Combined InCl3- and amine-catalyzed intramolecular addition of α-disubstituted aldehydes onto unactivated alkynes

Article abstract of DOI:10.1021/ol100729t

The combination of enamine-type catalysis to the indium-catalyzed activation of alkynes allows the efficient preparation of functionalized cyclopentanes bearing a quaternary stereogenic center. A broad range of formylalkynyl derivatives has been prepared.

Full text of DOI:10.1021/ol100729t

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2582-2585
Combined InCl3- and Amine-Catalyzed
Intramolecular Addition of r-Disubstituted
Aldehydes onto Unactivated Alkynes
Benjamin Montaignac, Maxime R. Vitale, Veronique Michelet,* and
Virginie Ratovelomanana-Vidal*
ENSCP, Chimie ParisTech, UMR 7223, Laboratoire Charles Friedel, 11 rue P. et M.
Curie, 75231 Paris Cedex 05, France
Veronique-michelet@chimie-paristech.fr; Virginie-Vidal@chimie-paristech.fr
Received April 6, 2010
ABSTRACT
The combination of enamine-type catalysis to the indium-catalyzed activation of alkynes allows the efficient preparation of functionalized
cyclopentanes bearing a quaternary stereogenic center. A broad range of formylalkynyl derivatives has been prepared. The InCl3/(Cy)(i-Pr)NH
system efficiently promotes the carbocyclization reaction of r-disubstituted aldehydes in good to excellent yields.
Over the past 30 years, transition-metal catalysis1 and then
organocatalysis2 have known tremendous growth. Despite
the broad range of reactions that have been rendered
possible through the use of one of these two types of
catalysis, there still remain substrates that are unreactive
or too sluggish in reactivity. In this context, the concept
of combining metal catalysis to organocatalysis has
recently flourished and has led to the discovery of several
new reactions that would not have been possible without
this unusual association.3 More specifically, it was recently
described that the combination of a catalytic quantity of
secondary amine and of a catalytic amount of a metal
complex (either gold, copper, or palladium) allowed the
carbocyclization of keto- or formylalkynes to cyclo-
pentenes.4 Such a process relies on the formation of a
key enamine intermediate, in which the alkyne moiety is
activated by the metal complex. Although the carbocy-
clization reaction goes through the formation of cyclo-
pentanes, in almost all of the cases described in the
literature, the presence of an acidic proton (R ) H) triggers
a rearrangement to the more stable conjugated cyclo-
pentenes with the inconvenient loss of the stereogenic
center formerly generated (Scheme 1).
(1) (a) Cornils, B.; Hermann, W. A. Applied Homogeneous Catalysis
with Organometallic Compounds; Wiley-VCH: New York, 1996. (b) Beller,
M.; Bolm, C. Transition Metals in Organic Synthesis, 2nd ed.; Wiley-VCH:
Weinheim, 2004. (c) Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Compre-
hensiVe Asymmetric Catalysis; Springer: Berlin, 1999. (d) Ojima, I. Catalytic
Asymmetric Synthesis, 2nd ed.; Wiley-VCH: New York, 2000.
(2) (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726.
(b) List, B. Synlett 2001, 1675. (c) List, B. Tetrahedron 2002, 58, 2481.
(d) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (e)
Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis; Wiley-VCH:
Weinheim, 2005. (f) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719.
(g) Lelais, G.; MacMillan, D. W. C. Aldrichim. Acta 2006, 39, 79. (h) Gaunt,
M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug DiscoVery Today
2007, 12, 8. (i) Dalko, P. I. EnantioselectiVe Organocatalysis; Wiley-VCH:
Weinheim, 2007.
Kirsch et al. have reported that the combination of
gold(I)-based catalyst and amine promoted the cyclization
(3) (a) Shao, Z.; Zhang, H. Chem. Soc. ReV. 2009, 38, 2745, and
references cited therein. (b) Zhou, J Chem.sAsian J. 2010, 5, 422.
(4) (a) Binder, J. T.; Crone, B.; Haug, T. T.; Menz, H.; Kirsch, S. F.
Org. Lett. 2008, 10, 1025. (b) Yand, T.; Ferrali, A.; Campbell, L.; Dixon,
D. J. Chem. Commun. 2008, 2923. (c) Zhao, G.-L.; Ullah, F.; Deiana, L.;
Lin, L.; Zhang, Q.; Sun, J.; Ibrahem, I.; Dziedzic, P.; Co´rdova, A.
Chem.sEur. J. 2009, 16, 1585. (d) Jensen, K. L.; Franke, P. T.; Arro´niz,
C.; Kobbelgaard, S.; Jørgensen, K. A. Chem.sEur. J. 2010, 16, 1750. (e)
Yu, C.; Zhang, Y.; Zhang, S.; He, J.; Wang, W. Tetrahedron Lett. 2010,
51, 1742.
10.1021/ol100729t  2010 American Chemical Society
Published on Web 05/12/2010

