InCl3/CyNH2 cocatalyzed carbocyclization reaction: An entry to α-disubstituted exo -methylene cyclopentanes

Article abstract of DOI:10.1021/jo1018552

An efficient and cheap synthetic approach to functionalized exo-methylene cyclopentanes has been developed from α-disubstituted formyl-alkynes by merging amine catalysis with the indium activation of alkynes. We uncovered the crucial role of the amine cocatalyst and the development of a new cooperative catalytic system allowed the cyclization of a broad range of substrates. A mechanistic study was realized in order to rationalize the determining influence of the amine cocatalyst.

Full text of DOI:10.1021/jo1018552

pubs.acs.org/joc
would not be possible by either catalysis alone.4 In this
InCl3/CyNH2 Cocatalyzed Carbocyclization
Reaction: An Entry to r-Disubstituted
exo-Methylene Cyclopentanes
context, enamine organocatalysis was successfully combined
to several transition metal activation processes, such as ruth-
enium, palladium, gold, or copper C-C bond formation.5 In
the context of combining enamine organocatalysis to the
metal activation of alkynes, some limitations arise in the case
of gold and copper,5g-k where either an internal isomeriza-
tion of the exomethylene function occurred or moderate
yields are obtained for disubstituted aldehydes.5g We re-
cently investigated the carbocyclization of R-disubstituted
formyl-alkynes in the presence of indium (Scheme 1).6
Benjamin Montaignac, Maxime R. Vitale,
ꢀ
Virginie Ratovelomanana-Vidal,* and Veronique Michelet*
E.N.S.C.P., Chimie ParisTech, UMR 7223,
Laboratoire Charles Friedel, 11 rue P. et M. Curie,
75231 Paris Cedex 05, France
virginie-vidal@chimie-paristech.fr;
veronique-michelet@chimie-paristech.fr
SCHEME 1. Combination of Enamine Catalysis to the Metal-
Catalyzed Activation of Alkynes
Received September 20, 2010
Despite the efficiency of the dual catalytic system com-
posed of a secondary amine, (Cy)(i-Pr)NH, and an indium
salt, InCl3 for R-methyl and R-phenyl substrates, we encoun-
tered a more sluggish reactivity of n-butyl, benzyl, or iso-
propyl corresponding substrates, which led to their degrada-
tion in our initially optimized reaction conditions. Con-
sidering the high added value of the cyclopentane core,7 its
preparation still requires investigations to allow an efficient
and cheap process. We wish to report here an efficient co-
operative catalytic system based on the catalytic use of a
primary amine and the mechanistic implications during the
carbocyclization process.
To find an efficient catalytic system for the carbocycliza-
tion of R-disubstituted aldehydes, the model n-butyl-substi-
tuted alkynyl derivative 1 was initially submitted to 20 mol %
of InCl3 salts in the presence of 20 mol % of various amines in
1,2-dichloroethane at 100 °C (Table 1). The use of (Cy)-
(i-Pr)NH led mainly to the formation of degradation pro-
ducts after prolonged reaction times (Table 1, entry 1). We
anticipated that this lack of reactivity could arise from the
An efficient and cheap synthetic approach to functionalized
exo-methylene cyclopentanes has been developed from
R-disubstituted formyl-alkynes by merging amine catalysis
with the indium activation of alkynes. We uncovered the
crucial role of the amine cocatalyst and the development of a
new cooperative catalytic system allowed the cyclization of a
broad range of substrates. A mechanistic study was realized
in order to rationalize the determining influence of the amine
cocatalyst.
The twentieth century has been the arena of catalysis and
has witnessed the emergence of transition metal catalysis1
and organocatalysis.2 In 2003, Krische et al. reported that a
phosphine organocatalyst in association to a catalytic amount
of a palladium (0) complex allowed the cycloallylation of
enones.3 Since this seminal work, the concept of merging
organocatalysis to transition metal catalysis has flourished
and has opened the way to several new reactivities which
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2007, 9, 5063. (e) Vulovic, B.; Bihelovic, F.; Matovic, R.; Saicic, R. N.
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Org. Lett. 2008, 10, 1025. (h) Yang, T.; Ferralli, A.; Campbell, L.; Dixon,
D. J. Chem. Commun. 2008, 2923. (i) Zhao, G.-L.; Ullah, F.; Deiana, L.; Lin,
S.; Zhang, Q.; Sun, J.; Ibrahem, I.; Dziedzic, P.; Cordova, A. Chem.-Eur. J.
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Jørgensen, K. A. Chem.-Eur. J. 2010, 16, 1750. (k) Yu, C.; Zhang, Y.;
Zhang, S.; He, J.; Wang, W. Tetrahedron Lett. 2010, 51, 1742.
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8322 J. Org. Chem. 2010, 75, 8322–8325
Published on Web 11/05/2010
DOI: 10.1021/jo1018552
r
2010 American Chemical Society

