Enantioselective ficini reaction: Ruthenium/PNNP-catalyzed [2+2] cycloaddition of ynamides with cyclic enones

Article abstract of DOI:10.1002/anie.201007753

(Chemical Equation Presented) Chiral cyclobuteneamides made easy: Double chloride abstraction from the ruthenium/PNNP complex 1 in the presence of unsaturated β-keto esters 2 gives the dicationic adducts [Ru(2)(PNNP)] ²⁺ (3) that catalyze the [2+2] cycloaddition of a variety of ynamides 4 to produce cyclo-buteneamides 5 with high yield and enantioselectivity (see scheme).

Full text of DOI:10.1002/anie.201007753

Communications
DOI: 10.1002/anie.201007753
Asymmetric Catalysis
Enantioselective Ficini Reaction: Ruthenium/PNNP-Catalyzed
[2+2] Cycloaddition of Ynamides with Cyclic Enones**
Christoph Schotes and Antonio Mezzetti*
Recent synthetic advances have turned ynamides into broadly
available substrates whose reactivity can be finely tuned.[1] In
particular, the cross-coupling of amides with alkynyl bro-
mides gives broad access to widely substituted ynamides.[2]
Thus, the last few years have witnessed a surge of their use as
nitrogen-containing building blocks in organic chemistry that
undergo addition at the a or b positions, oxidative or
reductive coupling, oxidation, ring-closing metathesis, cyclo-
isomerization, and cycloaddition reactions.[1] Although a vast
number of new transformations have been reported, stereo-
selective reactions with ynamides, and in particular enantio-
selective ones, are still rare.[3] A straightforward application of
ynamides is the Ficini reaction, whose original version is a
thermally driven, stepwise [2+2] cycloaddition of an ynamine
with a cyclic enone (Scheme 1).[4]
nitrogen canter gave low diastereoselectivity.[6] To the best of
our knowledge, no enantioselective reaction has been
reported yet. Therefore, a catalytic approach to the problem
seems more efficient and in dire need.
Our research group has recently reported that the
dicationic ruthenium/PNNP complex 1, upon activation with
(Et3O)PF6 (Scheme 2),[7] catalyzes the asymmetric Diels–
Scheme 2. Substrate coordination to the ruthenium/PNNP fragment.
PNNP=(1S,2S)-N,N’-bis{o-(diphenylphosphino)benzylidene}cyclohex-
ane-1,2-diamine.
Alder reaction of a-methylene b-keto ester 2a with a number
of dienes.[8] This [2+4] cycloaddition reaction is the first
asymmetric synthesis of alkoxycarbonyltetrahydro-1-inda-
nones and gives access to enantiomerically pure estrone
derivatives. More generally, this is a relatively rare example of
the use of unsaturated b-keto esters in a cycloaddition
reaction.[9]
Scheme 1. The original Ficini reaction with ynamines.
The advantage of using ynamides in the Ficini reaction
instead on ynamines is that the electron-withdrawing group
decreases the reactivity of the triple bond. This decrease in
reactivity inhibits the thermal reaction and allows for a
catalytic approach, and in particular for enantioselective
reactions. Despite this being a straightforward development,
the first example of a catalytic reaction of ynamides with
enones was reported only very recently.[5] The performance of
these combined AgI/CuII catalysts is modest, though, and an
ynamide bearing a chiral auxiliary on the nitrogen atom gave
1:1 diastereomeric mixture. In general, [2+2] cycloaddition
reactions with ynamides are rare, and chiral auxiliaries on the
As an extension to this approach, we report herein the
first enantioselective Ficini reaction between ynamides 4 and
the unsaturated b-keto ester 2a to give the corresponding
amidocyclobutenes 5a–k with high yield and enantioselectiv-
ity (Scheme 3). A preliminary screening of ynamides showed
that the substrates of choice contain an electron-donating
substitutent (R2) and an electron-withdrawing substitutent
(R3), respectively, whose appropriate combination imparts
good reactivity to the ynamide in catalysis, but still low
enough to inhibit the uncatalyzed background reaction at
elevated temperatures.