Scheme 1
.
R-Addition of Aldehydes onto Unactivated Alkynes
Table 1. Optimization of Reaction Conditions
through Combined Catalysis
time
(h)
1a/2a,a
entry
[M]
amine
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15c
RuCl3
FeCl3
NiCl2
RhCl3
IrCl3
AgNTf2
In(OTf)3
In(NTf2)3
InCl3
(i-Pr)2NH
(i-Pr)2NH
(i-Pr)2NH
(i-Pr)2NH
(i-Pr)2NH
(i-Pr)2NH
(i-Pr)2NH
(i-Pr)2NH
(i-Pr)2NH
16
24
16
16
24
24
24
20
15
5
15
14
14
14
3
80/20
90/10
100/0
degradation
50/50
60/40
95/5
90/10
0/100, 73
degradation
>99/1
50/50
67/33
InCl3
of formyl alkyne derivatives to the corresponding cyclo-
pentenes (R ) H) and cyclopentanes (R ) Me) in 33-72%
yield.4a The scope described for this catalytic system in
the case of R-methyl-substituted aldehydes was very
limited, which prompted us to investigate further this kind
of carbocyclization reaction. We report herein a new
multicatalytic system, composed of an indium salt and
an amine, which allows the general and efficient carbocy-
clization of a broad range of R-disubstituted formyl
alkynes to the corresponding functionalized cyclopentanes
bearing a quaternary stereogenic center.
At the outset of our study, the model substrate 1a was
submitted to catalytic amounts (20 mol %) of different
metal salts in the presence of a catalytic amount of
(i-Pr)2NH (20 mol %) in 1,2-dichloroethane at 80 °C
(Table 1). Among the different metal catalysts tested,
RuCl3, FeCl3, NiCl2, and RhCl3 proved to be rather
ineffective in promoting the desired carbocyclization
reaction (entries 1-4). The use of IrCl3 or AgNTf2 allowed
the reaction to take place, but the conversions of 1a to 2a
were too slow to constitute good catalytic systems (entries
5 and 6). We next tested the use of indium salts, which
have been described by Nakamura et al. to be quite
effective catalysts for the addition of ꢀ-keto ester to
unactivated alkynes.5 In(OTf)3 and In(NTf2)3 poorly
catalyzed the cyclization (entries 7 and 8), whereas InCl3
allowed the complete conversion of the starting material
and afforded the desired cyclopentane 2a in 73% isolated
yield (entry 9).
(i-Pr)2NH
pyrrolidine
(Cy)2NMe
(Cy)(i-Pr)NH
(Cy)(i-Pr)NH
InCl3
InCl3
InCl3
InCl3
0/100, 82
0/100, 82
a Determined by GC of the crude reaction mixture. b Isolated yields
after column chromatography. c Reaction performed at 100 °C, 1 M in
substrate.
conversion (entries 12 and 13). The use of (Cy)(i-Pr)NH
allowed a cleaner reaction to take place (entry 14). This
last catalytic system was further improved by performing
the reaction at 100 °C together with an increase of the
substrate concentration to 1 M (entry 15). Given these
reaction conditions, the cyclopentane 2a was obtained in
good yield (82%) within 3 h. Two control experiments
were done by suppressing each one of the catalysts. The
absence of indium trichloride led to the recovery of the
starting material (entry 11), and the absence of the amine
promoted a complete degradation of 1a (entry 10). These
experiments confirmed the necessity of both catalysts to
be present for the carbocyclization to take place.
To investigate the scope and limitations of this new
catalytic system, a broader range of formyl alkynes has
been prepared (Scheme 2). Various R-methylene aldehydes
(R ) Me, Ph, n-Bu, Bn) 3a-d were converted to their
corresponding iodo ketals, which upon condensation with
dimethyl propargylmalonate afforded the alkynyl deriva-
tives 4a-d. Hydrolysis of these ketals gave access to
aldehyde substrates 1a-d, whereas the reduction of their
methyl ester groups led to the corresponding diols.
Functionalization of the alcohol moieties followed by
deprotection of aldehyde afforded dimethyl ethers 5a,b,
dibenzyl ethers 6a,b, disilyl ether 7a, and diacetate 8a.
Alternatively, the link between the formyl and the alkyne
groups was replaced by a gem-diphenylsulfone 9a or
The influence of the amine catalyst was then evaluated.
The reactions in the presence of pyrrolidine or (Cy)2NMe
were much slower and led, respectively, to 50% and 33%6
(5) (a) Tsuji, H.; Tanaka, I.; Endo, K.; Yamagata, K.; Nakamura, M.;
Nakamura, E. Org. Lett. 2009, 11, 1845. (b) Itoh, Y.; Tsuji, H.; Yamagata,
K.; 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, K. J. Am. Chem. Soc. 2003, 125, 13002.
(6) It is noteworthy that several unidentified byproducts were also
detected by gas chromatography.
Org. Lett., Vol. 12, No. 11, 2010
2583

