Copper-catalyzed Ficini [2 + 2] cycloaddition of ynamides

Article abstract of DOI:10.1021/ol101418d

The Ficini [2 + 2] cycloaddition using N-sulfonyl-substituted ynamides is described, featuring the utility of CuCl₂ and AgSbF₆ as catalysts. This work represents the first successful example of ynamides participating in a thermal [2 + 2] cycloaddition with enones.

Full text of DOI:10.1021/ol101418d

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3780-3783
Copper-Catalyzed Ficini [2 + 2]
Cycloaddition of Ynamides
Hongyan Li, Richard P. Hsung,* Kyle A. DeKorver, and Yonggang Wei
DiVision of Pharmaceutical Sciences and Department of Chemistry,
UniVersity of Wisconsin, Madison, Wisconsin 53705
rhsung@wisc.edu
Received June 18, 2010
ABSTRACT
The Ficini [2 + 2] cycloaddition using N-sulfonyl-substituted ynamides is described, featuring the utility of CuCl2 and AgSbF6 as catalysts.
This work represents the first successful example of ynamides participating in a thermal [2 + 2] cycloaddition with enones.
More than 40 years ago, Ficini1 disclosed perhaps the most
useful carbon-carbon bond-forming reaction involving
Scheme 1. Ficini’s Ynamine-[2 + 2] Cycloadditions
ynamines:2 a thermally driven stepwise [2 + 2] cycloaddi-
tion3 of ynamine [1] with cyclic enones, leading to the
formation of cyclobutenamine 3 (Scheme 1).4-6 In the last
15 years, ynamides have emerged as a superior synthetic
(1) For a seminal review on Ficini [2 + 2] cycloaddition using ynamines,
see: Ficini, J. Tetrahedron 1976, 32, 1448.
(2) For two other comprehensive reviews on ynamine chemistry, see:
(a) Himbert, G. Methoden Der Organischen Chemie (Houben-Weyl); Kropf,
H.,; Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart, 1993; pp
3267-3443. (b) Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar,
C.; Wei, L.-L. Tetrahedron 2001, 57, 7575.
(3) For a review on thermal [2 + 2] cycloaddition reactions, see:
Baldwin, J. E. ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Pattenden, G., Eds.; Pergamon Press: New York, 1991; Vol. 5, p 63.
(4) (a) Ficini, J.; Krief, A. Tetrahedron Lett. 1969, 10, 1431. (b) Ficini,
J.; Touzin, A.-M. Tetrahedron Lett. 1972, 13, 2093. (c) Ficini, J.; Touzin,
A.-M. Tetrahedron Lett. 1972, 13, 2097. (d) Ficini, J.; Touzin, A.-M.
Tetrahedron Lett. 1974, 15, 1447. (e) Ficini, J.; Falou, S.; d’Angelo, J.
Tetrahedron Lett. 1977, 18, 1931. For cycloadditions to quinone, see: (f)
equivalent of ynamines.7,8 Beautiful chemistry in the area
of [2 + 2] cycloadditions has followed by way of Tam’s
Ru-catalyzed ynamide-[2 + 2] cycloaddition of norbornene,9
Danhesier’s thermal cycloaddition of ketenes,10 and formal
Ficini, J.; Krief, A. Tetrahedron Lett. 1967, 8, 2497
.
(5) For related examples that were contemporary, see: (a) Franck-
Neuman, M. Tetrahedron Lett. 1966, 7, 341. (b) Grubbs, R. H. Ph.D.
Dissertation, Columbia University, 1968. (c) Kuehne, M. E.; Linde, H. J.
Org. Chem. 1972, 37, 4031
.
(7) For comprehensive reviews on chemistry of ynamides, see: (a)
DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Shi, Z.; Zhang, Y.;
HsungR. P. Chem. ReV. 2010, 110, ASAP. (b) Evano, G.; Coste, A.; Jouvin,
K. Angew. Chem., Int. Ed. 2010, 49, 2840.
(6) For Ficini’s later work, see: (a) Ficini, J.; Guingant, A.; d’Angelo,
J.; Stork, G. Tetrahedron Lett. 1983, 24, 907. (b) Ficini, J.; Krief, A.;
Guingant, A.; Desmaele, D. Tetrahedron Lett. 1981, 22, 725
.
10.1021/ol101418d  2010 American Chemical Society
Published on Web 08/06/2010

