Highly regio- And stereoselective addition of 1,3-diketones to internal alkynes catalyzed by cationic iridium complex

Article abstract of DOI:10.1021/ol9020095

The first regio- and stereoselective addition of 1,3-diketones to unfunctionalized internal alkynes under neutral conditions is achieved by using [Ir(cod)₂]SbF₆ as a catalyst.

Full text of DOI:10.1021/ol9020095

ORGANIC
LETTERS
2009
Vol. 11, No. 21
5038-5041
Highly Regio- and Stereoselective
Addition of 1,3-Diketones to Internal
Alkynes Catalyzed by Cationic Iridium
Complex
Gen Onodera, Minoru Kato, Ryo Kawano, Yuri Kometani, and Ryo Takeuchi*
Department of Chemistry and Biological Science, Aoyama Gakuin UniVersity,
5-10-1 Fuchinobe, Sagamihara, Kanagawa 229-8558, Japan
takeuchi@chem.aoyama.ac.jp
Received August 29, 2009
ABSTRACT
The first regio- and stereoselective addition of 1,3-diketones to unfunctionalized internal alkynes under neutral conditions is achieved by
using [Ir(cod)2]SbF6 as a catalyst.
The addition of 1,3-dicarbonyl compounds to carbon-carbon
multiple bonds substituted with an electron-withdrawing
group has been widely used as the Michael reaction in
organic synthesis.1 Recently, much attention has been paid
to the catalytic addition of active methylene compounds to
unfunctionalized carbon-carbon double bonds under neutral
conditions. Suitable substrates for hydroalkylation have been
reported to be alkenes,2,3 conjugated dienes,3e,g,4 allenes,5
and cyclic enol ethers.3g,4b Further, intramolecular hy-
droalkylation to unfunctionalized carbon-carbon double
bonds has been reported.6 Although intramolecular hy-
droalkylation to carbon-carbon triple bonds, which is known
as the Conia-ene reaction, has recently been applied to the
synthesis of carbocycles,7 the addition of an active methylene
compound to an unfunctionalized carbon-carbon triple bond
under neutral conditions has been unexplored. Applicable
alkynes are limited to terminal alkynes.8,9 Indium triflate8
and rhenium complexes9 are used as catalysts for this
addition. To expand the reaction scope and enhance the
selectivity, a new catalytic reaction is needed. To the best
of our knowledge, the addition of 1,3-dicarbonyl compounds
to unfunctionalized internal alkynes has not been reported.10
In the course of our study on iridium-catalyzed carbon-carbon
bond formation,11 we found the first regio- and stereoselec-
(1) (a) Perlmutter, P.; Conjugate Addition Reactions in Organic Syn-
thesis; Pergamon: Oxford, UK, 1992. (b) For transition-metal catalysis, see:
Christoffers, J. Eur. J. Org. Chem. 1998, 1259.
(2) (a) Hirase, K.; Iwahama, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem.
2002, 67, 970. (b) Motokura, K.; Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani,
K.; Kaneda, K. Angew. Chem., Int. Ed. 2006, 45, 2605
.
(3) (a) Yao, X.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 6884. (b) Yao,
X.; Li, C.-J. J. Org. Chem. 2005, 70, 5752. (c) Kischel, J.; Michalik, D.;
Zapf, A.; Beller, M. Chem. Asian J. 2007, 2, 909. (d) Duan, Z.; Xuan, X.;
Wu, Y. Tetrahedron Lett. 2007, 48, 5157. (e) Rueping, M.; Nachtsheim,
B. J.; Kuenkel, A. Synlett 2007, 1391. (f) Liu, P. N.; Zhou, Z. Y.; Lau,
C. P. Chem.sEur. J. 2007, 13, 8610. (g) Li, Y.; Yu, Z.; Wu, S. J. Org.
(5) Trost, B. M.; Ja¨kel, C.; Plietker, B. J. Am. Chem. Soc. 2003, 125,
4438.
