Copper(i)-amine metallo-organocatalyzed synthesis of carbo- and heterocyclic systems

Article abstract of DOI:10.1039/c2ob06449a

The efficient and atom economical synthesis of 5-membered cyclic structures has been achieved through the combination of amino catalysis and metal catalysis. The discovery of a novel metallo-organocatalytic system merging the use of a catalytic copper(i)

Full text of DOI:10.1039/c2ob06449a

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PAPER
Copper(I)–amine metallo-organocatalyzed synthesis of carbo- and
heterocyclic systems†‡
Benjamin Montaignac,a,b Victor Östlund,a,b Maxime R. Vitale,a,b Virgnie Ratovelomanana-Vidal*a,b and
Véronique Michelet*a,b
Received 24th August 2011, Accepted 21st December 2011
DOI: 10.1039/c2ob06449a
The efficient and atom economical synthesis of 5-membered cyclic structures has been achieved through
the combination of amino catalysis and metal catalysis. The discovery of a novel metallo-organocatalytic
system merging the use of a catalytic copper(I) complex and a catalytic amount of cyclohexylamine
allowed the room temperature preparation of a broad range of skeletons such as cyclopentanes, indanes,
pyrrolidines and tetrahydrofuran, important structural cores of many biologically relevant molecules.
Mechanistic studies were presented.
Introduction
During recent years, the emergence of a new concept that
merges transition metal catalysis1 to organocatalysis2 has been
highlighted.3 The success of such original approach relies on the
fact that the association of both kinds of activations allowed
several new types of reactivities and/or original ways of control-
ling stereoselectivities to be unveiled.3 Several groups including
us have been interested in this concept in the presence of various
transition metals and carbophilic Lewis acids.3–6 In 2008,
Dixon’s and Kirsch’s groups respectively described the carbo-
cyclization of keto and formyl alkynes through the combination
of metal catalysis with aminocatalysis (Scheme 1).4,5 Whereas
both dual catalytic systems were highly efficient for the synthesis
of cyclopentene cores, the preparation of analogous cyclopen-
tanes bearing a quaternary stereogenic center was comparatively
less studied. For this particular transformation, Kirsch et al.
described, on a limited substrate scope, a catalytic system based
on the use of a secondary amine and a rather high catalyst
Scheme 1 Aim of this work.
loading of a gold(I) complex. In 2010, we reported that the car-
bocyclization of α-disubstituted formyl alkynes could be suc-
biologically relevant molecules including prostaglandins.8 As a
cessfully realized using a catalytic quantity of a secondary or
primary amine, and a catalytic amount of cheap indium trichlo-
major drawback of these metallo-organocatalytic systems, the
ride.6,7 These indium/amine based catalytic systems allowed,
rather harsh reaction conditions generated by elevated tempera-
ture (100 °C) and by highly Lewis acidic indium trichloride9
with good to excellent yields, the preparation of a broad variety
of cyclopentanes, an important structural core of many
limited their use to the synthesis of carbon tethered 5-membered
cyclic systems. In the search of a milder combination, we
recently turned our attention toward the use of copper(I) tran-
sition metal complexes. Balme et al. previously reported that the
copper(I) catalyzed anti-carbocupration of stabilized nucleo-
aE.N.S.C.P., Chimie-ParisTech, UMR 7223, Laboratoire Charles Friedel
(LCF), 75005 Paris, France. Fax: +33-1-4407-1062
bCNRS UMR 7223, 75005 Paris, France. E-mail: virginie-vidal@
chimie-paristech.fr, veronique-michelet@chimie-paristech.fr
†Dedicated to Dr C. Bruneau on the occasion of his 60th birthday.
