Reactivity and selectivity of 1,3-diyn-6-enes in electrophilic transition metal-catalyzed reactions

Article abstract of DOI:10.1021/ol062335c

1,3-Diyne is an excellent source of alkynyl metal carbene species upon activation with an electrophilic metal catalyst. The products from this bond reorganization process suggest that the metal carbene species, generated from the preferential participatio

Full text of DOI:10.1021/ol062335c

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5413-5416
Reactivity and Selectivity of
1,3-Diyn-6-enes in Electrophilic
Transition Metal-Catalyzed Reactions
Eun Jin Cho, Mansuk Kim, and Daesung Lee*
Department of Chemistry, UniVersity of Wisconsin, Madison, Wisconsin 53706
dlee@chem.wisc.edu
Received September 21, 2006
ABSTRACT
1,3-Diyne is an excellent source of alkynyl metal carbene species upon activation with an electrophilic metal catalyst. The products from this
bond reorganization process suggest that the metal carbene species, generated from the preferential participation of an acetate over an
alkene in the first step, undergo an efficient metallotropic [1,3]-shift followed by termination via cyclopropanation.
The metal-catalyzed reactions of 1,n-enynes (n ) typically
5-7) are versatile synthetic tools whereby unsaturated cyclic
molecular frameworks can be generated efficiently.1 One
topical subject of research involving enynes of type 1 is their
activation by an electrophilic metal catalyst. When the alkyne
is not terminal (R ) alkyl or aryl group), allenyl actetate 3
is the most frequently observed final product or intermediate
for the subsequent reaction, which is believed to proceed
through an intermediate 2 via the [1,3]-migration of an
acetate (Scheme 1).2 On the other hand, when the alkyne is
terminal (R ) H), a pathway leading to product 5 is generally
preferred. The formation of 5 is the consequence of two
possible reaction pathways that involve alkylidene species
4 and 7. Although evidence from theoretical calculations3
Scheme 1
(1) Reviews: (a) Bruneau, C. Angew. Chem., Int. Ed. 2005, 44, 2328.
(b) Echavarren, A. M.; Nevado, C. Chem. Soc. ReV. 2004, 33, 431. (c)
Lloyd-Jones, G. C. Org. Biomol. Chem. 2003, 1, 215. Reviews for gold-
catalyzed reactions: (d) Ma, S.; Yu, S.; Gu, Z. Angew. Chem., Int. Ed.
2006, 45, 200. (e) Hashimi, A. S. K. Angew. Chem., Int. Ed. 2005, 44,
6990. (f) Ho¨ffmann-Ro¨der, A.; Krause, N. Org. Biomol. Chem. 2005, 3,
387. (g) Hashimi, A. S. K. Gold Bull. 2004, 37, 51. (h) Dyker, G. Angew.
Chem., Int. Ed. 2000, 39, 4237.
(2) Formation of allene as a final product or an intermediate, see: (a)
Marion, N.; Diez-Gonzalez, S.; de Fremont, P.; Nolan, S. P. Angew. Chem.,
Int. Ed. 2006, 45, 3647. (b) Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006,
128, 1442. (c) Buzas, A.; Istrate, F.; Gagosz, F. Org. Lett. 2006, 8, 1957.
(d) Zhao, J.; Hughes, C. O.; Toste, F. D. J. Am. Chem. Soc. 2006, 128,
7436. (e) Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804. (f) Cariou, K.;
Mainetti, E.; Fensterbank, L.; Malacria, M. Tetrahedron 2004, 60, 9745.
10.1021/ol062335c CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/20/2006

