturated diketone 5 was
formed in excellent yield from diketone 3. The reaction of
diketone 5 with acetophenone 1d provided product 4 in high
yield. Based on those experiments, we concluded that the
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c) R. P. Chopade, J. Louie, Adv. Synth. Catal. 2006, 348, 2307 –
2327; d) S. Kotha, E. Brahmachary, K. Lahiri, Eur. J. Org. Chem.
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1.4 (see the Supporting Information for details). Hence, the
abstraction of any of the six hydrogen atoms is not the rate-
limiting step. The use of trideuterated acetophenone ([D3]-
1k) in the cyclotrimerization resulted in the trideuterated
product ([D3]-2k), with a deuterium incorporation of > 95%.
Therefore, the observed diastereoselectivity of the reaction is
not a result of epimerization after formation of the cyclo-
propane.
On the basis of the above preliminary results, a plausible
mechanism is shown in Figure 2b. Initially, the CuII complex is
generated by oxidation of CuI in the presence of DTBP.[6,11] In
the next step, acetophenone 1 is oxidized in its enol form 1’ by
a CuII species to afford radical 6. Subsequent dimerization of 6
leads to the formation of diketone 7. Diketone 7 subsequently
undergoes the next step of oxidation through its enol form 7’
to form radical 8, which is trapped by the CuII species to form
organocuprate 9. Intermediate 9 then undergoes a b-hydride
elimination to yield unsaturated diketone 10 with complete
trans selectivity. Subsequent addition of radical 6 to 10 leads
to the formation of radical 11, which is trapped by the CuII
species to form intermediate 12. In a next step, 12 is converted
into the key metallocycle 13 through ligand exchange of the
enol form 12’. Reductive elimination of the CuI species from
intermediate 13 results in the stereoselective formation of
cyclopropane 2.
In conclusion, we have discovered an extraordinary
[1+1+1] cyclotrimerization for the synthesis of cyclopropane
rings. For the first time, cyclotrimerization was applied to the
stereoselective synthesis of small saturated carbocycles from
nonfunctionalized acetophenone derivatives. The discovery is
based on an unprecedented copper-catalyzed cascade process.
The cyclotrimerization showed broad scope. Mechanistic
studies revealed the reaction had a novel radical pathway.
This general catalytic [1+1+1] cyclotrimerization reaction
allows direct access to the stereoselective synthesis of cyclo-
propanes and provides an inspiration for the development of
novel methods for the synthesis of saturated carbocycles by
cyclotrimerization.
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Received: January 24, 2016
Published online: && &&, &&&&
4
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Communications
Cyclotrimerization
Give it a tri: Copper-catalyzed oxidative
[1+1+1] cyclotrimerization of acetophe-
none derivatives under mild reaction
conditions and with a broad reaction
scope has been developed. This trans-
formation is a radical cascade process
that allows saturated carbocycles to be
S. Manna,
A. P. Antonchick*
&&&& — &&&&
[1+1+1] Cyclotrimerization for the
Synthesis of Cyclopropanes
obtained by cyclotrimerization through
3
À
functionalization of C(sp ) H bonds.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
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5
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