Montaignac et al.
JOCNote
TABLE 1. Optimization of the Amine Catalyst for Hindered Substrates
TABLE 2. Substrate Scope of the InCl3/CyNH2 Catalytic System
entry
amine
t (h)a
yield (%)b
1 ref6
2
3
4
5
6
7
8
Cy(i-Pr)NH
Bn2NH
BnMeNH
(n-Pr)2NH
Et2NH
n-BuNH2
BnNH2
CyNH2
i-PrNH2
(()-PhMeCHNH2
t-BuNH2
72
62
80
62
62
40
48
0.7
6
2.5
40
24
100
6
36
36
25
nd
nd
34
81
73
74
nd
47
48
22
80c
80d
9
10
11
12
13
14
15
16
C6H5NH2
p-MeOC6H4NH2
p-NO2C6H4NH2
CyNH2
1
7
CyNH2
aTime to reach full GC conversion of 2. bIsolated yield. c10 mol % of
InCl3. d5 mol % of InCl3.
enhanced allylic strains generated by bulky groups in
R-position of the aldehyde moiety and the rather encumbered
secondary amine (Cy)(i-Pr)NH during the enamine forma-
tion. Less bulky secondary amines such as Bn2NH, BnMeNH,
(n-Pr)2NH, or Et2NH were therefore tested. Although those
amines allowed the desired cyclopentane 2 to be formed to
some extent, the reactivity was still sluggish and the formation
of several unidentified byproducts was observed. As a result,
only moderate yields (25-36%) could be obtained while using
secondary amines (Table 1, entries 2-5).
The use of linear primary amines such as n-butylamine or
N-benzylamine resulted in slow cyclization reactions in com-
petition with degradation processes (Table 1, entries 6 and 7).
A striking difference was observed when more hindered and
more electron-rich R-disubstituted primary amines were
used. Indeed, CyNH2, i-PrNH2, or racemic PhMeCHNH2
allowedthecarbocyclizationreaction, veryrapidlyandcleanly,
and led to the desired cyclopentane 2 in 73-81% isolated
yields (Table 1, entries 8-10). On the other hand, the use of
R-trisubstituted primary amine t-BuNH2 only led to degra-
dation (Table 1, entry 11). Anilines with different electronic
properties were also evaluated. Although aniline and p-OMe
aniline induced the formation of the desired cyclopentane,
the cyclization reactions were slow and led only to moderate
isolated yields (47-48%) (Table 1, entries 12 and 13). A
faster reaction took place with the electron-poor p-NO2
aniline; however, 2 was obtained in poor yield (Table 1,
entry 14). Therefore, CyNH2 was selected as amine catalyst
for the cyclization of hindered substrates. Notably, the use of
lower indium catalyst loadings was not detrimental to the
carbocyclization reaction. Indeed, 10 mol % of InCl3 did not
significantly affect the kinetics of the cyclization, nor the
yield in cyclopentane 2 (Table 1, entry 15), whereas 5 mol %
of InCl3 resulted in a slower, yet clean, reaction (Table 1,
entry 16). Consequently, the catalytic system composed of
10 mol % of InCl3 and 20 mol % of CyNH2 was chosen for
aIsolated yield. b20 mol % of InCl3, 160 h. 1H NMR of the crude
indicates a 20/80 9/10 ratio and the formation of several unidentified
byproducts. cdr=1.75/1 determined by 1H NMR of the crude reaction
mixture (major diastereomer is shown).
the cyclizations of a broader range of R-branched formyl
alkynes (Table 2).
The InCl3/CyNH2 catalytic system proved to be very eff-
cient for the carbocyclization of other hindered substrates
such as n-butyl-substituted substrate 3 and benzyl-substituted
substrates 5 and 7. Indeed, cyclopentanes 4, 6, and 8 were
all obtained in good yields up to 99% (Table 2, entries 1-3).
J. Org. Chem. Vol. 75, No. 23, 2010 8323