Chem. 2008, 73, 5647
.
(4) (a) Leitner, A.; Larsen, J.; Steffens, C.; Hartwig, J. F. J. Org. Chem.
2004, 69, 7552. (b) Nguyen, R.-V.; Yao, X.-Q.; Bohle, D. S.; Li, C.-J.
Org. Lett. 2005, 7, 673. (c) Nguyen, R.-V.; Li, C.-J. J. Am. Chem. Soc.
(6) For selected examples, see: (a) Pei, T.; Widenhoefer, R. A. J. Am.
Chem. Soc. 2001, 123, 11290. (b) Qian, H.; Widenhoefer, R. A. J. Am.
Chem. Soc. 2003, 125, 2056. (c) Pei, T.; Wang, X.; Widenhoefer, R. A.
J. Am. Chem. Soc. 2003, 125, 648.
2005, 127, 17184
.
10.1021/ol9020095 CCC: $40.75
Published on Web 10/01/2009
 2009 American Chemical Society

tive addition of 1,3-diketones to unfunctionalized internal
alkynes under neutral conditions.
(entries 2, 3, and 4). AgSbF6 and NaSbF6 did not show any
catalytic activity (entries 7 and 8). These results clearly
showed that the cationic iridium species was the catalytically
active species for this reaction. The use of PPh3 or P(OPh)3
as an additional ligand inhibited the reaction.
1-Phenyl-1-propyne (1a) reacted with acetylacetone (2a)
in the presence of a catalytic amount of cationic iridium
complex under refluxing 1,2-dichloroethane to give 3aa. The
product was obtained as an enol form. Notably, the reaction
proceeded under neutral conditions. The catalyst was screened
by reacting 1a with 2a. The results are summarized in Table
1. A neutral iridium complex [Ir(cod)Cl]2 did not show any
The addition of acetylacetone (2a) to various internal
alkynes (1b-l) in the presence of 5 mol % of [Ir(cod)2]SbF6
under refluxing 1,2-dichloroethane was examined (Table 2).
Table 2. The Reaction of Alkynes (1a-l) with Acetylacetone
(2a)a
Table 1. The Reaction of 1-Phenyl-1-propyne (1a) with
Acetylacetone (2a)a
time yield
E/Z
catalyst
entry (loading (mol %))
time yield
(h)
E/Z of
entry
R1
R2
1
products (h) (%)b 3/4c of 3d
(%)b
3aa/4aac
3aad
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me 1a 3aa, 4aa
Et 1b 3ba, 4ba
Et 1b 3ba, 4ba
nPr 1c 3ca, 4ca
1
1
2
1
91 >99/1 96/4
76
84
73
80
64
74
88
95/5 91/9
95/5 89/11
96/4 94/6
95/5 69/31
95/5 92/8
95/5 48/52
97/3 98/2
1
2
3
4
5
6
7
8
[Ir(cod)Cl]2 (4)
[Ir(cod)2]BF4 (8)
[Ir(cod)2]PF6 (8)
[Ir(cod)2]OTf (8)
[Ir(cod)2]SbF6 (8)
[Ir(cod)2]SbF6 (5)
AgSbF6 (8)
24
0
62
66
82
92
91
0
24
24
1
>99/1
>99/1
>99/1
>99/1
>99/1
53/47
56/44
58/42
98/2
nPr 1c 3ca, 4ca 12
nBu 1d 3da, 4da
nBu 1d 3da, 4da 24
Me 1e 3ea, 4ea
4-methylphenyl Me 1f 3fa, 4fa
1
0.2
4-chlorophenyl
1
1
24
24
96/4
0.5 90 >99/1 91/9
10 4-methoxyphenyl Me 1g 3ga, 4ga 0.3 92 >99/1 93/7
NaSbF6 (8)
0
11 1-naphthyl
12 2-naphthyl
13 Ph
Me 1h 3ha, 4ha
Me 1i 3ia, 4ia
Ph 1j 3ja, 4ja
Me 1k 3ka, 4ka
nBu 1l 3la, 4la
1
1
1
1
88
89 >99/1 94/6
83 85/15
77 >99/1 96/4
99/1 94/6
a Reaction conditions: 1a (1.0 mmol) and 2a (3.0 mmol) in the presence
of a catalyst in 1,2-dichloroethane (5 mL). b Isolated yield. c Determined
by 1H NMR. d The stereochemistry of 3aa was determined by NOESY
14e 1-cyclohexenyl
15 2-thienyl
1
0.2 82 >99/1 9/91
analysis, and the ratio was determined by H NMR.