‡Electronic supplementary information (ESI) available: General cycliza-
tion procedure and analytical descriptions of all substrates and carbocy-
philes onto non-activated alkynes could be realized at room
temperature.10 On the other hand, Dixon et al. used such metal
complexes for the preparation of cyclopentenes,4a and also
reported the use of copper(I) complexes in association with a
clization products. See DOI: 10.1039/c2ob06449a
2300 | Org. Biomol. Chem., 2012, 10, 2300–2306
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cinchona based thiourea organocatalyst for a room temperature
and enantioselective version of the Conia-ene reaction of β-keto
esters.11 Following our previous communication concerning an
original copper(I) based metallo-organocatalytic system allowing
the mild carbocyclization of a broad range of carbon and few
nitrogen tethered substrates,12 we report herein a comprehensive
study including the synthesis of cyclopentane, indane, pyrroli-
dine and tetrahydrofuran skeletons (Scheme 1) and presenting
mechanistic insights.
entries 4–5), which could be further enhanced using an equi-
molar amount of triphenylphosphane additive, to reach 70%
after 64 h (Table 1, entry 6). Following this last result, the
addition of 10 mol% triphenylphosphane to this copper complex
was tried but led to a significant drop of reactivity (Table 1,
entry 7). To evaluate the importance of the counter-anion, the
perchlorate and trifluoromethanesulfonate salt of these tetrakis
copper(I) complexes were also tested but both gave either similar
or shoddier results (Table 1, entries 8–9). The influence of the
phosphane additive was then considered, but neither the more
electron rich tricyclohexylphosphane, nor the electron poorer tris
(p-trifluoromethylphenyl)phosphane improved the efficiency of
the catalytic system (Table 1, entries 10–11). Finally, the use of
copper(I) trifluroromethanesulfonate–benzene complex allowed
the reaction to be complete in 16 h at room temperature, provid-
ing the targeted cyclopentane 2 in an encouraging 65% isolated
yield (Table 1, entry 12). However, attempts to improve both the
catalytic activity and the yield with this copper source while
adding triphenylphosphane additive were unsuccessful (Table 1,
entry 13). Considering the well-known instability of copper(I)
trifluoromethanesulfonate–arene complexes, we then considered
generating the copper(I) catalytic species by the in situ reduction
of copper(II) salts.13,4a
Although the reduction of copper(II) trifluoromethanesulfonate
by an equimolar amount of triphenylphosphane led to moderate
reactivity (Table 1 entry 14), the use of four equivalents of phos-
phane allowed full conversion in 22 h yielding 2 in good 86%
yield (Table 1, entry 15). Under these reaction conditions,
several other copper(II) salts including CuBr2, Cu(OAc)2 and
CuSO4·5H2O were tested but none of them provided a better
result than the one obtained with Cu(OTf)2 precatalyst (Table 1,
entries 16–18). For the purpose of our study, we thus selected
the catalytic system consisting of 5 mol% Cu(OTf)2, 20 mol%
triphenylphosphane and 20 mol% of cyclohexylamine.
Results and discussion
The optimization of the catalytic system was obtained while
investigating the carbocyclization reaction of the model substrate
1. A recent study in our group demonstrated the strong influence
of the amine co-catalyst over the reaction pathway of related
metallo-organocatalyzed carbocyclization reactions.6b Accord-
ingly, cyclohexylamine was selected as the best organocatalyst
partner due to its high aptitude for generating enamine inter-
mediates from α-disubstituted aldehydes. The screening of
different copper sources was carried out at room temperature in
1,2-dichloroethane with 5 mol% of metal catalyst loading,
20 mol% of organocatalyst and, in some cases, 5–20 mol% of
additive (Table 1). Firstly, copper(I) iodide was evaluated and
showed poor reactivity, with or without triphenylphosphane
additive and despite long reaction times (Table 1, entries 1–3).
This led us to use the presumably more electrophilic tetrakis
acetonitrile copper(I) complexes. A slight improvement of the
conversion was observed with the tetrafluoroborate salt (Table 1,
Table 1 Optimization of copper based metallo-organocatalytic systems
The scope of this catalytic system was then studied starting
with the evaluation of a range of α-methyl carbon tethered
formyl-alkynes (Table 2). The use of bulkier diisopropyl- or
dibenzylmalonate links did not influence the efficiency of the
carbocyclization reaction, as cyclopentanes 4 and 6 were isolated
in 82% and 89% yield respectively (Table 2, entries 1–2). Fortu-
nately, this catalytic system displayed a good tolerance to many
functional groups such as ether, ester and silylether moieties,
leading to the corresponding carbocyclized products 8, 10, 12
and 14 in yields above 90% (Table 2, entries 3–6). While react-
ing the nonsymmetrical tethered substrate 15, a good global
yield was obtained, although a poor diastereoselectivity of this
process was observed (Table 2, entry 7). Interestingly, the gem-
disulfone 17 smoothly cyclized under these conditions whereas
this particular substrate led to retro-Michael side process under
our previously developed CyNH2/InCl3 catalytic system
(Table 2, entry 8).6b
Diversely α-substituted carbon tethered substrates were pre-
pared and submitted to cyclization in order to assess the
influence of the α-substitution pattern of the aldehyde moiety.