and experiments4 favorably suggests the involvement of
intermediate 4 over that of 6/7, the preference among these
reaction pathways should depend on the interplay of many
factors,5 the most important of which seems to be the nature
of the R substituent.6 Given the cationic charge development
on the alkyne moiety upon complexation of electrophilic
metals, the role of R as an electron-releasing group seems
to be pivotal in determining the fate of the initially formed
alkyne-metal complex, generating intermediates 2, 4, or 6.
This hypothesis is further supported by the reactions of
related enynes of type 8, where the nature of X determines
the formation of intermediates 9 and 11, which eventually
generate products 10/10′ and 12, respectively (Scheme 2).7
Table 1. Reactivity of Alkene vs Acetate as the Initiatora
Scheme 2
a With 5 mol % catalyst loading under balloon pressure of CO. b All
yields are isolated yields after 4 h of total reaction time. c The E/Z ratios
were determined by H NMR before purification. d The E/Z ratios change
during the purification.
1
We envisioned that the use of 1,3-diyne moiety in 1, where
R ) alkyne, would not only bias the electronics of the
reacting alkyne to form metal carbenes but also allow these
initially formed alkylidene intermediates to undergo metal-
lotropic [1,3]-shift,8 thereby promoting the mode of reaction
pathway not available for the monoalkyne-containing enyne
1. Herein we report a unique selectivity profile of 1,3-diynes
upon electrophilic metal activation to form alkynyl al-
kylidenes and their subsequent facile metallotropic [1,3]-
shift.
First, the reactivity of 1,3-diynes 13a9 that contain both
the competing tethered alkene and propargylic acetoxy group
was examined with several different metal complexes.10 From
a brief screening, a platinum-based catalyst system PtCl2/
CO in toluene at 80 °C, a condition used by Fu¨rstner for the
reactions of enynes of type 1,11,12 was found to be most
(3) (a) Soriano, E.; Ballesteros, P.; Marco-Contelles, J. Organometallics
2005, 24, 3182. (b) Nieto-Oberhuber, C.; Paz Mun˜oz, M.; Bun˜uel, E.;
Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. Angew. Chem., Int. Ed.
2005, 44, 6146.
(4) (a) Fu¨rstner, A.; Hannen, P. Chem. Eur. J. 2006, 12, 3006. For a
slightly different mechanistic interpretation, see: (b) Fehr, C.; Galindo, J.
Angew. Chem., Int. Ed. 2006, 45, 2901.
(5) For the Rautenstrauch reaction involving 3-acetoxy-1,4-enynes, see:
(a) Faza, O. N.; Lopez, C. S.; Alvarez, R.; de Lera, A. R. J. Am. Chem.
Soc. 2006, 128, 2434. (b) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem.
Soc. 2005, 127, 5802. (c) Rautenstrauch, V. J. Org. Chem. 1984, 49, 950.
(6) For reactions of 3-acetoxy-1,4- and 1,5-enynes with electron-
withdrawing carboxylate substituent, see: (a) Prasad, B. A. B.; Yoshimoto,
F. K.; Sarpong, R. J. Am. Chem. Soc. 2005, 127, 12468. (b) Reference 2f.
(7) For a theoretical calculations for divergent skeletal rearrangement
of 1,6-enynes, see ref 3b.
(8) [1,3]-Shift: (a) Kim, M.; Lee, D. J. Am. Chem. Soc. 2005, 127, 18024.
(b) Kim, M.; Miller, R. L.; Lee, D. J. Am. Chem. Soc. 2005, 127, 12818.
(c) Barluenga, H.; de la Rua´, R. B.; de Sa´a, D.; Ballesteros, A.; Toma´s, M.
Angew. Chem., Int. Ed. 2005, 44, 4981. (d) van Otterlo, W. A. L.; Ngidi,
E. L.; de Koning, C. B.; Fernandes, M. A. Tetrahedron Lett. 2004, 45,
659. (e) Padwa, A.; Austin, D. J.; Gareau, Y.; Kassir, J. M.; Xu, S. L. J.
Am. Chem. Soc. 1993, 115, 2637. [1,1.5]-Shift: (f) Casey, C. P.; Dzwiniel,
T. L. Organometallics 2003, 22, 5285. (g) Casey, C. P.; Dzwiniel, T. L.;
Kraft, S.; Guzei, I. A. Organometallics 2003, 22, 3915. (h) Ortin, Y.;
Sournia-Saquet, A.; Lugan, N.; Mathieu, R. Chem. Commun. 2003, 1060.
(i) Casey, C. P.; Kraft, S.; Powell, D. R. J. Am. Chem. Soc. 2000, 122,
3771. (j) Casey, C. P.; Kraft, S.; Powell, D. R. Organometallics 2001, 20,
2651. (k) Casey, C. P.; Kraft, S.; Kavana, M. Organometallics 2001, 20,
3795. (l) Casey, C. P.; Kraft, S.; Powell, D. R. J. Am. Chem. Soc. 2002,
124, 2584. Also see recent examples of the closely related bond shift of
free alkynyl carbenes: (m) Bowling, N. P.; Halter, R. J.; Hodges, J. A.;
Seburg, R. A.; Thomas, P. S.; Simmons, C. S.; Stanton, J. F.; McMahon,
R. J. J. Am. Chem. Soc. 2006, 128, 3291 and references therein.
(9) For the preparation of diynes, see the Supporting Information.
(10) Pt- and Au-catalyzed rearrangement of 1,3-diynes, see: (a) Cho,
E. J.; Kim, M.; Lee, D. Eur. J. Org. Chem. 2006, 3074. See also [RuCl2-
(CO)3]2-catalyzed reaction: (b) Miki, K.; Ohe, K.; Uemura, S. J. Am. Chem.
Soc. 2006, 128, 9270.
(11) Representative examples of PtCl2-catalyzed reactions with/without
CO: (a) Fu¨rstner, A.; Davies, P. W.; Gress, T. J. Am. Chem. Soc. 2005,
127, 8244. (b) Mamane, V.; Gress, T.; Krause, H.; Fu¨rstner, A. J. Am. Chem.
Soc. 2004, 126, 8654. (c) Harrak, Y.; Blaszykowski, C.; Bernard, M.; Cariou,
K.; Mainetti, E.; Mourie`s, V.; Dhimane, A.-L.; Fensterbank, L.; Malacria,
M. J. Am. Chem. Soc. 2004, 126, 8656. (d) Nevado, C.; Ferrer, C.;
Echavarren, A. M. Org. Lett. 2004, 6, 3191. (e) Mainetti, E.; Mourie`s, V.;
Fensterbank, L.; Malacria, M.; Marco-Contelles, J. Angew. Chem., Int. Ed.
2002, 41, 2132. (f) Fu¨rstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc.
2000, 122, 6785. (g) Chatani, N.; Furukawa, N.; Sakurai, H.; Murai, S.
Organometallics 1996, 15, 901.
(12) The current reaction resulted in a low conversion without CO.
5414
Org. Lett., Vol. 8, No. 23, 2006