a Reaction conditions: 1 (1.0 mmol) and 2a (3.0 mmol) in the presence
of [Ir(cod)2]SbF6 (0.05 mmol) in 1,2-dichloroethane (5 mL). b Isolated yield.
Determined by H NMR. d The stereochemistry of 3 was determined by
c
1
NOESY analysis, and the ratio was determined by 1H NMR. e 10 mol % of
catalyst was used.
catalytic activity for the reaction (entry 1). On the other hand,
cationic iridium complexes showed catalytic activity to give
3aa in good to excellent yields (entries 2-5). The counter-
anion of these complexes had a profound effect on the
reaction. [Ir(cod)2]SbF6 gave the best result (entry 5).
Carbon-carbon bond formation was regiospecific and oc-
curred at the alkyne carbon substituted with a phenyl group.
The E-selectivity of the newly formed carbon-carbon double
bond in 3aa was 98%. The catalyst loading could be reduced
to 5 mol % without reducing the yield or selectivity (entry
6). While the regioselectivities with [Ir(cod)2]BF4,
[Ir(cod)2]PF6, and [Ir(cod)2]OTf were the same as that with
[Ir(cod)2]SbF6, the yields and stereoselectivities decreased
We subjected 1-phenyl-1-alkynes to the reaction to compare
the effect of the length of the alkyl substituent. Both the
yield and stereoselectivity decreased as the alkyl substituent
was extended from methyl to n-butyl (entries 1, 2, 4, and
(8) (a) Nakamura, M.; Endo, K.; Nakamura, E. J. Am. Chem. Soc. 2003,
125, 13002. (b) Nakamura, M.; Fujimoto, T.; Endo, K.; Nakamura, E. Org.
Lett. 2004, 6, 4837. (c) Nakamura, M.; Endo, K.; Nakamura, E. Org. Lett.
2005, 7, 3279. (d) Nakamura, M.; Endo, K.; Nakamura, E. AdV. Synth.
Catal. 2005, 347, 1681. (e) Zhang, J.; Blazecka, P. G.; Angell, P.; Lovdahl,
M.; Curran, T. T. Tetrahedron 2005, 61, 7807. (f) Endo, K.; Hatakeyama,
T.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2007, 129, 5264. (g)
Angell, P.; Blazecka, P. G.; Lovdahl, M.; Zhang, J. J. Org. Chem. 2007,
72, 6606. (h) Fujimoto, T.; Endo, K.; Tsuji, H.; Nakamura, M.; Nakamura,
E. J. Am. Chem. Soc. 2008, 130, 4492.
(7) For recent examples, see: (a) Kennedy-Smith, J. J.; Staben, S. T.;
Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526. (b) Staben, S. T.; Kennedy-
Smith, J. J.; Toste, F. D. Angew. Chem., Int. Ed. 2004, 43, 5350. (c) Gao,
Q.; Zheng, B.-F.; Li, J.-H.; Yang, D. Org. Lett. 2005, 7, 2185. (d) Corkey,
B. K.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168. (e) Ochida, A.;
Ito, H.; Sawamura, M. J. Am. Chem. Soc. 2006, 128, 16486. (f) Pan, J.-H.;
Yang, M.; Gao, Q.; Zhu, N.-Y.; Yang, D. Synthesis 2007, 2539. (g) Deng,
C.-L.; Song, R.-J.; Guo, S.-M.; Wang, Z.-Q.; Li, J.-H. Org. Lett. 2007, 9,
5111. (h) Ito, H.; Makida, Y.; Ochida, A.; Ohmiya, H.; Sawamura, M. Org.