Montaignac et al.
JOCNote
SCHEME 2. Possible Mechanisms
SCHEME 3. Carbocyclization of Deuterium-Labeled and Non-
teminal Alkyne Substrates 13-D and 27
to the vinyl indium species I,9 which, after protodemetalation
and hydrolysis, would afford the carbocyclization product
(Scheme 2, path A). The second pathway would imply an
indium enolate, resulting from the amine-induced R-deproto-
nation of the aldehyde moiety. Nakamura et al. recently de-
monstrated that such indium enolate species are involved in the
addition of 1,3-dicarbonyl compounds onto alkynes, and that
the carbometalation step then proceeds in a cis manner.10
According to this second reaction mechanism the vinyl indium
II would be generated, and would evolve, after protodemetala-
tion, to the corresponding cyclopentane (Scheme 2, path B).
To obtain some insights on the nature of the reaction
mechanism(s) involved, the deuterium-labeled substrate 13-D
and the nonterminal alkyne 27 were prepared and engaged
with the InCl3/CyNH2 catalytic systems. The use of the
InCl3/CyNH2 catalytic system afforded exclusively a single
isomer of 14-D with 100% deuterium at the cis position,11
and no D-H scrambling was detected. In the case of the
methyl-substituted alkyne 27, the CyNH2-based catalytic
system led exclusively to the formation of the (Z) isomer of
28 (Scheme 3, eq 2).11 The primary amine CyNH2 would
therefore promote the enamine/anti-carbometalation reac-
tion mechanism (Scheme 2, path A).
As expected, when the reaction was conducted in the pre-
sence of the much hindered precursor 9 (R=i-Pr), a signi-
ficant decrease of reactivity was observed but 10 was isolated
in 28% yield (Table 2, entry 4).
This new catalytic system was also evaluated in the carbo-
cyclizations of diversily functionalized methyl-substituted
and phenyl-substituted formyl-alkynes, 11, 13, 15, 17, 21, 23,
and 25. It is noteworthy that, in all cases better results were
obtained both in terms of reactivity and isolated yield than in
the presence of the (Cy)(i-Pr)NH/InCl3 catalytic system that
we previously described6 (Table 2, entries 4-8 and 10-12).
The reaction of the dissymmetric substrate 19 provided
cyclopentanes 2f in excellent yield and moderate diasteros-
electivity (Table 2, entry 9).
The presence of both the InCl3 and amine catalysts was
required for the carbocyclizations to take place, thus emphasiz-
ing the necessity of combining catalysis for this reaction.8
Mechanistically, two pathways may be envisioned. The nucleo-
philic addition of a secondary or primary amine on the
aldehyde moiety would lead to the formation of an enamine,
whereas InCl3 would be responsible for the activation of the
alkyne moiety. Following this hypothesis, the anti nucleophilic
addition of the enamine on the activated alkyne would lead
We also compared these results with the previously re-
ported system: when the (Cy)(i-Pr)NH/InCl3 catalytic system
(10) For an example of InCl3-catalyzed cis-addition to alkynes, see: (a) Tsuji,
H.; Tanaka, I.; Endo, K.; Yamagata, K.-I.; Nakamura, M.; Nakamura, E.
Org. Lett. 2009, 11, 1845. (b) Itoh, Y.; Tsuji, H.; Yamagata, K.-I.; Endo, K.;
Tanaka, I.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2008, 130,
17161. (c) Fujimoto, T.; Endo, K.; Tsuji, H.; Nakamura, M.; Nakamura, E.
J. Am. Chem. Soc. 2008, 130, 4492. (d) Tsuji, H.; Yamagata, K.; Itoh, Y.;
Endo, K.; Nakamura, M.; Nakamura, E. Angew. Chem., Int. Ed. 2007, 46,
8060. (e) Endo, K.; Hatakeyama, T.; Nakamura, M.; Nakamura, E. J. Am.
Chem. Soc. 2007, 129, 5264. (f) Nakamura, M.; Endo, K.; Nakamura, E.
J. Am. Chem. Soc. 2003, 125, 13002.
(8) The reaction without InCl3 leads to the recovery of the starting
material, whereas the absence of amine promotes the rapid degradation of
the cyclization precursor.
(9) For an example of InCl3-catalyzed trans-addition to alkynes, see:
Miura, K.; Fujisawa, N.; Toyohara, S.; Hosomi, A. Synlett 2006, 1883.
(11) Alkene geometry was determined by NOESY NMR experiments.
Please see the Supporting Information for more details.
8324 J. Org. Chem. Vol. 75, No. 23, 2010