[2 + 2] processes through enyne cycloisomerizations using
platinum or gold catalysts developed by Malacria11 and
Cossy.12 However, a thermally driven stepwise [2 + 2]
cycloaddition in a Ficini manner using ynamides remained
elusive.13 Our own efforts in trying to develop this cycload-
dition reaction lasted for 13 years. We report here our first
success in a Ficini [2 + 2] cycloaddition of ynamides.
Scheme 2. Thermal Ficini [2 + 2] Cycloadditions of Ynamide
Over the last 15 years, we failed numerous attempts at a
successful Ficini [2 + 2] cycloaddition of ynamides using
lactam- or oxazolidinone-substituted ynamides under thermal
and/or Lewis-acidic conditions.14 In the current pursuit of
this cycloaddition, we chose to employ N-sulfonyl-substituted
ynamides because the nitrogen pair of the sulfonamido group
is more delocalized toward the alkyne.15 Therefore, N-
sulfonyl-substituted ynamides possess enhanced nucleophi-
licity over simple amide- or urethane-substituted ynamides,
and they are also less stable than amide- or urethane-
substituted ynamides.
Our next best option would appear to again involve Lewis
acids, which had not been successful over the years when
using lactam- or oxazolidinone-substituted ynamides.14 More
specifically, our efforts were derailed when using Lewis acids
because hydro-halogenations of ynamides, leading to R-
halogenated enamides, were a serious competing path-
way.14,16,17 In addition, when hydro-halogenation is not
competing, possible hydrolysis under these suitable Lewis
acids represents another challenge associated with ynamides.
Consequently, much of ynamide chemistry7a has been limited
to halo-substituted Lewis acids that do not involve metals
such as Mg, Ti, Sn, Si, B, Al, or In [i.e., CuX2 or ZnX2 is
feasible] or Lewis acids with OTf serving as the counter-
anion. As a result, we screened a small sample of Lewis
acids as summarized in Table 1.
However, to our disappointment, N-sulfonyl-substituted
ynamides such as 7 and 10 did not undergo any desired
thermal cycloaddition (Scheme 2). Even when we used
quinone and adopt the more electron-rich para-methoxy
benzensulfonyl group [Mbs] as shown in ynamide 10, no
appreciable amount of the desired cycloadduct 9b was
observed, thereby further underscoring the superior stability
of ynamides over ynamines.
(8) For recent examples, see: (a) Li, H.; Antoline, J. E.; Yang, J.-H.;
Al-Rashid, Z. F.; Hsung, R. P. New J. Chem. 2010, 34, 1309. (b) Kramer,
S.; Madsen, J. L. H.; Rottla¨nder, M.; Skrydstrup, T. Org. Lett. 2010, 12,
2758. (c) Banerjee, B.; Litvinov, D. N.; Kang, J.; Bettale, J. D.; Castle,
S. L. Org. Lett. 2010, 12, 2650. (d) Gourdet, B.; Rudkin, M. E.; Lam, H. W.
Org. Lett. 2010, 12, 2554. (e) Jia, W.; Jiao, N. Org. Lett. 2010, 12, 2000.
(f) DeKorver, K. A.; Hsung, R. P.; Lohse, A. G.; Zhang, Y. Org. Lett.
2010, 12, 1840. (g) Burley, G. A.; Davies, D. L.; Griffith, G. A.; Lee, M.;
Singh, K. J. Org. Chem. 2010, 75, 980. (h) Yamasaki, R.; Terashima, N.;
Sotome, I.; Komagawa, S.; Saito, S. J. Org. Chem. 2010, 75, 480.
(9) (a) Riddell, N.; Villeneuve, K.; Tam, W. Org. Lett. 2005, 7, 3681.
(b) Cockburn, N.; Karimi, E.; Tam, W. J. Org. Chem. 2009, 74, 5762.
(10) Kohnen, A. L.; Mak, X. Y.; Lam, T. Y.; Dunetz, J. R.; Danheiser,
R. L. Tetrahedron 2006, 62, 3815.
Table 1. Cu(II)-Catalyzed Ynamide-[2 + 2] Cycloaddition
(11) (a) Marion, F.; Coulomb, J.; Courillon, C.; Fensterbank, L.;
Malacria, M. Org. Lett. 2004, 6, 1509. (b) Marion, F.; Coulomb, J.; Servais,
A.; Courillon, C.; Fensterbank, L.; Malacria, M. Tetrahedron 2006, 62, 3856.
Also see: (c) Soriano, E.; Marco-Contelles, J. J. Org. Chem. 2005, 70, 9345.
(12) (a) Couty, S.; Meyer, C.; Cossy, J. Angew. Chem., Int. Ed. 2006,
45, 6726. (b) Couty, S.; Meyer, C.; Cossy, J. Tetrahedron 2009, 65, 1809.
(13) For a beautiful equivalent of this reaction using ynol-ethers and
AgNTf2, see: Sweis, R. F.; Schramm, M. P.; Kozmin, S. A. J. Am. Chem.
Soc. 2004, 126, 7442.
temp time yield
[°C]
entry
R
solvent
catalyst [mol %]
[h]a [%]b
(14) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P.; Coverdale, H. A.;
Frederick, M. O.; Shen, L.; Zificsak, C. A. Org. Lett. 2003, 5, 1547.
1
2
3
4
5
6
7
8
9
10: H CH3CN In(OTf)2 [30]
10: H CH3CN Sc(OTf)3 [30]
10: H CH3CN Cu(OTf)2 [10]
10: H CH3CN AgSbF6 [10]
10: H CH3CN AgSbF6 [10]
-15
1
1
4
5
2
--c
--c
--d
--d
--d
-15
25-80
0-80
50-120
10: H CH2Cl2 CuCl2/AgSbF6 [20/42] -78-25 10 e5d e
,
12: Me CH2Cl2 CuCl2/AgSbF6 [20/60]
12: Me CH2Cl2 CuCl2/AgSbF6 [20/60]
12: Me CH2Cl2 CuCl2/AgSbF6 [20/60]
-40
-15
0
1
1
1
72
77
76
(15) While sulfonamides [R1(SO2)-N(H)R2] are more acidic than amides
R1CO2N(H)R2 in general because of the overall stability difference between
the respective conjugate bases [as one referee kindly pointed out], sulfonyl-
substituted ynamides [or enamides] are more reactive and less stable than
simple amide or urethane-substituted ynamides [or enamide]. The nitrogen
lone pair in the former is more delocalized into the alkyne [or alkene motif]
and more into the carbonyl group in the latter. Likewise, but in a reverse
sense, for iminium ion chemistry, sulfonyl-substituted iminium species are
more stable and less reactive than straight N-acyl iminium ions because
the nitrogen lone pair in the former is more involved in the π-donation to
the carbocation. See: Royer, J.; Bonin, M.; Micouin, L. Chem. ReV. 2004,
104, 2311.
a Time for syringe pump addition of a solution of 10 [or 12] and enone.
b Isolated yields. c Hydrolysis of 10 was the major outcome. d No
reactionsrecovered starting material 10. e Polymerization was the major
outcome in addition to hydrolysis.
Initial failure is quite evident in entries 1-6 when using
ynamide 10. However, after observing a trace amount of the
Org. Lett., Vol. 12, No. 17, 2010
3781