The more sterically hindered gem-diphenylsulfone 9a
also led to cyclopentane 15a in good yield, despite a longer
reaction time (entry 5). Notably, this reaction was extended
to the synthesis of pyrrolidine 16a starting from the
N-tosyl precursor 10a (entry 6). This carbocyclization
reaction was not limited to substrates bearing a methyl
group in the R position relative to the aldehyde moiety
(R ) Me). Indeed, phenyl-substituted precursors 1b, 5b,
and 6b were efficiently cyclized under the optimized
reaction conditions (entries 7-9). Unexpectedly, n-Bu-
and Bn-substituted substrates 1c and 1d were very sluggish
to react under the optimized reaction conditions and led
to degradation products (entries 10 and 11). However,
reinvestigation of the catalytic system for these two
substrates revealed that the catalytic use of the less
sterically demanding primary amine CyNH2 allowed a
clean carbocyclization leading to aldehydes 2c and 2d in
71% and 77% isolated yield (entries 12 and 13).
Mechanistically, it is reasonable to consider that the
condensation of the amine organocatalyst on the aldehyde
moiety of the substrate allows the formation of a transient
enamine, whereas InCl3 is accountable for the η2 activation
of the alkyne group.7 The corresponding intermediate I,
upon nucleophilic addition of the enamine on the alkyne
moiety, may evolve toward the iminium vinylindate II8
which, after hydrolysis and protodemetalation, produces
the carbocyclization product as well as allows the
regeneration of both the amine and indium catalysts
(Scheme 3).
a
Scheme 2. General Synthesis of Substrates 1a-d and 5-10
a Key: (i) TMSCl, NaI, ethylene glycol, MeCN; (ii) dimethyl propar-
gylmalonate, NaH, DMF; (iii) HClaq, acetone, H2O or dioxane/HCOOH/
H2O; (iv) LiAlH4, THF; (v) NaH, MeI, or BnBr/n-Bu4NI (cat.), THF/DMF;
(vi) TBDPSCl, imidazole, CH2Cl2; (vii) Ac2O, (i-Pr)2NEt, CH2Cl2; (viii)
NaH, DMF; (ix) K2CO3, DMF.
N-tosyl 10a groups via alkylation of the corresponding
propargyl compounds with the iodide obtained from 3a
followed by the hydrolysis of the ketal moieties.
Under the optimized reaction conditions, the dimethyl
ether 5a and dibenzyl ether 6a afforded in good yields
the corresponding carbocyclization products 11a (89%)
and 12a (87%) (Table 2, entries 1 and 2). The efficient
cyclizations of disilyl ether 7a and diacetate 8a further
demonstrated the good functional group tolerance of this
catalytic system (entries 3 and 4).
Scheme 3. Proposed Mechanism
Table 2. Carbocyclization of Substrates 1b-d and 5-10
time
(h)
product,
yielda (%)
entry substrate
R
Z
1
2
3
4
5
6
7
8
9
10
11
12c
13c
5a
6a
7a
8a
9a
10ab
1b
5b
6b
1c
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
C(CH2OMe)2
C(CH2OBn)2
C(CH2OTBDPS)2
C(CH2OAc)2
C(SO2Ph)2
13
13
22
18
43
62
5
15
15
24
24
15
15
11a, 89
12a, 87
13a, 88
14a, 74
15a, 75
16a, 66
2b, 61
11b, 86
12b, 79
2c, -
NTs
C(CO2Me)2
C(CH2OMe)2
C(CH2OBn)2
In summary, we have developed a new catalytic system
based on (Cy)(i-Pr)NH and InCl3 for the efficient car-
n-Bu C(CO2Me)2
Bn C(CO2Me)2
n-Bu C(CO2Me)2
Bn C(CO2Me)2
1d
1c
1d
2d, -
2c, 71
2d, 77
(7) The formation of an indium enolate intermediate as proposed by
Nakamura et al. in the case of alkynyl ꢀ-keto esters cannot be totally ruled
out as the use of the tertiary amine base (Cy)2NMe led to some reactivity
(Table 1).
(8) The steroselectivity of the addition of the enamine toward the alkyne
moiety may be syn or anti and is currently under investigation.
a Isolated yields after column chromatography. b Reaction performed
at 80 °C. c CyNH2 was used instead of (Cy)(i-Pr)NH.
2584
Org. Lett., Vol. 12, No. 11, 2010

bocyclization of R-disubstituted aldehydes onto unacti-
vated alkynes. We demonstrated that this combination
allows the clean cyclization of a broad range of substrates
with high yields and a remarkable functional group
tolerance. The investigation of an enantioselective version
of this reaction is currently underway and will be reported
in due course.
Ministe`re de l’Education et de la Recherche for financial
support. B.M. is grateful to the Ministe`re de l’Education et
de la Recherche for a grant (2009-2012).
Supporting Information Available: Experimental pro-
cedures, characterization of new compounds, and copies
1
of H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by the Centre
National de la Recherche Scientifique (CNRS) and the
OL100729T
Org. Lett., Vol. 12, No. 11, 2010
2585