Results are gathered in Table 3. The α-ethyl dimethylmalonate
substrate 19 required a longer reaction time to reach full conver-
sion of the starting material and yielded 67% of cyclopentane 20
(Table 3, entry 1). Similarly, the α-n-butyl and α-benzyl analogs
reacted slowly, and 90 h were required for completion.
Copper source
Entry (5 mol%)
Additive
(x mol%)
Time (h) SM/Pa
1
2
CuI
CuI
—
—
PPh3 (15)
—
—
PPh3 (5)
PPh3 (10)
PPh3 (5)
PPh3 (5)
PCy3 (5)
P(p-CF3C6H4)3
(5)
16
2 w
16
16
64
64
64
64
64
48
48
>95/5
50/50
>95/5
88/12
66/34
30/70
85/15
30/70
70/30
50/50
35/65
3
4
5
6
7
8
9
10
11
CuI
[Cu(MeCN)4]BF4
[Cu(MeCN)4]BF4
[Cu(MeCN)4]BF4
[Cu(MeCN)4]BF4
[Cu(MeCN)4]ClO4
[Cu(MeCN)4]OTf
[Cu(MeCN)4]BF4
[Cu(MeCN)4]BF4
12
13
14
15
16
17
18
Cu(OTf)·½benzene
Cu(OTf)·½benzene
Cu(OTf)2
Cu(OTf)2
CuBr2
Cu(OAc)2
CuSO4·5H2O
—
16
16
16
22
16
16
16
<5/95b
87/13
76/24
<5/95c
90/10
85/15
>95/5
PPh3 (15)
PPh3 (5)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
a Determined from 1H NMR of the crude reaction mixture. b 65%
isolated yield. c 86% isolated yield.
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Table 2 Carbocyclization reactions of α-methyl substituted carbon
tethered substrates
Table 3 Carbocyclization reactions of diversely α-substituted carbon
tethered substrates
Entry
1
Substrate R/R′
19 Et/CO2Me
Product
t (h)
Yielda (%)
67
Yielda
(%)
Entry Substrate R
Product
t (h)
64
1
3 CO2i-Pr
16
82
2
3
4
21 n-Bu/CO2Me
23 Bn/CO2Me
25 Ph/CO2Me
64
90
48b
62
2
5 CO2Bn
17
89
90
28
68
3
4
5
6
7
8
7 CH2OMe
9 CH2OBn
16
16
19
22
17
17
92
95
93
94
93c
92
90c
d
5
27 n-Bu/CH2OMe
29 Bn/CH2OMe
31 Ph/CH2OMe
33 n-Bu/CH2OBn
35 Bn/CH2OBn
37 Ph/CH2OBn
136
72
24
90
72
54
—
11 CH2OAc
13 CH2OSiR′3
15 CH2OBn/
6
87
90
92
87
92
b
7
b
CH2OSiR′3
8
17 SO2Ph
9
a Isolated yield. b OSiR′3
diastereoisomer is shown (determined by NOESY NMR experiment).
= = 60/40, major
OSi(t-Bu)(Ph)2. c dr
10
Corresponding cyclopentanes 22 and 24 were obtained in moder-
ate 62% and 68% yields respectively, due to the appearance of
some unidentified by-products after extended reaction times
(Table 3, entries 2–3). This trend was confirmed with the
α-phenyl substituted substrate 25 for which the cyclization was
inefficient at room temperature and needed to be run at 50 °C in
order to observe reasonable reactivity. Under these modified
reaction conditions, cyclopentane 26 was obtained in 90% iso-
lated yield (Table 3, entry 4). Notably, the cyclizations of the
a Isolated yield. b Incomplete conversion was observed: 21/22 = 20/80.