Lett. 2008, 10, 5051. (i) Tsuji, H.; Yamagata, K.-i.; Itoh, Y.; Endo, K.;
Nakamura, M.; Nakamura, E. Angew. Chem., Int. Ed. 2007, 46, 8060. (j)
Itoh, Y.; Tsuji, H.; Yamagata, K.-i.; Endo, K.; Nakamura, M.; Nakamura,
E. J. Am. Chem. Soc. 2008, 130, 17161. (k) Deng, C.-L.; Zou, T.; Wang,
Z.-Q.; Song, R.-J.; Li, J.-H. J. Org. Chem. 2009, 74, 412. (l) Yang, T.;
Ferrali, A.; Sladojevich, F.; Campbell, L.; Dixon, D. J. J. Am. Chem. Soc.
2009, 131, 9140.
(9) Kuninobu, Y.; Kawata, A.; Takai, K. Org. Lett. 2005, 7, 4823.
(10) Indium-catalyzed reaction of 1-haloalkynes with 1,3-dicarbonyl
compounds was reported: Tsuji, H.; Fujimoto, T.; Endo, K.; Nakamura,
M.; Nakamura, E. Org. Lett. 2008, 10, 1219.
(11) (a) Takeuchi, R.; Kashio, M. Angew. Chem., Int. Ed. Engl. 1997,
36, 263. (b) Takeuchi, R.; Kashio, M. J. Am. Chem. Soc. 1998, 120, 8647.
(c) Takeuchi, R.; Tanabe, K. Angew. Chem., Int. Ed. 2000, 39, 1975. (d)
Takeuchi, R. Synlett 2002, 1954. (e) Takeuchi, R.; Nakaya, Y. Org. Lett.
2003, 5, 3659. (f) Kezuka, S.; Okado, T.; Niou, E.; Takeuchi, R. Org. Lett.
2005, 7, 1711. (g) Kezuka, S.; Tanaka, S.; Ohe, T.; Nakaya, Y.; Takeuchi,
R. J. Org. Chem. 2006, 71, 543. (h) Takeuchi, R.; Kezuka, S. Synthesis
2006, 3349. (i) Onodera, G.; Watabe, K.; Matsubara, M.; Oda, K.; Kezuka,
S.; Takeuchi, R. AdV. Synth. Catal. 2008, 350, 2725.
Org. Lett., Vol. 11, No. 21, 2009
5039

6). The yield decreased from 91% to 64% and the E-
selectivity decreased from 96% to 92%. Despite this decrease
in yield and E-selectivity, the regioselectivity was almost
the same regardless of the length of the alkyl substituent. A
longer reaction time improved the yield, but decreased the
E-selectivity (entries 3, 5, and 7). We next examined the
effect of a substituent on the aromatic ring on the reaction
(entries 8-10). The yields were almost the same regardless
of the substituent. The reactions of 1f and 1g were slightly
more regioselective than that of 1e, while the reaction of 1e
was more stereoselective than those of 1f and 1g. 1-(1-
Naphthyl)-1-propyne (1h), 1-(2-naphthyl)-1-propyne (1i), and
diphenylacetylene (1j) reacted smoothly with 2a to give the
product in yields of 83-89% (entries 11-13). The reaction
of conjugated enyne 1k with 2a gave the product in 77%
yield (entry 14). This result showed that the addition was
chemoselective. 1,3-Diketone 2a added to a carbon-carbon
triple bond exclusively. A carbon-carbon double bond was
inert for the addition. A heteroaromatic ring was tolerated
for the addition. 1-(2-Thienyl)-1-hexyne (1l) reacted with
2a to give 3la in 82% yield (entry 15). The stereochemistry
of 3la was unambiguously determined by 2D-NOESY.
