Selectivity in the Ruthenium-catalyzed Alder ene reactions of di- and triynes

Article abstract of DOI:10.1021/ja0719430

Ruthenium-catalyzed Alder ene reactions between diynes and triynes with terminal alkenes gave the corresponding enynes and enediynes with high regio- and site-selectivity. The selectivity profile clearly indicates that one of the alkynyl moieties of 1,3-diynes not participating in the reaction determines the regiochemistry, whereas the interplay between steric hindrance and polar substituents at the propargylic sites determines the site-selectivity. Copyright

Full text of DOI:10.1021/ja0719430

Published on Web 05/08/2007
Selectivity in the Ruthenium-Catalyzed Alder Ene Reactions of Di- and
Triynes
Eun Jin Cho and Daesung Lee*
Department of Chemistry, UniVersity of Wisconsin, Madison, Wisconsin 53706
Received March 20, 2007; E-mail: dlee@chem.wisc.edu
Table 1. Regioselectivity with Symmetrical 1,3-Diynesa
The efficient construction of unsaturated molecular frameworks
with desired regio- and stereochemistries remains one of the major
challenges in organic chemistry. The metal-catalyzed merger of
alkynes and alkenes1 serves this purpose, albeit the regioselectivity
generally suffers in intermolecular processes. Specifically, in the
Ru-catalyzed Alder ene reaction,2 regioselectivity is unpredictable,
leading to the formation of a mixture of linear and branched isomers
in varying ratios.3 To improve selectivity, Trost et al.4 used silylated
alkyne 1 to generate a branched isomer 3, while Lee et al.5 used
borylated alkyne 2, which provided a branched isomer 4 with
unusual cis-stereochemistry (eq 1).
yield of
ratio
entry
R
11 (%)b
(11:11′)
1
2
3
4
5
a
b
c
d
e
Ph
CH2OAc
51
67
70
72
68
1:0
1:0
1:0
1:0
1:0
CH(CH3)OAc
CH(CH3)O(p-NO2)Bz
CH(CH2CH2Ph)OAc
a Reactions performed with 10 mol % of RuCp(CH3CN)3PF6 at 25 °C
in acetone (0.15 M) for 5 min. Carbonate protecting group facilitates the
isolation of products. Less than 10 mol % of catalyst loading resulted in
longer reaction times and incomplete conversion. b Isolated yield.
Table 2. Site-Selectivity with Unsymmetrical 1,3-Diynesa
yield of
14 (%)b
ratio
entry
R1
R2
13
+
(13:14)
1
2
3
4
5
6
7
8
a
b
c
d
e
f
H
H
Bu
Bu
Bu
69
30
60
59
55
73
80
70
1:0
1:0
1:13.4
1:3.0
1:1.3
0:1
In search of a new regio-directing element complementary to
the silyl and boronate substituents controlling the regio- and
stereochemistry of the reaction, we envisioned the use of an alkyne
moiety such as in 1,3-diyne 5,6 where the alkyne substituent,
attached directly to the reacting alkyne moiety, is expected to exert
a strong impact for the favorable formation of one of the pairs of
regioisomers 6/7 and 8/9 (eq 2).7 Herein, we report the highly
regioselective Alder ene reaction of 1,3-diynes (and 1,3,5-triynes)
to give 6/7 over 8/9, where the site-selectivity (a consequence of
reactivity difference between the two alkyne moieties in unsym-
metrical 1,3-diynes) between 6 and 7 is controlled by judicious
selection of R1 and R2.
First, the regioselectivity profile of the Alder ene reaction was
examined with symmetrical 1,3-diynes 10a-e to avoid any potential
site-selectivity problem. With 3-butenyl ethyl carbonate in acetone
(0.15 M) with a cationic ruthenium complex [RuCp(CH3CN)3PF6],8
substrates 10a-e gave single regioisomeric ene products (branched
isomers) 11a-e in good yields (Table 1, entries 1-5) without
contamination of the other regioisomer 11′. Two salient features
of these reactions are the perfect regioselectivity for the branched
isomer 11 and the lack of reactivity of its alkyne moiety toward
the second Alder ene reaction, thereby giving only monoalkene
adducts. The high regioselectivity is the consequence of a strong
directing effect of the alkyne moiety, whereas the site-selective
reaction of 10 over 11 is probably the result of the higher reactivity
of 1,3-diynes than that of the corresponding 3-branched 1,3-enynes.9
Having identified the uniform regioselectivity, we next examined
the steric and polar heteroatom substituent effect3b,10 for site-
CH2CH2OH
CH2OH
CH2CH2OH
CH2CH2CH2OH
Bu
CH2OH
CH2CH2OH
Bu
SiEt3
SiEt3
SiEt3
g
h
0:1
0:1
a Reactions performed with 10 mol % of RuCp(CH3CN)3PF6 at 25 °C
in acetone (0.15 M) for 5 min. b Isolated yield.