[*] MSc C. Schotes, Prof. Dr. A. Mezzetti
Departement Chemie und Angewandte Biowissenschaften
ETH Zꢀrich
8093 Zꢀrich (Switzerland)
Fax: (+41)44-632-1310
E-mail: mezzetti@inorg.chem.ethz.ch
[**] We thank Mr. Raphael Aardoom (ETH Zꢀrich) for the X-ray analysis
and the ETH Zꢀrich for financial support to C.S. (grant no. TH-08
07-1). PNNP=(1S,2S)-N,N’-bis{o-[diphenylphosphino)benzylide-
ne}cyclohexane-1,2-diamine.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007753.
Scheme 3. Enantioselective Ficini reaction. Bn=benzyl, Mbs=4-
methoxybenzenesulfonyl, Ms=methanesulfonyl, Ts=4-toluenesulfonyl.
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Angew. Chem. Int. Ed. 2011, 50, 3072 –3074

Table 1: Enantioselective Ficini reaction.[a]
An X-ray study of enantiomerically pure tert-butyl-7-[N-
benzyl-4-methylphenylsulfonamido]-6-cyclohexyl-2-oxobicy-
clo[3.2.0]hept-6-ene-1-carboxylate (5a) shows the 1R,5S ab-
solute configuration (Figure 1),[11] and is in agreement with an
attack of the ynamide from the upper enantioface of the
coordinated enone (Figure 2). The shielding by one phenyl
Entry Product R1
R2 R3
Yield [%] ee [%]
1
2
3
5a
5b
5c
5c
5d
5e
5 f
5g
5h
5i
c-C6H11
c-C6H11
Ph
Ph
Ph
Ph
Ph
n-C6H13
n-C6H13
n-C6H13
CH2OBn
Bn Ts
Me Ts
Bn Ts
Bn Ts
Me Ts
Me Ms 69
Me Mbs 75
Bn Ts
97 (75)[b] 90 (>99.5)[b]
88
72
66
64
92
90
92
87
83
61
78
70
78
70
76
53
57
4[c]
5
6
7
8
9
10
11
12
99
Me Ms 94
Me Mbs 99
Me Ts
5j
5k
60
86
97
84
(CH2)2OSiMe2tBu Bn Ts
c-C6H11
c-C6H11
13[d] 5l
Bn Ts
Bn Ts
14[d] 5m
[a] Reaction conditions: See the Experimental Section. [b] After a single
recrystallization from n-hexane. [c] At room temperature. [d] See
Scheme 4.
The catalysis results are summarized in Table 1. By and
large, bulky substituents at the a position of the ynamide
(R1 = c-C6H11 or Ph) are required for high enantioselectivity
(entries 1–7), whereas high yields are achieved when R1 is a
good electron donor (entries 1, 2, and 8–10). The cyclohexyl-
substituted ynamides 4a and 4b give the best combination of
very high yield and enantioselectivity up to 92% ee (entries 1
and 2). Product 5a was obtained as a single enantiomer by
recrystallization from n-hexane. It should be noted that
various functional groups (entries 11 and 12) are also
tolerated by the protocol. In all reactions, a nearly stoichio-
metric amount of the alkyne is used (1.1 equiv), and high
yields are obtained. This is notable for a reaction that forms
an all-carbon stereogenic center at the bridgehead position of
a highly strained unsaturated [3.2.0] bicycle.
Figure 1. ORTEP plot of 5a. Hydrogen atoms are omitted for clarity
and the ellipsoids are drawn at 30% probability
ring of the PNNPligand ensures high enantiofacial selectivity,
as we have shown for the Diels–Alder reactions with 2a and
catalyst 1/(Et3O)PF6 (2 equiv),[8] as well as for the analogous
saturated b-keto esters. The latter substrates undergo Michael
addition,[7b,c] hydroxylation,[12] as well as electrophilic fluori-
nation reactions,[10] with high enantioselectivity in the pres-
ence of the same ruthenium/PNNP catalyst.