c Reaction performed at 50 °C. d 27/28 = 30/70
n-butyl and the benzyl substrates 21 and 23 were not signifi-
cantly improved working at 50 °C. Therefore, the bulkiness of
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Table 4 Metallo-organocatalytic preparation of pyrrolidines
the R group in the α position of the aldehyde moiety seems to
have a key influence on the efficiency of cyclization, larger
groups inducing a substantial decrease in reactivity. Analogous
substrates in which the methylester moieties were replaced either
by methoxymethyl or benzyloxymethyl groups were also
engaged in the process. Aside from the peculiar sluggish reactiv-
ity of the n-butyl gem-dimethoxymethyl substrate 27 (Table 3,
entry 5), most of these precursors gave better results than their
malonate counterparts, both in term of isolated yields and reac-
tion times. Accordingly, gem-dimethoxymethyl cyclopentanes
30 and 32 were obtained in good yields, 87% and 90% respect-
ively (Table 3, entries 6–7), and their gem-dibenzyloxymethyl
equivalents 34, 36 and 38 were generated in an average yield of
90% (Table 3, entries 8–10).
Subsequently, we focused on the metallo-organocatalytic
cyclization of aromatic tethered substrates as it would allow the
preparation of indanes, important constituents of biologically
active natural products and compounds exhibiting pharmacologi-
cal properties (Scheme 2).14
Gratifyingly, the dual catalytic system described herein
allowed the clean carbocyclization of the synthesized formyl
alkynes 39, 40, and 41 and led to the corresponding indanyl
derivatives 42, 43 and 44 in good to excellent yields (Scheme 2,
79–91%). In contrast with the previously studied carbon tethered
formyl alkynes (Tables 2 and 3), scarce influence of the R group
in regard to the efficiency or rate of the cyclization reactions was
observed while using these aromatic tethered substrates.
We then envisioned the use of this copper(I) based metallo-
organocatalytic system for the preparation of pyrrolidines, like-
wise key skeletons in many biologically active natural and non-
natural substance.15 Therefore, several nitrogen tethered sub-
strates were prepared and submitted to cyclization (Table 4).
Starting from the N-tosyl α-methyl substituted substrate 45, a
very smooth reaction led in only two hours to the desired N-tosyl
pyrrolidine 46 in 86% yield (Table 4, entry 1). This reaction
could also be efficiently realized starting from the N-benzoyl
protected analogous substrate 47 (79%, Table 4, entry 2). Simi-
larly, the α-n-butyl and the functionalized α-benzyloxyethyl N-
tosyl pyrrolidines 50 and 52 were obtained in good yields in few
hours (Table 4, entries 3–4). The α-benzyl and α-phenyl sub-
strate 53 and 55 afforded their corresponding heterocyclized
derivatives with excellent yields despite longer reaction times
(23–24 h, Table 4, entries 5–6). In the case of 53, difficulties in
monitoring the cyclization led us to arbitrarily conduct the reac-
tion in 24 h in order to ensure full conversion of the starting
material. However, in the case of the phenyl substituted substrate
55, the intermediate formation of 2-phenylpropenal was
observed by 1H NMR spectroscopy,16 which clearly indicated
Entry
1
Substrate R/PG
Product
t (h)
Yielda (%)
86
45 Me/Ts
2
2
3
4
47 Me/COPh
4
6
4
79
91
89
49 n-Bu/Ts
51 (CH2)2OBn/NTs
5
6
53 Bn/NTs
55 Ph/NTs
23
24
96
91
a Isolated yield.
that, in this particular case, a parallel reversible retro-Michael
process also took place. This side-reaction could explain why the
overall cyclization rate of the phenyl substituted substrate 55
decreased, and why 24 h were required for completion. Notably,
we encountered a comparable retro-Michael side process in the
case of the oxygen tethered substrate 57. Its cyclization led to
the corresponding derivative 58 in 51% yield, thus expanding
our metallo-organocatalytic approach to the synthesis of tetra-
hydrofuran cores (Scheme 3).
In order to evaluate the efficiency of this metallo-organo-
catalytic system for the formation of larger rings such as
Scheme 2 Metallo-organocatalytic preparation of indanes.