Table 2. Selectivity of 5-Exo vs 6-Endo Ring Closurea
Table 3. Differential Reactivity of Alkene vs Acetatea
a With 5 mol % catalyst loading. b All yields are isolated yields. c The
1
ratios were determined by H NMR before purification.
a With 5 mol % catalyst loading. b All yields are isolated yields.
toluene at 80 °C provided exclusively the 5-exo-product 16a
in 96% yield after 12 h without any formation of the 6-endo-
product (entry 1).14 However, 15b gave a mixture of 5-exo-
product 16b and 6-endo-product 17b in 6.3% and 23% yield
at 30% conversion (entry 2), while 15c gave 16c and 17c in
25% and trace amount, respectively (entry 3).15 The N-
toluensulfonyl group-containing substrate 15d gave only
6-endo-product 17d (entry 4). The observed product distribu-
tion clearly showed the role of the heteroatom substituent
to affect the reaction course of 1,3-diyne substrates 15a-d
to form 16a-c and 17b-d, which follows the general trend
depicted in Scheme 2. Furthermore, this result strongly
supports the notion that the reactions in Table 1 should
involve the initial acetate and benzoate participation rather
than the alkene.16
Next, the selectivity between propargylic polar functional
groups (acetate or bromide) and the tethered alkenes for the
carbenoid reaction in the termination step was examined
(Table 3). Symmetrical substrate 18a containing two acetates
and two alkenes provided an Z/E mixture of products 19a
in 80% yield (Z/E ) 1.3:1) (entry 1). Similarly, substrate
18b gave exclusive formation of 19b with slightly lower yield
effective, generating 14a in 88% yield with Z/E ) 2.5:1
(entry 1, Table 1). Under the same conditions, substrate 13b
containing a phenyl instead of methyl group gave better yield
and selectivity (entry 2). Heteroatom substituents in the tether
of 13c and 13d are tolerant, providing comparable yields
and selectivity for 14c and 14d, respectively (entries 3 and
4). Substrates 13e and 13f with a tertiary p-nitrobenzoate
provided excellent yields of products 14e and 14f (entries 5
and 6). The formation of bicyclo[3.1.0]hexane moieties in
products 14a-f strongly indicates that the acetate/benzoate
should be the kinetically more reactive initiating functional-
ity, directing these reactions to occur following the path
similar to 1 f 6 f 7 in Scheme 1. If the reaction initially
occurred via the participation of the tethered alkene, the final
products 14c, 14d, and 14f from substrates 13c, 13d, and
13f should have contained bicyclo[4.1.0]heptene moiety
based on the general reactivity pattern (via intermediate 11)
shown in Scheme 2.
To confirm our belief that transformation of 13a-f
involved an initial acetate or benzoate participation rather
than the alkene, as well as to gain further insight into the
role of diynes in 5-exo/6-endo type ring closure selectivity
in Scheme 2, symmetrical diynes 15a-d were examined
(Table 2).13 Treatment of substrate 15a with PtCl2/CO in
(14) A gold-catalyzed reaction of 15a to generate 16a was reported
recently, see: Lopez, S.; Herrero-Gomez, E.; Perez-Galan, P.; Nieto-
Oberhuber, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 6029.
(15) Unstable enol ether 17b could be isolated only when the reaction
was stopped at low conversion; however, 17c was too unstable to be isolated
under the reaction conditions.
(16) The preferential participation of acetate in these reactions is the
opposite to the reactivity observed and predicted by that of monoynes with
propargylic acetates, see refs 3a and 4a.
(13) The reaction of 15a,b with PtCl2, AuCl3, Ph3PAuCl, PdCl2(PhCN)2,
and [Rh(OAc) ] gave low conversion.
2
2
Org. Lett., Vol. 8, No. 23, 2006
5415