possible product 11 when using CuCl2 and AgSbF6 [entry
6], we speculated that 10 was polymerizing under these
reactions conditions. Therefore, we turned to ynamide 12
with a Me group as the terminal substitution. Gratifyingly,
we found that cycloadduct 1318 could be attained in good
yields at three different low temperatures within an hour
[entries 7-9]. This result represents the first successful Ficini
[2 + 2] cycloaddition using ynamides. Cycloadduct 13 was
unambiguously assigned using X-ray (Figure 1). It is
Figure 2. Scope of the ynamide-[2 + 2] cycloaddition. (a) All
reactions were carried out in anhyd CH2Cl2 [ynamide conc ) 0.17
M] using 4 Å MS, 20 mol % of CuCl2, and 60 mol % of AgSbF6;
CuCl2 and AgSbF6 were premixed at rt for 1 h prior to the addition
of a respective ynamide and enone [1.20 equiv] as a combined
solution via a syringe pump over 1 h at 0 °C; the reaction was
stirred for an additional 30 min to 1 h before isolation. (b) Isolated
yields.
Figure 1. X-ray structure of the [2 + 2] cycloadduct 13.
noteworthy that the amido-cyclobutene motif is quite robust.
The pericyclic ring opening does not occur readily since the
allowed thermal conrotatory ring opening would lead to a
trans-cycloalkenone.19
Moreover, the [2 + 2] cycloadducts such as 13 could be
subjected to hydrolytic conditions and further undergo retro-
Claisen via the intermediacy of diketone 29 (Scheme 3),
The generality of this cycloaddition could be established
from examples shown in Figure 2. Several features are: (a)
The N-sulfonyl group does not need to be Mbs [entries 1, 2,
and 10]; (b) acyclic enones are also suitable [entries 5 and
6];20 (c) the alkyne substitutions [entries 7, 8, 14, and 15]
and substitutions on the nitrogen atom [entries 11-15] can
be varied, which should significantly enhance the potential
applications of these cycloadducts.
Scheme 3. Stereoselective Hydrolysis of the Cycloadduct 13
(16) Kurtz, K. C. M.; Hsung, R. P.; Zhang, Y. Org. Lett. 2006, 8, 231.
(17) For R-halogenations of ynamides observed using Pd(0) and Rh(I),
see: (a) Tracey, M. R.; Zhang, Y.; Frederick, M. O.; Mulder, J. A.; Hsung,
R. P. Org. Lett. 2004, 6, 2209. (b) Oppenheimer, J.; Johnson, W. L.; Tracey,
M. R.; Hsung, R. P.; Yao, P.-Y.; Liu, R.; Zhao, K. Org. Lett. 2007, 9,
2361.
(18) See Supporting Information.
(19) (a) Ficini, J.; Dureault, A. Tetrahedron Lett. 1977, 18, 809. Also
see (b) Bu¨chi, G.; Burgess, E. M. J. Am. Chem. Soc. 1960, 82, 4333. (c)
Corey, E. J.; Bass, J. D.; Le Mahisu, R.; Mitra, R. B. J. Am. Chem. Soc.
1964, 86, 5570.
(20) Conjugation appears to be a key, as cyclohexenyl methyl ketone
did not give i when reacted with ynamide 12. On the other hand,
cyclohexenyl nitrile gave a completely different product pyrimidine iii,
thereby suggesting a cyclotrimerization process. Regiochemistry of iii was
assigned using NOE [see Supporting Information].
leading to keto-ester 30.21 Intriguingly, while anhydrous
conditions led to 30 in 76% yield, when using MeOH-H2O
as solvent, keto-imide 3122 was found in addition to 30. Ficini
also observed ketoamide formation but only under neutral
or basic hydrolytic conditions, and its formation likely
(21) Mikami, K.; Terada, M.; Nakai, T. J. Org. Chem. 1991, 56, 5456.
(22) Keto-imide 31 could be further hydrolyzed to 30-syn and 30-anti
in 1:1 ratio using the same conditions.
3782
Org. Lett., Vol. 12, No. 17, 2010