Although the configuration was assigned to be Z by CIP
priority rules, the syn-addition of 2a to a carbon-carbon
triple bond was the same as those of other alkynes (1a-k).
We next examined the addition of 2a to terminal alkynes.
Phenylacetylene (1m) reacted with acetylacetone (2a) under
the same reaction conditions as internal alkynes to give 3ma
in 39% yield (Scheme 1). A terminal alkyne did not give a
Table 3. The Reaction of Trimethylsilylalkynes (1o-s) with
Acetylacetone (2a)a
time yield
(h)
entry
Ar
1
products
(%)b
3/4c
1
2
3
4
5
4-OHC-C6H4-
4-CH3CO-C6H4-
4-EtO2C-C6H4-
4-O2N-C6H4-
1o 3oa, 4oa
1p 3pa, 4pa
1q 3qa, 4qa
1r 3ra, 4ra
5
24
24
48
24
49
81
78
69
60
>99/1
>99/1
>99/1
93/7
4-CH2dCH-C6H4- 1s 3sa, 4sa
>99/1
a Reaction conditions: 1 (1.0 mmol) and 2a (3.0 mmol) in the presence
of [Ir(cod)2]SbF6 (0.05 mmol) in 1,2-dichloroethane (5 mL). b Isolated yield.
c Determined by
1H NMR.
Table 4. The Reaction of 1-Phenyl-1-propyne (1a) with
1,3-Diketones (2)a
Scheme 1
satisfactory yield. We could overcome this drawback by
using a trimethylsilyl alkyne as an alternative to a terminal
alkyne. The reaction of 1-phenyl-2-trimethylsilylacetylene
(1n) with 2a gave 3ma in 76% yield with perfect regiose-
lectivity (Scheme 1) (vide infra). Carbon-carbon bond
formation took place at the alkyne carbon substituted with a
phenyl group.
We examined the chemoselectivity of the reaction (Table
3). Acetyl, ester, and nitro groups were tolerated under the
reaction conditions (entries 2, 3, and 4). The products were
obtained in yields of 69-81%. Notably, formyl and alkenyl
groups were tolerated under the reaction conditions (entries
1 and 5). The reaction of substrates substituted with a formyl
group and an alkenyl group gave the respective products in
yields of 49% and 60%. 1,3-Diketone 2a did not add to these
functional groups. Good chemoselectivity was observed.
The reaction of 1-phenyl-1-propyne (1a) with various 1,3-
diketones was studied. The results are summarized in Table
4. The products were obtained in yields of 84-93%. 1,3-
a Reaction conditions: 1a (1.0 mmol) and 2 (3.0 mmol) in the presence
of [Ir(cod)2]SbF6 (0.05 mmol) in 1,2-dichloroethane (5 mL). b Isolated yield.
Determined by H NMR. d The stereochemistry of 3 was determined by
c
1
NOESY analysis, and the ratio was determined by 1H NMR. e Products
were obtained as enol form. f The stereochemistry of 3ad was determined
by the 13C-1H coupling constant. g The structure of 3ae was unambiguously
determined by X-ray crystallography.12
Diketone substituted with a bulky group such as isopropyl,
tert-butyl, or phenyl (2c-e) smoothly added to 1a to give
(12) An ORTEP drawing of 3ae is shown in the Supporting Information
as Figure S1.
5040
Org. Lett., Vol. 11, No. 21, 2009

the respective product (entries 2, 3, and 4). Cyclic 1,3-
diketones (2h,i) as well as acyclic 1,3-diketones (2a-g) could
be used for the addition. The yields with cyclic 1,3-diketones
were almost the same as those with acyclic 1,3-diketones
(entries 8 and 9). Unsubstituted 1,3-diketones (2b-f) added
to a carbon-carbon triple bond with perfect regioselectivity
(entries 1-5). With 2-substituted-1,3-diketones (2g-i), the
addition was less regioselective due to steric hindrance at
the 2-position in 1,3-diketone. The regioselectivities were
91-99%. The stereochemistry of 3ad-af was unambigu-
ously determined by 2D-NOESY. Although the configration
of 3ad-af was assigned to be Z due to CIP-priority rules
(entries 3-5), the addition of 2d-f to a carbon-carbon triple
bond was syn, which was the same as that observed for other
1,3-diketones.