(67%) (Z/E ) 1.2:1) (entry 2). The reaction of substrate 18c
that contains two different acetates provided 19c and 19c′
in 33% and 57% yield, respectively (entry 3). Product 19c
is the result of initiation of the reaction from the left-hand
side acetate of 18c followed by metallotropic [1,3]-shift and
termination with the other acetate, whereas product 19c′ is
the consequence of initiation from the right-hand side acetate
followed by metallotropic [1,3]-shift and the termination of
the putative alkylidene intermediate via cyclopropanation.
Reaction of substrate 18d containing a bromide provided 19d
as a sole product in marginal yield, which we believe is the
consequence of the initiation from the acetate and termena-
tion by the alkene via cyclopropanation (entry 4).
The observed product distribution clearly suggests that
acetates preferentially participate at the initial formation of
carbenoid intermediates whereas the tethered alkenes par-
ticipate in the termination step favorably. The general
reactivity and selectivity trend is illustrated with substrate
18a in Scheme 3. The formation of Z/E-mixtures of the vinyl
acetate moiety in these products endorses this conclusion,
where the vinyl acetate formed during the formation of
carbenoid intermediates generally gives a mixture of Z/E-
stereochemistry, while that formed from the termination step
selectively generates E-stereochemistry.10a
In conclusion, we have demonstrated that 1,3-diynes
behave in predictable yet distinctive manners compared to
simple enynes under electrophilic transition metal-mediated
reaction conditions. This characteristic behavior of 1,3-diynes
is presumably caused by the slightly electron-withdrawing
nature of the alkynyl substituent, which not only renders the
preferred formation 5-exo-type alkylidenes (similar to 9) but
also allows for the subsequent [1,3]-metallotropic shift.
Several salient features of reactions with this functionality
include the following: (a) an acetate is more reactive than
the tethered alkene as an initiator, generating [1,2]-acetate
migrated alkylidene intemediate whereas an alkene is a better
terminator than an acetate/bromide to generate the cyclo-
propane moiety, (b) allene products are not formed at all
under current reaction conditions, (c) 5-exo/6-endo type
alkylidene formation depends on the heteroatom substituent
in the tether, and (d) facile metallotropic [1,3]-shift of the
intermediate alkylidenes occurred whenever possible.
Scheme 3
Acknowledgment. We thank NSF (CHE 0401783) and
the Sloan Foundation for financial support of this work as
well as the NSF and NIH for NMR and mass spectrometry
instrumentation.
Supporting Information Available: General procedures
and characterization data of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL062335C
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Org. Lett., Vol. 8, No. 23, 2006