activated via the cationic Cu(II) catalyst [see Possibility A
in Figure 3]. However, there may be another possibility. That
is, the cationic Cu(II) species is activating the alkyne
[Possibility B], leading to an intermediate that could par-
ticipate in a cuprate-like 1,4-addition. While we are not sure
of the oxidation state of such copper species, this proposed
possibility resonates with our earlier proposal of the inter-
mediacy of C to explain the exclusive syn addition of “H-X”
[hydro-halogenation] to ynamides that was observed when
using catalysts such as MgX2,14 TiCl4,16 or Rh(I)Cl(Ph3P)3.17
We are currently exploring such a mechanistic possibility.
We have uncovered here the Ficini [2 + 2] cycloaddition
using ynamides. These reactions could be catalyzed using
CuCl2 and AgSbF6. Efforts are underway to develop synthetic
applications of this cycloaddition reaction.
Figure 3. Mechanistic considerations.
proceeded through an aminal intermediate.1,4,23 The modest
syn-selectivity was also reported in Ficini’s related work,4,23
and the saponified 30-syn was used by Ficini in their
synthesis of (()-juvabione.24
Lastly, a simple and straightforward mechanistic consid-
eration would be that this is stepwise cycloaddition with a
nucleophilic 1,4-addition by the ynamide onto the enone
Acknowledgment. We thank the NIH [GM066055] for
funding. We thank Dr. Vic Young of the University of
Minnesota for providing X-ray structural analysis. We also
thank Professor Steve Burke of the University of Wisconsin
for valuable discussions.
Supporting Information Available: Experimental pro-
cedures as well as NMR spectra and characterizations are
available for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(23) (a) Ficini, J.; Guingant, A. NouV. J. Chim. 1980, 4, 421. (b) Ficini,
J.; Desmaele, D.; Touzin, A.-M. Tetrahedron Lett. 1983, 24, 1025. (c) Ficini,
J.; Eman, A.; Touzin, A.-M. Tetrahedron Lett. 1976, 17, 679
.
(24) Ficini, J.; d’Angelo, J.; Noire´, J. J. Am. Chem. Soc. 1974, 96, 1213.
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