selectivity (Table 2). For terminal 1,3-diynes 12a and 12b, the
sterically least hindered terminal alkyne moiety participated in the
reaction to generate 13a and 13b exclusively (entries 1 and 2). On
the other hand, the internal 1,3-diynes 12c-e provided mixtures
of 13c-e and 14c-e in varying ratio (entries 3-5), which showed
clear evidence of the regiochemistry-directing effect of a polar
hydroxyl group in a distance-dependent manner. In the case of 1,3-
diynes 12f-h with a silyl group on one of the alkyne moieties, the
dominant role of the steric hindrance of the silyl group directed
the reaction to occur on the other alkyne, irrespective of the presence
or absence of the regiochemistry-directing hydroxyl group, provid-
ing single products 14f-h (entries 6-8).
The generality of regio- and site-selectivity shown in Tables 1
and 2 was further confirmed with reactions between more diverse
1,3-diynes having different steric environments at propargylic sites
and various reacting alkene counterparts (Table 3). With diyne 12g,
reactions employing different alkenes did not perturb the efficiency
and selectivity (entries 1-4), providing expected products 13k-
n. Replacing propargylic hydroxyl with an acetoxy group in 12j
9
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J. AM. CHEM. SOC. 2007, 129, 6692-6693
10.1021/ja0719430 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Selectivity of Reactions with Unsymmetrical 1,3-Diynesa
to the general preference for C in reactions with Co,7b Ta,7c Zr,7d
Ni,7g,i and Rh,7h,l where the di- and triynes enter the metallacycle
with the alkynyl substituent R to the metal (biggest lobe of their
LUMO â to the metal).12,13
In conclusion, we have realized an unusually high level of regio-
and site-selectivity in the Alder reactions of 1,3-diynes and 1,3,5-
triynes. The selectivity profile clearly indicates that one of the
alkynyl moieties of 1,3-diynes not participating in the reaction
determines the regiochemistry, whereas the interplay between steric
hindrance and polar substituents at the propargylic sites determines
the site-selectivity. The synthetic scope and utility of these
reactions,14 as well as the effect of the alkyne moiety for controlling
regiochemistry, is under investigation.
Acknowledgment. We thank the NIH (CA106673) and the
Sloan Foundation for partial financial support of this work, as well
as the NSF and NIH for NMR and mass spectrometry instrumenta-
tion. Dr. Monica Ivancic’s help in running an NOE experiment for
compound 13o is greatly acknowledged.
Supporting Information Available: General procedures and
characterization of represented compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
a Reactions performed with 10 mol % of RuCp(CH3CN)3PF6 at 25 °C
in acetone (0.15 M) for 5 min. b Isolated yield. c Ratio between 13p and
its site-selective isomer. d The reason for the formation of the minor isomer
is unclear at this point.
References
(1) Reviews: (a) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. ReV.
2001, 101, 2067. (b) Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV.
2002, 102, 813.
(2) For a review of Alder ene reaction, see: Trost, B. M.; Frederiksen, M.
U.; Rudd, M. T. Angew. Chem., Int. Ed. 2005, 44, 6630.
Scheme 1. Ruthenium-Catalyzed Alder Ene Reaction of Triynes
(3) (a) Trost, B. M.; Indolese, A. J. Am. Chem. Soc. 1993, 115, 4361. (b)
Trost, B. M.; Indolese, A. F.; Mu¨ller, T. J. J.; Treptow, B. J. Am. Chem.
Soc. 1995, 117, 615. (c) Trost, B. M.; Shen, H. C.; Pinkerton, A. B.
Chem.sEur. J. 2002, 10, 2341.
(4) (a) Trost, B. M.; Machacek, M.; Schnaderbeck, M. J. Org. Lett. 2000, 2,
1761. (b) Trost, B. M.; Machacek, M. R. Angew. Chem., Int. Ed. 2002,
41, 4693. (c) Trost, B. M.; Machacek, M. R.; Ball, Z. T. Org. Lett. 2003,
5, 1895.
(5) Hansen, E. C.; Lee, D. J. Am. Chem. Soc. 2005, 127, 3252.