Although formally a [2+2] cycloaddition, the reaction
between the ynamide and the enone is likely to occur stepwise
The smaller ethyl esters 2b and 2c gave lower enantio-
selectivity (entries 13, 14 and Scheme 4), which confirms that
a bulky ester group is pivotal, as observed in the Diels–Alder
reaction[8] and with the saturated analogues.[7,10] Interestingly,
the cyclohexenone derivative 2c performs similarly to 2b, and
thus suggests an analogous optimization potential for six-
membered unsaturated b-keto esters.
Scheme 4. Scope of the b-keto ester. Reaction conditions as in
Scheme 3.
Figure 2. Calculated (MM) model for the approach of ynamide 4a to
complex 3. Light blue N, dark blue Ru, magenta P, red O, yellow S.
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Communications
2840 – 2859; b) K. A. DeKorver, H. Li, A. G. Lohse, R. Hayashi,
Z. Lu, Y. Zhang, R. P. Hsung, Chem. Rev. 2010, 110, 5064 – 5106.
[2] Seminal article on efficient ynamide synthesis: a) Y. Zhang, R. P.
Hsung, M. R. Tracey, K. C. M. Kurtz, E. L. Vera, Org. Lett. 2004,
6, 1151 – 1154; see also: b) M. O. Frederick, J. A. Mulder, M. R.
Tracey, R. P. Hsung, J. Huang, K. C. M. Kurtz, L. Shen, C. J.
Douglas, J. Am. Chem. Soc. 2003, 125, 2368 – 2369; c) T.
Hamada, X. Ye, S. S. Stahl, J. Am. Chem. Soc. 2008, 130, 833 –
835; d) A. Coste, G. Karthikeyan, F. Couty, G. Evano, Angew.
Chem. 2009, 121, 4445 – 4449; Angew. Chem. Int. Ed. 2009, 48,
4381 – 4385; Angew. Chem. 2009, 121, 4445 – 4449.
[3] To the best of our knowledge, two enantioselective reactions
with ynamides have been reported: a) R. K. Friedman, T. Rovis,
J. Am. Chem. Soc. 2009, 131, 10775 – 10782; b) K. Tanaka, K.
Takeishi, K. Noguchi, J. Am. Chem. Soc. 2006, 128, 4586 – 4587;
for an application of the same protocol, see: c) J. Oppenheimer,
W. Johnson, R. Figueroa, R. Hayashi, R. Hsung, Tetrahedron
2009, 65, 5001 – 5012.
by nucleophilic attack of the b-carbon atom of the ynamide
onto the electrophilic position of the enone, as Ficini
originally suggested for enamines (Scheme 1).[4] The elec-
tronic demand requires that the nitrogen atoms, and therefore
its R1 and R2 substituents point toward the complex.
Molecular modeling (MM) calculations show that the bulky
R1 and R2 groups fold away from the PNNP backbone as
ynamide 4a approaches the coordinated enone in the open
chiral space of complex 3, and this minimizes the steric
interactions in the transition state (Figure 2).[13]
We speculate that the ruthenium/PNNP fragment is
particularly effective in stabilizing the intermediate enolate
by virtue of its double positive charge. Therefore, the
dicationic nature of 3 is possibly the key feature needed to
ensure catalytic activity. To the best of our knowledge, this is
the first asymmetric [2+2] cycloaddition of ynamides to an
enone (Ficini reaction). The catalyst system based on
1/(Et3O)PF6 (2 equiv) is highly efficient in terms of yield
and enantioselectivity, and the scope of the reaction is
promising. The coordination of the unsaturated b-keto ester
to the chiral, oxophilic ruthenium/PNNP fragment is a more
efficient strategy for enantioselection than introducing a
chiral auxiliary at the ynamide nitrogen atom,[5,6] which is
remote from the triple bond. Besides using ynamides, the
reaction is a further, but still rare example of the use of an
unsaturated b-keto ester as the substrate for a cycloaddition
reaction.