Montaignac et al.
JOCNote
or the formation of an enamine that evolves through anti-
carbometalation.
SCHEME 4
Experimental Section
General Procedure for the Carbocyclization Reactions. In a
sealed vial were successively introduced freshly purified formyl
alkyne (0.4 mmol, 1 equiv), a freshly prepared 0.2 M solution
of amine in DCE (400 μL, 0.08 mmol, 0.2 equiv), and InCl3
(0.08 mmol, 0.2 equiv). The reaction mixture was stirred at
100 °C until GC or TLC analysis indicated complete conversion,
and then 1 mL of an aqueous solution of AcOH (1/1 v/v) was
added at room temperature. The resulting mixture was stirred
15 min at room temperature and then was extracted with
CH2Cl2, dried over MgSO4, and concentrated under reduced
pressure. The crude material was purified by silica gel flash
chromatography to afford the desired cyclopentane.
4,4-Bis(benzyloxymethyl)-1-butyl-2-methylene-cyclopentane-
carbaldehyde (4): 94% yield; colorless oil; 1H NMR (300 MHz,
C6D6) δ 9.21 (s, 1H), 7.35-7.03 (m, 10H), 4.98 (t, J=1.8 Hz,
1H), 4.76 (t, J=2.0 Hz, 1H), 4.45-4.18 (m, 4H), 3.34 (s, 4H),
2.54 (d, J=14.0 Hz, 1H), 2.38 (dt, J=15.9, 1.8 Hz, 1H), 2.24
(d, J=15.0 Hz, 1H), 1.69-1.52 (m, 1H), 1.60 (d, J = 15,0 Hz, 1H),
1.42-1.27 (m, 1H), 1.21-0.93 (m, 4H), 0.77 (t, J=6.8 Hz, 3H);
13C NMR (75 MHz, C6D6) δ 200.1, 152.2, 139.3, 139.3, 128.5,
127.7, 109.4, 73.8, 73.6, 73.4, 73.4, 61.1, 46.3, 40.7, 36.4, 35.6,
27.2, 23.5, 14.1; HRMS calcd for C27H34O3Na 429.24002, found
429.23960.
was used, a mixture of deuterated and nondeuterated adducts
was obtained. The cyclization product 14-D was formed with
13% deuterium at the cis position (Ha) and 39% deuterium at
the trans position (Hb) (Scheme 3, eq 3).
A considerable amount of D-H exchange occurred dur-
ing the reaction, which led to the formation of 30% diproto-
nated 14-H2 together with the formation of 18% dideuter-
ated 14-D212 (Scheme 3, eq 3).
The secondary amine based catalytic system consistently
led to the formation of a (E)/(Z) mixture of cyclopentane
28 (Scheme 3, eq 4), where the (E) isomer was formed
preferentially.
Considering that the high Lewis acidity of InCl3 could be
responsible of a thermodynamically favored isomerization
of the double bond postcyclization, we engaged (Z)-14-D
and (Z)-28 with the secondary amine based catalytic system
(Scheme 4). However, no isomerization was observed in
those reaction conditions after 18 h. Therefore, in contrast
with the previous case, the secondary amine (Cy)(i-Pr)NH
would favor the enolate/cis-carbometalation pathway (Scheme 2,
path B) in competition with the enamine/anti-carbometala-
tion process.
In summary, we have developed an efficient and cheap
system based on the combination of InCl3 and a primary
amine CyNH2 that allowed the carbocyclization of R-disub-
stituted aldehydes onto unactivated alkynes to form readily
functionalized cyclopentanes. This study showed that the
primary amine-based catalytic system has a broad scope as it
could be used for the cyclization of hindered R-disubstituted
aldehydes. From the mechanistic point of view, we demon-
strated that the amine cocatalyst has a direct influence on
reaction pathway. It favors either the formation of an indium
enolate reactive species that undergoes a cis-carbometalation,
1-Benzyl-4,4-bis(benzyloxymethyl)-2-methylene-cyclopenta-
necarbaldehyde (8): 99% yield; colorless oil; 1H NMR (300 MHz,
C6D6) δ 9.32 (s, 1H), 7.25-6.89 (m, 15H), 4.98 (t, J=2.0 Hz, 1H),
4.78(t, J=2.0 Hz, 1H), 4.21 (s, 4H), 3.23(s, 2H), 3.17 (s, 2H), 2.97
(d, J=13.8 Hz, 1H), 2.67 (d, J=13.8 Hz, 1H), 2.27 (d, J=14.3 Hz,
1H), 2.21-2.13 (m, 2H), 1.78 (d, J = 14.3 Hz, 1H); 13C NMR
(75 MHz, C6D6) δ 199.6, 152.0, 139.3, 139.2, 137.8, 130.6, 128.5,
128.5, 126.8, 110.3, 73.7, 73.4, 73.3, 73.3, 62.0, 46.6, 42.3, 41.1,
35.4; HRMS calcd for C30H32O3Na 463.22437, found 463.22372.
Acknowledgment. This work was financially supported by
the Centre National de la Recherche Scientifique (CNRS)
ꢁ
and the Ministere de l’Education et de la Recherche. B.M. is
grateful to the Ministere de l’Education et de la Recherche
ꢁ
for a grant (2009-2012). The authors thank Dr. M.-N.
Rager (Chimie ParisTech) for 2D and NOESY experiments.
Supporting Information Available: Experimental proce-
dures, full characterization, and copies of 1H, 13C, and NOESY
NMR spectra of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(12) An acetylenic D-H exchange (64% D-36% H) was observed when
submitting 13-D to 20 mol % (Cy)(i-Pr)NH at 100 °C in DCE during 2 h
without InCl3. Thus, the scrambling may result from an acid-base equilibrium.
J. Org. Chem. Vol. 75, No. 23, 2010 8325