E-selectivity was 94%, which was the same as that in the
reaction with nondeuterium-labeled 1,3-diketone. The posi-
tion at which a deuterium atom was incorporated clearly
suggested that the reaction proceeded via the syn-addition
of 1,3-diketone to the carbon-carbon triple bond.
A plausible reaction pathway is shown in Scheme 3. A
cationic iridium (+1) species reacts with 1,3-diketone to give
Scheme 3
To examine whether (E)-3aa isomerized to (Z)-3aa under
the reaction conditions, we reacted a 99:1 mixture of (E)-
and (Z)-3aa under refluxing 1,2-dichloroethane for 24 h in
the presence of 5 mol % of [Ir(cod)2]SbF6. The E/Z ratio
changed from 99/1 to 39/61. Thus, it is clear that initially
formed E-product isomerizes to Z-product. The addition
proceeds via the syn-addition of 2a to a carbon-carbon triple
bond.
We next performed a deuterium-labeling experiment. The
reaction of 1-phenyl-1-propyne (1a) with 3-deuterio-3-
methyl-2,4-pentadione (2g-d, D: 91%) was examined (Scheme
2). The products 3g-d and 4g-d were obtained in 76% yield.
cationic iridium (+3) enolate 5. The electron deficiency of
the cationic iridium species promotes alkyne coordination
to give electron-deficient alkyne species 6,13 which is highly
reactive toward a nucleophile such as a Michael acceptor.
Nucleophilic attack of iridium enolate to alkyne gives species
7. A six-membered transition state facilitates this nucleophilic
attack. Reductive elimination from species 7 gives the
product. An alkyne carbon substituted with a phenyl group
is more electrophilic due to the inductive effect of the phenyl
group,14 and this leads to high regioselectivity for the
nucleophilic attack to give 3.
Scheme 2
The reaction of silylalkyne (1n) gives a desilylation
product (Scheme 1). After the addition of 2a to 1n,
protodesilylation of a vinylsilane product by HIr+ species
formed from excess 2a occurs.15
In summary, we have developed a regio- and stereoselec-
tive addition of 1,3-diketones to unfunctionalized internal
alkynes under neutral conditions. Further studies on expand-
ing the scope of this addition are currently in progress.
A deuterium atom was incorporated at the vinyl position (D:
73-78%) exclusively. The decrease in deuterium incorpora-
tion in the product can be reasonably explained by the fact
that nondeuterium-labeled 1,3-diketones are more reactive
than deuterium-labeled 1,3-diketones. The reaction of 1a with
2g was completed in 1 h, while the reaction of 1a with 2g-d
was completed in 7 h. The result showed that the reaction
of 1a with 2g was faster than that of 1a with 2g-d. Three
equivalents of diketone were used for the reaction. Diketone
consisted of 2.73 equiv of 2g-d and 0.27 equiv of 2g, since
the deuterium content was 91%. Since 0.27 equiv of 2g
reacted with 1a faster than 2.73 equiv of 2g-d, the deuterium
content in the product decreased from 91% to 73-78%. The
Acknowledgment. This research was supported financially
by a grant from the Research Institute of Aoyama Gakuin
University.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds, and
crystallographic data in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL9020095
(13) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817.
(14) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165.
(15) For transition metal-catalyzed protodesilylation of vinylsilane, see:
Bandodakar, B. S.; Nagendrappa, G. J. Organomet. Chem. 1992, 430, 373.
Org. Lett., Vol. 11, No. 21, 2009
5041