Scheme 3 Metallo-organocatalytic preparation of tetrahydrofuran 58.
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Scheme 4 Cyclization of homo-propargyl compounds and a non-term-
inal alkyne.
cyclohexanes or piperidines, substrates 59 and 61 were prepared
and submitted to cyclization (Scheme 4). In both cases, the cata-
lytic system described herein did not promote the desired cycli-
zation at room temperature whereas prolonged heating of the
reaction mixture at 50 °C led to complete degradation of starting
materials. Therefore, this method, although fairly efficient for the
synthesis of 5-membered carbo- and heterocycles, seemed
inadequate for the formation of analogous 6-membered rings.
Additionally, the cyclization of the non-terminal alkyne 63 gave
rise, at room temperature, to its slow degradation which was con-
sistent with the previously reported sluggish copper(I)-mediated
5-exo-dig cyclization of malonates onto disubstituted alkynes,10b
and underlined the poor stability of such precursors. Conse-
quently, this methodology could not be extended to the use of
formyl alkynes possessing a disubstituted alkynyl moiety.
The reaction rate discrepancies observed during the investi-
gation of this broad range of carbon, aromatic, nitrogen and
oxygen tethered substrates prompted us to look at mechanistic
implications. We suggest that the rate determining step of this
reaction, apart from the cases in which retro-Michael took place,
would be the attack of the transient enamine onto the copper(I)
activated alkyne moiety,17 and moreover, that it would occur
according to a chair like transition state (Scheme 5).
This mechanistic picture is supported by the fact that hindered
carbon tethered substrates, in which R is different from a methyl
group, were more sluggish to react (Table 2). On one hand, the
development of deleterious 1,3-diaxial strains would disfavor the
required transition state conformation and therefore slow down
the cyclization process. On the other hand, aromatic and nitrogen
tethered precursors were poorly dependant on the steric hin-
drance generated by the group in α-position of the aldehyde
moiety. With respect to these precursors, we could assume that
the sp2 geometry18 at the 3 position would set the transition state
free from these detrimental 1,3-diaxial strains, and thus their car-
bocyclization reactions were facilitated.
Scheme 6 Investigation of the carbocupration stereoselectivity.
was carried out on the deuterium labelled compound 9-D
(Scheme 6). Taking into account the well-known ability of
copper(I) to promote the formation of copper acetylides from
terminal alkynes, a D–H scrambling could be observed. There-
fore this study was realized at incomplete conversion in order to
limit this undesired process. At first, the carbocyclization was
realized with 5 mol% Cu(OTf)2, 20 mol% PPh3 and 20 mol%
CyNH2 and led to diversely deuterated or non-deuterated carbo-
1
cycles A–D. Analysis of the H NMR spectrum in the ethylenic
region of the crude reaction mixture gave the relative ratios of A,
C and D,20 respectively 47%, 43% and 10%. This would imply
a predominant anti-carbocupration pathway, since the labelled
carbocycle A was mainly formed during this process (Scheme 5,
conditions a). The participation of syn-carbocupration could not
be fully excluded, considering the presence of a small amount of
D. Since the formation of D could either be rationalized through
a syn-carbometallation followed by protodemetallation, or, less
straightforwardly, could result from a D–H exchange/anti-carbo-
cupration/deuterodemetallation pathway, the same experiment
was repeated with a stoichiometric amount of cyclohexylamine.
The presence of a larger quantity of amine would allow, while
acting as a proton source, to distinguish between this two pro-
cesses since deuterodemetallation should be depressed compared
to protodemetallation (Scheme 5, conditions b). Under these
reaction conditions, as expected, a higher relative amount of C
was observed, and more interestingly, the formation of D was
limited compared to the formation of A. Therefore, the formation
of D probably came from the D–H exchange/anti-carbocupra-
tion/deuterodemetallation pathway, and thus, in overall, carbo-
cupration occurred in an anti-stereoselective manner.