(6) Diynes were synthesized via a CuCl-catalyzed coupling reaction between
terminal alkynes and 1-bromoalkynes: Marino, J. P.; Nguyen, H. N. J.
Org. Chem. 2002, 67, 6841.
or with Boc in 12k maintained the yield and selectivity, giving
13o and 13p, respectively (entries 5 and 6). Unexpectedly, substrate
12l, having a tertiary and a primary propargylic acetoxy groups,
gave a mixture of 13q and 13r with a marginal selectivity (3.5:1),
which indicates that the steric factor alone, unless it is a silyl group,
might not be enough for high selectivity. A boronate containing
diyne 12m showed the same regio- and site-selectivity, generating
product 13s with minor stereochemical scrambling (entry 9).11
Moreover, the regio- and site-selectivity of triynes 15a and 15b
to generate ene products 16a and 16b was found to be identical to
that of 1,3-diynes, except for the formation of minor double ene
product 17b (4%). Resubjection of isolated 16b gave only 15%
yield of 17b with mostly recovered 16b (Scheme 1).
(7) For regioselective metal-catalyzed intermolecular reactions involving
multi-ynes, see: (a) Takeda, A.; Ohno, A.; Kadota, I.; Gevorgyan, V.;
Yamamoto, Y. J. Am. Chem. Soc. 1997, 119, 4547. (b) Varela, J.; Castedo,
L.; Saa´, C. J. Am. Chem. Soc. 1998, 120, 12147. (c) Boring, E.; Sabat,
M.; Finn, M. G.; Grimes, R. N. Organometallics 1998, 17, 3865. (d)
Bredeau, S.; Delmas, G.; Pirio, N.; Richard, P.; Donnadieu, B.; Meunier,
P. Organometallics 2000, 19, 4463. (e) Saito, S.; Yamamoto, Y. Chem.
ReV. 2000, 100, 2901. (f) Camacho, D. H.; Saito, S.; Yamamoto, Y. J.
Am. Chem. Soc. 2002, 124, 924. (g) Jeevanandam, A.; Korivi, R. P.;
Huang, I.; Cheng, C. Org. Lett. 2002, 4, 807. (h) Huddleston, R. R.; Jang,
H.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 11488. (i) Deaton, K.
R.; Gin, M. S. Org. Lett. 2003, 5, 2477. (j) Jiang, M. X.; Rawat, M.;
Wulff, W. D. J. Am. Chem. Soc. 2004, 126, 5970. (k) Kim, M.; Miller,
R. L.; Lee, D. J. Am. Chem. Soc. 2005, 127, 12818. (l) Cho, C.; Krische,
M. J. Org. Lett. 2006, 8, 3873.
(8) (a) Slugovc, C.; Ruba, E.; Schmid, R.; Kirchner, K.; Mereiter, K. Monatsh.
Chem. 2000, 131, 1241. (b) Trost, B. M.; Older, C. M. Organometallics
2002, 21, 2544.
The observed regioselectivity of Alder ene reactions of 1,3-diynes
and 1,3-5-triynes is believed to be the consequence of the favorable
formation of metallacyclopentene A over C. The strong regio-
directing effect of the adjacent alkyne moiety is the result of its
more effective anion-stabilizing capacity via a conjugated ruthenium
carbenoid character, as shown in zwitterionic resonance form B
compared to that of R2 in the regioisomeric C, as proposed by Trost
for the ene reaction between 4-hydroxy-2-alkynoate and terminal
alkenes.10 However, the sense of regioselectivity for the exclusive
formation of metallacyclopentene A is highly unusual compared
(9) Reactions with 1,3-diynes gave near completion within 5 min as opposed
to 1-4 h for enynes: Trost, B. M.; Papillon, J. P. N.; Nussbaumer, T. J.
Am. Chem. Soc. 2005, 127, 17921.
(10) Trost, B. M.; Mu¨ller, T. J. J.; Martinez, J. J. Am. Chem. Soc. 1995, 117,
1888.
(11) We believe that the lower reactivity of the borylated alkyne is caused by
the electronic deactivation of boronate not by its steric hindrance.
(12) Stockis, A.; Hoffmann, R. J. Am. Chem. Soc. 1980, 102, 2952.
(13) The preferred alkynyl substituent â to a metal in metallacyclobutenes
formed from di- and triynes with metal carbenes; see refs 7j and 7k.
(14) A total synthesis of (3R,9R,10R)-panaxytriol utilizing Alder ene products
13o and 16b will be reported elsewhere.
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