[4] J. Ficini, Tetrahedron 1976, 32, 1449 – 1486.
[5] H. Li, R. P. Hsung, K. A. DeKorver, Y. Wei, Org. Lett. 2010, 12,
3780 – 3783.
[6] Selected papers: a) N. Riddell, K. Villeneuve, W. Tam, Org. Lett.
2005, 7, 3681 – 3684; b) K. Villeneuve, N. Riddell, W. Tam,
Tetrahedron 2006, 62, 3823 – 3836; for a related enantioselective
[2+2+2] cycloaddition, see reference [3a].
[7] a) (Et3O)PF6 (2 equiv) abstracts both chloro ligands as EtCl
from complex 1 and the resulting Et2O molecules bind to the
oxophilic ruthenium/PNNP fragment, see: b) F. Santoro, M.
Althaus, C. Bonaccorsi, S. Gischig, A. Mezzetti, Organometallics
2008, 27, 3866 – 3878; c) M. Althaus, C. Bonaccorsi, A. Mezzetti,
F. Santoro, Organometallics 2006, 25, 3108 – 3110; d) C. Bonac-
corsi, M. Althaus, C. Becker, A. Togni, A. Mezzetti, Pure Appl.
Chem. 2006, 78, 391 – 396.
[8] C. Schotes, A. Mezzetti, J. Am. Chem. Soc. 2010, 132, 3652 –
3653.
[9] B. M. Trost, C. H Jiang, Synthesis 2006, 369 – 396.
[10] M. Althaus, C. Becker, A. Togni, A. Mezzetti, Organometallics
2007, 26, 5902 – 5911.
Experimental Section
Typical procedure: [RuCl2(PNNP)] (1; 10 mg, 0.012 mmol, 0.1 equiv)
and (Et3O)PF6 (6 mg, 0.024 mmol, 0.20 equiv) were stirred in CH2Cl2
(1 mL) in a Young Schlenk tube at room temperature overnight. A
color change from red to brown indicated the formation of the
catalytically active complex. Then a solution of unsaturated b-keto
ester (2a–c; 0.12 mmol, 1 equiv) in CH2Cl2 (1 mL) was added. After
10 min, the ynamide (4a–k; 0.13 mmol, 1.1 equiv) was added. The
Young Schlenk tube was closed and the mixture was heated to 558C.
After 24 h, the solvent was evaporated under reduced pressure, and
the oily residue was subject to flash chromatography on silica. See the
Supporting Information for detailed procedures of substrate synthesis
and product characterization.
[11] The value of the Flack parameter in dicates that the absolute
configuration is 1R,5S. This assignment has been confirmed by
reduction of the carbonyl function of 5a and esterification of the
resulting alcohol with (À)-camphanic acid chloride to give 6. See
the Supporting Information for synthetic details and X-ray
structures. CCDC 802191 (6) and 802192 (5a) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[12] P. Y. Toullec, C. Bonaccorsi, A. Mezzetti, A. Togni, Proc. Natl.
Acad. Sci. USA 2004, 101, 5810 – 5814.
[13] The transition state (TS) in Figure 2 has been modeled starting
from the X-ray data of 3 and imposing a bond length of 2.0 ꢀ
between the C1 atom of the ynamide and C3 atom of the enone.
Interestingly, a C1’-C2’-C3-C2 torsion angle of 08 is obtained for
the TS without imposing any additional constraint. See the
Supporting Information for the details of MM calculations.
Received: December 9, 2010
Revised: January 20, 2011
Published online: February 25, 2011
Keywords: alkynes · asymmetric catalysis · cycloaddition ·
.
Ficini reaction · ruthenium
[1] Recent review articles: a) G. Evano, A. Coste, K. Jouvin, Angew.
Chem. 2010, 122, 2902 – 2921; Angew. Chem. Int. Ed. 2010, 49,
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