To reinforce this mechanistic explanation and confirm the
initial hypothesis of an anti-carbocupration step,19 the reaction
Finally, we propose the following catalytic cycle in which the
metallo-organocatalytic process would involve the amine catalyst
as accountable for the formation of a nucleophilic enamine (in
tautomerism with its imine form), whereas the in situ generated
copper(I) complex would enhance the electrophilicity of the
alkynyl residue. Both activations would then trigger the carbo-
cyclization process through an anti-carbocupration pathway
Scheme 5 Transition state proposal.
2304 | Org. Biomol. Chem., 2012, 10, 2300–2306
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2 (a) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2001, 40, 3726;
(b) A. Berkessel and H. Groger, Asymmetric Organocatalysis: From Bio-
mimetic Concepts to Application in Asymmetric Synthesis, Wiley-VCH,
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3 For reviews, see: (a) A. Duschek and S. F. Kirsch, Angew. Chem., Int.
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4 (a) T. Yang, A. Ferralli, L. Campbell and D. J. Dixon, Chem. Commun.,
2008, 2923; (b) J. T. Binder, B. Crone, T. T. Haug, H. Menz and
S. F. Kirsch, Org. Lett., 2008, 10, 1025.
5 For other examples combining aminocatalysis to metal catalysis, see:
(a) I. Ibrahem and A. Córdova, Angew. Chem., Int. Ed., 2006, 45, 1952;
(b) Q. Ding and J. Wu, Org. Lett., 2007, 9, 4959; (c) F. Bihelovic,
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(g) K. L. Jensen, P. T. Franke, C. Arróniz, S. Kobbelgaard and
K. A. Jørgensen, Chem.–Eur. J., 2010, 16, 1750; (h) S. Lin, G.-L. Zhao,
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Scheme 7 Proposed metallo-organocatalytic cycle.
following a chair like transition state, and the catalysts would be
regenerated by hydrolysis and protodemetallation of the transient
iminium vinylcopper accompanied by the liberation of the
desired carbocyclized carbaldehyde (Scheme 7).
Conclusions
In summary, we report herein an original metallo-organocatalytic
system that combines both the use of catalytic quantities of
cyclohexylamine with the use of a copper(I) catalyst. This cataly-
tic system allowed the efficient room temperature carbocycliza-
tion reactions of a broad range of α-disubstituted formyl alkynes
leading to a high variety of 5-membered cyclic skeletons includ-
ing cyclopentanes, indanes, pyrrolidines and tetrahydrofuran, in
good to excellent yields. Differences in cyclization rates in
addition to deuterium labelling experiments tend to suggest a
chair like transition state in which an anti-stereoselective carbo-
cupration ring closure operates. Further investigations concerning
a tandem Michael addition/carbocyclization process, as well as
an enantioselective version of this reaction are currently ongoing
and will be reported in due course.
6 (a) B. Montaignac, M. R. Vitale, V. Michelet and V. Ratovelomanana-
Vidal, Org. Lett., 2010, 12, 2582; (b) B. Montaignac, M. R. Vitale,
V. Ratovelomanana-Vidal and V. Michelet, J. Org. Chem., 2010, 75,
8322.
7 For other examples of alkyne activation with indium salts, see:
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E. Nakamura, Org. Lett., 2009, 11, 1845; (b) Y. Itoh, H. Tsuji, K.-
I. Yamagata, K. Endo, I. Tanaka, M. Nakamura and E. Nakamura, J. Am.
Chem. Soc., 2008, 130, 17161; (c) T. Fujimoto, K. Endo, H. Tsuji,
M. Nakamura and E. Nakamura, J. Am. Chem. Soc., 2008, 130, 4492;
(d) H. Tsuji, K. Yamagata, Y. Itoh, K. Endo, M. Nakamura and
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Acknowledgements
This work was supported by the Centre National de la Recherche
Scientifique (CNRS) and the Ministère de l’Education et de la
Recherche for financial support. B. M. is grateful to the Minis-
tère de l’Education et de la Recherche for a grant (2009-2012).
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19 The stereoselectivity of carbocupration is generally anti (see ref. 10),
however, in scarce examples it may occur in a syn manner (ref. 11).
20 The presence of B was detected by analyzing the aldehydic 1H-NMR
region but the relative ratio was negligible (<5%).
2306 | Org. Biomol. Chem., 2012, 10, 2300–2306
This journal is © The Royal Society of Chemistry 2012